Conditions: Advanced Breast Cancer HER2-positive Breast Cancer Brain Metastases Leptomeningeal Metastasis
Keywords: Breast cancer HER2 Brain metastases Metastatic unresectable pretreated
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

Brief summary:
This is a multicenter, international, open-label, single-arm, multicohort, two-stage optimal Simon's design, phase II clinical trial

Detailed description:
Pretreated, unresectable locally advanced or metastatic Human Epidermal Growth Factor Receptor 2 (HER2)-positive or HER2-low expressing breast cancer (BC) with untreated or treated brain metastases (BMs) or leptomeningeal carcinomatosis (LMC).

Arms:
arm 1: * Cohort 1: HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery.);
* Cohort 2: HER2-positive or HER2-low BC with asymptomatic untreated BM;
* Cohort 3: HER2-positive BC with progressing BMs after local treatment;
* Cohort 4: HER2-low expressing BC with progressing BMs after local treatment;
* Cohort 5: HER2-positive or HER2-low expressing BC with LMC.

Interventions: intervention 1: Trastuzumab deruxtecan
Intervention descriptions: intervention 1: After having confirmed eligibility and entered into the clinical trial, patients will be treated with trastuzumab deruxtecan (DS-8201a) at 5.4 mg/Kg administered as an intravenous (IV) infusion on Day of 21-day cycle (Q3W), initially for at least 90 minutes, then, if there is no infusion-related reaction, for a minimum of 30 minutes.

In patients with hormone receptor (HR)-positive status (estrogen receptor \[ER\] and/or progesterone receptor \[PgR\]) administration of endocrine therapy is not allowed.

In patients allocated in study cohort 5, administration of intrathecal therapy is not allowed

Protocol document:
Prot_000.pdf: 
 
EudraCT#: 2019-001739-29 
 Study Code: MEDOPP243 
CSP Version: 5.0, 18-Jan-2022 
 
 
 
 
Clinical Study Protocol (CSP) 
 
A Multicenter, Open-Label, Single-Arm, Multicohort Phase II Clinical Trial of Trastuzumab 
Deruxtecan (DS-8201a) in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive 
Advanced Breast Cancer with Brain Metastases and/or Leptomeningeal Carcinomatosis 
 
DS-8201a for trEatment of aBc, BRain mets, And Her2[+] disease 
–The DEBBRAH Study– 
 
 
 
Study Drug: 
Trastuzumab deruxtecan (DS-8201a) 
EudraCT#: 
2019-001739-29 
Clinical Trials.gov#: 
NCT04420598 
Study Code: 
MEDOPP243 
CSP Version and Date:  
version 5.0. 18-Jan-2022 
 
CSP Revision History: 
• 
Initial approved version: 
Version 2.0, 28-Apr-2020 
• 
Amendment 1: 
Version 3.0, 10-Jul-2020 
• 
Amendment 2: 
NA 
• 
Amendment 3: 
Version 4.0, 30-Dec-2020 
• 
Amendment 4: 
Version 5.0, 18-Jan-2022 
 
 
 
 
 


 
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Page 2 of 135 
I. SPONSOR’S SIGNATURE PAGE 
 
CSP Title: “A Multicenter, Open-Label, Single-Arm, Multicohort Phase II Clinical Trial of 
Trastuzumab Deruxtecan (DS-8201a) in Human Epidermal Growth Factor Receptor 2 (HER2)-
Positive Advanced Breast Cancer with Brain Metastases and/or Leptomeningeal Carcinomatosis 
– The DEBBRAH Study” 
 
Study Code: MEDOPP243 
 
CSP Version and Date: Version 5.0, 18-Jan-2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEDSIR Medical Scientist 
 
Signature 
 
Signature date 
 (DD-MM-YYYY) 
 
 
 
 


 
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Page 3 of 135 
II. KEY CONTACT DETAILS 
 
Sponsor 
Name: 
 
Medica Scientia Innovation Research (MEDSIR) 
Contact Name:  
Alicia García-Sanz, PhD 
Address: 
 
Torre Glòries, Av Diagonal 211, 27th floor, 08018 – Barcelona, Spain 
Phone / Fax:  
+34 93 221 41 35 / +34 93 299 23 82 
E-mail: 
 
alicia.garcia@medsir.org 
 
Scientific Global Coordinator 
Name: 
 
Position:  
 
Medical Oncologist 
Institution: 
 Oncology Department, International Breast Cancer Center (IBCC), 
Quiron Group, Barcelona, Spain 
Email: 
 
 
Clinical Study Coordinator 
Name: 
 
Position:  
 
Institution: 
 
Email: 
 
 
Chief Investigator 
Name: 
 
Position:  
 
Institution: 
 
  
Email: 
 
 
Sponsor’s Medical Monitor 
Name: 
 
Address: 
 
Hospital Professor Doutor Fernando Fonseca EPE, Lisbon, Portugal  
IC 19 276, 2720-276 Amadora. 
Phone / Fax:  
E-mail: 
 
 
Sponsor’s Safety Risk Management 
Address: 
 
Torre Glòries, Av Diagonal 211, 27th floor, 08018 – Barcelona (Spain) 
Phone / Fax:  
+34 93 221 41 35 / +34 93 299 23 82 
E-mail: 
 
pharmacovigilance@medsir.org 
 


 
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III. STEERING COMMITTEE 
 
Name 
Role 
Clinical Expert 
Clinical Expert 
Clinical Expert 
Sponsor’s Medical Monitor 
Clinical Expert 
Clinical Expert 
Clinical Expert 
 
 
 
 
 


 
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IV. DECLARATION OF INVESTIGATORS 
 
CSP Title: “A Multicenter, Open-Label, Single-Arm, Multicohort Phase II Clinical Trial of 
Trastuzumab Deruxtecan (DS-8201a) in Human Epidermal Growth Factor Receptor 2 (HER2)-
Positive Advanced Breast Cancer with Brain Metastases and/or Leptomeningeal Carcinomatosis 
– The DEBBRAH Study”. 
Study Code: MEDOPP243 
CSP Version and Date: Version 5.0, 18-Jan-2022 
 
! 
I have received, reviewed and understood the following: 
1. 
Clinical Study Protocol (CSP) version 5.0, 18-Jan-2022 
2. 
Trastuzumab deruxtecan (DS-8201a) Investigator’s Brochure (IB) with details of 
clinical and nonclinical data that are relevant to the study of the product in human 
subjects. 
! 
I have been adequately informed about the development of the investigational product to 
date. I will confirm the receipt of updated IB. I have read this CSP and agree that it contains 
all the information required to conduct the study. I agree to conduct the study as set out in 
this CSP. 
! 
I fully understand that any changes instituted by the Investigator(s) without previous 
agreement with the Sponsor would constitute a violation of the CSP, including any ancillary 
studies or procedures performed on study patients (other than those procedures necessary 
for the wellbeing of the patients). I am aware that I cannot deviate from or apply changes to 
the CSP without prior approval or the favorable opinion of the Institutional Review Board (IRB) 
or Ethics Committee (EC) and/or before Sponsor’s agreement to avoid immediate risk to the 
trial patients. If this occurs, I agree to inform the Sponsor as to the deviation or changes in 
writing and their reasons, as soon as possible. 
! 
I will not enroll the first subject in the study until I have received approval from the appropriate 
IRB/EC and until all legal and regulatory requirements in my country have been fulfilled. 
! 
The study will be conducted in accordance with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and its amendments, the 
International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines 
(ICH E6[R2] GCP) and applicable regulations and laws. 
! 
I agree to obtain, in the manner described in this CSP and in (ICH E6[R2] GCP), written 
informed consent form (ICF) by the subject or witnessed verbal ICF to participate for all 
subjects whose participation in this study is proposed to and before any subject’s study 
specific procedure is done. 


 
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Page 6 of 135 
! 
I will ensure that the study drug supplied by the Sponsor are being used only as described in 
this CSP. 
! 
I am aware of the requirements for the correct reporting of serious adverse events, and I 
commit to document and to report such events as required by the Sponsor and in accordance 
with Health Authority Regulatory requirements. 
! 
I agree to supply – upon request – the Sponsor or Sponsor’s representative with evidence of 
current laboratory accreditation, the name and address of the laboratory, and a list of normal 
values and ranges. 
! 
I agree with the use of results of the study for the purposes of national and international 
registration, publication, and information for medical and pharmaceutical professionals. 
! 
I agree to keep all source documents and case report forms as specified in the relevant 
sections of this CSP. 
! 
I will provide all required Regulatory Authority forms, up-to-date curriculum vitae of myself, 
sub-Investigators and of any member of my study team (if requested) before the study starts, 
which may be submitted to regulatory authorities. 
! 
I am aware of the possibility of being audited by the Sponsor or its delegate or inspected by 
regulatory authorities for the performance of this study. I will permit monitoring, auditing and 
inspection and provide direct access to source data/documents and reports for these 
purposes. 
! 
Furthermore, I confirm herewith that the Sponsor is allowed to enter and utilize my 
professional contact details and function in an electronic database for internal purposes and 
for submission to Health Authorities worldwide. 
 
 
 
Name:  _____________________________________________________________________ 
 
 
 
Signature: _________________________ 
 
Date: __________________________ 
 
 
 


 
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V. CLINICAL STUDY PROTOCOL SYNOPSIS 
 
CSP Title: 
“A Multicenter, Open-Label, Single-Arm, Multicohort Phase II Clinical 
Trial of Trastuzumab Deruxtecan (DS-8201a) in Human Epidermal 
Growth Factor Receptor 2 (HER2)-Positive Advanced Breast Cancer 
with Brain Metastases and/or Leptomeningeal Carcinomatosis – The 
DEBBRAH Study” 
CSP Short Title 
DS-8201a for trEatment of aBc, BRain mets, And Her2[+] disease –
The DEBBRAH Study– 
Study Code: 
MEDOPP243 
EudraCT Number: 
2019-001739-29 
Investigational 
Medicine Product: 
Trastuzumab deruxtecan (DS-8201a) 
Trial Design: 
This is a multicenter, international, open-label, single-arm, multicohort, 
two-stage optimal Simon’s design, phase II clinical trial. 
Target Disease: 
Pretreated, unresectable locally advanced or metastatic Human 
Epidermal Growth Factor Receptor 2 (HER2)-positive or HER2-low 
expressing breast cancer (BC) with untreated or treated brain 
metastases (BMs) or leptomeningeal carcinomatosis (LMC). 
Patients: 
Male and pre- and post-menopausal female patients age ≥ 18 years 
with pretreated unresectable locally advanced or metastatic HER2-
positive or HER2-low expressing BC with stable, treated or untreated 
BMs, or patients progressing after treatment for BMs or patients with 
LMC. Evidence of measurable brain disease is required. Patients are 
not eligible if they are candidates for a local treatment with a radical 
intention. 
Patients with untreated BMs are those that have not received any local 
treatment for their central nervous system (CNS) involvement (surgery 
and/or stereotactic radiotherapy [SRS] and/or whole-brain radiation 
therapy [WBRT] are considered appropriate). 
The operational definition of patients with stable BM are patients that 
have been for at least four weeks asymptomatic with or without 
corticosteroids. The highest dose of corticosteroids acceptable is 
dexamethasone 8 mg twice daily or any equivalent. 


 
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After confirmed eligibility, patients will be assigned to one of the 
following five study cohorts: 
• 
Cohort 1: HER2-positive BC with non-progressing BM (after 
WBRT and/or SRS and or surgery.); 
• 
Cohort 2: HER2-positive or HER2-low BC with asymptomatic 
untreated BM; 
• 
Cohort 3: HER2-positive BC with progressing BMs after local 
treatment; 
• 
Cohort 4: HER2-low expressing BC with progressing BMs after 
local treatment; 
• 
Cohort 5: HER2-positive or HER2-low expressing BC with LMC. 
Number of Patients: 
39 patients (N=8 patients in the cohort 1; N=10 in the cohort 2; N=7 in 
the cohort 3; N=7 in the cohort 4; N=7 in the cohort 5). 
Study Objectives: 
Primary objective: 
Cohort 1 
• 
To assess efficacy −defined as 16 weeks progression-free survival 
(PFS) per Response Assessment in Neuro-Oncology Brain 
Metastases (RANO-BM) and Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1− of trastuzumab deruxtecan (DS-
8201a) in patients with pretreated unresectable locally advanced 
or metastatic HER2-positive BC with non-progressing BM (after 
WBRT and/or SRS and or surgery). 
 
 Cohorts 2, 3, and 4 
• 
To assess efficacy −defined as intracranial overall response rate 
(ORR−IC) per RANO-BM– of trastuzumab deruxtecan (DS-8201a) 
in patients with pretreated unresectable locally advanced or 
metastatic BC: 
a) 
HER2-positive or HER2-low expressing with untreated 
BMs (Cohort 2); 
b) 
HER2-positive with progressing BMs after local treatment 
(Cohort 3); 
c) 
HER2-low expressing with progressing BMs after local 
treatment (Cohort 4). 


 
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Cohort 5 
• 
To assess efficacy −defined as OS− of trastuzumab deruxtecan 
(DS-8201a) in patients with pretreated unresectable locally 
advanced or metastatic HER2-positive or HER2-low expressing 
BC with LMC. 
 
Secondary objectives: 
Cohort 1 
• 
To assess efficacy −defined as PFS, ORR, CBR, time to response 
(TTR), duration of response (DOR), and best percentage of 
change in tumor burden per RANO-BM (for IC lesions) and 
RECIST 1.1 (extracranial lesions and overall lesions)– after 
treatment 
with 
trastuzumab 
deruxtecan 
(DS-8201a) 
in 
this 
population. 
• 
To assess OS in this population. 
• 
To assess the safety and tolerability of trastuzumab deruxtecan 
(DS-8201a) by NCI-CTCAE v.5.0. 
 
Cohorts 2, 3, and 4 
• 
To assess efficacy –defined as PFS, CBR, TTR, DOR, and best 
percentage of change in tumor burden per RANO-BM (for IC 
lesions) and RECIST 1.1 (for extracranial lesions and overall 
lesions); and ORR per RECIST 1.1 (for extracranial lesions and 
overall lesions). 
• 
Time to WBR and/or SRS (only for cohort 2), defined as the time 
from the treatment initiation to time of CNS disease progression 
that requires treatment with WBR and/or SRS, and determined 
locally by the investigator through the use of RANO-BM and 
RECIST 1.1 criteria. 
• 
To assess the safety and tolerability of trastuzumab deruxtecan 
(DS-8201a) by NCI-CTCAE v.5.0. 
• 
To assess OS in this population. 
 


 
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Cohort 5 
• 
To assess efficacy −defined as PFS, ORR, CBR, TTR, DOR, and 
best percentage of change in tumor burden per RANO-BM (IC 
lesions) and RECIST 1.1 (extracranial lesions and overall lesions) 
• 
To assess the safety and tolerability of trastuzumab deruxtecan 
(DS-8201a) by NCI-CTCAE v.5.0. 
 
Exploratory objectives: 
Cohorts 1, 2, 3, 4, and 5 
• 
To assess 
using the 
and its 
in this population. 
• 
To evaluate predictive or prognostic biomarkers (plasma and/or 
tissue and/or CSF) associated with disease activity status or 
response to treatment in this population. 
• 
To identify possible mechanisms of resistance to study treatments 
through the comparative analysis of potential biomarkers from 
paired pre-treatment and post-progression tumor and/or blood 
and/or CSF samples from this population. 
Study Endpoints: 
Primary endpoint:  
Cohort 1 
o 
16 weeks-PFS, defined as the period of time from treatment 
initiation to the first occurrence of disease progression or death 
from any cause, whichever occurs first. Progression will be 
determined locally by the investigator through the use of RANO-
BM criteria for IC lesions and RECIST criteria v.1.1 for both 
extracranial lesions and overall (IC and extracranial) lesions. 
 
Cohorts 2, 3 and 4 
o 
ORR-IC, defined as a complete response (CR) or partial response 
(PR), determined locally by the investigator through the use of 
RANO-BM criteria. 
 
Cohort 5 


 
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o 
OS defined as the time from treatment initiation to death from any 
cause. Patients without documented death at the time of the final 
analysis will be censored at the date of the last follow-up. 
 
Secondary endpoints: 
Cohort 1 
o 
PFS, defined as the period of time from treatment initiation to the 
first occurrence of disease progression or death from any cause, 
whichever occurs first. Progression will be determined locally by 
the investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions 
o 
ORR, defined as a CR or PR, determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
CBR, defined as an objective response (CR or PR), or stable 
disease (SD) for at least 24 weeks, determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
TTR, defined as the time from the treatment initiation to time of the 
first objective tumor response observed for patients who achieved 
a CR or PR, determined locally by the investigator through the use 
of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
o 
DoR, defined as the time from the first occurrence of a 
documented objective response to disease progression or death 
from any cause, whichever occurs first, determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
OS, defined as the time from treatment initiation to death from any 
cause. Patients without documented death at the time of the final 
analysis will be censored at the date of the last follow-up. 
o 
Best percentage of change from baseline in the size of tumor 
lesions, defined as the biggest decrease, or smallest increase if 


 
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no decrease will be observed, and determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
Adverse events (AEs) will be evaluated using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v.5.0.  
 
Cohorts 2, 3, and 4 
o 
PFS, defined as the period of time from treatment initiation to the 
first occurrence of disease progression or death from any cause, 
whichever occurs first. Progression will be determined locally per 
RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both 
extracranial lesions and overall (IC and extracranial) lesions. 
o 
ORR, defined as a CR or PR, determined locally by the 
investigator through the use of RECIST criteria v.1.1 for both 
extracranial lesions and overall (IC and extracranial) lesions. 
o 
CBR, defined as an objective response (CR or PR), or SD for at 
least 24 weeks, and determined locally by the investigator through 
the use of RANO-BM criteria for IC lesions and RECIST criteria 
v.1.1 for both extracranial lesions and overall (IC and extracranial) 
lesions. 
o 
TTR, defined as the time from the treatment initiation to time of the 
first objective tumor response (tumor shrinkage of ≥ 30%) 
observed for patients who achieved a CR or PR, determined 
locally by the investigator through the use of RANO-BM criteria for 
IC lesions and RECIST criteria v.1.1 for both extracranial lesions 
and overall (IC and extracranial) lesions. 
o 
DOR, defined as the time from the first occurrence of a 
documented objective response to disease progression or death 
from any cause, whichever occurs first, determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
OS, defined as the time from treatment initiation to death from any 
cause. Patients without documented death at the time of the final 
analysis will be censored at the date of the last follow-up. 


 
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o 
Best percentage of change from baseline in the size of tumor 
lesions, defined as the biggest decrease, or smallest increase if 
no decrease will be observed, and determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
Time to WBR and/or SRS (only for cohort 2), defined as the time 
from the treatment initiation to time of CNS disease progression 
that requires treatment with WBR and/or SRS, and determined 
locally by the investigator through the use of RANO-BM and 
RECIST criteria. 
o 
AEs will be evaluated using the NCI CTCAE v.5.0 
 
Cohort 5 
o 
ORR, defined as a CR or PR, determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
PFS, defined as the period of time from treatment initiation to the 
first occurrence of disease progression or death from any cause, 
whichever occurs first. Progression will be determined locally by 
the investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
CBR, defined as an objective response (CR or PR), or SD for at 
least 24 weeks, determined locally by the investigator through the 
use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 
for both extracranial lesions and overall (IC and extracranial) 
lesions. 
o 
TTR, defined as the time from the treatment initiation to time of the 
first objective tumor response observed for patients who achieved 
a CR or PR, determined locally by the investigator through the use 
of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
o 
DoR, defined as the time from the first occurrence of a 
documented objective response to disease progression or death 
from any cause, whichever occurs first, determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions 


 
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and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
Best percentage of change from baseline in the size of tumor 
lesions, defined as the biggest decrease, or smallest increase if 
no decrease will be observed, and determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions 
and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
AEs will be evaluated using the NCI CTCAE v.5.0 
 
Exploratory endpoints: 
Cohorts 1, 2, 3, 4, and 5 
o 
Overall change from baseline in 
), 
and 
; Time 
to 
in 
; Time to 
in 
; Time 
to 
. 
o 
Relationship between tissue- and/or blood- and/or CSF-based 
biomarkers and patient clinical characteristics (e.g., baseline 
features) and outcome (e.g., 
). 
Selection Criteria: 
Inclusion criteria: 
Patients must meet ALL of the following inclusion criteria to be eligible 
for enrolment into the study: 
1. 
Signed Informed Consent Form (ICF) prior to participation in any 
study-related activities. 
2. 
Male or female patients ≥ 18 years at the time of signing ICF. 
3. 
Eastern Cooperative Oncology Group (ECOG) performance 
status of 0-1 for Cohorts 1 to 4 and 0-2 for cohort 5. 
4. 
Life expectancy ≥ 12 weeks. 
5. 
Histologically confirmed invasive breast cancer based on local 
testing on the most recent analyzed biopsy of the following breast 
cancer (BC) subtypes per 2018 American Society of Clinical 
Oncology 
(ASCO)/College 
of 
American 
Pathologists 
(CAP) 
criteria: 


 
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• 
Cohort 1 and 3: HER2 positive status 
• 
Cohort 4: HER2-low expressing status 
• 
Cohort 2 and 5: both HER2 positive and HER2-low 
expressing status 
Note 1: According to the 2018 ASCO-CAP guidelines, HER2-
positive status is defined as HER2 immunohistochemistry (IHC) 
3+, in situ hybridization (ISH) ≥ 2.0, or average HER2 copy number 
≥ 6.0 signals. HER2-low expressing status defined as IHC 2+ / 
ISH-negative or IHC 1+ (ISH-negative or untested). 
Note 2: Central confirmation of HER2 is not required for study 
entry. However, tissue blocks, or slides, must be submitted to 
confirm BC subtype by a Sponsor-designated central laboratory 
retrospectively. 
6. 
Unresectable locally advanced or metastatic disease documented 
by computerized tomography (CT) scan or magnetic resonance 
imaging (MRI) that is not amenable to resection with curative 
intent. 
7. 
At least one brain lesion needed to be measurable (≥10 mm on 
T1-weighted, gadolinium-enhanced MRI) (study cohorts 2 to 4) 
or 
leptomeningeal 
carcinomatosis 
(LMC) 
with 
positive 
cerebrospinal fluid (CSF) cytology (study cohort 5). 
• 
Study cohort 1: History of BM that are non-progressing 
after WBRT and/or SRS and or surgery. 
• 
Study cohort 2: Presence of asymptomatic BM without 
clinical requirement for local intervention (WBRT and/or 
SRS and/or surgery). 
• 
Study cohorts 3 and 4: Evidence of new and/or 
progressive BM following previous WBRT and/or SRS 
and/or surgery.  
• 
Study cohort 5: Evidence of LMC with positive CSF 
cytology. 
8. 
Previous treatments: 


 
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• 
For HER2-positive patients have been previously treated 
with a taxane and at least one HER2-targeted therapy in 
the advanced scenario. 
• 
For HER2-low-expressing patients that also are endocrine 
receptor negative must have been previously treated with 
at least one chemotherapy regimen. If endocrine receptor 
positive, patients must have been previously treated with 
at least one chemotherapy and one endocrine regimen in 
the metastatic setting.  
9. 
Patients must agree to collection of blood samples at the time of 
inclusion, at cycle 2 of treatment, and upon progression or study 
termination. 
Note: In study cohort 5: Patients must agree to perform spinal 
taps or must be willing to have an Ommaya reservoir placed for 
CSF assessment, at baseline, every three weeks for 12 weeks 
(corresponding to the first 5 cycles of treatment) and every six 
weeks thereafter. 
10. Willingness and ability to provide tumor biopsy (if feasible) from 
metastatic lesions or breast primary tumor both at the time of the 
inclusion and after disease progression in order to perform 
exploratory studies. 
Note: If feasible, patients should provide a tissue sample at 
baseline from metastases amenable to biopsy (at sites of 
locoregional recurrence [skin, chest wall, breast or lymph nodes], 
or distant recurrence [bone, liver, lung or abdomen]) or as 
alternative from breast primary tumor, that will be obtained 
between progression to the prior regimen and inclusion in the 
study. Patients for whom tissue sample cannot be obtained (e.g., 
non-measurable disease, inaccessible tumor or subject safety 
concern) may submit an archived metastatic tumor specimen only 
upon agreement from the Sponsor. If feasible, an additional tissue 
sample should be collected at the end of treatment visit for patients 
who discontinue treatment due to disease progression. 
11. Patients should have left ventricular ejection fraction (LVEF) ≥ 
50% 
by 
either 
an 
echocardiogram 
(ECHO) 
or 
multigated 
acquisition (MUGA) scan within 28 days before enrolment. 


 
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12. Adequate hematologic and organ function within 14 days before 
the first study treatment on Day 1 of Cycle 1, defined by the 
following: 
• 
Hematological: White blood cell (WBC) count ≥ 3.0 x 
109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, 
platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9.0 g/dL. 
(Platelet, red blood cell transfusion as well as G-CSF 
administration are not allowed within 1 week of screening 
assessments).  
• 
Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (× 
ULN) (< 3 x ULN in the case of documented Gilbert’s 
disease and/or liver metastases); aspartate transaminase 
(AST) and alanine transaminase (ALT) ≤ 3 × ULN (in the 
case of liver metastases ≤ 5 × ULN); alkaline phosphatase 
(ALP) ≤ 2 × ULN (≤ 5 × ULN in the case of liver and/or 
bone metastases ≤ 5 × ULN), serum albumin ≥ 2.5 g/dL 
• 
Renal: Serum creatinine ≤ 1.5 × ULN or creatinine 
clearance 
≥ 
30 
mL/min 
based 
on 
Cockcroft−Gault 
equation (*Cockcroft-Gault equation: CLcr (mL/min)= 
([{140 – age in years} × {ACTUAL WEIGHT in kg}] divided 
by [{72 × serum creatinine in mg/dL} multiplied by 0.85 if 
female]) 
• 
Coagulation: 
International 
Normalized 
Ratio 
(INR)/Prothrombin 
Time 
(PT) 
and 
either 
partial 
thromboplastin or activated Partial Thromboplastin Time 
(aPTT) ≤ 1.5 × ULN (except for patients receiving 
anticoagulation therapy). 
Note: Patients receiving heparin treatment should have an 
aPTT) between 1.5 and 2.5 × ULN (or patient value before 
starting heparin treatment). Patients receiving coumarin 
derivatives should have an INR between 2.0 and 3.0 assessed 
in two consecutive measurements one to four days apart. 
Patients should be on a stable anticoagulant regimen. 
13. Has adequate treatment washout period before enrollment, as 
indicated: 


 
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a. 
Major surgery: > 4 weeks; 
b. 
Radiation therapy: > 4 weeks (palliative stereotactic radiation 
therapy to other areas ≥ 2 weeks); 
c. 
Anticancer systemic treatment (including immunotherapy, 
retinoid therapy, hormonal therapy): ≥ 3 weeks (≥ 2 weeks or 
5 half-lives, whichever is longer, for small-molecule targeted 
agents such as 5-fluorouracil-based agents, folinate agents, 
weekly paclitaxel; ≥ 6 weeks for nitrosureas or mitomycin C);  
d. 
Antibody based anti-cancer therapy: ≥ 4 weeks; 
e. 
Chloroquine/Hydroxychloroquine>14 days 
14. Resolution of all acute toxic effects of prior anti-cancer therapy to 
grade ≤ 1 as determined by the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI−CTCAE) v.5.0 
(except for alopecia or other toxicities). Subjects with chronic 
Grade 2 toxicities may be eligible per the discretion of the 
Investigator after consultation with the Sponsor Medical Monitor or 
designee (e.g., Grade 2 chemotherapy-induced neuropathy). 
15. Male and female subjects of reproductive/childbearing potential 
must agree to use a highly effective form of contraception or avoid 
intercourse during and upon completion of the study and for at 
least 7 months for females and 4 months for males after the last 
dose of study drug. Methods considered as highly effective 
methods of contraception include:  
• 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation: 
i. 
Oral 
ii. 
Intravaginal 
iii. 
Transdermal 
• 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation: 
iv. 
Oral 
v. 
Injectable 
vi. 
Implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 


 
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• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Complete sexual abstinence defined as refraining from 
heterosexual intercourse during and upon completion of 
the study and for at least 7 months after the last dose of 
study 
drug. 
Periodic 
abstinence 
(calendar, 
symptothermal, 
post-ovulation 
methods) 
is 
not 
an 
acceptable method of contraception. 
Note: Non-child-bearing potential defined as pre-menopausal 
females with a documented tubal ligation or hysterectomy; or 
postmenopausal defined as 12 months of spontaneous 
amenorrhea (in questionable cases, a blood sample with 
simultaneous follicle-stimulating hormone [FSH] > 40 mIU/mL 
and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory). 
Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of 
the contraception methods outlined for women of child-bearing 
potential if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation 
of 
post-menopausal 
status 
prior 
to 
study 
randomization/enrollment. For most forms of HRT, at least 2-
4 weeks will elapse between the cessation of therapy and the 
blood draw; this interval depends on the type and dosage of 
HRT. Following confirmation of their post-menopausal status, 
they can resume use of HRT during the study without use of a 
contraceptive method. 
16. Male subjects must agree to not freeze or donate sperm starting 
at Screening and throughout the study period, and at least 4 
months after the final study drug administration. Preservation of 
sperm should be considered prior to enrolment in this study. 
17. Female subjects must agree to not donate, or retrieve for their own 
use, ova from the time of Screening and throughout the study 
treatment period, and for at least 7 months after the final study 
drug administration. 


 
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18. Patients who are willing and able to comply with scheduled visits, 
treatment plan, laboratory tests, post-treatment follow-up and 
other study procedures. 
 
Exclusion criteria: 
Patients will be excluded from the study if they meet ANY of the 
following criteria: 
1. 
Inability to comply with study and follow-up procedures. 
2. 
Previous treatment with trastuzumab deruxtecan (DS-8201a) or 
any other antibody drug conjugate (ADC) which consists of an 
exatecan derivative that is a topoisomerase 1 inhibitor. 
3. 
Medical history of myocardial infarction (MI) within 6 months 
before enrollment, symptomatic congestive heart failure (New 
York Heart Association Class II to IV). Subjects with troponin levels 
above ULN at screening (as defined by the manufacturer), and 
without any MI related symptoms should have a cardiologic 
consultation before enrollment to rule out MI. 
4. 
Corrected QT interval (QTc) prolongation to > 470 ms (females) or 
>450 ms (males) based on average of the screening triplicate12-
lead ECG. 
5. 
History 
of 
(non-infectious) 
interstitial 
lung 
disease 
(ILD)/pneumonitis 
that 
required 
steroids, 
has 
current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be 
ruled out by imaging at screening. 
6. 
Clinically significant corneal disease in the opinion of the 
Investigator. 
7. 
Spinal cord compression. 
8. 
Multiple primary malignancies within 3 years, except adequately 
resected non-melanoma skin cancer, curatively treated in-situ 
disease, other solid tumors curatively treated, or contralateral 
breast cancer.  
9. 
History of severe hypersensitivity reactions to either the drug 
substances or inactive ingredients in the drug product. 
10. History of severe hypersensitivity reactions to other monoclonal 
antibodies. 
11. Uncontrolled 
infection 
requiring 
IV 
antibiotics, 
antivirals, 
or 
antifungals. 


 
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12. Patients with 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.  
13. Known human immunodeficiency virus (HIV) infection, or active 
hepatitis B or C infection. Patients positive for hepatitis C (HCV) 
antibody are eligible only if polymerase chain reaction is negative 
for HCV RNA.  
14. Female patients who are pregnant or breastfeeding or planning to 
become pregnant. 
15. Treatment with other systemic therapy for metastatic disease 
including chemotherapy, immunotherapy, targeted therapy (small 
molecules/ monoclonal antibodies), or endocrine therapy. 
16. Major surgery (defined as requiring general anesthesia) or 
significant traumatic injury within 4 weeks of start of study drug, or 
patients who have not recovered from the side effects of any major 
surgery, or patients who may require major surgery during the 
study. 
17. Radiotherapy within 4 weeks or limited-field palliative radiotherapy 
within 2 weeks prior to study enrolment, or patients who have not 
recovered from radiotherapy-related toxicities to baseline or grade 
≤ 1 and/or from whom ≥ 25% of the bone marrow has been 
previously irradiated.  
18. Use of concurrent investigational agents or other concomitant 
anticancer therapies. 
19. Use of intrathecal therapy for LMC 
20. Active bleeding diathesis, previous history of bleeding diathesis, 
or chronic anti-coagulation treatment (the use of low molecular 
weight heparin is allowed as soon as it is used as prophylaxis 
intention). 
21. Serious concomitant systemic disorder (e.g., active infection 
including HIV, active hepatitis, liver cirrhosis, end stage chronic 
renal disease) incompatible with the study (at the discretion of 
investigator). 
22. Any of the following within 6 months of enrollment: severe/unstable 
angina, ongoing cardiac dysrhythmias of NCI−CTCAE v.5.0 grade 
≥2, coronary/peripheral artery bypass graft, cerebrovascular 


 
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accident including transient ischemic attack, or symptomatic 
pulmonary embolism. 
23. Uncontrolled electrolyte disorders of NCI−CTCAE v.5.0 grade ≥ 2. 
24. Lung-specific intercurrent clinically significant illnesses including, 
but not limited to, any underlying pulmonary disorder (e.g. 
pulmonary emboli within three months of the study randomization  
25. Any autoimmune, connective tissue or inflammatory disorders 
(e.g., Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where 
there is documented, or a suspicion of pulmonary involvement at 
the time of screening. Full details of the disorder should be 
recorded in the eCRF for patients who are included in the study. 
26.  Prior pneumonectomy 
 
Treatment: 
After having confirmed eligibility and entered into the clinical trial, 
patients will be treated with trastuzumab deruxtecan (DS-8201a) at 5.4 
mg/Kg administered as an intravenous (IV) infusion on Day 1 of a 21-
day cycle (Q3W), initially for at least 90 minutes, then, if there is no 
infusion-related reaction, for a minimum of 30 minutes. 
In patients with hormone receptor (HR)-positive status (estrogen 
receptor [ER] and/or progesterone receptor [PgR]) administration of 
endocrine therapy is not allowed. 
In patients allocated in study cohort 5, administration of intrathecal 
therapy is not allowed. 
Study 
Procedures, 
Efficacy and Safety 
Assessments: 
Patient visits: 
Visits are organized in programmed cycles of 21 days (if there are no 
treatment delays due to the occurrence of AEs). All visits must occur 
within ± 2 working days from the scheduled date, unless otherwise 
noted in the schedule of assessments. 
Assessments scheduled for Day 1 (before treatment) of all cycles must 
be performed within 48 hours prior to study treatment administration, 
unless otherwise indicated in the schedule of assessments, to confirm 
to the patient if treatment can be followed up. 
If a mandatory procedure described in the protocol falls on a bank 
holiday and/or weekend, this procedure should be performed on the 
day before or after the holiday (i.e. within a period of ± 2 working days). 


 
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End of treatment (EoT) visit will be performed within 40 days (± 7 days) 
after the last dose of study treatment. Afterwards, follow-up contacts 
will continue every 12 weeks (± 14 days) up to the end of study (EoS) 
and survival status and new anticancer therapy information will be 
collected. Telephone contact is acceptable. 
EoS will occur at 12 months after the last patient included in the study, 
unless premature termination of the study. 
 
Tumor assessments: 
• 
Evaluation of chest, abdomen, and pelvis: 
This assessment should be done preferably by CT scan or MRI in case 
of contrast allergy, within 28 days prior to the first administration of 
study medication, every six weeks (± 3 days) from the first dose of 
study treatment for the first six months and, thereafter, every nine 
weeks (± 5 days) until the EoS visit. 
In the event a positron emission tomography (PET)/CT scan is used 
for tumor assessments, CT portion of PET/CT is usually of lower 
quality, and should not be used instead of dedicated diagnostic CT. If 
the CT scan is of high quality, with oral and intravenous contrast, may 
be used with caution. Additional information from PET may bias CT 
assessment. 
• 
Brain imaging: 
A brain MRI will be performed within 28 days prior to the first 
administration of study medication, every six weeks (± 3 days) for first 
six months, then every nine weeks (± 5 days), unless clinically 
suspected brain progression. 
Additionally, for patients included in the study cohort 5, assessment of 
neuroaxis by MRI together with spinal tap for CSF collection should be 
obtained 
every 
3 
weeks 
(± 
2 
days) 
for 
the 
first 
12 
weeks 
(corresponding to the first 5 cycles of treatment), every 6 weeks 
thereafter, and at the time of treatment progression or study 
termination. 
Tumor response in CNS will be assessed for all patients, unless they 
withdraw from the study for any reason not attributable to disease 
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criteria 
and 
who 
have 
not 
received 
an 
acceptable 
complete 
assessment of the disease. The measurable and non-measurable 
disease must be documented at screening and be re-assessed at 
every tumor assessment thereafter. 
• 
Bone scan: 
Bone scan is mandatory at baseline For patients with bone lesions 
identified at baseline, bone scan will be performed every 24 weeks (± 
7 days), unless clinically or biochemically suspected bone progression. 
If no bone involvement is demonstrated, then it is no necessary to 
repeat the bone assessment unless clinically or biochemically 
suspected bone progression. If an isotope-based bone scan was 
performed > 28 days but ≤ 60 days prior to start of study treatment, the 
bone scan does not need to be repeated. 
 
PROs assessments: 
PRO will be assessed using the EORTC QLQ-C30 and EORTC QLQ 
BR23 questionnaires. Patients will complete each questionnaire prior 
to any study or medical procedure: at baseline, Day 1 of cycles 2-4, 
then on Day 1 of every other subsequent cycle starting with cycle 6 
(e.g. cycles 6, 8, 10, etc.), at the end-of-treatment visit and during 
follow-up 
period 
until 
start 
of 
alternative 
anti-cancer 
therapy. 
Completed questionnaires are always considered source document 
and must be filed accordingly. Patients must complete these 
instruments in clinic (cannot be taken home) and prior to having any 
tests and to any discussion of their progress with healthcare personnel 
at the site. Interviewer administration in clinic may be used under 
special circumstances (e.g., patient forgot their glasses or feels too ill). 
The questionnaire will be given to the patient in the appropriate 
language for the site. Patients discontinuing treatment for any reason 
including progression disease or any other reason should have a 
tumor and PROs assessment prior to start alternative anticancer 
treatment. 
 
Safety assessments: 


 
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The occurrence and all grade of side effects observed throughout the 
study will be listed and tabulated according to type and dose level. Any 
AEs that the investigator reports as unrelated to the drug will also be 
reported. In this study, side effects will be assessed according to the 
NCI–CTCAE v.5.0 criteria. 
Biological samples: 
Tumor samples for molecular analysis: 
If feasible, patients should provide a tissue sample at the time of study 
entry and at disease progression from metastases amenable to biopsy 
(at sites of locoregional recurrence [skin, chest wall, breast or lymph 
nodes], or distant recurrence [bone, liver, lung or abdomen]) or, as 
alternative, from breast primary tumor. 
Exploratory studies will be performed on tumor biopsies, or formalin-
fixed and paraffin-embedded (FFPE) or frozen tumor samples 
(blocks), or unstained glass slides.  
 
Blood samples for molecular analysis: 
These samples will be collected during the screening period, after two 
cycles of study treatment, and upon progression or study termination. 
 
CSF samples for molecular analysis: 
In study cohort 5, patients must agree to provide CSF for exploratory 
analysis, at baseline, every 3 weeks for 12 weeks (corresponding to 
the first 5 cycles of treatment) and every 6 weeks thereafter, and at the 
time of treatment progression or study termination. 
Statistics: 
Sample size: 
A maximum of 39 patients with pretreated unresectable locally 
advanced or metastatic HER2-positive or HER2-low expressing 
patients will be recruited in five study cohorts, as follows: 
 
Cohort 1: 4 patients in the first step, up to a total of 8 patients. 
Cohort 2: A maximum of 10 patients. 
Cohort 3: A maximum of 7 patients. 


 
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Cohort 4: A maximum of 7 patients. 
Cohort 5: A maximum of 7 patients. 
 
Justification of total sample size: 
The primary endpoint for this study in the cohort of patients with stable 
BMs (cohort 1) is the PFS at 16 weeks. The primary endpoint for this 
study in the cohorts of patients with untreated or progression BMs 
(cohorts 2 to 4) is the best ORR-IC. The primary endpoint in the cohort 
of patients with LMC (cohort 5) is the OS. 
The trial uses a two-stage optimal Simon’s design for the cohort 1, a 
one-stage A’Hern design for the cohorts 2 to 4, and a one-stage 
survival design for the cohort 5. The analysis in the cohort 1 will be 
one-sided, based on stochastic ordering of uniformly minimum 
variance unbiased estimator (UMVUE). The analyses in the cohorts 2 
to 4 will be one-sided, based on stochastic binomial exact test. The 
sample size for the LMC cohort was based on a one arm time-to-event 
design. The analysis will be based on maximum likelihood exponential 
test. 
The local type I and II errors for all designs will be 0.05 and 0.2, 
respectively. 
 
Futility interim analyses in cohort 1: 
A futility interim analysis has been planned in cohort 1. The recruitment 
will not be stopped during the interim analysis. However, after the 
interim analysis, if the number of patients achieving the primary 
endpoint is equal or less than futility boundary in each cohort, the 
accrual in the cohort must be stopped. The stopping rule is: 
Cohort 1: All 4 patients with progressive disease or death at 16 weeks. 
Feasibility interim analyses in each cohort: 
At the halfway point of the recruitment period, the Steering Committee 
will evaluate if the accrual objective for the first stage was achieved in 
each study cohorts (4, 5, 3, 3 and 3 patients for cohorts 1, 2, 3, 4 and 
5, respectively). If this accrual objective has not achieved in a cohort, 


 
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the Steering Committee will propose a corrective action plan or finalize 
the study in this cohort. 
Study Periods: 
Recruitment period: Estimated enrolment period will be at least 18 
months.  
End of study (EoS): EoS will occur at 12 months after the last patient 
included in the study, unless premature termination of the study. 
 
 


 
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VI. ABBREVIATIONS 
 
Abbreviation 
Definition 
95%CI 
95% confidence intervals 
ABC 
Advanced breast cancer 
ADC 
Antibody-drug conjugate 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
aPTT 
Activated Partial Thromboplastin Time 
ASCO/ CAP 
American Society of Clinical Oncology/College of American Pathologists 
AST 
Aspartate transaminase 
BBB 
Blood-brain barrier 
BCRP 
Breast cancer resistance protein 
BM 
Brain metastases 
BTB 
Blood–tumor barrier 
cfDNA 
Cell-free deoxyribonucleic acid 
Cmax 
Maximum serum concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CSF 
Cerebrospinal fluid 
CSP 
Clinical Study Protocol 
CT 
Computerized tomography 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DSE CSPV 
Daiichi Sankyo Europe Clinical Safety and Pharmacovigilance 
DSUR 
Development Safety Update Report 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


 
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Abbreviation 
Definition 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
EMA 
European Medicines Agency 
EORTC 
European Organization for Research and Treatment of Cancer 
EoS 
End of Study 
EoT 
End of Treatment 
ER 
Estrogen receptor 
ESA 
Erythropoiesis-stimulating agent 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
G-CSF 
Granulocyte-colony stimulating factor 
GDPR 
General Data Protection Regulation 
GGT 
Gamma-glutamyl transferase 
GM-CSF 
Granulocyte-macrophage-colony stimulating factor 
HER2 
Human Epidermal Growth Factor Receptor 2 
hERG 
Human ether-a-go-go-related gene 
HIV 
Human immunodeficiency virus 
HR 
Hormone receptor 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
IC 
Intracranial 
IC50 
Inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
ILD 
Interstitial lung disease 
IMP 
Investigational medicinal product 
INR 
International Normalized Ratio 
IRB 
Institutional review board 
ISH 
In situ hybridization 
IT 
Intrathecal 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 


 
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Abbreviation 
Definition 
LMC 
Leptomeningeal carcinomatosis 
LVEF 
Left ventricular ejection fraction 
MATE 
Multidrug and toxin extrusion 
MBC 
Metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRP 
Multidrug resistance-associated protein 
MUGA 
Multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NE 
Non-evaluable 
NGS 
Next-generation sequencing 
OATP 
Organic anion transporting polypeptide 
ORR 
Overall response rate 
OS 
Overall survival 
P-gp 
P-glycoprotein 
PCR 
Polymerase chain reaction 
PD-L1 
Programmed Death-ligand 1 
PD1 
Programmed death 1 
PET 
Positron emission tomography 
PFS 
Progression Free Survival 
PgR 
Progesterone receptor 
PP 
Per protocol 
PR 
Partial response 
PRO 
Patient reported outcome 
PT 
Prothrombin Time 
Q3W 
Day of 21-day cycle 
QLQ 
Quality of Life Questionnaire 
QOL 
Quality of life 
QTc 
Corrected QT interval 
QTcF 
QTc corrected as per Fridericia 
RANO-BM 
Response Assessment in Neuro-Oncology Brain Metastases 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT 
Radiation therapy 
SAE 
Serious adverse event 


 
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Abbreviation 
Definition 
SD 
Stable disease 
SD 
Stable disease 
SOC 
System-organ class 
SRS 
stereotactic radiotherapy 
TEAE 
Treatment-emergent adverse event 
TBL 
Total bilirubin 
TNBC 
Triple-negative breast cancer 
TQ 
Targeted Questionnaire 
T-DXs 
Trastuzumab deruxtecan (DS-8201a) 
TTR 
Time to response 
ULN 
Upper limit of normal 
UMVUE 
Uniformly minimum variance unbiased estimator 
UPN 
Unique patient number 
Vss 
Volume of distribution at steady state 
WBC 
White blood cell 
WBRT 
Whole-brain radiation therapy 
 
 
 


 
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VII. TABLE OF CONTENTS 
 
I. SPONSOR’S SIGNATURE PAGE ............................................................................................ 2 
II. KEY CONTACT DETAILS ........................................................................................................ 3 
III. STEERING COMMITTEE ........................................................................................................ 4 
IV. DECLARATION OF INVESTIGATORS .................................................................................. 5 
V. CLINICAL STUDY PROTOCOL SYNOPSIS ........................................................................... 7 
VI. ABBREVIATIONS ................................................................................................................. 28 
VII. TABLE OF CONTENTS ....................................................................................................... 32 
VIII. LIST OF TABLES ............................................................................................................... 36 
1 BACKGROUND AND STUDY RATIONALE ........................................................................... 37 
1.1 
Introduction .................................................................................................................. 37 
 
Central Nervous System Metastases in Breast Cancer Patients .............................. 37 
 
Meningeal Carcinomatosis in Breast Cancer Patients .............................................. 39 
 
Blood-Tumor Barrier Permeability and Drug Efficacy ................................................ 39 
 
Trastuzumab Deruxtecan (DS-8201a) (T-DXd) ......................................................... 40 
1.2 
STUDY RATIONALE ..................................................................................................... 45 
2 STUDY OBJECTIVES AND ENDPOINTS .............................................................................. 46 
2.1 
COHORT 1 .................................................................................................................... 46 
 
Study Objectives ........................................................................................................ 46 
 
Study Endpoints ........................................................................................................ 47 
2.2 
COHORT 2, 3, and 4 ..................................................................................................... 48 
 
Study Objectives ........................................................................................................ 48 
 
Study Endpoints ........................................................................................................ 49 
2.3 
COHORT 5 .................................................................................................................... 50 
 
Study Objectives ........................................................................................................ 50 
 
Study Endpoints ........................................................................................................ 51 
3 STUDY OVERVIEW ................................................................................................................ 53 
3.1 
Study Design ................................................................................................................ 53 
3.2 
Study Treatment Management .................................................................................... 54 
3.3 
Duration of Study Treatment ...................................................................................... 55 
3.4 
EoT and EoS Visits ...................................................................................................... 55 
4 PATIENT SELECTION ............................................................................................................ 57 
4.1 
Target Study Population ............................................................................................. 57 
4.2 
Inclusion Criteria .......................................................................................................... 57 
4.3 
Exclusion Criteria ........................................................................................................ 61 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................................... 64 
5.1 
Patient Entry Procedure .............................................................................................. 64 
5.2 
Study Assessments ..................................................................................................... 65 
 
Schedule of Assessments ......................................................................................... 65 
 
Visit Schedule ............................................................................................................ 65 
 
Demographic Data and Medical History .................................................................... 66 


 
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Vital Signs .................................................................................................................. 66 
 
Physical Examination ................................................................................................ 67 
 
Tumor and Response Evaluations ............................................................................ 67 
 
Laboratory Assessments ........................................................................................... 69 
 
Pregnancy and Assessment of Fertility ..................................................................... 70 
 
Electrocardiograms (ECGs) and Cardiac Function Assessment ............................... 72 
 
ECOG performance status ........................................................................................ 73 
 
PRO Assessments .................................................................................................... 73 
 
Biological Samples for Exploratory Analysis ............................................................. 75 
6 STUDY DRUGS INFORMATION ............................................................................................ 77 
6.1 
Formulation, Packaging, and Handling ..................................................................... 77 
 
Trastuzumab deruxtecan (DS-8201a) ....................................................................... 77 
6.2 
Dosage and Administration ........................................................................................ 77 
6.3 
Treatment Modification ............................................................................................... 78 
 
Dose Reduction Levels .............................................................................................. 78 
6.4 
Potential Drug-Drug Interaction ................................................................................. 85 
6.5 
General Concomitant Medication and Supportive Care Guidelines ....................... 86 
6.6 
Prohibited Therapies ................................................................................................... 87 
6.7 
Drug Storage and Drug Accountability ...................................................................... 88 
7 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .............................................. 90 
7.1 
AEs Definitions ............................................................................................................ 90 
7.2 
SAEs .............................................................................................................................. 92 
7.3 
AESIs to Report immediately ...................................................................................... 94 
7.4 
Treatment-emergent adverse event (TEAE) .............................................................. 95 
7.5 
AEs Reporting and Other Safety Related Issues Reporting .................................... 95 
7.6 
SAE Reporting and Timeframe ................................................................................... 96 
7.7 
Expedited Reporting to Health Authorities, Investigators, IRBs, and ECs ............ 97 
7.8 
Other Safety-Related Reports ..................................................................................... 97 
7.9 
Pregnancy Reporting ................................................................................................... 98 
8 STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................................. 99 
8.1 
Determination of Sample Size .................................................................................... 99 
8.2 
Justification of Sample Size ....................................................................................... 99 
 
Cohort 1 ..................................................................................................................... 99 
 
Cohort 2 ................................................................................................................... 100 
 
Cohort 3 ................................................................................................................... 100 
 
Cohort 4 ................................................................................................................... 100 
 
Cohort 5 ................................................................................................................... 100 
8.3 
Analysis Sets .............................................................................................................. 101 
 
Full Analysis and Safety Set .................................................................................... 101 
 
Per-Protocol Set ...................................................................................................... 101 
 
Exploratory Evaluable Set ....................................................................................... 101 
 
Analysis Set Schedule ............................................................................................. 101 
8.4 
Response Assessment .............................................................................................. 101 
 
RECIST v.1.1 Criteria .............................................................................................. 101 
 
RANO-BM criteria .................................................................................................... 103 


 
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8.5 
Primary Efficacy Endpoints ...................................................................................... 103 
8.6 
Secondary Efficacy Endpoints ................................................................................. 104 
8.7 
Exploratory Endpoints .............................................................................................. 105 
 
Analysis of Baseline and Demographic Variables ................................................... 106 
 
Decision Rules and Adjustment of Alpha in the Study ............................................ 106 
 
Primary Efficacy Analysis ........................................................................................ 106 
 
Secondary Efficacy Analysis ................................................................................... 107 
 
Exploratory Analysis ................................................................................................ 107 
8.8 
Safety Analysis .......................................................................................................... 108 
8.9 
Interim Analyses ........................................................................................................ 108 
8.10 Missing Data Management ........................................................................................ 109 
8.11 Steering Committee Review ...................................................................................... 109 
9 ETHICAL CONSIDERATIONS .............................................................................................. 110 
9.1 
Regulatory and Ethics Compliance .......................................................................... 110 
9.2 
IRBs/IECs .................................................................................................................... 110 
9.3 
Informed Consent ...................................................................................................... 110 
9.4 
Data Protection .......................................................................................................... 111 
10 SOURCE DOCUMENTATION, STUDY MONITORING, AND QUALITY ASSURANCE .... 112 
10.1 Source Data Documentation ..................................................................................... 112 
10.2 Study Monitoring and Source Data Verification ..................................................... 113 
10.3 Retention of Records ................................................................................................. 113 
10.4 Data Quality Assurance ............................................................................................. 114 
11 DATA MANAGEMENT ........................................................................................................ 115 
11.1 Data Entry and Management ..................................................................................... 115 
11.2 Data Clarification ....................................................................................................... 115 
11.3 Data Coding Procedures ........................................................................................... 115 
12 STUDY MANAGEMENT ..................................................................................................... 116 
12.1 Discontinuation of the Study .................................................................................... 116 
12.2 Protocol amendments ............................................................................................... 116 
12.3 Protocol Deviations ................................................................................................... 116 
12.4 Publication Policy Protection of Trade Secrets ...................................................... 116 
13 REFERENCES .................................................................................................................... 118 
14 Appendices ........................................................................................................................ 125 
14.1 Appendix 1. Schedule of Assessments and Study Procedures ............................ 125 
14.2 Appendix 2. Response Evaluation Criteria According to RANO-BM Criteria (Lin et 
al. 2015) ............................................................................................................................... 130 
14.3 Appendix 3. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law. ..................................................................................................... 132 
14.4 14.4 Appendix 4. Instructions related to Severe acute respiratory syndrome 
coronavirus 2 (SARS-COV-2) ............................................................................................ 134 
Prior and Concomitant Medications ................................................................................. 134 


 
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VIII. LIST OF TABLES 
 
Table 1. Clinical Trials Investigating Trastuzumab Deruxtecan (DS-8201a) ______________ 43 
Table 2. ECOG Performance Status Scale ________________________________________ 73 
Table 3. Dose Reductions for Trastuzumab Deruxtecan (DS-8201a) ___________________ 78 
Table 4. Toxicity Management Guidelines by using NCI−CTCAE v.5.0 __________________ 79 
Table 5. Time Point Response in Patients with Target (+/–Non-Target) Disease _________ 102 
 
 
 


 
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1 
BACKGROUND AND STUDY RATIONALE 
1.1 
Introduction 
• 
Central Nervous System Metastases in Breast Cancer Patients 
Breast cancer is the second-leading cause of central nervous system (CNS) metastases among 
solid malignancies (Weil et al. 2005). In cohort studies, the incidence is about 5% and this number 
increases to 15% in advanced breast cancer (ABC) (Schouten et al. 2002; Barnholtz-Sloan et al. 
2004). Moreover, autopsy studies indicate that brain metastases (BM) are found in 30% of 
patients with ABC (Lee 1983) and some of them asymptomatic and not diagnosed before death. 
Patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive or triple-negative 
breast cancer (TNBC) have a higher risk of developing BMs than patients with luminal-like 
disease (Kennecke et al. 2010). A previous study analyzing 155 CNS screening images from 
patients recruited in clinical trials showed that HER2 overexpression in addition to the number of 
metastatic sites are predictive of CNS involvement by multivariate analysis (Miller et al. 2003). 
Treatment for HER2-positive patients with BMS depends on factors such as patient prognosis, 
symptoms, resectability, number and size of metastases, whether they are diffuse and previous 
therapy. Patients should receive appropriate local therapy and systemic therapy. Additional 
options include best supportive care, enrolment in clinical trial and/or palliative care. Current 
treatment options for BM comprise local approaches such as radiation therapy with or without 
surgery. Whole-brain radiation therapy (WBRT) is commonly used for patients with multiple 
metastases, whereas stereotactic radiotherapy (SRS) is principally recommended for those with 
less than four different metastatic localizations. On the other hand, neurosurgery is reserved for 
single metastases or in specific cases such as bleeding or mass effect-causing lesions. 
Very recently, formal expert consensus-based guideline recommendations on the management 
of BMs for patients with HER2-positive ABC was released (Ramakrishna et al. 2018). Following 
revision of 622 publications, the authors stated no additional evidence was identified that would 
warrant a change to the 2014 recommendations and stressing out the importance of the research 
in BM in BC patients to find more effective treatments (Ramakrishna et al. 2018). 
The landscape of medical treatment for patients with BMs from HER2-positive breast cancer is 
quite uncertain, traditionally attributed to difficulties in reaching optimal concentrations in the 
metastatic environment of BM (Fabi et al. 2018). Introduction of anti-HER2 targeted therapy has 
significantly improved overall survival (OS) among patients with HER2-positive BC. The 
widespread use of trastuzumab −a humanized anti-HER2 monoclonal antibody that targets the 
extracellular domain of the receptor− also has allowed to unmask a population in whom CNS 
progression is a significant source of morbidity and mortality (Lin and Winer 2007). CNS 
metastases are common among patients receiving trastuzumab-based therapy, including patients 
responding outside the CNS (Bendell et al. 2003). Interestingly, the CNS metastasis events have 


 
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been reported in several of the trastuzumab-based studies in adjuvant setting. A numeric increase 
in the number of CNS metastases as first event has been observed in the trastuzumab treatment 
arms from in two North American trials: North Central Cancer Treatment Group NCCTG N9831 
trial (NCT00005970) (Combination Chemotherapy With or Without Trastuzumab in Treating 
Women With HER2-Overexpressing Breast Cancer) (Romond et al. 2005; Perez et al. 2011) and 
the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 trial (NCT00004067) 
(Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating 
Women With Node-Positive Breast Cancer That Overexpresses HER2) (Romond et al. 2012; 
Perez et al. 2014). This trend was also observed in the HERA trial (NCT00045032), a randomized 
trial comparing one or two years of trastuzumab given every three weeks in patients with HER2-
positive early BC (Piccart-Gebhart et al. 2005). 
Besides the biological perspective of more propensity to CNS metastasis, it also seems that 
trastuzumab has poor penetration in CNS. Although, there are some evidences of better 
penetration of trastuzumab in cerebrospinal fluid (CSF) under conditions of an impaired blood-
brain barrier (BBB), such as in patients with meningeal carcinomatosis or following radiotherapy 
(Stemmler et al. 2007). 
After developing of BMs, OS resulted widely affected. Historical series in patients with from breast 
cancer who were treated with WBRT report a median overall survival less than six months 
(Mahmoud-Ahmed et al. 2002). With better disease control outside CNS, mostly conferred by the 
use of anti-HER2 targeted therapy, OS improved in this group of patients, after diagnoses of BM. 
Some studies have reported median survival after CNS recurrence of up to 23 months, in patients 
treated with trastuzumab (Gori et al. 2007; Melisko et al. 2008). Unlike other tumors, like non-
small cell lung tumors and acute lymphoblastic leukemia, prophylactic cranial irradiation remains 
experimental for BC patients. 
Few prospective trials have been conducted addressing treatment of BMs in BC and patients with 
progressive BMs are often excluded from clinical trials, usually because of their poor prognosis, 
because most of systemic treatments fail to penetrate the BBB and also due to high risk of CNS 
hemorrhage or toxicity (Gounder and Spriggs 2011). 
RegistHER (NCT00105456) was a multicenter, observational, prospective US cohort study of 
patients with HER2-positive metastatic breast cancer (MBC) (Yardley et al. 2014; Brufsky et al. 
2011). In this study, 377 (37,3%) of the 1.012 patients enrolled developed CNS metastases. The 
role of trastuzumab was prospectively assessed and was associated with a statistically significant 
improvement in median OS following diagnosis of CNS disease (17,5 vs. 3,8 months) (Brufsky et 
al. 2011). Some retrospective studies also showed some OS benefit with trastuzumab after 
development of BMs (Church et al. 2008; Park et al. 2009; Bartsch et al. 2007; Dawood et al. 
2008). 
 


 
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• 
Meningeal Carcinomatosis in Breast Cancer Patients 
Meningeal 
carcinomatosis 
−also 
known 
as 
leptomeningeal 
carcinomatosis 
(LMC) 
or 
carcinomatous meningitis− is an aseptic inflammatory reaction caused by diffuse spread of 
malignant cells throughout the subarachnoid space. Definitive diagnosis is made with cytologic 
identification of malignant cells within the CSF. LMC likely comprises about 11-20% of CNS 
metastasis (Altundag et al. 2007; H.-J. Kim et al. 2012). 
CNS metastasis in BC has been associated with reduced overall survival, with the shortest 
prognosis generally observed in cases of LMC. Prospective studies have found a median OS of 
9-30.3 weeks (Scott and Kesari 2013). 
There is currently no generally accepted standard of care for treatment of breast cancer LMC. 
Like in other BMs treatment, patient performance status, preferences and prognosis must be 
taken into account. Surgical treatment might be necessary for complications, like hydrocephalus. 
Radiation therapy (RT) and/or chemotherapy (intravenous [IV]) or intrathecal [IT]) can be used. 
Targeted agents, like trastuzumab, can also play a role in HER2-positive disease. RT can be 
administered as WBRT modality, which had shown some benefit when integrated in a 
multimodality approach in BC patients (J. H. Kim, Jenrow, and Brown 2018) or to palliate 
symptoms, for example, to relieve pain from nerve root compression. IV high dose methotrexate 
seems to improve OS over RT alone, but has important systemic toxicity (Boogerd et al. 2004). 
IT chemotherapy, using methotrexate, lipossomic cytarabine or thiotepa, has the advantage of 
drug being delivered directly in CNS. However, distribution is dependent on normal CSF 
circulation and side effects include ventriculitis/ arachnoiditis, leukoencephalopathy and bacterial 
meningitis associated with the presence of an intraventricular reservoir (Chamberlain 2012). Case 
reports and small series (less than 10 patients) also showed some benefit of treatment with 
capecitabine for BC patients who develop LM (Ekenel et al. 2007). There are also some case 
reports and reporting the use of trastuzumab IT (Oliveira et al. 2011; Figura et al. 2018; Lu et al. 
2015; Zagouri et al. 2013). 
The dose and schedule of IT trastuzumab was highly variable in literature. A phase I trial 
(NCT01373710) concluded that maximum tolerated dose and recommended phase II weekly 
dose of IT trastuzumab in patients with HER2-BC and LMC is 150 mg (Bonneau et al. 
2018). Based on these encouraging results, phase II is ongoing. 
 
• 
Blood-Tumor Barrier Permeability and Drug Efficacy 
The BBB is often considered a challenge in the treatment of BM in patients with HER2-positive 
breast cancer, since it may affect drug delivery and penetration (Kabraji et al. 2018). However, 
abnormal angiogenesis in tumors leads to the formation of blood vessels that lack normal 
physiological structure, resulting in a compromised BBB, which is referred as the blood–tumor 


 
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barrier (BTB). In contrast to the normal BBB, the leaky BTB often allows for the extravasation of 
larger molecules, including antibodies (Kabraji et al. 2018; Askoxylakis et al. 2016). 
Lapatinib (Tykerb®) −a reversible dual exc inhibitor which interrupts the HER2 and Epidermal 
Growth Factor Receptor (EGFR) pathways by binding to the ATP-binding pocket of their protein 
kinase domain− was studied in BC patients previously treated with trastuzumab who developed 
progressive BMs, and at least one measurable metastatic brain lesion. Altogether these studies 
confirmed the modest CNS antitumor activity of lapatinib, but also that responding patients had 
an improved time to progression (Lin et al. 2008, 2009). 
The combination of lapatinib with cytotoxic agents such as capecitabine (Xeloda®) –an orally 
fluoropyrimidine carbamate– demonstrated to enhance treatment response in HER2-positive 
MBC patients with untreated BM. In the LANDSCAPE trial (NCT00967031) –a single-arm phase 
II, open-label, multicenter study– 45 HER2-positive MBC patients with newly diagnosed BM, not 
previously treated with WBRT, capecitabine, or lapatinib were enrolled. The CNS overall 
response rate was 65,9% and median time to whole-brain irradiation was 8,3 months (Bachelot 
et al. 2013). 
The development of antibody-drug conjugates (ADCs) represents a promising strategy for 
patients with metastatic BC affecting SNC with a compromised BBB. Trastuzumab-emtansine (T-
DM1) (Kadcyla®) is an ADC in which emtansine, a specific derivate of mertansine or DM1, is 
stably bound to trastuzumab. TDM-1 was studied in MBC patients, after trastuzumab- and taxane-
based therapy, in the EMILIA trial (Verma et al. 2012). A retrospective analysis of this phase III 
trial suggested a possible activity of T-DM1 in HER2-positive MBC patients with non-progressing 
BM previously treated with local therapy with a favorable safety profile and prolonged extracranial 
disease control (Krop et al. 2015). 
A sub-analysis of an Italian retrospective analysis of effectiveness and safety of T-DM1 also 
showed that T-DM1 is active in BC patients with BMs, with overall response rate of 35,1% and a 
disease control rate of 53,3% (Fabi et al. 2018). 
 
• 
Trastuzumab Deruxtecan (DS-8201a) (T-DXd) 
Trastuzumab deruxtecan (DS-8201a) is a monoclonal antibody targeting HER2 conjugated to a 
cytotoxic chemotherapeutic agent at a drug-to-antibody ratio of 7-8. MAAL-9001, a humanized 
IgG1 monoclonal antibody produced in-house with reference to the amino acid sequence of 
trastuzumab, is used as the antibody component, and MAAA-1181a, a derivative of exatecan, a 
topoisomerase I inhibitor, is used as the drug component. T-DXd is composed of MAAL-9001 and 
MAAA-1181a bound together by a maleimide tetrapeptide linker. 
 


 
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1.1.1.1 
Non-Clinical Studies 
Pharmacology 
The results of in vitro cell growth inhibition studies conducted using several cancer cell lines have 
shown that trastuzumab deruxtecan (DS-8201a) has a more potent growth inhibition effect 
against HER2-positive cells than MAAL-9001, suggesting that the conjugation of MAAA-1181a 
enhances the growth inhibition of trastuzumab deruxtecan (DS-8201a). Moreover, no growth 
inhibition was observed in HER2-negative cells, confirming the HER2 specificity of trastuzumab 
deruxtecan (DS-8201a). This exhibited antitumor activity in a tumor-bearing mouse model of 
human breast cancer cell line (KPL-4). In studies conducted in a tumor-bearing mouse model 
utilizing grafted tumor tissue obtained from breast cancer patients, trastuzumab deruxtecan (DS-
8201a) 
exhibited 
antitumor 
activity 
both 
in 
an 
HER2 
high-expressing 
model 
with 
an 
immunohistochemistry (IHC) score of 2+ and fluorescent in situ hybridization (FISH) positive, and 
also in an HER2 low-expressing model with an IHC score of 1+ and FISH-negative. 
(T-DXd) has an HER2-mediated Akt phosphorylation inhibition effect and an antibody dependent 
cellular cytotoxic (ADCC) activity and has also been confirmed to cause deoxyribonucleic acid 
(DNA) damage and induce apoptosis, effects that are assumed to be the result of MAAA-1181a, 
which has topoisomerase I inhibitory activity. T-DXd (DS-8201a) is considered to exhibit HER2-
specific cell growth inhibition and antitumor activity via a novel mechanism of action that combines 
the pharmacological activities of MAAL-9001, the antibody component, with those of MAAA-
1181a, the drug component. 
 
Safety pharmacology 
In telemetered male cynomolgus monkeys treated with single intravenous doses of trastuzumab 
deruxtecan (DS-8201a), no effects on the cardiovascular system, the respiratory system, or the 
central nervous system were observed at dose levels up to 78.8 mg/kg. In addition, in human 
ether-a-go-go-related gene (hERG) studies of MAAA-1181a, MAAA-1181a did not inhibit the 
hERG channel current – responsible for the rapidly activating component of delayed rectifier 
potassium current - at concentrations of up to 10μmol/L (approximately 5000 ng/mL). 
 
Pharmacokinetics and Drug Metabolism 
The volume of distribution at steady state (Vss) was close to the plasma volume. The majority of 
administered trastuzumab deruxtecan (DS-8201a) circulates in plasma unchanged. The plasma 
concentrations of MAAA-1181a, the drug that is release from trastuzumab deruxtecan (DS-
8201a), were quite low to the decline in the blood concentration, suggesting no accumulation or 
retention in specific tissues. The plasma protein binding ratios of MAAA-1181a (10ng/mL to 


 
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100ng/mL) were 90.3% to 92.5% in mice, 94.2% to 96.7% in rats, 86.5% to 89.1% in monkeys, 
and 96.8% to 98.0% in humans. Cytochrome P450(CYP) 3A4 was the primary CYP enzyme 
involved in the metabolism of MAAA-1181a.No human-specific metabolites were detected in 
hepatocytes in vitro. In rats, the major excretion pathway was the fecal/biliary route. MAAA-1181a 
was the most abundant component of radioactivity in urine, feces, and bile. In monkeys, 
radioactivity from administered 14C-trastuzumab deruxtecan (DS-8201a) was predominantly 
excreted into feces. MAAA-1181a was the most abundant catabolite in urine and feces. MAAA-
1181a did not exhibit any potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, or CYP3A nor to induce CYP3A4, CYP1A2, or CYP2B6, at concentrations of up to 30 
μmol/L. 
In vitro, MAAA-1181a was a substrate for organic anion transporting polypeptide (OATP) 1B1, 
OATP1B3, multidrug and toxin extrusion (MATE) 2-K, P-glycoprotein (P-gp), breast cancer 
resistance protein (BCRP), and multidrug resistance-associated protein (MRP) 1. 
 
Toxicology 
The common adverse findings with both trastuzumab deruxtecan (DS-8201a) and MAAA-1181a 
studies 
were 
intestinal 
and 
lymphatic/hematopoietic 
system 
toxicities. 
For 
trastuzumab 
deruxtecan (DS-8201a) treatment, pulmonary, testicular, skin and renal toxicities were observed 
while heart, liver, and corneal toxicities were found only in the MAAA-1181a study. In intermittent 
intravenous dose toxicity studies with MAAL-9001in rats and cynomolgus monkeys (every 3 
weeks [Q3W], 6 weeks), no MAAL-9001-related toxic changes were observed. In a human cross-
reactivity study of trastuzumab deruxtecan (DS-8201a) with a panel of human tissues, 
trastuzumab deruxtecan (DS-8201a)-related cell membrane staining was found only in the 
placenta. In a cross-reactivity study of trastuzumab deruxtecan (DS-8201a) with selected 
cynomolgus monkey tissues (e.g., brain, liver, kidney, lung, heart, intestines, lymphoid organs, 
testis, and skin), no membranous staining was noted in any tissues. In an in vitro 3T3 NRU 
phototoxicity study, MAAA-1181a was found to be phototoxic to Balb/c 3T3 mouse fibroblasts. 
However, in an in vivo single dose phototoxicity study of MAAA-1181a in pigmented rats, no 
phototoxic reaction was noted at 3mg/kg, the highest dose tested. The genotoxicity studies of 
MAAA-1181a indicated that MAAA-1181a had no potential to induce gene mutation in bacteria 
but had the potential to induce structural chromosome aberrations in mammalian cultured cells. 
 
1.1.1.2 
Clinical Studies 
To date, there are 12 clinical studies investigating trastuzumab deruxtecan (DS-8201a), that are 
showed in Table 1: 


 
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Table 1. Clinical Trials Investigating Trastuzumab Deruxtecan (DS-8201a) 
Study Code 
Study 
Phase 
Title 
Reference 
DS8201-A-J101 
(NCT02564900) 
I 
Phase 1, two-part, multicenter, non-randomized, 
open-label, multiple dose first-in-human study of 
DS8201a in subjects with advanced solid malignant 
tumors  
(Iwata 
et 
al. 
2018; S. Modi 
et al. 2019; Doi 
et al. 2017) (S. 
Modi 
et 
al. 
2019)(S. 
Modi 
et al. 2019) 
DS8201-A-J102 
(NCT03366428) 
I 
Phase 
1, 
multicenter, 
open-label, 
multiple-dose 
study of DS-8201a to assess the effect on the QT 
interval 
and 
pharmacokinetics 
in 
subjects 
with 
HER2-expressing metastatic and/or unresectable 
breast cancer 
 
DS8201-A-A103 
(NCT03368196) 
I 
Phase 1, multicenter, open-label study of DS8201a 
to assess safety and pharmacokinetics in subjects 
with 
HER2-positive 
advanced 
and/or 
refractory 
gastric, gastroesophageal junction adenocarcinoma, 
or breast cancer 
 
DS8201-A-A104 
(NCT03383692): 
I 
Phase 1, multicenter, open-label, single sequence 
crossover study to evaluate drug-drug interaction 
potential 
of 
OATP1B/CYP3A 
inhibitor 
on 
the 
pharmacokinetics of DS8201a in subjects with 
HER2-expressing advanced solid malignant tumors 
 
DS8201-A-U105 
(NCT03523572) 
Ib 
Phase 1b, multicenter, open-label study of DS-
8201a in combination with nivolumab, an anti-PD-1 
antibody 
for 
subjects 
with 
HER2-expressing 
Advanced Breast and Urothelial Cancer 
 
DS8201-1-U201 
(NCT03248492) 
II 
Phase 2, multicenter, open-label study of DS8201a 
for unresectable and/or metastatic breast cancer 
subjects previously treated with T-DM1 - DESTINY-
Breast01 
(Baselga et al. 
2018) 
DS8201-A-J202 
(NCT03329690) 
II 
Phase 2, multicenter, open-label study of DS8201a 
in subjects with HER2-expressing advanced gastric 
or gastroesophageal junction adenocarcinoma 
(Shitara et al. 
2019) 
DS8201-A-J203 
(NCT03384940) 
II 
Phase 2, multicenter, open-label study of DS-8201a 
in 
subjects 
with 
HER2-expressing 
advanced 
colorectal cancer 
 
DS8201-A-U204 
(NCT03505710) 
II 
Phase 2, multicenter, open-label, 2-cohort study of 
trastuzumab deruxtecan (DS-8201a) for HER2-over-
expressing 
or 
–mutated, 
unresectable 
and/or 
metastatic non-small cell lung cancer (NSCLC) 
 
DS8201 –A-
U301 
(NCT03523585) 
III 
Phase 3 multicenter randomized open-label active-
controlled study of DS-8201a versus treatment of 
investigator's 
choice 
for 
HER2-positive, 
unresectable 
and/or 
metastatic 
breast 
cancer 
subjects pretreated with prior standard of care HER2 
Therapies, including T-DM1 
(André 
et 
al. 
2019) 
DS8201-A-U302 
(NCT03529110) 
III 
Phase 3 multicenter randomized open-label, active-
controlled study of DS-8201a Versus T-DM1 for 
HER2-Positive, 
unresectable 
and/or 
Metastatic 
Breast Cancer Subjects Previously Treated With 
trastuzumab and taxane - DESTINY-Breast03 
 
DS8201-A-U303 
(NCT03734029) 
III 
Phase 3, Multicenter, Randomized, Open-label, 
Active Controlled Trial of DS-8201a, an Anti-HER2 
 


 
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Study Code 
Study 
Phase 
Title 
Reference 
ADC, Versus Treatment of Physician's Choice for 
HER2-low, Unresectable and/or Metastatic Breast 
Cancer Subjects 
 
Efficacy 
The majority of referred trials are still ongoing, most of them estimated to be completed between 
2019 and 2022. 
Preliminary results are available from part I of phase I trial (A-J101), where patients with 
advanced/unresectable or metastatic breast cancer or gastric or gastroesophageal junction 
adenocarcinoma that is refractory to or intolerable with standard treatment, or for which no 
standard treatment is available, received trastuzumab deruxtecan (DS-8201a). In 23 evaluable 
patients, including 6 with low HER2-expressing tumors, 10 patients achieved an objective 
response (43%, 95% CI 23,2-65,5) and disease control was achieved in 21 (91%, 95% CI 72,0 – 
98,9). In this heavily pretreated study population, trastuzumab deruxtecan (DS-8201a) showed 
antitumor activity, even in low HER2-expressing tumors (Doi et al. 2017). 
In part II of the same trial, cohorts included patients with BC, gastric cancer and other HER2 
expressing tumors. In BC patients with a median of 5 prior regimens in metastatic setting (46 
patients with HER2 positive, previous treated with TDM-1, and 10 with HER2 low expressing), 37 
were evaluable for response at the time of data cutoff. Overall response rate (ORR) was 41%, 
including 1 complete response (CR). Disease control rate (DCR) was 97%. Median duration of 
treatment was not reached. For the evaluable patients who had previous received T-DM1, 
treatment with trastuzumab deruxtecan (DS-8201a) achieved an ORR of 41% (11/27) and DCR 
of 100% (27/27). In the subset of this patients who also had received previous pertuzumab and 
T-DM1, the confirmed ORR was 44% (11/25). In patients with low-expressing HER2 BC, the ORR 
was 40% (4/10), DCR was 90% (9/10) (Shanu Modi et al. 2017). 
 
Clinical Safety 
In the said phase I dose escalation trial, no dose-limiting toxic effects, substantial cardiovascular 
toxic effects or deaths occurred. Most common grade 3 adverse events (AEs) were decreased 
lymphocyte (n=3) and decreased neutrophil count (n=2); grade 4 anemia was reported by 1 
patient. Three serious AEs- febrile neutropenia, intestinal perforation, and cholangitis- were 
reported by one patient each (Doi et al. 2017). Of the 46 BC patients in part 2, the most common 
AEs of any grades were nausea, decreased appetite, vomiting, alopecia, and diarrhea. Only 2 
patients experienced grade 4 AEs (thrombocytopenia and neutropenia) and 46 % (21/46) 
experienced grade 3 AEs (most commonly anemia, neutropenia, thrombocytopenia, leukopenia, 
lymphocytopenia, and vomiting) (Shanu Modi et al. 2017). 


 
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1.2 
STUDY RATIONALE 
Currently, there are not specifically approved drugs for MBC patients with BM and/or LMC and 
consensus guidelines on systemic treatment after BM and/or LMC in MBC patients are lacking. 
Clinical trials commonly exclude MBC patients with BM and/or LMC from participation. Routine 
exclusion of such patients limits applicability of trial results and obfuscates potential benefit in this 
subpopulation. For this reason, it is essential to design specific clinical trials for MBC patients with 
BM and/or LMC. 
Preliminary results from studies on trastuzumab deruxtecan (DS-8201a) −a HER2-targeted ADC 
with novel topoisomerase I inhibitor payload and linker technology− in BC are very promising, 
even in heavy pre-treated patients with MBC. 
The aim of this two-step, multicenter, international, open-label, single-arm, multicohort phase II 
trial is to evaluate the efficacy of trastuzumab deruxtecan (DS-8201a) in patients with HER2-
positive or HER2-low-expressing MBC with BM, and patients with HER2-positive MBC with LMC. 
To our knowledge, it will be the first prospective study to evaluate the role of an ADC in patients 
with HER2-positive and HER2-low expressing MBC patients with BMs, and patients with HER2-
positive MBC with LMC. Because other anti-HER2 drugs will be explored in this setting as well, 
some data with trastuzumab deruxtecan (DS-8201a) are needed in HER2-positive MBC patients 
with BM and/or LMC. If this trial is positive, trastuzumab deruxtecan (DS-8201a) will be used in 
MBC regardless the presence of CNS involvement. It might also represent the first therapeutic 
option specifically evaluated in HER2-low-expressing MBC patients with BMs. 
 
 
 


 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
COHORT 1  
• 
Study Objectives 
Primary Objective 
• 
To assess efficacy −defined as 16 weeks PFS per Response Assessment in Neuro-Oncology 
Brain Metastases (RANO-BM) and Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally 
advanced or metastatic HER2-positive BC with non-progressing BM (after WBRT and/or SRS 
and or surgery). 
 
Secondary Objectives 
Efficacy 
• 
To assess efficacy −defined as PFS, ORR, CBR, time to response (TTR), duration of 
response (DOR), and best percentage of change in tumor burden per RANO-BM (for IC 
lesions) and RECIST 1.1 (extracranial lesions and overall lesions)–after treatment with 
trastuzumab deruxtecan (DS-8201a) in this population. 
• 
To asses OS in this population,  
 
Safety 
• 
To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) in this population 
by NCI-CTCAE v.5.0. 
 
Exploratory Objectives 
• 
To assess 
using 
and its 
in this population. 
• 
To evaluate predictive or prognostic biomarkers (plasma and/or tissue and/or CSF) 
associated with disease activity status or response to treatment in this population. 
• 
To identify possible mechanisms of resistance to study treatments through the comparative 
analysis of potential biomarkers from paired pre-treatment and post-progression tumor and/or 
blood and/or CSF samples from this population. 
 


 
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• 
Study Endpoints 
Primary Endpoint 
16 weeks-PFS, defined as the period of time from treatment initiation to the first occurrence 
of disease progression or death from any cause, whichever occurs first. Progression will be 
determined locally by the investigator through the use of Response Assessment in Neuro-
Oncology Brain Metastases (RANO-BM) criteria (IC lesions) and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
 
Secondary Endpoints 
Efficacy 
o 
PFS defined as the period of time from treatment initiation to the first occurrence of disease 
progression or death from any cause, whichever occurs first. Progression will be determined 
locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST 
criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. 
o 
ORR, defined as a CR or PR, determined locally by the investigator through the use of RANO-
BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
CBR, defined as an objective response (CR or PR), or stable disease (SD) for at least 24 
weeks, determined locally by the investigator through the use of RANO-BM criteria for IC 
lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and 
extracranial) lesions. 
o 
TTR, defined as the time from the treatment initiation to time of the first objective tumor 
response observed for patients who achieved a CR or PR, determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
o 
DOR, defined as the time from the first occurrence of a documented objective response to 
disease progression or death from any cause, whichever occurs first, determined locally by 
the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 
for both extracranial lesions and overall (IC and extracranial) lesions. 
o 
OS, defined as the time from treatment initiation to death from any cause. Patients without 
documented death at the time of the final analysis will be censored at the date of the last 
follow-up. 
o 
Best percentage of change from baseline in the size of tumors, defined as the biggest 
decrease, or smallest increase if no decrease will be observed and determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
 


 
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Safety 
o 
Adverse events (AEs) will be evaluated using the National Cancer Institute (NCI)−Common 
Terminology Criteria for Adverse Events (CTCAE) v.5.0.  
 
Exploratory Endpoints 
• 
Overall change from baseline i
, 
and 
; Time 
to 
in 
; Time to 
in 
; Time to 
. 
o 
Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical 
characteristics (e.g., baseline features) and outcome (e.g., duration of 
). 
 
2.2 
COHORT 2, 3, and 4 
• 
Study Objectives 
Primary Objective 
• 
To assess efficacy −defined as intracranial overall response rate (ORR−IC) per RANO-BM– 
of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally 
advanced or metastatic BC: 
a) 
HER2-positive or HER2-low expressing with untreated BMs (cohort 2); 
b) 
HER2-positive with progressing BMs after local treatment (cohort 3); 
c) 
HER2-low expressing with progressing BMs after local treatment (cohort 4). 
 
Secondary Objectives 
Efficacy 
• 
To assess efficacy –defined as PFS, CBR, TTR, DOR, and best percentage of change in 
tumor burden per RANO-BM (for IC lesions) and RECIST 1.1 (for extracranial lesions and 
overall lesions); and ORR per RECIST 1.1 (for extracranial lesions and overall lesions). 
• 
Time to WBR and/or SRS (only for cohort 2), defined as the time from the treatment initiation 
to time of CNS disease progression that requires treatment with WBR and/or SRS, and 
determined locally by the investigator through the use of RANO-BM and RECIST 1.1 criteria. 
• 
To assess OS in this population. 
 
Safety 


 
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• 
To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) by NCI-CTCAE 
v.5.0. 
 
Exploratory Objectives 
• 
To assess 
using the 
and 
, 
in 
study cohorts 2, 3, and 4. 
• 
To evaluate predictive or prognostic biomarkers (plasma and/or tissue and/or CSF) 
associated with disease activity status or response to treatment in study cohorts 2, 3, and 4. 
• 
To identify possible mechanisms of resistance to study treatments through the comparative 
analysis of potential biomarkers from paired pre-treatment and post-progression tumor and/or 
blood and/or CSF samples from patients of study cohorts 2, 3, and 4. 
 
• 
Study Endpoints 
Primary Endpoint 
o 
ORR-IC, defined as a complete response (CR) or partial response (PR), and determined 
locally by the investigator through the use of RANO-BM criteria. 
 
Secondary Endpoints 
Efficacy 
o 
PFS, defined as the period of time from treatment initiation to the first occurrence of disease 
progression or death from any cause, whichever occurs first. Progression will be determined 
locally per RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial 
lesions and overall (IC and extracranial) lesions. 
o 
ORR, defined as a CR or PR, determined locally by the investigator through the use of 
RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. 
o 
CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, and 
determined locally by the investigator through the use of RANO-BM criteria for IC lesions and 
RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. 
o 
TTR, defined as the time from the treatment initiation to time of the first objective tumor 
response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, 
determined locally by the investigator through the use of RANO-BM criteria for IC lesions and 
RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. 
o 
DOR, defined as the time from the first occurrence of a documented objective response to 
disease progression or death from any cause, whichever occurs first, determined locally by 


 
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the investigator though the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1. 
for both extracranial lesions and overall (IC and extracranial) lesions. 
o 
OS, defined as the time from treatment initiation to death from any cause. Patients without 
documented death at the time of the final analysis will be censored at the date of the last 
follow-up. 
o 
Best percentage of change from baseline in the size of tumor lesions, defined as the biggest 
decrease, or smallest increase if no decrease will be observed, and determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
o 
Time to WBRT and/or SRS (only for cohort 2), defined as the time from the treatment initiation 
to time of CNS disease progression that requires treatment with WBR and/or SRS, and 
determined locally by the investigator through the use of RANO-BM and RECIST 1.1 criteria. 
 
Safety 
o 
AEs will be evaluated using the NCI-CTCAE v.5.0. 
 
Exploratory Endpoints 
• 
Overall change from baseline in 
, 
and 
; Time 
to 
in 
; Time to 
in 
; Time to 
. 
o 
Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical 
characteristics (e.g., baseline features) and outcome (e.g., duration of 
). 
 
2.3 
COHORT 5 
• 
Study Objectives 
Primary Objective 
• 
To assess efficacy −defined as OS− of trastuzumab deruxtecan (DS-8201a) in patients with 
pretreated unresectable locally advanced or metastatic HER2-positive or HER2-low 
expressing BC with LMC. 
 
Secondary Objectives 
Efficacy 


 
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• 
To assess efficacy −defined as PFS, ORR, CBR, TTR, DOR, and best percentage of change 
in tumor burden per RANO-BM (IC lesions) and RECIST 1.1 (extracranial lesions and overall 
lesions) 
Safety 
• 
To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) by NCI-CTCAE 
v.5.0. 
 
Exploratory Objectives 
• 
To assess 
using the 
and its 
, 
in this 
population. 
• 
To evaluate predictive or prognostic biomarkers (plasma and/or tissue and/or CSF) 
associated with disease activity status or response to treatment in this population. 
• 
To identify possible mechanisms of resistance to study treatments through the comparative 
analysis of potential biomarkers from paired pre-treatment and post-progression tumor and/or 
blood and/or CSF samples from this population. 
 
• 
Study Endpoints 
Primary Endpoint 
o 
OS defined as the time from treatment initiation to death from any cause. Patients without 
documented death at the time of the final analysis will be censored at the date of the last 
follow-up. 
 
Secondary Endpoints 
Efficacy 
o 
ORR, defined as a CR or PR, determined locally by the investigator through the use of RANO-
BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
o 
PFS, defined as the period of time from treatment initiation to the first occurrence of disease 
progression or death from any cause, whichever occurs first during at least first 12 months. 
Progression will be determined locally by the investigator through the use of RANO-BM 
criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC 
and extracranial) lesions. 


 
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o 
CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, determined 
locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST 
criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. 
o 
TTR, defined as the time from the treatment initiation to time of the first objective tumor 
response observed for patients who achieved a CR or PR, determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
o 
DOR, defined as the time from the first occurrence of a documented objective response to 
disease progression or death from any cause, whichever occurs first, determined locally by 
the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 
for both extracranial lesions and overall (IC and extracranial) lesions. 
o 
Best percentage of change from baseline in the size of tumor lesions, defined as the biggest 
decrease, or smallest increase if no decrease will be observed, and determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
 
Safety 
o 
AEs will be evaluated using the NCI-CTCAE v.5.0. 
 
Exploratory Endpoints 
o 
Overall change from baseline in 
, 
and 
; Time 
to 
in 
; Time to 
in 
; Time to 
. 
o 
Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical 
characteristics (e.g., baseline features) and outcome (e.g., duration of 
). 
 
 
 


 
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3 
STUDY OVERVIEW 
3.1 
Study Design 
This is a multicenter, open-label, single-arm, multicohort, two-stage optimal Simon’s design, 
phase II clinical trial that is designed to evaluate the safety, tolerability, and efficacy of 
trastuzumab deruxtecan (DS-8201a) for pretreated patients with unresectable locally advanced 
or metastatic HER2-positive or HER2-low expressing BC with untreated or treated BMs or LMC. 
After signing informed consent form (ICF) and confirmed eligibility, patients will be assigned 
to one of the following five study cohorts: 
• 
Cohort 1: HER2-positive BC with non-progressing BM (after WBRT and/or SRS);(N = 8); 
• 
Cohort 2: HER2-positive or HER2-low BC with asymptomatic, untreated BMs (N = 10); 
• 
Cohort 3: HER2-positive BC with progressing BMs after local treatment (N = 7); 
• 
Cohort 4: HER2-low expressing BC with progressing BMs after local treatment (N = 7); 
• 
Cohort 5: HER2-positive or HER2-low expressing BC with LMC (N = 7). 
Enrolment will start for all cohorts at the same time.  
A futility interim analysis has been planned in cohort 1. The recruitment will not be stopped during 
the interim analysis. However, after the interim analysis, if the number of patients achieving the 
primary endpoint is equal or less than futility boundary in each cohort, the accrual in the cohort 
must be stopped. The stopping rule is: 
Cohort 1: All 4 patients with progressive disease or death at 16 weeks. 
Additionally a feasibility interim analyses has been planned in each cohort. At the halfway point 
of the recruitment period, the Steering Committee will evaluate if the accrual objective for the first 
stage was achieved in each study cohorts (4, 5, 3, 3 and 3 patients for cohorts 1, 2, 3, 4 and 5, 
respectively). If this accrual objective has not achieved in a cohort, the Steering Committee will 
propose a corrective action plan or finalize the study in this cohort 
For estimation of PFS, TTR, ORR, DOR, CBR, OS, 12-week CNS disease stabilization, and best 
percentage of change in target tumor lesions, tumor assessment will be based on RANO-BM 
criteria and on RECIST v.1.1 criteria for estimation in non-target tumor lesions (Brain MRI and 
chest/pelvis and abdomen CT) (see Appendices 
Appendix 1) and will be performed every six weeks (± 3 days) for the first six months and, 
thereafter, every nine weeks (± 5 days) until disease progression. If patient interrupts treatment 
without confirmation on disease progression, tumor assessment will continue until event is 
confirmed unless patient starts new anti-cancer treatment, withdrawal of consent, death, or the 
end of the study, whichever occurs first. Tumor assessments will be performed on the specified 
schedule regardless of treatment delays. 


 
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In addition, for patient allocated in the study cohort 5, CSF analysis will be performed at base line, 
every three weeks for 12 weeks (corresponding to the first 5 cycles of treatment) and every six 
weeks thereafter and at the time of disease progression, treatment discontinuation, the start of 
new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever 
occurs first. 
Bone scans will be only performed every 24 weeks (± 7 days) for patients with bone lesions 
identified at baseline, unless clinically or biochemically suspected bone progression. 
Safety assessments will include the incidence, nature, and severity of AEs and laboratory 
abnormalities graded per the NCI−CTCAE v.5.0. Laboratory safety assessments will include the 
regular monitoring of hematology, blood chemistry, coagulation, and pregnancy test (see 
Appendices 
Appendix 1). 
To perform exploratory studies, patients must have consented to provide sufficient newly obtained 
tumor biopsy tissue with the exception of patients for whom tumor biopsies cannot be obtained 
(e.g., inaccessible tumor or subject safety concern) that may submit an archived metastatic tumor 
specimen only upon agreement from the Sponsor. Patients will also be given the option of 
providing a tissue biopsy sample obtained at disease progression for exploratory analyses; this 
decision will not affect overall study eligibility. Furthermore, patients have agreed to give blood 
samples (liquid biopsy) at the time of inclusion, after two cycles of study treatment, and upon 
progression or study termination. Moreover, patient allocated in the study cohort 5, must have 
consented to provide CSF samples for their analysis at baseline, at base line, every three weeks 
for 12 weeks (corresponding to the first 5 cycles of treatment) and every six weeks thereafter and 
at the time of disease progression or study termination. 
 
3.2 
Study Treatment Management 
After having confirmed eligibility and entered into the clinical trial, patients will be treated with 
trastuzumab deruxtecan (DS-8201a) at 5.4 mg/Kg administered as an IV infusion on Day of 21-
day cycle (Q3W), initially for at least 90 minutes, then, if there is no infusion-related reaction, for 
a minimum of 30 minutes. 
In patients with hormone receptor (HR)-positive status (estrogen receptor [ER] and/or 
progesterone receptor [PgR]) administration of endocrine therapy is not allowed. 
In patients allocated in study cohort 5, administration of intrathecal therapy is not allowed. 
 


 
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3.3 
Duration of Study Treatment 
The study treatment period is defined as the time between the study entry and the last dose of 
trastuzumab deruxtecan (DS-8201a) received within the trial. 
If at any time the constraints of this protocol are considered to be detrimental to the patient’s 
health and/or the patient no longer wishes to continue with the protocol therapy, the study 
treatment should be discontinued and the reason(s) for discontinuation documented in the clinical 
records of the patient and corresponding case report form (CRF). 
Study treatment may continue until one of the following criteria applies: 
• 
Radiologically confirmed and documented unequivocal disease progression in the brain as 
assessed by magnetic resonance imaging (MRI). 
• 
AEs that according to the protocol or in the judgment of the investigator may cause severe or 
permanent harm or which rule out continuation of study drug. 
Note: See detailed criteria for study treatment discontinuation due to toxicity in Section 7.4. 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
• 
Serious non-compliance with the study protocol. 
• 
Death. 
• 
Lost to follow-up. 
• 
Patient withdraws consent. 
• 
The study site or the Sponsor decides to close the study. 
All patients who have not progressed and are still in receipt of study treatment at the End of Study 
(EoS), as defined in Section 3.4, will continue to receive the drug until trastuzumab deruxtecan 
(DS-8201a) is available in a reimbursement setting and the Sponsor will provide the study drug 
satisfying the Ethics Committee (EC)’s requirements. In this case, the patient would be followed 
appropriately as per standard clinical practice. 
 
3.4 
EoT and EoS Visits 
Patients discontinuing the study treatment period will enter to the End of Treatment (EoT) visit. 
The first safety assessment (EoT visit) will be scheduled for all patients within 40 days (± 7 days) 
after the last dose of study treatment. All AEs related to investigational medicinal product (IMP) 
will be followed up by the investigator until the event or its sequelae resolve or stabilize at the 
level acceptable to the investigator, and the Sponsor concurs with that assessment. 


 
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Afterwards, follow-up contacts will continue every 12 weeks (± 14 days) up to the EoS and survival 
status and new anticancer therapy information will be collected. Telephone contact is acceptable. 
The EoS is defined as the last patient last visit. This will be the last data collection point, which 
can be a clinic visit or a laboratory sample. EoS will occur at 12 months after the last patient 
included in the study, unless premature termination of the study. 
 
 
 


 
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4 
PATIENT SELECTION 
This study can fulfil its objectives only if appropriate patients are enrolled. The following eligibility 
criteria are designed to select patients for whom the protocol treatment is considered appropriate. 
All relevant medical and non-medical conditions should be taken into consideration when deciding 
whether this protocol is suitable for a particular patient. 
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
 
4.1 
Target Study Population 
Male and pre- and post-menopausal female patients age ≥ 18 years with pretreated unresectable 
locally advanced or metastatic HER2-positive or HER2-low expressing BC with stable, treated or 
untreated BMs, or patients progressing after treatment for BMs or patients with LMC. Evidence 
of measurable brain disease is required. Patients are not eligible if they are candidates for a local 
treatment with a radical intention. 
Patients with untreated BMs are those that have not received any local treatment for their CNS 
involvement (surgery and/or SRS and/or WBRT are considered appropriate). 
The operational definition of patients with stable BM are patients that have been for at least four 
weeks asymptomatic with or without corticosteroids. The highest dose of corticosteroids 
acceptable is dexamethasone 8 mg twice daily or any equivalent. 
 
4.2 
Inclusion Criteria 
Patients must meet ALL of the following inclusion criteria to be eligible for enrolment into the 
study: 
Patients must meet ALL of the following inclusion criteria to be eligible for enrolment into the 
study: 
1. 
Signed Informed Consent Form (ICF) prior to participation in any study-related activities. 
2. 
Male or female patients ≥ 18 years at the time of signing ICF. 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 for Cohorts 1 
to 4 and 0-2 for cohort 5. 
4. 
Life expectancy ≥ 12 weeks. 
5. 
Histologically confirmed invasive breast cancer based on local testing on the most recent 
analyzed biopsy of the following breast cancer (BC) subtypes per 2018 American Society of 
Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria: 
• 
Cohort 1 and 3: HER2 positive status 


 
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• 
Cohort 4: HER2-low expressing status 
• 
Cohort 2 and 5: both HER2 positive and HER2-low expressing status 
Note 1: According to the 2018 ASCO-CAP guidelines, HER2-positive status is defined as 
HER2 immunohistochemistry (IHC) 3+, in situ hybridization (ISH) ≥ 2.0, or average HER2 
copy number ≥ 6.0 signals. HER2-low expressing status defined as IHC 2+ / ISH-negative or 
IHC 1+ (ISH-negative or untested). 
Note 2: Central confirmation of HER2 is not required for study entry. However, tissue blocks, 
or slides, must be submitted to confirm BC subtype by a Sponsor-designated central 
laboratory retrospectively. 
6. 
Unresectable locally advanced or metastatic disease documented by computerized 
tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to 
resection with curative intent. 
7. 
At least one brain lesion needed to be measurable (≥10 mm on T1-weighted, gadolinium-
enhanced MRI) (study cohorts 2 to 4) or leptomeningeal carcinomatosis (LMC) with positive 
cerebrospinal fluid (CSF) cytology (study cohort 5). 
a) 
Study cohort 1: History of BM that are non-progressing after WBRT and/or 
SRS and/or surgery. 
b) 
Study cohort 2: Presence of asymptomatic BM without clinical requirement for 
local intervention (WBRT and/or SRS and/or surgery). 
c) 
Study cohorts 3 and 4: Evidence of new and/or progressive BM following 
previous WBRT and/or SRS and/or surgery.  
d) 
Study cohort 5: Evidence of LMC with positive CSF cytology.  
8. 
Previous treatments: 
a) 
HER2-positive patients must have been previously treated with a taxane and at least one 
HER2-targeted therapy in the advanced scenario. 
b) 
For HER2-low-expressing patients that also are endocrine receptor negative must have 
been previously treated with at least one chemotherapy regimen. If endocrine receptor 
positive, patients must have been previously treated with at least one chemotherapy and 
one endocrine regimen in the metastatic setting. 
9. 
Patients must agree to collection of blood samples at the time of inclusion, at cycle 2 of 
treatment, and upon progression or study termination. 
Note: In study cohort 5: Patients must agree to perform spinal taps or must be willing to 
have an Ommaya reservoir placed for CSF assessment, at base line, every three weeks for 
12 weeks (corresponding to the first 5 cycles of treatment) and every six weeks thereafter. 
10. Willingness and ability to provide tumor biopsy (if feasible) from metastatic lesions or 
breast primary tumor both at the time of the inclusion and after disease progression in order 
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Note: If feasible, patients should provide a tissue sample at baseline from metastases 
amenable to biopsy (at sites of locoregional recurrence [skin, chest wall, breast or lymph 
nodes], or distant recurrence [bone, liver, lung or abdomen]) or as alternative from breast 
primary tumor, that will be obtained between progression to the prior regimen and inclusion 
in the study. Patients for whom tissue sample cannot be obtained (e.g., non-measurable 
disease, inaccessible tumor or subject safety concern) may submit an archived metastatic 
tumor specimen only upon agreement from the Sponsor. If feasible, an additional tissue 
sample should be collected at the end of treatment visit for patients who discontinue treatment 
due to disease progression. 
11. Patients should have left ventricular ejection fraction (LVEF) ≥ 50% by either an 
echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before 
enrolment. 
12. Adequate hematologic and organ function within 14 days before the first study treatment 
on Day 1 of Cycle 1, defined by the following: 
• 
Hematological: White blood cell (WBC) count ≥ 3.0 x 109/L, absolute neutrophil 
count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9.0 
g/dL. (Platelet or red blood cell transfusion as well as G-CSF administration are 
not allowed within 1 week of screening assessments).  
• 
Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (× ULN) (< 3 x ULN in the 
case of documented Gilbert’s disease and/or liver metastases); aspartate 
transaminase (AST) and alanine transaminase (ALT) ≤ 3 × ULN (in the case of 
liver metastases ≤ 5 × ULN); alkaline phosphatase (ALP) ≤ 2 × ULN (≤ 5 × ULN 
in the case of liver and/or bone metastases ≤ 5 × ULN), at baseline, serum 
albumin ≥ 2.5 g/dL. 
• 
Renal: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min based 
on Cockcroft−Gault equation CLcr (mL/min) =(*Cockcroft-Gault equation: ([{140 
– age in years} × {ACTUAL WEIGHT in kg}] divided by [{72 × serum creatinine 
in mg/dL} multiplied by 0.85 if female])). 
• 
Coagulation: International Normalized Ratio (INR)/Prothrombin Time (PT) and 
either partial thromboplastin or activated Partial Thromboplastin Time (aPTT) ≤ 
1.5 × ULN (except for patients receiving anticoagulation therapy). 
Note: Patients receiving heparin treatment should have an aPTT between 1.5 
and 2.5 × ULN (or patient value before starting heparin treatment). Patients 
receiving coumarin derivatives should have an INR between 2.0 and 3.0 
assessed in two consecutive measurements one to four days apart. Patients 
should be on a stable anticoagulant regimen. 
13. Has adequate treatment washout period before enrollment, as indicated: 
• 
Major surgery: > 4 weeks; 


 
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• 
Radiation therapy: > 4 weeks (if palliative stereotactic radiation to other areas ≥ 
2 weeks); 
• 
Anticancer systemic treatment (including immunotherapy, retinoid therapy, 
hormonal therapy): ≥ 3 weeks (≥ 2 weeks or 5 half-lives, whichever is longer, for 
small-molecule targeted agents such as 5-fluorouracil-based agents, folinate 
agents, weekly paclitaxel; ≥ 6 weeks for nitrosureas or mitomycin C) 
• 
Antibody based anti-cancer therapy: ≥ 4 weeks; 
• 
Chloroquine/Hydroxychloroquine>14 days 
14. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined 
by the National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI−CTCAE) v.5.0 (except for alopecia or other toxicities). Subjects with chronic Grade 2 
toxicities may be eligible per the discretion of the Investigator after consultation with the 
Sponsor Medical Monitor or designee (e.g., Grade 2 chemotherapy-induced neuropathy). 
15. Male and female subjects of reproductive/childbearing potential must agree to use a 
highly effective form of contraception or avoid intercourse during and upon completion of the 
study and for at least 7 months for females and 4 months for males after the last dose of 
study drug. Methods considered as highly effective methods of contraception include:  
 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
i. 
Oral 
ii. 
Intravaginal 
iii. 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
i. 
Oral 
ii. 
Injectable 
iii. 
Implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Complete sexual abstinence defined as refraining from heterosexual 
intercourse during and upon completion of the study and for at least 7 months 
after the last dose of study drug. Periodic abstinence (calendar, symptothermal, 
post-ovulation methods) is not an acceptable method of contraception. 


 
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Note: Non-child-bearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 12 
months of spontaneous amenorrhea (in questionable cases, a blood sample with 
simultaneous follicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 
pg/mL [< 147 pmol/L] is confirmatory). Females on hormone replacement 
therapy (HRT) and whose menopausal status is in doubt will be required to use 
one of the contraception methods outlined for women of child-bearing potential 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of post-menopausal status prior to study 
enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the 
cessation of therapy and the blood draw; this interval depends on the type and 
dosage of HRT. Following confirmation of their post-menopausal status, they 
can resume use of HRT during the study without use of a contraceptive method 
16. Male subjects must agree to not freeze or donate sperm starting at Screening and throughout 
the study period, and at least 4 months after the final study drug administration. Preservation 
of sperm should be considered prior to enrolment in this study. 
17. Female subjects must agree to not donate, or retrieve for their own use, ova from the time of 
Screening and throughout the study treatment period, and for at least 7 months after the final 
study drug administration. 
18. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, post-treatment follow-up and other study procedures. 
 
4.3 
Exclusion Criteria 
Patients will be excluded from the study if they meet ANY of the following criteria: 
1. 
Inability to comply with study and follow-up procedures. 
2. 
Previous treatment with trastuzumab deruxtecan (DS-8201a) or any other antibody drug 
conjugate (ADC) which consists of an exatecan derivative that is a topoisomerase 1 inhibitor. 
3. 
Medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic 
congestive heart failure (New York Heart Association Class II to IV). Subjects with troponin 
levels above ULN at screening (as defined by the manufacturer) and without any MI related 
symptoms should have a cardiologic consultation before enrollment to rule out MI 
 
4. 
Corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms (males) based 
on average of the screening triplicate12-lead ECG. 


 
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5. 
History of (non-infectious) interstitial lung disease (ILD) / pneumonitis that required steroids, 
has current ILD / pneumonitis, or where suspected ILD / pneumonitis cannot be ruled out by 
imaging at screening. 
6. 
Clinically significant corneal disease in the opinion of the Investigator. 
7. 
Spinal cord compression. 
8. 
Multiple primary malignancies within 3 years, except adequately resected non-melanoma skin 
cancer, curatively treated in-situ disease, other solid tumors curatively treated, or contralateral 
breast cancer.  
9. 
History of severe hypersensitivity reactions to either the drug substances or inactive 
ingredients in the drug product. 
10. History of severe hypersensitivity reactions to other monoclonal antibodies. 
11. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals. 
12. Patients with 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.  
13. Known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. 
Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction 
is negative for HCV RNA. 
14. Female patients who are pregnant or breastfeeding or planning to become pregnant. 
15. Treatment with other systemic therapy for metastatic disease including chemotherapy, 
immunotherapy, targeted therapy (small molecules/ monoclonal antibodies), or endocrine 
therapy. 
16. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 
4 weeks of start of study drug, or patients who have not recovered from the side effects of 
any major surgery, or patients who may require major surgery during the study. 
17. Radiotherapy within 4 weeks or limited-field palliative radiotherapy within 2 weeks prior to 
study enrolment, or patients who have not recovered from radiotherapy-related toxicities to 
baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously 
irradiated.  
18. Use of concurrent investigational agents or other concomitant anticancer therapies. 
19. Use of intrathecal therapy for LMC. 
 
20. Active bleeding diathesis, previous history of bleeding diathesis, or chronic anti-coagulation 
treatment (the use of low molecular weight heparin is allowed as soon as it is used as 
prophylaxis intention). 
21. Serious concomitant systemic disorder (e.g., active infection including HIV, active hepatitis, 
liver cirrhosis, end stage chronic renal disease) incompatible with the study (at the discretion 
of investigator). 


 
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22. Any of the following within 6 months of enrollment: severe/unstable angina, ongoing cardiac 
dysrhythmias of NCI−CTCAE v.5.0 grade ≥2, coronary/peripheral artery bypass graft, 
cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary 
embolism. 
23. Uncontrolled electrolyte disorders of NCI−CTCAE v.5.0 grade ≥ 2. 
24. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any 
underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study 
randomization  
25. Any autoimmune, connective tissue or inflammatory disorders (e.g., Rheumatoid arthritis, 
Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary 
involvement at the time of screening. Full details of the disorder should be recorded in the 
eCRF for patients who are included in the study. 
26.  Prior pneumonectomy. 
 
 
 


 
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5 
STUDY ASSESSMENTS AND PROCEDURES 
The schedule of activities to be performed during the study is provided in the ¡Error! No se 
encuentra el origen de la referencia.. All activities must be performed and documented for each 
patient.  
Patients will be closely monitored for safety and tolerability throughout the study. Patients should 
be assessed for toxicity prior to each dose; dosing will occur only if the clinical assessment and 
local laboratory test values are acceptable. 
 
5.1 
Patient Entry Procedure 
Written ICF from the patient must be (or the patient’s legally authorized representative) signed 
and dated before his or her participation in the study and before performing any study specific 
procedure. 
Before giving their consent, patients will be informed about the nature of the study drug and will 
receive pertinent information regarding study objectives, study treatment, follow-up procedures, 
biological samples collection and its legal implications, possible benefits, and potential risk and 
AEs. Patients will be also informed that they have the right to withdraw from the study at any time 
and for any reason, without being required to state their reasons for doing so. This decision will 
not affect any future medical treatment. 
After receiving the document, the patient will read it (or receive information verbally in front 
witnesses) and will sign the previously approved ICF. The patient will receive a signed copy of 
the ICF and ICFs for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrollment. The investigator will maintain a screening log to record details 
of all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. After a failed screening attempt, one re-screening will be allowed to patient who did 
not meet one or more criteria required for participation in this study. A potential re-screened 
patient should sign a new ICF before any screening test or study related procedure is performed. 
At inclusion, each patient will be given a unique patient number (UPN) for this study, provided by 
the Sponsor. All data will be recorded in the appropriate case report form (CRF) using this 
identification number. 
Confirmation of patient’s eligibility for study participation will be recorded in the CRF. The 
investigator is responsible for safeguarding patient information (e.g., age, name, address, 
telephone number, and study identification number), ensuring access to this information by Health 


 
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Authorities if necessary. These records will remain confidential for the period of time established 
by current legislation. 
 
5.2 
Study Assessments 
• 
Schedule of Assessments 
Study assessments are outlined in Appendices 
Appendix 1. 
 
• 
Visit Schedule 
All screening tests and evaluations must be completed within the protocol scheduled time 
windows and reviewed to confirm that patients meet all eligibility criteria within 28 days prior to 
the first administration of study medication, unless these procedures have already been 
conducted during this time period as part of the patient´s routine clinical care. The investigator 
will maintain a screening log to record details of all patients screened and to confirm eligibility or 
record reasons for screening failure, as applicable. 
Visits are organized in programmed cycles of 21 days (if there are no treatment delays due to the 
occurrence of AEs). All visits must occur within ± 3 working days from the scheduled date, unless 
otherwise noted in the schedule of assessments. 
Assessments scheduled for Day 1 (before treatment) of all cycles must be performed within 48 
hours prior to study treatment administration, unless otherwise indicated in the schedule of 
assessments, to confirm to the patient if treatment can be followed up. 
If a mandatory procedure described in the protocol falls on a bank holiday and/or weekend, this 
procedure should be performed on the day before or after the holiday (i.e. within a period of ± 2 
working days). 
EoT visit will be performed within 40 days (± 7 days) after the last dose of study treatment. 
Afterwards, follow-up contacts will continue every 12 weeks (± 14 days) up to the EoS and survival 
status and new anticancer therapy information will be collected. Telephone contact is acceptable. 
EoS will occur at 12 months after the last patient included in the study, unless premature 
termination of the study. 
 


 
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• 
Demographic Data and Medical History 
Demographic data, general medical history, and prior medical history of breast cancer will be 
collected during the screening period. 
Demographic data includes age, sex, and self-reported race/ethnicity. 
General medical history includes clinically significant diseases, surgical interventions, history of 
smoking, alcoholism, drug addiction, as well as any medications (e.g., prescribed drugs, over-
the-counter drugs, medicinal plants, homeopathic remedies, or food supplements) used by the 
patient for the 4 weeks prior to screening visit. 
Previous medical history of breast cancer (including prior antineoplastic treatments and 
procedures including radiotherapy and surgeries) will be also assessed with further detail. In 
particular, it will be evaluated the number of chemotherapy regimens for unresectable locally 
advanced or MBC, including start and stop date and best response, and the prior use of 
chemotherapeutic and target therapy agents either in the early, locally advanced, or metastatic 
setting. 
Moreover, patients will complete a medication diary each day to assess the actual intake of 
medication taken outside of the clinic/hospital setting. Patients will receive the diary on the first 
day of each cycle, with site staff completing information on any prescribed medication, including 
the recommended dosage and route of administration. Patients should use the diary to record 
any medication (prescribed or over-the-counter) taken on that cycle of treatment. 
 
• 
Vital Signs 
Vital signs will be measured during the screening period (within 14 days before enrollment), and 
as defined in the Appendix 1. Schedule of Assessments and Study Procedures. On Day 1 of the 
three initial cycles of treatment vital signs must be assessed prior and after trastuzumab 
deruxtecan (DS-8201a) infusion, and pre-infusion on Day 1 of subsequent cycles. These will 
include the measurement of height (only during screening) and weight, respiratory rate, pulse 
rate, systolic and diastolic blood pressure while the patient is in a seated position after resting for 
at least five minutes, and oral, axillary, or tympanic temperature. Abnormal or significant changes 
in vital signs from baseline should be recorded as AEs, if ap propriate. Pulse oximetry will be 
performed at screening -14 days and on Day 1of every cycle, and until the safety follow-up visit 
40 days after last dose. During Cycle 1, pulse oximetry will be assessed on Day 1 prior and after 
infusion of trastuzumab deruxtecan, on Day 8 and Day 15. On Day 1 pre-dose measurements 
will be taken thereafter. 
 


 
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• 
Physical Examination 
A complete physical examination will be performed during the screening period (within 14days 
before enrolment) and on Day 1 of each cycle. This examination should include an evaluation of 
head, eyes, ears, nose, and throat as well as cardiovascular, dermatological, musculoskeletal, 
respiratory, digestive, genitourinary, and neurological systems. 
Moreover, an ophthalmologic assessment that includes visual acuity testing, slit lamp examination 
and fundoscopy will be performed at screening (within 28 days before enrollment), and EoT and 
as clinically indicated. 
In addition, this physical exam should also include, as part of tumor assessment, evaluation of 
the breast and regional lymph nodes as well as the presence and degree of increase of other 
lymph nodes, hepatomegaly, and splenomegaly. 
Changes to abnormalities identified during the baseline period should be recorded at all 
subsequent physical examinations. New or worsening abnormalities should be recorded as AEs, 
if applicable. 
 
• 
Tumor and Response Evaluations 
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation. Tumor response will be assessed for all patients, unless they 
withdraw from the study for any reason not attributable to disease progression confirmed 
radiologically or clinically as per RECIST v.1.1 criteria and who have not received an acceptable 
complete assessment of the disease. The measurable and non-measurable disease must be 
documented at screening and be re-assessed at every tumor assessment thereafter. 
Tumor assessment during the screening period should include an evaluation of all known and/or 
suspected lesions/sites of the disease, including color photography of skin lesions, based on the 
baseline assessment of target and non-target lesions according to RECIST v.1.1 criteria as the 
reference for comparison at each subsequent tumor assessment. The same radiographic 
procedure employed at screening should be used throughout the study (e.g., the use of the same 
contrast protocol for CT scans). 
At baseline, all patients should be assessed as follows: 
• 
Evaluation of chest, abdomen, and pelvis: 
o 
This assessment should be evaluated preferably by CT scan or MRI in case of contrast 
allergy, since these methods are the best currently available and reproducible techniques 
to measure lesions selected for response assessment, within 28 days prior to the first 
administration of study medication. 


 
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o 
In the event a positron emission tomography (PET)/CT scan is used for tumor 
assessments, CT portion of PET/CT is usually of lower quality, and should not be used 
instead of dedicated diagnostic CT. If the CT scan is of high quality, with oral and 
intravenous contrast, may be used with caution. Additional information from PET may 
bias CT assessment. 
o 
After baseline, this evaluation will be performed every 6 weeks (± 3 days) from the first 
dose of study treatment for the first 6 months and, thereafter, every 9 weeks (± 5 days) 
until progression or the EoS visit. 
 
• 
Bone scan: 
o 
Bone scan is mandatory at baseline. For patients with bone lesions identified at baseline, 
bone scan will be performed every 24 weeks (± 7 days), unless clinically or biochemically 
suspected bone progression. 
o 
If no bone involvement is demonstrated, then it is no necessary to repeat the bone 
assessment unless clinically or biochemically suspected bone progression. 
o 
If an isotope-based bone scan was performed > 28 days but ≤ 60 days prior to start of 
study treatment, the bone scan does not need to be repeated. 
o 
Bone scan should be used only to identify presence of bone lesions and if bone lesions 
are present, confirmation and accurate measurement must be done with CT scan or MRI. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT scan or MRI can 
be considered as measurable lesions if the soft tissue component meets the definition of 
measurability. Blastic bone lesions are non-measurable. If a bone scan cannot be 
performed during the course of the study because of the unavailability of the Tc-99m 
isotope, the investigator may choose an alternative imaging modality. 
 
• 
Brain imaging: 
o 
A brain MRI will be performed within 28 days prior to the first administration of study 
medication. 
o 
After baseline, this evaluation will be performed every 6 weeks (± 3 days) for first 6 
months, then every 9 weeks (± 5 days), unless clinically suspected brain progression. 
Additionally, for patients included in the study cohort 5, assessment of neuroaxis by MRI 
together with spinal tap for CSF collection should be obtained every 3 weeks (± 2 days) for the 


 
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first 12 weeks (corresponding to the first 5 cycles of treatment), every 6 weeks thereafter, and at 
the time of treatment progression or study termination. 
Tumor response in CNS will be assessed for all patients, unless they withdraw from the study for 
any reason not attributable to disease progression confirmed radiologically or clinically as per 
RANO-BM criteria and who have not received an acceptable complete assessment of the 
disease. The measurable and non-measurable disease must be documented at screening and 
be re-assessed at every tumor assessment thereafter. 
CNS disease assessment should be evaluated by MRI. Tumor assessment at baseline should 
include an assessment of all known and/or suspected lesions, based on the baseline evaluation, 
defined according to the RANO-BM criteria (Lin et al. 2015). 
If clinically indicated, CT scan or MRI of other areas of disease as appropriate should be 
performed. Any potentially measurable lesion that has been previously treated with radiotherapy 
should be considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy administration, it can be considered 
as a measurable lesion. 
Patients who discontinue treatment without evidence of disease progression will be followed 
every nine weeks (± 5 days) for tumor assessments until documented progression, elective 
withdrawal from the study, the start of new anti-cancer treatment, or study completion or 
termination. 
Each assessment will be performed as scheduled according to the calendar regardless of any 
dosing delay to prevent the introduction of bias into the assessment of efficacy. Failure to perform 
any of the required disease assessments will result in the inability to determine disease status for 
that time point. 
At the investigator’s discretion, CT scans, MRI, and/or bone scans may be obtained at any time 
when clinically indicated or if progressive disease is suspected. For symptomatic deterioration 
attributed to disease progression, every effort should be made to document progression through 
the use of objective criteria per RECIST v.1.1. 
 
• 
Laboratory Assessments 
Laboratory tests will be performed at the study site's local laboratory during the screening period 
and within 48 hours prior to Day 1 of each cycle (including Cycle 1, Day 1). This assessment does 
not need to be repeated at Cycle 1, Day 1 if it was performed at screening within 48 hours prior 
to start of study treatment. During cycle 1, laboratory assessments will be performed on Day 8 
and Day 15. These tests should include:  


 
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• 
Hematological test: hemoglobin, hematocrit, red blood cell count, platelet count, WBC with 
differential count [ANC, lymphocytes, monocytes, eosinophils and basophils] Performed at 
screening (within -14days) 
• 
 Coagulation: INR/PT and PTT/aPTT. Performed only at screening (within -14 days) and 
EoT. 
• 
 Blood chemistry: with renal function analysis (serum creatinine, creatinine clearance 
according to the Cockroft-Gault formula), liver function (AST, ALT, ALP, gamma-glutamyl 
transferase [GGT], total and direct bilirubin), glucose, sodium, potassium, calcium, chloride, 
magnesium, uric acid, total protein, albumin, and lactate dehydrogenase. Performed at 
screening (within -14days) 
In addition, the following tests are essential assessments at screening, before Cycle 1, Day 1 
dosing: 
• 
Urinalysis (within -14 days) 
• 
Screening viral serology (within -14 days): HIV, HBsAg, total HBcAb, HCV antibody; 
additional tests for HBV DNA or HCV RNA will be required to confirm eligibility in patients 
with a positive antibody result; Patients positive for hepatitis C (HCV) antibody are eligible 
only if polymerase chain reaction is negative for HCV RNA 
 
Collect blood sample for Troponin (preferably high-sensitivity troponin-T). Troponin tests will be 
performed at screening and at the end of treatment (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. If ECG is abnormal, follow institutional guidelines. If 
troponin levels are above the upper limit of normal and below the level of myocardial infarction as 
defined by the manufacturer (CTCAE Grade 1) at baseline, no repeat testing is required if the 
troponin level is not Grade 3.  
 
• 
Pregnancy and Assessment of Fertility 
Only female patients of childbearing potential must undergo serum pregnancy test at screening 
(within -14 days) to confirm eligibility in the trial and within one week prior to start of study 
medication (with result available prior to dosing). This assessment does not need to be repeated 
at Cycle 1 Day 1 if it was performed at screening within 48 hours prior to start of study treatment. 
Thereafter a urine pregnancy test (with results available prior to dosing) every treatment cycle. A 
serum test should be performed to confirm any positive urine pregnancy test during the trial. 
Post-menopausal status is defined as: 


 
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• 
Age ≥ 60 years, 
• 
OR Age < 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, 
tamoxifen, toremifen, or ovarian suppression), and with a documented estradiol level in the 
postmenopausal range according to local institutional/laboratory standard, 
• 
OR prior bilateral ovariectomy. 
 
Male and female subjects of reproductive/childbearing potential must agree to use a highly 
effective form of contraception or avoid intercourse during and upon completion of the study and 
for at least 7 months for females and 4 months for males after the last dose of study drug. Methods 
considered as highly effective methods of contraception include:  
1. 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
• Oral 
• Intravaginal 
• Transdermal 
2. 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
• Oral 
• Injectable 
• Implantable 
3. 
Intrauterine device (IUD) 
4. 
Intrauterine hormone-releasing system (IUS) 
5. 
Bilateral tubal occlusion 
6. 
Vasectomized partner 
7. 
Complete sexual abstinence defined as refraining from heterosexual intercourse during and 
upon completion of the study and for at least 7 months after the last dose of study drug. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable 
method of contraception. 
Non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation 
or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in 
questionable cases, a blood sample with simultaneous follicle-stimulating hormone [FSH] > 40 
mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory). Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one 
of the contraception methods outlined for women of child-bearing potential if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-
menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will 
elapse between the cessation of therapy and the blood draw; this interval depends on the type 


 
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and dosage of HRT. Following confirmation of their post-menopausal status, they can resume 
use of HRT during the study without use of a contraceptive method 
Male subjects must not freeze or donate sperm starting at Screening and throughout the study 
period, and at least 7 months after the final study drug administration. Preservation of sperm 
should be considered prior to enrolment in this study. 
Female subjects must not donate, or retrieve for their own use, ova from the time of Screening 
and throughout the study treatment period, and for at least 7 months after the final study drug 
administration. 
In case of pregnancy during study treatment or within 7 months after the last dose of IMP, the 
patient must permanently stop study treatment immediately, withdraw from the trial, and the 
pregnancy must be reported on the Clinical Trial Pregnancy Form as specified in Section 7.9. 
Male patients will be instructed through the ICF to immediately inform the Investigator if their 
partner becomes pregnant during the study or within 7 months after the last dose of IMP. 
 
• 
Electrocardiograms (ECGs) and Cardiac Function Assessment 
All patients must have a standard 12-lead ECG and an LVEF measurement of at least 50% by 
ECHO (preferably) or MUGA scan at baseline. 
LVEF (ECHO or MUGA) assessment must be done within 28 days prior to Cycle 1, Day 1. 
Afterwards, cardiac function evaluation should be repeated before infusion (48 h) on Cycle 5 Day 
1 and every 4 cycles and in the end of treatment visit. 
Triplicate ECGs will be performed at baseline (within -1 4 days) and every 4th cycle 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 will be recorded in the eCRF.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. Lead 
placement should be as consistent as possible. ECG recordings must be performed after the 
patient has been resting in a supine position for at least ten minutes. All ECGs are to be obtained 
prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood 
draws). Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG resting 
period and during ECG recording. 


 
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For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper copies of ECG tracings will be kept as part of the patient's permanent study file at the site. 
After screening (within -14 days), subsequent ECGs will be performed in triplicate in close 
succession if an abnormality is noted or if clinically indicted. ECGs will be taken at every 4th cycle. 
If at a particular post-dose timepoint the mean QTcF is > 500 ms and/or > 60 ms longer than the 
baseline value, another ECG must be recorded, ideally within the next five minutes, and ECG 
monitoring should continue until QTcF has stabilized on two successive ECGs. The Medical 
Monitor should be notified and standard-of-care treatment may be instituted per the discretion of 
the investigator.  
 
• 
ECOG performance status 
Performance status will be measured using the ECOG performance status scale (Table 2). It is 
recommended, where possible, that a patient’s performance status be assessed by the same 
person throughout the study. ECOG PS will be assessed at screening (Day-14 to Day -1), Day 1 
of each cycle and at the EoT visit.  
 
Table 2. ECOG Performance Status Scale 
Grade 
Scale 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, i.e., light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
(http://www.ecog.org/general/perf_stat.html) 
 
• 
PRO Assessments 
Patient-reported GHS/QoL, functioning and symptoms will be assessed using the EORTC QLQ-
C30 and the breast cancer module QLQ-BR23 questionnaires at baseline, Day 1 of cycles 2-4, 


 
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then on Day 1 of every other subsequent cycle starting with cycle 6 (e.g. cycles 6, 8, 10, etc.), at 
the end-of-treatment visit, and every three months thereafter until start of alternative anti-cancer 
therapy. 
Patients will complete each questionnaire prior to any study or medical procedure. Completed 
questionnaires are always considered source document and must be filed accordingly. 
Patients must complete these instruments in clinic (cannot be taken home) and prior to having 
any tests and to any discussion of their progress with healthcare personnel at the site. Interviewer 
administration in clinic may be used under special circumstances (e.g., patient forgot their glasses 
or feels too ill). 
The questionnaire will be given to the patient in the appropriate language for the site. 
Patients discontinuing treatment for any reason including progression disease or any other reason 
should have a tumor and PROs assessment prior to start alternative anticancer treatment. 
The EORTC-QLQ-C30 is a 30-item questionnaire, composed of five multi-item functional 
subscales (physical, role, emotional, cognitive, and social functioning), three multi-item symptom 
scales (fatigue, nausea/vomiting, and pain), a global QOL subscale, and six single item symptom 
scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, 
constipation, diarrhea, and the financial impact of cancer). The questionnaire employs 28 4-point 
Likert scales with responses from "not at all" to "very much" and two 7-point Likert scales for 
global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For 
functional and global QOL scales, higher scores represent a better level of functioning/QOL. For 
symptom-oriented scales, a higher score represents more severe symptoms. A 10-point or higher 
change in scores from baseline is considered clinically significant. We will evaluate change from 
baseline between EORTC QLQ-C30 functional and symptom scale scores. 
The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-
QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual 
enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, 
arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with 
responses from 'not at all' to 'very much'. All scores are converted to a 0 to 100 scale. For 
functional scales, higher scores represent a better level of functioning. We will evaluate change 
from baseline between EORTC-QLQ-BR23 functional and symptom scale scores. 
Using both questionnaires it will be evaluated: 
• 
Overall change from baseline in patient−reported GHS/QoL, functioning and symptoms. 
• 
Time to Deterioration in global QOL defined as time to 10 point or greater decrease in global 
QOL scores from baseline with no subsequent increase in scores above that threshold. 


 
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• 
Time to deterioration in pain defined as time between baseline and first occurrence of 
increase of ≥10 points in pain. Deterioration will be defined increase in score of 10 points or 
greater from baseline. 
 
• 
Biological Samples for Exploratory Analysis 
5.2.1.1 
Tumor Samples 
If feasible, patients should provide a tissue sample at the time of study entry from metastases 
amenable to biopsy (at sites of locoregional recurrence [skin, chest wall, breast or lymph nodes], 
or distant recurrence [bone, liver, lung or abdomen]) that will be obtained between progression to 
the prior regimen and inclusion in the study. As alternative, patients should provide a tissue 
sample from breast primary tumor. Patients for whom tissue sample cannot be obtained (e.g., 
non-measurable disease, inaccessible tumor or subject safety concern) may submit an archived 
metastatic tumor specimen only upon agreement from the Sponsor. 
If feasible, an additional tissue sample should be collected at the end of treatment visit for patients 
who discontinue treatment due to disease progression. 
Exploratory studies will be performed on tumor biopsies, or formalin-fixed and paraffin-embedded 
(FFPE) or frozen tumor samples (blocks), or unstained glass slides. 
Details on tumor tissue samples preparation, processing, storage, and shipment will be provided 
in a separate study manual. 
Note: Tissue blocks, or slides, must be submitted to confirm BC subtype by a Sponsor-designated 
central laboratory retrospectively 
 
5.2.1.2 
Blood Samples 
Blood samples are required for all patients during the screening period, after two cycles of study 
treatment, and upon progression or study termination. 
An aliquot from any of those time-points will be preserved to collect cell-free deoxyribonucleic 
acid (cfDNA) analysis and compare genomic DNA data from tissue samples and cfDNA data from 
liquid biopsies. 
Details on blood samples processing will be provided in a separate study manual. 
 


 
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5.2.1.3 
CSF Samples 
In study cohort 5, in addition to CSF samples for LMC clinical monitoring, patients must agree to 
provide CSF for exploratory analysis, at baseline, every 3 weeks for 12 weeks (corresponding to 
the first 5 cycles of treatment) and every 6 weeks thereafter, and at the time of treatment 
progression or study termination.  
Centralized analysis of CSF-derived epithelial-cells, lymphocytes, and cfDNA (together with 
comparison with cfDNA from blood samples) will be performed. 
Details on CSF samples processing and cytoblock will be provided in a separate study manual. 
 
5.2.1.4 
Molecular Assessments 
The multiple assays, described below, may be performed with the material derived from tumor 
samples and/or the blood samples collected from each patient as part of this study. We will use 
both a 
-
and a 
-
approach. It is likely that not all assays described 
below will be performed on samples provided by each patient, possibly because of insufficient 
material or inadequate sample quality. 
We anticipate that as molecular and genomic technologies improve, as yet unspecified 
technologies will be applied.  
Biomarker samples (blood, tissue, and CSF) for mandatory exploratory biomarker research 
include, but not limited to, the following assays and assay platforms: 
• 
-
that may impact exposure or other responses, or 
-
(
) results interpretation; 
• 
and 
-
by 
or 
(
)-
based methods in tumor tissue and cfDNA; 
• 
Expression analysis of 
related to 
, 
, and 
(e.g., 
); 
• 
IHC-based analysis or quantitative digital IHC of markers of 
and 
, 
such as 
, 
, 
(
), and 
-
(
-
), 
among others. 
When a patient withdraws from the study, samples collected prior to the date of withdrawal 
may still be analyzed, unless the patient specifically requests that the samples be destroyed, or 
local laws require destruction of the samples. However, if samples have been tested prior to 
withdrawal, results from those tests will remain as part of the overall research data. 


 
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Given the complexity and exploratory nature of the analyses, data derived from exploratory 
studies, including germline mutations, will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be available 
in accordance with the effective Sponsor policy on study data publication. 
 
6 
STUDY DRUGS INFORMATION 
6.1 
Formulation, Packaging, and Handling  
Study drug packaging will be overseen by the Sponsor’ and bear a label with the identification 
required by local law, the protocol number, drug identification, and dosage. The packaging and 
labelling of the study drug will be in accordance with local regulations. The study drug must be 
stored according to the details on the Product Information. The drug label indicates the storage 
temperature. Upon arrival of IMPs at the site, site personnel should check them for damage, verify 
proper identity, quantity, integrity of seals, and temperature conditions, and report any deviations 
or product complaints upon discovery. 
 
• 
Trastuzumab deruxtecan (DS-8201a) 
After having confirmed eligibility and entered into the clinical trial, patients will be treated with 
trastuzumab deruxtecan (DS-8201a) at 5.4 mg/Kg administered as an IV infusion Q3W, initially 
for at least 90 minutes, then, if there is no infusion-related reaction, for a minimum of 30 minutes. 
In patients with HR-positive status (ER- and/or PgR-positive) administration of endocrine therapy 
is not allowed. 
In patients allocated in study cohort 5, administration of intrathecal therapy is not allowed. 
 
6.2 
Dosage and Administration 
Trastuzumab deruxtecan (DS-8201a) will be supplied in the dosage form as follows: 
• 
100 mg in a sterile lyophilized powder dosage form in a single-use vial (Lyo-DP) to be 
reconstituted with 5 mL of water for injection to 20 mg/mL. 
 


 
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6.3 
Treatment Modification 
Safety and tolerability of all patients will be closely monitored throughout study treatment and the 
follow-up period. Patients will be assessed in order to detect any AEs before administering new 
study treatment during each treatment visit.  
All dose modifications (interruption, reduction and/or discontinuation) should be based on the 
worst preceding toxicity (CTCAE v.5.0.). Specific criteria for interruption, re-initiation, dose 
reduction and/or discontinuation of trastuzumab deruxtecan are listed in table 4, below which is 
applicable only to TEAEs that are assessed as related to use of trastuzumab deruxtecan by the 
investigator(s). For non-drug related TEAEs, follow standard clinical practice. Appropriate clinical 
experts should be consulted as deemed necessary.  
 
• 
Dose Reduction Levels 
 Dose reductions are allowed from 5.4 mg/kg to 4.4 mg/kg and a second dose reduction to 3.2 
mg/kg. Once the dose of trastuzumab deruxtecan (DS-8201a) has been reduced because of 
toxicity, all subsequent cycles should be administered at that lower dose level unless further dose 
reduction is required. No more than two dose reductions of trastuzumab deruxtecan (DS-8201a) 
per patient will be allowed (see Table 3). Any patient requiring a trastuzumab deruxtecan (DS-
8201a) dose reduction below 3.2 mg/Kg should be discontinued. Dose re-escalation is not 
allowed. 
Note: The patient’s weight at screening (baseline) will be used to initially calculate the dose. If the 
patient’s weight changed by > 10% of the baseline weight, the dose will be recalculated. 
Table 3. Dose Reductions for Trastuzumab Deruxtecan (DS-8201a) 
Dose Level 1 
Trastuzumab Deruxtecan (DS-8201a) 
Starting dose 
5.4 mg/kg 
First dose reduction 
4.4 mg/kg 
Second dose reduction 
3.2 mg/kg 
Third dose reduction 
Not permitted 
1 If the patient continues to experience specified drug-related AEs after the 
second reduction, the treatment should be discontinued. 
 
Dose Interruption and Modification /Toxicity Management Guidelines: 


 
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A dose can be delayed for up to 28 days (49 days from the last infusion date) 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 trastuzumab deruxtecan dosing is temporarily withheld 
for any reason may have future cycles scheduled based on the date of the last trastuzumab 
deruxtecan dose. 
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. Please 
refer to Appendix 4 for additional information on dose modification. 
Table 4: Dose Interruption and Modification /Toxicity Management Guidelines 
Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for trastuzumab 
deruxtecan 
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, 
IV 
fluids); 
prophylactic 
medications indicated for ≤ 24 hrs) 
Administration 
of 
trastuzumab 
deruxtecan 
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. 
Subsequent administrations should be conducted at the 
reduced rate. 
Grade 3 or 4  
(Prolonged 
or 
life-threatening 
consequences, 
urgent 
intervention 
indicated) 
Administration 
of 
trastuzumab 
deruxtecan 
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 Decreased and/or White Blood Cell Count Decreased 
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 
Delay dose until resolved,  
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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for trastuzumab 
deruxtecan 
temperature of ≥ 38 °C for more than 
one hour) 
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 
Anaemia 
Grade 3  
(Hemoglobin 
(Hb) 
<8.0 g/dL); 
transfusion indicated 
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4  
Life 
threatening 
consequences; 
urgent intervention indicated 
Delay dose until resolved to ≤ Grade 2, then reduce dose 1 
level 
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 trastuzumab deruxtecan  
LVEF 40% to ≤ 45% and decrease is 
< 10% (absolute value) from 
baseline 
Continue treatment with trastuzumab deruxtecan  
Repeat LVEF assessment within 3 weeks 
LVEF 40% to ≤ 45% and decrease is 
≥ 20% (absolute value) from 
baseline 
Interrupt trastuzumab deruxtecan dosing 
Repeat LVEF assessment within 3 weeks. 
If LVEF has not recovered to within 10% (absolute value) from 
baseline, 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. 


 
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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for trastuzumab 
deruxtecan 
If LVEF < 40% or > 20% drop from baseline is confirmed, 
discontinue subject from study treatment 
Electrocardiogram QTc Prolonged 
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 
Grade 4  
(Torsade de pointes or polymorphic 
ventricular 
tachycardia 
or 
signs/symptoms 
of 
serious 
arrhythmia) 
Discontinue subject from study treatment 
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 feve, rule out ILD/pneumonitis.  
If the AE is confirmed to have an etiology 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 PKanalysis as soon as 
ILD/pneumonitis 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. 
 


 
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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for trastuzumab 
deruxtecan 
• 
Monitor and closely follow-up in 2 to 7 days for onset 
of clinical symptoms and pulse oximetry 
 
• 
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 patient 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,  
• 
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 
etiologies as described above. 
• 
Escalate care as clinically indicated. 


 
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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for trastuzumab 
deruxtecan 
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) 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  
• 
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 increased 
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 aminostransferase (AST) or alanine aminotransferase (ALT) with simultaneous Total 
bilirubin (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 aminotransaminase (AST) or alanine aminotransaminase (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  


 
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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for trastuzumab 
deruxtecan 
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 11if 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 
Blood Bilirubin increased 
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 
trastuzumab deruxtecan 
 
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 
trastuzumab deruxtecan 
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 Increased 


 
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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for trastuzumab 
deruxtecan 
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 
If resolved in > 7 days from day of onset, reduce dose 1 level 
Diarrhea/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 
 
In addition, Investigators may consider dose reductions or discontinuations of the study drug 
according to the subject’s condition and after discussion with Sponsor’s Medical Monitor or 
designee. 
6.4 
Potential Drug-Drug Interaction 
Nonclinical pharmacokinetic studies have indicated that MAAA-1181a −one of the components of 
trastuzumab deruxtecan (DS-8201a)− is primarily metabolized by CYP3A4 and is a substrate for 
transporters OATP-1B1 and -1B3, MATE2-K, P-gp, BCRP, and MRP1. Concomitant use of strong 
CYP3A4 
inhibitors 
(e.g., 
boceprevir, 
clarithromycin, 
itraconazole, 
ketoconazole, 


 
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lopinavir/ritonavir, nefazodone, telaprevir, telithromycin, voriconazole) or OATP inhibitors (e.g., 
lopinavir/ritonavir, cyclosporine, rifampicin) should be avoided. On a second level, patients must 
also avoid concomitant use of strong inhibitors of MATE2-K, P-gp, BCRP, or MRP1. 
MAAA-1181a did not show any potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A (inhibitory concentration [IC50] >50 μmol/L). MAAA-1181a did 
not show any potential to induce CYP3A4, CYP1A2, and CYP2B6 up to 30 μmol/L. MAAA-1181a 
did not inhibit OAT3, OCT1, OCT2, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, and BSEP (IC50 
>30 μmol/L). MAAA-1181a inhibited OAT1 and OATP1B1 with IC50 values of 12.7 and 14.4 
μmol/L, respectively, although the values were much higher than the maximum serum 
concentration (Cmax) of MAAA-1181a in humans (9.25 ng/mL [0.019 μmol/L]) at 8.0 mg/kg of 
DS-8201a. 
 
6.5 
General Concomitant Medication and Supportive Care Guidelines 
Concomitant treatment and prior medication are defined as non-IMP. Concomitant treatment 
includes any prescribed medication or herbal medicines between the 21 days prior to the 
administration of the first treatment dose and the last safety follow-up visit. All concomitant 
treatments will be recorded. After study discontinuation, information will only be collected on any 
anti-cancer drugs taken by the patient until EoS. 
Information on concomitant medication will include start date, end date, brand or generic name, 
route of administration, dose, and treatment indication. 
Information on prior medication will include details on prior anti-cancer therapies. 
No pre-medication for study drug administration is required; however, pre-medication is allowed 
at the investigator’s discretion. 
The following concomitant treatments are permitted during the study: 
• 
Corticosteroids are allowed as long as patients have been on a stable dose for at least four 
weeks. The highest allowed dose is dexamethasone 8 mg twice daily or an equivalent 
• 
Erythropoiesis-stimulating agents (ESA) are allowed (such as Procrit®, Aranesp®, Epogen®) 
for the supportive treatment of anemia. Blood transfusions are permitted during the study as 
well as iron administration. 
• 
The prophylactic use of granulocyte-colony stimulating factor (G-CSF) and granulocyte-
macrophage-colony stimulating factor (GM-CSF) is not allowed during the first treatment 
cycle but can be used for cases of neutropenia arising during treatment, in accordance with 
the National Comprehensive Cancer Network (NCCN) guidelines. 
• 
The use of medication for the treatment of diarrhea, nausea, or vomiting is permitted. 


 
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• 
The use of bisphosphonates or denosumab is allowed if treatment starts within 2 weeks of 
the active study treatment for the control of bone pain, prevention and/or treatment of bone 
metastases, and treatment of osteoporosis.  
• 
Palliative radiotherapy is permitted to treat painful bone metastases.  
• 
Strong inhibitors of CYP3A4, OATP, MATE2-K, P-gp, BCRP or MRP1 should be avoided 
• 
Based on the currently available clinical safety data, it is recommended that patients receive 
prophylactic anti-emetic agents prior to infusion of T-DXd and on subsequent days. 
Antiemetics such as 5-hydroxytryptamine receptor (5-HT3) antagonists or Neurokinin-1 
(NK1) receptor antagonists and/or steroids (e.g. dexamethasone) should be considered and 
administered in accordance with the prescribing information or institutional guidelines 
• 
Any medications deemed necessary to ensure patient safety and well-being may be 
administered at the discretion of the investigator with the exception of prohibited therapies 
described in below Section. 
 
6.6 
Prohibited Therapies 
Use of the therapies described below is prohibited during the study treatment period (collectively, 
these will be referred to as non-protocol therapy): 
Any therapies intended for the treatment of cancer, other than trastuzumab deruxtecan (DS-
8201a) whether they are approved by national Health Authorities or experimental, including 
cytotoxic chemotherapy, immunotherapy, endocrine therapy, biologic or targeted agents and 
other investigational therapeutic agents. Patients are not allowed to participate in other clinical 
trials while they are participating in the DEBBRAH trial. The Sponsor must be notified if a patient 
receives any of these during the study. 
 
• 
Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, antibody, 
retinoid, or anti-cancer hormonal treatment [concurrent use of hormones for noncancer-
related conditions (e.g. insulin for diabetes and hormone replacement therapy) is acceptable]. 
• 
Any concurrent cancer-related surgery is prohibited throughout the duration of the active 
treatment phase of the study unless it is life-saving. 
• 
Radiotherapy (except for palliative radiation to known metastatic sites as long as it does not 
affect assessment of response or interrupt treatment for more than the maximum time 
specified in dose modification section). 
• 
Radiotherapy to the thorax. 


 
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• 
Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive 
medications except for managing adverse events; (Inhaled steroids or intra articular steroid 
injections are permitted in this study.) 
• 
Subjects with bronchopulmonary disorders who require intermittent use of bronchodilators 
(such as albuterol) will not be excluded from this study.  
• 
Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during the 
study treatment. Refer to appendix 4 for further details 
 
In general, the following treatments are not prohibited but they are not recommended during 
the treatment phase: 
• 
Chronic daily immunosuppressive therapies including systemic corticosteroids are allowed 
with a daily dose of at least 16 mg/day of dexamethasone or equivalent. 
• 
Herbal medicines. 
• 
Use of tobacco products, e-cigarettes and vaping is strongly discouraged but not prohibited. 
• 
Hematopoietic growth factors may be used for prophylaxis or treatment based on the clinical 
judgment of the Investigator. 
• 
Concomitant use of dietary supplements, medications not prescribed by the Investigator, and 
alternative/complementary treatments is discouraged, but not prohibited. 
• 
Prophylactic or supportive treatment of study-drug induced AEs will be otherwise as per 
investigator’s discretion and institutional guidelines. 
 
Moreover, CSF administration, platelet and red blood cell transfusions is not allowed within 1 
week prior to screening assessment. 
 
6.7 
Drug Storage and Drug Accountability 
Storage conditions stated in the Study Reference Safety Document (e.g., Investigator’s Brochure 
[IB], or Local Product Document) may be superseded by the label storage information. 
Investigators and site staff are reminded to continuously monitor room storage temperatures and 
ensure that thermometers are working correctly as required for proper storage of IMP. These 
include thermometers for both the room storage and refrigerator storage. Any temperature 
excursions must be reported immediately to the Sponsor and documented. Once a deviation is 
identified, the IMP must be quarantined and not used until the Sponsor provides documentation 
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At the end of the trial, the Sponsor will provide instructions as to disposition of any unused IMP. 
If the Sponsor authorizes destruction at the trial site, the investigator must ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by the Sponsor. Destruction must be adequately 
documented. 
Trastuzumab deruxtecan (DS-8201a) must be stored in their original container according to 
labelled storage conditions: under refrigeration at 2-8°C (protected from light).  
Medication should be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements. Returned medication should be stored separately from medication that 
needs to be dispensed. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by the 
study site should be recorded on the Drug Inventory Log. In particular, to ensure adequate 
records, trastuzumab deruxtecan (DS-8201a) will be accounted for as instructed by the Sponsor. 
 
 
 


 
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7 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
Safety assessments will consist of monitoring and recording protocol-defined AEs, adverse 
events of special interest (AESIs), and SAEs; measurement of protocol-specified hematology, 
clinical chemistry, measurement of protocol-specified vital signs; and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study drug(s). 
The Sponsor or its designee is responsible for reporting relevant SAEs to competent authorities, 
other applicable regulatory authorities, and participating investigators, in accordance with 
International Conference on Harmonization (ICH) guidelines, European Clinical Trials Regulation 
(Regulation (EU) No 536/2014), and/or local regulatory requirements. 
The Sponsor or its designee is responsible for reporting unexpected fatal or life-threatening 
events associated with the use of the study drug to the regulatory agencies and competent 
authorities within seven calendar days after being notified of the event. The Sponsor or its 
designee will report other relevant SAEs associated with the use of the study medication to the 
appropriate competent authorities (according to local guidelines), investigators, and central 
IRBs/ECs by a written safety report within 15 calendar days of notification. 
All SAEs must be reported to DSE CSPV team address: debbrah.SAE@medsir.org 
 
 
7.1 
AEs Definitions 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporarily associated with the 
use of an IMP, regardless of whether it is considered related to the IMP or not. 
An abnormal test finding should only be reported as an AE if meets any of the following criteria: 
• 
Is associated with accompanying symptoms and a general diagnostic term, including the 
symptoms and the abnormal test finding, cannot be defined. 
• 
Requires additional diagnostic testing or medical/surgical intervention, leads to a change in 
study drug(s) dosing or discontinuation from the study. 
• 
Needs additional concomitant drug treatment. 
• 
Is considered to be an AE by the investigator or by the Sponsor. 
 


 
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Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE. 
Clearly related signs, symptoms, and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. Any additional 
events that fall outside this definition should also be reported separately. 
All AEs must be recorded in the CRF 
The causal relationship between an AE and the IMP will be defined as follows: 
• 
Unrelated: The temporal association between the AE and the administration of the IMP 
makes a causal relationship unlikely, or the patient’s clinical state or the study 
procedure/conditions provide a sufficient explanation for the AE. 
• 
Related: The temporal association between the AE and the administration of the IMP makes 
a causal relationship possible, and the patient’s clinical state or the study 
procedure/conditions do not provide a sufficient explanation for the AE. 
 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the IMP. If the investigator does not know whether or not the 
IMP caused the event, then the event will be handled as “related to IMP” for reporting purposes. 
The descriptions and grading scales found in the revised NCI−CTCAE v.5.0 will be utilized for all 
toxicity reporting. A copy of the NCI−CTCAE v.5.0 can be downloaded from the CTEP website: 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf).  
- 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
- 
Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*. 
- 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
- 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
- 
Grade 5 Death related to AE. 


 
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* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious event. For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it meets one of the criteria 
for SAEs, listed below. Seriousness rather than severity serves as a guide for defining regulatory 
reporting obligations. 
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. 
 
7.2 
SAEs 
Per definition, a SAE is defined as any AE that either: 
• 
Results in death (e.g., the AE actually causes or leads to death). 
• 
Is life-threatening (e.g., the AE, in the view of the investigator, places the patient at 
immediate risk of death when it occurs). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person ability to conduct normal life functions). 
• 
Constitutes a congenital anomaly/birth defect (in a neonate/infant born to a mother exposed 
to the IMP. 
 
Definition of life-threatening: An AE is life-threatening if the patient was at immediate risk of death 
from the event as it occurred, e.g., does not include an event that might have caused death if it 
had occurred in a more serious form. For instance, drug induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening even though drug induced 
hepatitis can be fatal. 
Definition of hospitalization: AEs requiring hospitalization should be considered serious. In 
general, hospitalization means that the patient has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment which would not have 
been appropriate at the study site. When in doubt as to whether hospitalization occurred or was 
necessary, the AE should be considered as serious. 


 
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Hospitalization for elective surgery or routine clinical procedures, which are not the result of an 
AE, need not to be notified according to immediate reporting criteria. If anything untoward is 
reported during any procedure, this must be reported as an AE and either ‘serious’ or ‘non-serious’ 
attributed according to the usual criteria. 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE not 
to be notified according to immediate reporting criteria. Examples include: 
• 
Admission for treatment of a pre-existing condition not associated with the development of a 
new AE or with a worsening of the pre-existing condition (e.g., for work-up of persistent pre-
treatment lab abnormality). 
• 
Social admission (e.g., patient has no place to sleep). 
• 
Administrative admission (e.g., for yearly physical examination). 
• 
Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol). 
• 
Optional admission not associated with a precipitating clinical AE (e.g., for elective cosmetic 
surgery). 
• 
Hospitalization for observation without a medical AE. 
• 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation and/or for the individual patient. 
• 
Admission exclusively for the administration of blood products. 
 
Definition of clinically/medically significant event: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered a SAE when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. Clinically/medically significant events 
MUST be reported as SAEs. 
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. Details of the overdose including trastuzumab 
deruxtecan dosage, clinical course, associated AEs, and outcome must be captured in the 
Narrative form of the CRF.  


 
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7.3 
AESIs to Report immediately 
AESIs must be reported by the investigator to the Sponsor expeditiously (see Section 7.6), 
regardless of their seriousness (e.g. no more than 24 hours after learning of the event). AESIs for 
this study include: 
• 
Hepatic events (both serious and non-serious) which meet the potential drug-induced liver 
injury as assessed by laboratory criteria for Hy’s law defined as an elevated (ALT or AST). 
The following laboratory abnormalities are indicative of possible Hy’s law cases and must be 
reported as an AESI: 
o 
AST and/or ALT elevations >3 times the ULN with concurrent elevation of total bilirubin 
>2 times the ULN (or clinical jaundice if total bilirubin measures are not available), except 
in patients with documented Gilbert’s syndrome. For patients with Gilbert’s syndrome, 
elevation of direct bilirubin >2 times the ULN should be used instead. 
In addition, 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, 
QT prolongation, LVEF decrease, and Infusion related reactions. Management Guidance for 
these AESIs are detailed on section 6.3 Treatment Modification. 
• 
Interstitial Lung Disease (IDL) 
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, literature and available safety information for drugs of similar 
class. Refer to the current IB for a summary of preliminary clinical study data 
 
• 
Left Ventricular Dysfunction  
LVEF decrease in association with T-Dxd is considered to be important potential risk 
based on the available pre-clinical data, literature and available safety information for 
drugs of similar class. Refer to the current IB for a summary of preliminary clinical trial 
data. 
 
Subjects receiving T-Dxd should be monitored for signs and symptoms of any of the 
toxicities observed in nonclinical studies and clinical studies with other drugs of similar 
class. 
 


 
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7.3.1.1 
Other non-product specific AESI requiring expeditiously reporting 
• 
Suspected transmission of an infectious agent by a medication, whereby any organism, virus, 
or 
infectious 
particle 
(e.g. 
prion 
protein 
transmitting 
transmissible 
spongiform 
encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. 
Transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings indicating an infection in a patient exposed to a medicinal product. This term only 
applies when contamination of a medication is suspected and does not apply to infections 
supported by the mode of action, e.g. immunosuppression. 
7.4 
Treatment-emergent adverse event (TEAE) 
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 
 
7.5 
AEs Reporting and Other Safety Related Issues Reporting 
For serious and non-serious AEs, the reporting period to the Sponsor (or its designated 
representative) begins from the time that the patient provides ICF. 
Disease progression/worsening of breast cancer will not be recorded as an AE on the Adverse 
Event eCRF. However, events associated with disease progression, such as [as 
thrombocytopenia, may be recorded as AEs. 
Death due to disease progression should be recorded on the Death eCRF. 
 
Reporting period for SAEs/AESIs that are NOT related with the study IMP and also all non-
serious AEs is as follows: 
 
• 
If patient discontinues treatment, until 40 calendar days after the last administration of the 
study IMP. 
• 
If patient still on treatment at the time of the EoS visit (see definition on Section 3.4) until the 
EoS visit. 
All study patients will be carefully monitored for the occurrence of AEs (including SAEs and 
AESIs) during the above specified AE reporting period. 
If the investigator becomes aware of a SAE/AESI at any time after the end of administration 
of study treatment and believes that it is possibly related to trastuzumab deruxtecan (DS-8201a) 
(a serious adverse reaction to trastuzumab deruxtecan (DS-8201a)), the investigator should 


 
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notify the serious adverse reaction to the Sponsor immediately irrespective of the time elapsed 
since last administration of the study IMP. 
For all grade ≥ 3 AEs with causal relationship to the IMP, follow-up by the Investigator may be 
required until the event or its sequelae resolve or stabilize at the level acceptable to the 
Investigator, and the Sponsor concurs with that assessment. 
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. Please 
refer to Appendix 4 for additional information on dose modifications 
 
7.6 
SAE Reporting and Timeframe 
Reporting requirements will comply with all EU safety reporting requirements as detailed in 
Clinical Trials Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 
April 2014 on clinical trials on medicinal products for human use, repealing Directive 2001/20/EC 
and all applicable local regulations for safety reporting. 
The investigator or investigator’s team will report all protocol defined SAEs and AESIs to the 
Sponsor (MEDSIR) no later than 24 hours of any site study team staff becoming aware of the 
event as follows: 
• 
The full details of the SAE and/or AESI should be collected and fully documented using the 
SAE form and sent to the Sponsor (MEDSIR). 
• 
Follow-up information, copies of any relevant test results, event outcome and the opinion of 
the investigator as to the relationship between trastuzumab deruxtecan (DS-8201a) and the 
SAE and AESI, accompanied by other applicable documentation when it is requested, will be 
sent along with the SAE form, if available on the day the event is reported or as soon as 
possible if it is not. 
• 
The original SAE reporting form and the confirmation from the Sponsor must be kept with the 
CRF documentation at the study site(s). 
All SAE forms will be sent by the investigator or investigator’s team to the Sponsor (MEDSIR) 
according to the reporting instructions provided by MEDSIR at the site initiation visit and filed in 
the Investigator’s File. 
SAEs and AESIS will be followed until resolved, a stable outcome is reached, patient is lost to 
follow-up, or dies. 
As sponsor, MEDSIR will be responsible for ensuring that events are reported within the 
mandated timeframe to the European Medicines Agency (EMA), and other competent authorities, 
IRBs/ECs, and investigator(s), as necessary and in accordance with all applicable guidelines, 
approved directives and regulations. All safety reporting local regulatory requirements will be 
followed. 


 
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7.7 
Expedited Reporting to Health Authorities, Investigators, IRBs, and ECs 
To determine reporting requirements for single SAE cases, MEDSIR (as Sponsor) or its designee 
will assess the expectedness of these events using the following reference documents: 
- 
IB for trastuzumab deruxtecan (DS-8201a). 
 
MEDSIR (as Sponsor) or its designee will compare the severity of each event and the cumulative 
event frequency reported for the study with the severity and frequency reported in the applicable 
reference document. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
Within seven calendar days after being notified of the event, MEDSIR (as Sponsor) or its designee 
will report unexpected fatal or life-threatening events associated with the use of the study drug to 
the regulatory agencies and competent authorities, to the investigators and IRBs/ECs. MEDSIR 
(as Sponsor) or its designee will report other unexpected SAEs associated with the use of the 
study medication to the appropriate competent authorities (according to local guidelines), 
investigators, and central IRBs/ECs by a written safety report within 15 calendar days of 
notification. All safety expedited reports will be reported in accordance to all regulatory reporting 
obligations (including timelines) and local regulatory requirements. 
 
7.8 
Other Safety-Related Reports 
As Sponsor, MEDSIR will assess constantly the benefit/risk profile of the trial, that means a 
continuous evaluation of the safety profile of the drugs under investigation will be done using all 
available information. MEDSIR will provide the regulatory agencies and competent authorities 
and the investigators with any relevant information that may affect the benefit/risk profile of the 
trial. An annual Development Safety Update Report (DSUR) safety report for trastuzumab 
deruxtecan (DS-8201a) will be prepared and distributed by MEDSIR or its designee in accordance 
to all regulatory reporting obligations and local regulatory requirements. 
MEDSIR or its designee will report any finding of noncompliance (as failure to follow any 
applicable regulation or institutional policies that govern human subjects’ research) and/or serious 
noncompliance (as noncompliance that materially increases risks that result in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants) 
according to any reporting obligation and local regulatory requirements. 


 
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7.9 
Pregnancy Reporting 
Irrespective of the treatment received by the patient, any patient’s or patient’s partner pregnancy 
occurring during study treatment or within 30 days after completing therapy must be reported 
within 24 hours of investigator’s knowledge of the event. 
Pregnancies will be treated as SAEs and the investigator will complete a pregnancy form and 
forward it to the Sponsor according to the reporting instructions provided by MEDSIR at the site 
initiation visit and filed in the investigator’s File. 
The patient will be asked to provide follow-up information on the outcome of the pregnancy, 
including premature termination should the case arise. Spontaneous miscarriage and congenital 
abnormalities will also be reported as SAEs. 
The follow-up period will be deemed to have ended when the health status of the child has been 
determined at 12 months of the infant’s life. 
Additional follow-up information on any trastuzumab deruxtecan (DS-8201a)-exposed pregnancy 
and infant will be requested at specific time points (e.g., after having received the initial report, at 
the end of the second trimester, two weeks after the expected date of delivery, and at three, six, 
and 12 months of the infant’s life). 
Follow-up queries may be sent, asking for further information, if required for a comprehensive 
assessment of the case. 
 
 
 


 
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8 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
8.1 
Determination of Sample Size 
A maximum of 39 patients with pretreated unresectable locally advanced or metastatic HER2-
positive or HER2-low expressing patients will be recruited following the five study cohorts: 
• 
Cohort 1: Patients with HER2-positive BC and non-progressing BM (after WBRT and/or 
SRS);(N = 8); 
• 
Cohort 2: Patients with HER2-positive or HER2-low expressing BC with untreated BMs (N = 
10); 
• 
Cohort 3: Patients with HER2-positive BC and progressing BMs after local treatment (N = 7); 
• 
Cohort 4: Patients with HER2-low expressing and progressing BMs after local treatment (N 
= 7); 
• 
Cohort 5: Patients with HER2-positive BC and LMC (N = 7). 
 
8.2 
Justification of Sample Size 
The primary endpoint for this study, in the cohort of patients with stable BMs (cohort 1) is the PFS 
at 16 weeks. The primary endpoint for this study, in the cohorts of patients with untreated or 
progression BMs (cohorts 2 to 4) is the best ORR-IC. The primary endpoint for this study, in the 
cohort of patients with LMC (cohort 5) is the OS. 
The trial uses a two-stage optimal Simon’s design for the cohort 1, a one-stage A’Hern design for 
the cohorts 2 to 4, and a one-stage survival design for the cohort 5. The analysis in the cohort 1 
will be one-sided, based on stochastic ordering of uniformly minimum variance unbiased 
estimator (UMVUE). The analyses in the cohorts 2 to 4 will be one-sided, based on stochastic 
binomial exact test. The sample size for the LMC cohort was based on a one arm time-to-event 
design. The analysis will be based on maximum likelihood exponential test. 
The local type I and II errors for all designs will be 0.05 and 0.2, respectively. 
 
• 
Cohort 1 
We hypothesized that excluding a rate of patients without PFS events ≤5% while targeting an 
improvement of patients without PFS events to ≥40% would be an optimal approach to evaluation 
of the study strategy. Non evaluable patients enrolled in the initial stage can be replaced. We will 
accrual 4 patients in the first stage. We will stop this cohort if all 4 patients progressed at 16 
weeks. Otherwise, 4 additional patients will be accrued for a total of 8. At least 2 patients without 
progressive disease at 6 months among 8 patients enrolled will be adequate to justify the 
investigation of this strategy in further clinical trials. 


 
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• 
Cohort 2 
We hypothesized that excluding an ORR-IC ≤5% while targeting an improvement of the ORR-IC 
to ≥40% would be an optimal approach to evaluation of the study strategy. At least 3 patients with 
overall response among 10 patients will be adequate to justify the investigation of this strategy in 
further clinical trials. 
 
• 
Cohort 3 
We hypothesized that excluding an ORR-IC ≤5% while targeting an improvement of the ORR-IC 
to ≥40% would be an optimal approach to evaluation of the study strategy. At least 2 patients with 
overall response among 7 patients will be adequate to justify the investigation of this strategy in 
further clinical trials. 
 
• 
Cohort 4 
We hypothesized that excluding an ORR-IC ≤5% while targeting an improvement of the ORR-IC 
to ≥40% would be an optimal approach to evaluation of the study strategy. At least 2 patients with 
overall response among 7 patients will be adequate to justify the investigation of this strategy in 
further clinical trials. 
 
• 
Cohort 5 
The one-sided maximum likelihood exponential test had an 80% power to detect a 4-month 
increase in median OS over a 2-month median OS. We scheduled an 18-month accrual period 
and 6-month of follow-up period. At least 3 patients will be accrued in the first stage to evaluate 
the feasibility of this cohort. A total of 7 petiens will be accrued in this cohort. 
 
Stopping boundary based on accrual 
At the halfway point of the recruitment period, the steering committee will evaluate if the 
accrual objective for the first stage was achieved in every study cohort (4, 5, 3, 3 and 3 patients 
for cohorts 1, 2, 3, 4 and 5, respectively). If this accrual objective has not achieved in a cohort, 
the Steering Committee will propose a corrective action plan or finalize the study in this cohort. 
 


 
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8.3 
Analysis Sets 
• 
Full Analysis and Safety Set 
The full analysis and safety set includes patients who received at least one dose of study 
treatment. 
 
• 
Per-Protocol Set 
All patients who meet selection criteria, receive at least one drug exposure, and receive the per 
protocol (PP) required study drug exposure and processing. Criteria for determining the PP group 
assignment would be established by the Steering Committee before the statistical analysis 
begins. This analysis will only occur if this set differs by ≥ 10% from the full analysis set. 
 
• 
Exploratory Evaluable Set 
Exploratory analyses will be performed on those patients in the safety set who consented to 
participate in the exploratory research program and were evaluable for exploratory endpoints. 
 
• 
Analysis Set Schedule 
Primary and secondary endpoints will be analyzed on the full analysis set, and per-protocol sets. 
Full analysis set will be considered the primary population for the analysis. Exploratory analysis 
will be performed on 
. Safety analysis will be performed on the safety 
set. 
 
8.4 
Response Assessment 
Lesions will be classified as target and non-target at baseline, in accordance with RANO-BM 
criteria (for CNS lesions) and RECIST criteria v.1.1 (in case of non-CNS lesions). 
 
• 
RECIST v.1.1 Criteria 
The response assessment of the tumor is defined as best response, in terms of complete CR, 
PR, SD, PD and non-evaluable (NE) according the following Table 4: 
 


 
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Table 4. Time Point Response in Patients with Target (+/–Non-Target) Disease 
 
The objective tumor response for target lesions will be defined as follows: 
• 
CR: Complete disappearance of all target lesions. Any pathological lymph nodes (target or 
non-target) must have reduction in short axis to < 10 millimeter (mm). 
• 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters. 
• 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum diameters while on study. In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. The development of new, 
previously undetected lesions is also considered progression. 
• 
SD: Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
 
The tumor response for non-target lesions will be defined as follows: 
• 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10mm short axis). 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• 
PD: Unequivocal progression (see comments below) of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression). 
 


 
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• 
RANO-BM criteria 
Target lesions 
• 
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. 
• 
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. 
• 
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. 
• 
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. 
 
Non-target lesions 
Non-target lesions should be assessed qualitatively at each of the timepoints specified in 
the protocol. 
• 
CR: Requires all of the following: disappearance of all enhancing CNS non-target lesions, no 
new CNS lesions. 
• 
Non-CR or non-PD: Persistence of one or more non-target CNS lesion or lesions. 
• 
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 tumor-related non-enhancing (T2/FLAIR) CNS lesions. In the case of 
immunotherapy-based treatment, new lesions alone may not constitute progressive disease. 
 
8.5 
Primary Efficacy Endpoints 
The primary endpoint for this study, in the cohort of patients with stable BMs (cohort 1) is the PFS 
at 16 weeks. PFS is defined as the number of patients without PD or death at 16 weeks (non-
PFS event) divided by the number of patients in the analysis set. Progression will be assessed 
based on local Investigator’s assessment according RANO-BM criteria (for IC lesions) and 
RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.. We 
will consider a patient as PFS event if accomplish any of both criteria for progression or die from 


 
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any cause in absence of documented progressive disease. The schedule of tumor assessments 
has been defined in AAppendices 
Appendix 1. 
The primary endpoint for this study, in the cohorts of patients with untreated or progression BMs 
(cohorts 2 to 4) is the best ORR-IC. The ORR-IC is defined as the number of patients with CR or 
PR divided by the number of patients in the analysis set. Best overall response will be assessed 
based on local Investigator’s assessment according RANO-BM criteria. We will consider a patient 
as responder if accomplish the criteria at the same tumor evaluation. Patients without tumor 
response evaluation will be considered as no responder. 
The primary endpoint for this study, in the cohorts of patients with LMC (cohort 5) is the OS. OS 
is defined as the time from treatment initiation to death from any cause. Patients without 
documented death at the time of the final analysis will be censored at the date of the last follow-
up. 
 
8.6 
Secondary Efficacy Endpoints 
The secondary efficacy variables are PFS, ORR, DOR, TTR, OS and Maximum Tumor reduction: 
• 
ORR in cohort 1 to 4, as defined in secondary endpoint section.  
• 
OS in cohorts 1 to 4, as defined in secondary endpoint section. 
• 
PFS in cohorts 2 to 4, as defined in secondary endpoint section. 
• 
PFS in cohorts 2 to 4, defined as time to event outcome. PFS is defined as the period of time 
from treatment initiation to the first occurrence of disease progression or death from any 
cause, whichever occurs first. Progression will be determined locally per RANO-BM criteria 
for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and 
extracranial) lesions.. We will consider a patient as PFS event if accomplish any of both 
criteria for progression or die from any cause in absence of documented progressive disease. 
• 
CBR in cohorts 1 to 4, CBR is defined as an objective response (CR or PR), or SD for at least 
24 weeks, and determined locally by the investigator through the use of RANO-BM criteria 
for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and 
extracranial) lesions.. 
• 
TTR in Study cohort 1. TTR, defined as the time from the treatment initiation to time of the 
first objective tumor response observed for patients who achieved a CR or PR, determined 
locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST 
criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions 
• 
TTR in study cohorts 2 to 4. TTR defined as the time from the treatment initiation to time of 
the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who 
achieved a CR or PR, determined locally by the investigator through the use of RANO-BM 


 
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criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC 
and extracranial) lesions. 
• 
DOR in study cohorts 1 to 4, DOR is defined as the time from the first occurrence of a 
documented objective response to disease progression or death from any cause, whichever 
occurs first, as determined locally by the Investigator through the use of RANO-BM criteria 
for IC lesiosn and RECIST v.1.1 criteria, for both extracranial lesions and overall (IC and 
extracranial) lesions. In case of the patient first reaching PR and later CR, the duration of CR 
will be measured and reported separately, starting from the date when first documented, and 
ending when a progressive disease is diagnosed, or the patient dies. 
• 
Best percentage of change from baseline in the size of tumor lesions, defined as the biggest 
decrease, or smallest increase if no decrease will be observed, and determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
• 
Maximum tumor reduction in study cohorts 1 to 4. Maximum tumor reduction is defined as 
the biggest decrease, or smallest increase if no decrease will be observed, as determined 
locally by the Investigator through the use of RANO-BM criteria. 
 
8.7 
Exploratory Endpoints 
The objective of the statistical analyses of biomarkers is the identification of those markers or 
combinations of markers which show a positive (predictors of benefit) or negative (predictors of 
resistances) association with the clinical outcome of treatment. We will measure the clinical 
efficacy of those analysis in terms of 
. The biomarker analyses will be explorative. 
According to experience many biomarkers show 
across subjects 
and within subject. Frequently there is also some biochemical background of this 
, in 
that the 
process has a 
. Biomarkers with 
may 
cause problems when l
are to be used. When used as 
in 
, these biomarkers as well can 
. Therefore, s
or 
need to be found which 
these measurements into 
with an 
. Typical choices in the biomarker area are 
of the 
. These 
do not 
the order of the 
, such 
based on 
remain 
by the 
. The basic statistics and interdependencies of the different markers will be 
descriptively investigated. 
 


 
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• 
Analysis of Baseline and Demographic Variables 
The demographics and baseline characteristics including disease history and prior therapy are 
summarized using descriptive statistics. 
 
• 
Decision Rules and Adjustment of Alpha in the Study 
The study would be defined as positive at final analysis in the study cohort 1, if the rate of patients 
without PFS events in the trastuzumab deruxtecan (DS-8201a) arm is statistically significantly 
better (p<0.05) than expected under the null hypothesis (H0: % of pts without PFS events ≤ 5%). 
The analysis will be one-sided, based on stochastic ordering of UMVUE. 
The study would be defined as positive at final analysis in the study cohort 2, if the ORR in the 
trastuzumab deruxtecan (DS-8201a) arm is statistically significantly better (p<0.05) than expected 
under the null hypothesis (H0: ORR ≤ 5%). The analysis will be one-sided, based on binomial 
exact test. 
The study would be defined as positive at final analysis in the study cohort 3, if the ORR in the 
trastuzumab deruxtecan (DS-8201a) arm is statistically significantly better (p<0.05) than expected 
under the null hypothesis (H0: ORR ≤ 5%). The analysis will be one-sided, based on binomial 
exact test. 
The study would be defined as positive at final analysis in the study cohort 4, if the ORR in the 
trastuzumab deruxtecan (DS-8201a) arm is statistically significantly better (p<0.05) than expected 
under the null hypothesis (H0: ORR ≤ 5%). The analysis will be one-sided, based on binomial 
exact test. 
The study would be defined as positive at final analysis in the study cohort 5, if the median overall 
survival in the DS-8310a arm is statistically significantly better (p<0.05) than expected under the 
null hypothesis (H0: median OS ≤ 2 months). The analysis will be based on the one-sided 
maximum likelihood exponential test. 
 
• 
 Primary Efficacy Analysis 
We will describe number and proportion of patients without PFS, alive, or with overall response, 
at interim and final analyses. We will estimate these rates with the 95% confidence intervals 
(95%CI) based on stochastic ordering of UMVUE and Clopper-Pearson methods. The p-values 
will be calculated based on stochastic ordering of UMVUE methods and exact binomial test 
methods. 


 
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We will describe for time to event endpoints (OS) number and proportion of events, median 
survival time and survival rates, with corresponding 95% CI. We will use the Kaplan-Meier 
method. 
Analysis will be performed on the Full analysis and PP sets. ITT will be considered the primary 
set for the analysis. 
 
• 
 Secondary Efficacy Analysis 
We will describe number and proportion of patients with overall response, clinical benefit and 
without PFS. We will estimate the proportion with the 95% Pearson-Clopper confidence intervals. 
For time to event endpoints (PFS, ORR, CBR, TTR, DOR, and OS) we will use the Kaplan-Meier 
method. Number and proportion of events, median survival time and survival rates, with 
corresponding 95%Cl, will be calculated in study arm. For continuous outcome (Maximum Tumor 
reduction) we will use statistics of central tendency (median with 95%CI) and dispersion [range 
and interquartile range]. We provide waterfall plots of maximum tumor shrinkage from baseline.  
Analysis will be performed on the ITT, and PP sets. ITT will be considered the primary population 
for the analysis. For all tests, we will use two-sided p-values with alpha ≤ 0.05 level of significance. 
 
• 
Exploratory Analysis 
Changes in biomarkers will be evaluated on a 
regarding their association with 
treatment. Baseline and post-treatment values of 
biomarkers will be described with 
, 
, 
and 
in 
(copy numbers, 
immunoscore…). Baseline and post-treatment values of 
(
, 
and 
…) will be described with 
and 
. 
Change from baseline between values of quantitative biomarkers will be analyzed with 
and 
differences. The corresponding 95% confidence intervals, applicable test statistics and 
p-values will be presented. P-values and 95%CI for mean differences will be based on paired 
. P-values for ranks will be based on 
. The 95%CI for median difference 
will be based on bootstrap percentile method. Change from baseline between percentage of 
categorical biomarkers will be analyzed with 
. 
Markers will be evaluated on a univariate level regarding their change over potential for prediction 
of the clinical endpoints 
. Biomarker and response correlations with clinical 
will be investigated. It will be checked whether 
can improve the prediction 
and whether there is an interaction with the biomarkers. Further multivariate techniques (e.g. 


 
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, 
and 
) will be evaluated 
in order to study combinations of markers. Techniques to control 
and 
(
-
) will be also considered. Analysis will be performed on 
. 
 
8.8 
Safety Analysis 
Patient safety and AEs will be assessed using the NCI−CTCAE v.5.We will summarize AEs, AEs 
grade ≥ 3, SAEs (as described in previous section), premature withdrawal from study medication, 
laboratory parameters, exposure to study medication, concomitant medications, vital signs, 
ECOG performance status, and physical examination. 
The incidence of AEs and SAEs will be summarized according to the primary system-organ class 
(SOC) and within each SOC, by the Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term. Additional summaries by frequency tables will also be provided for the AEs. 
Patients with SAEs, who died or discontinue will be listed with the cause of the event. 
Laboratory parameters, hematology, and biochemistry, will be presented in shift tables of 
NCI−CTCAE grade at baseline versus worst grade during treatment. 
Other safety variables, such as exposure to study medication, concomitant medications, vital 
signs, and physical examination, ECOG performance status will be summarized over time and 
the percentage of patients in different categories will be presented by bar charts at different time 
points. 
 
8.9 
Interim Analyses 
Futility interim analyses in cohort 1. 
 
A futility interim analysis has been planned in cohort 1. The recruitment will not be stopped during 
the interim analysis. However, after the interim analysis, if the number of patients achieving the 
primary endpoint is equal or less than futility boundary the cohort may be stopped. Otherwise, the 
stage II recruitment will be open when the criteria to study continuation was achieved. However, 
the decision to stop or continue the trial should be endorsed by the steering committee after 
reviewing the interim safety and efficacy data. 
 
Feasibility interim analyses at each cohort 


 
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At the halfway point of the recruitment period, the steering committee will evaluate if the accrual 
objective for the first stage was achieved in each study cohorts (4, 5, 3, 3 and 3 patients for 
cohorts 1, 2, 3, 4 and 5, respectively). If this accrual objective has not achieved in a cohort, the 
Steering Committee will propose a corrective action plan or finalize the study in this cohort. 
 
8.10 
Missing Data Management 
Study variables could be missing for patients who withdrawn from the trial or for specific visits. 
We will report reasons for withdrawal. Patient with missing values in tumor response outcomes 
(ORR, CBR or without PFS events at 6 months) will considered as no responders, or last 
observation will be carried forward (maximum tumor reduction). Other outcomes will be managed 
with simple imputations methods. The effect that any missing data might have on results will be 
assessed via sensitivity analysis of study data sets. 
For PFS, TTR and DOR, patients without a date of disease progression or death will be analyzed 
as censored observations on the date of last tumor assessment. If no post-baseline tumor 
assessment is available, patients will be censored at the date of enrollment + 1 day. Data for 
patients with an event who missed two or more scheduled assessments immediately prior to the 
event will be censored at the last tumor assessment prior to the missed visits. 
For OS, patients who are not reported as having died will be analyzed as censored observations 
on the date they were last known to be alive. If no post-baseline data are available, OS will be 
censored at the date of enrollment + 1 day. 
 
8.11 
Steering Committee Review 
A Steering Committee will be established for this study. It will be composed by the study site 
Investigators, the Sponsor’s Medical Monitor, the Scientific Global Coordinator, and additional 
physicians with experience in experimental therapy management. 
The Steering Committee will meet on demand to review, discuss, and evaluate all of the gathered 
safety data. In case of any arising safety concern, these meetings can also be called at any time 
at request of a participating investigator. At these meetings, the Sponsor and the participating 
Investigators must reach a consensus on safety data. The Sponsor will prepare minutes from 
these meetings and circulate them to each Investigator for comment prior to finalization. 
Study site Investigators and the Sponsor will review patient data at least every six months. Each 
study site Investigator will monitor patient’s data for serious toxicities on an ongoing basis. 
 
 
 


 
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9 
ETHICAL CONSIDERATIONS 
9.1 
Regulatory and Ethics Compliance 
The study will be performed and reported in accordance with the guidelines of the ICH, and the 
ethical principles laid down in the Declaration of Helsinki. The study will be also compliance with 
European Directive 2001/20/EC and any applicable local regulations. 
 
9.2 
IRBs/IECs 
Conduct of the study must be approved by an appropriately constituted IRB/IEC. Approval is 
required for the study protocol, protocol amendments, ICFs, study subject information sheets, 
and advertising materials. The IRB/IEC must also be contacted in the event of any major protocol 
violation or any SAE. 
It is the Investigator’s responsibility to communicate with their local IRB/IEC to ensure accurate 
and timely information is provided at all phases during the study. 
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the IRB/EC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. Investigators are also responsible for promptly informing 
the IRB/EC/CA of any protocol amendments (approval is required before implementation of 
substantial amendments). 
In addition to the requirements to report protocol-defined AEs to the Sponsor, investigators are 
required to promptly report to their respective IRB/EC/CA all unanticipated problems involving risk 
to human patients. Some IRBs/ECs/CA may want prompt notification of all SAEs, whereas others 
require notification only about events that are serious, assessed to be related to study treatment, 
and are unexpected. Investigators may receive written safety reports or other safety related 
communications from the Sponsor. Investigators are responsible for ensuring that such reports 
are reviewed and processed in accordance with regulatory requirements and with the policies 
and procedures established by their IRB/EC/CA and archived in the site’s study file. 
 
9.3 
Informed Consent 
For each study subject, written ICF will be obtained prior to any protocol related activities. As part 
of this procedure, the study site Investigator or designee must explain orally and in writing the 
nature, duration, and purpose of the study, and the action of the drug in such a manner that the 
study subject is aware of the potential risks, inconveniences, or adverse effects that may occur. 
The study subject should be informed that he is free to withdraw from the study at any time. The 
subject will receive all information that is required by local regulations and ICH guidelines. 


 
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The ICF must be signed and dated by the patient before his participation in the study. The case 
history or clinical records for each patient shall document the informed consent process and that 
written ICF was obtained prior to participation in the study. 
A copy of each signed Consent Form must be provided to the patient. 
All signed and dated Consent Forms must remain in each patient’s study file and must be 
available for verification by study monitors at any time. 
The ICF should be revised whenever there are changes to procedures outlined in the ICF or when 
new information becomes available that may affect the willingness of the patient to participate. 
For any updated or revised Consent Forms, the case history for each patient shall document the 
informed consent process and that written ICF was obtained for the updated/revised Consent 
Form for continued participation in the study. The final revised IRB/EC-approved ICF must be 
provided to the Sponsor for regulatory purposes. 
 
9.4 
Data Protection 
The Sponsor will ensure the confidentiality of patient’s medical information in accordance with all 
applicable laws and regulations. 
The Sponsor as Data Controller according to the EU Data Protection Directive (95/46/EC) and 
the General Data Protection Regulation (2016/679) (GDPR) on the protection of individuals with 
regard to the processing of personal data and on the free movement of such data confirms 
herewith compliance to Directive 95/46/EC and GDPR in all stages of Data Management. 
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, the Sponsor monitors, representatives, and collaborators, 
and the IRB/EC for each study site, as appropriate. 
 
 
 


 
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10 
SOURCE DOCUMENTATION, STUDY MONITORING, AND QUALITY ASSURANCE 
10.1 
Source Data Documentation 
Source data refers to all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial. Source data are contained in source documents (original records or 
certified copies). 
Source documents are original documents, data, and records (i.e., hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, 
and at medico-technical departments involved in the clinical trial). 
Sponsor’s Quality Assurance group may assist in assessing whether electronic records generated 
from computerized medical record systems used at investigational sites can serve as source 
documents for the purposes of this protocol. 
If a site’s computerized medical record system is not adequately validated for the purposes of 
clinical research (as opposed to general clinical practice), applicable hardcopy source documents 
must be maintained to ensure that critical protocol data entered into the eCRFs can be verified. 
At a minimum, source documentation must be available to substantiate subject identification, 
eligibility, and participation; proper informed consent procedures; dates of visits; adherence to 
protocol procedures; adequate reporting and follow-up of AEs; administration of concomitant 
medication; study receipt/dispensing/return records; study administration information; and date of 
completion and reason. 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original records, laboratory reports, medical records) in order to ensure data 
completeness and accuracy as required by study protocol. The Investigator and/or site staff must 
make CRFs and source documents of subjects enrolled in this study available for inspection by 
MEDSIR or its representative at the time of each monitoring visit. 
The source documents must also be available for inspection, verification, and copying, as 
required by regulations, officials of the regulatory health authorities (i.e., Food and Drug 
Administration [FDA], EMA, and others), and/or ECs/IRBs. The Investigator and study site staff 
must comply with applicable privacy, data protection, and medical confidentiality laws for use and 
disclosure of information related to the study and enrolled subjects. 
The patient must also allow access to the patients’ medical records. Each patient should be 
informed of this prior to the start of the study. 


 
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10.2 
Study Monitoring and Source Data Verification 
Study progress will be monitored by MEDSIR or its representative (i.e., a Clinical Research 
Organization [CRO]) as frequently as necessary to ensure: 
That the rights and well-being of human subjects are protected; 
• 
The reported trial data are accurate, complete, and verifiable from the source documents; 
and 
• 
The conduct of the trial is in compliance with the current approved protocol/amendment(s), 
GCP, and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be identified in a handout located 
in the Investigator Site File. 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original records, laboratory reports, medical records, subject diaries) in order to ensure 
data completeness and accuracy as required by study protocol. The Investigator and/or site staff 
must make CRFs and source documents of subjects enrolled in this study available for inspection 
by the Sponsor or its representative at the time of each monitoring visit. 
 
10.3 
Retention of Records 
Investigators must retain all study records required by the applicable regulations in a secure and 
safe facility. The Investigator must consult a Sponsor representative before disposal of any study 
records and must notify the Sponsor of any change in the location, disposition, or custody of the 
study files. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. “Essential documents” are defined as 
documents that individually and collectively permit evaluation of the conduct of a trial and the 
quality of the data produced. These documents should be retained for a longer period, however, 
if required by the applicable e regulatory requirements or by an agreement with the Sponsor. The 
CHMP requires retention for the maximum period of time permitted by the institution, but not less 
than 15 years (ICH E6[R2], 4.9.5). It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained (ICH E6[R2], 
5.5.12). 


 
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The study site Investigator must not dispose of any records relevant to this study without either 
(1) written permission from the Sponsor or (2) providing an opportunity for the Sponsor to collect 
such records. The study site Investigator shall take responsibility for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated during 
this study. Such documentation is subject to inspection by the Sponsor and the FDA and/or EMA 
(or respective individual EU country regulatory authorities). 
These principles of record retention will also be applied to the storage of laboratory samples, 
provided that the integrity of the stored sample permits testing. 
 
10.4 
Data Quality Assurance 
During and/or after completion of the study, quality assurance auditor (s) named by the MEDSIR 
or the regulatory authorities may wish to perform on-site audits. The Investigators will be expected 
to cooperate with any audit and provide assistance and documentation (including source data) 
as requested. 
The Sponsor’s representatives are responsible for contacting and visiting the Investigator for the 
purpose of inspecting the facilities and, upon request, inspecting the various records of the clinical 
study (i.e., CRFs and other pertinent data) provided that patient confidentiality is respected. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH E6[R2] GCP and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from the Sponsor’s (or designee’s) Quality Assurance Department. 
Inspection of site facilities (i.e., pharmacy, drug storage areas, laboratories) and review of study-
related records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP (ICH E6 [R2]), and applicable country regulatory requirements. 
 
 
 


 
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11 
DATA MANAGEMENT 
11.1 
Data Entry and Management 
In this study, all data will be entered onto CRFs in a timely fashion by the Investigator and/or the 
Investigator’s dedicated site staff. 
The Investigator must review data recorded in the CRF to verify their accuracy. 
Reconciliation of the data will be performed by the designated CRO. At the conclusion of the 
study, the occurrence of any protocol violations will be identified and recorded as part of the 
clinical database. After these actions have been completed and the database has been declared 
to be complete and accurate, it will be locked and will become available for statistical data 
analysis. 
 
11.2 
Data Clarification 
As part of the conduct of the trial, MEDSIR may have questions about the data entered by the 
site, referred to as queries. The monitors and the Sponsor or designees are the only parties that 
can generate a query. 
 
11.3 
Data Coding Procedures 
Coding of AEs, medical history, and prior and concomitant medications will be performed using 
standard dictionaries as described in the Data Management Plan. 
 
 
 


 
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12 
STUDY MANAGEMENT 
12.1 
Discontinuation of the Study 
MEDSIR reserves the right to discontinue the study for safety or administrative reasons at any 
time. Should the study be terminated and/or the site closed for whatever reason, all investigational 
drugs pertaining to the study must be returned to MEDSIR Any actions required to assess or 
maintain study subject safety will continue as required, in spite of termination of the study. 
 
12.2 
Protocol amendments  
Any change or addition to this protocol requires a written protocol amendment or administrative 
letter that must be approved by MEDSIR, the Scientific Global Coordinator, the study site 
Investigator, and the IRB/IE/CA before implementation. This requirement for approval should in 
no way prevent any immediate action from being taken by the study site Investigator or MEDSIR 
in the interests of preserving the safety of all subjects included in the trial. If an immediate change 
to the protocol is felt to be necessary by the study site Investigator and is implemented for safety 
reasons, MEDSIR should be notified as soon as possible (within 24 hours if possible) and the 
IRB/IEC/CA should be informed as necessary. 
12.3 
Protocol Deviations 
The investigator should document and explain any protocol deviations. The investigator should 
promptly report any deviations that might have an impact on patient safety and data integrity to 
the Sponsor and to the IRB/EC in accordance with established IRB/EC policies and procedures. 
The Sponsor will review all protocol deviations and assess whether any represent a serious 
breach of Good Clinical Practice guidelines and require reporting to health authorities. As per the 
Sponsor's 
standard 
operating 
procedures, 
prospective 
requests 
to 
deviate 
from 
the 
protocol,including requests to waive protocol eligibility criteria, are not allowed. 
 
12.4 
Publication Policy Protection of Trade Secrets 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without prior written permission 
from the Scientific Global Coordinator and MEDSIR However, authorized regulatory officials, the 
Scientific Global Coordinator or the study site Investigator, and MEDSIR personnel (or their 
representatives) will be allowed full access to inspect and copy the records. All clinical 
investigational drug, patient bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by Scientific Global 
Coordinator or the study site Investigator and MEDSIR 


 
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The Sponsor will ensure that as far as possible results of this study will be published as 
scientific/clinical papers in high-quality peer-reviewed journals. Preparation of such manuscripts 
will be made with full collaboration of principal Investigators and in accordance with the current 
guidelines of Good Publication Practice. 
The Sponsor must be notified of any intent to publish data collected from the study and prior 
approval from Sponsor must be obtained prior to publication. 
 
 
 


 
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13 
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Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update.” Journal of 
Clinical Oncology 36 (27): 2804–7. https://doi.org/10.1200/JCO.2018.79.2713. 
Romond, Edward H., Jong-Hyeon Jeong, Priya Rastogi, Sandra M. Swain, Charles E. Geyer, 
Michael S. Ewer, Vikas Rathi, et al. 2012. “Seven-Year Follow-up Assessment of Cardiac 
Function in NSABP B-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide 
Followed by Paclitaxel (ACP) with ACP plus Trastuzumab as Adjuvant Therapy for Patients with 
Node-Positive, Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.” Journal of 
Clinical Oncology: Official Journal of the American Society of Clinical Oncology 30 (31): 3792–
99. https://doi.org/10.1200/JCO.2011.40.0010. 
Romond, Edward H., Edith A. Perez, John Bryant, Vera J. Suman, Charles E. Geyer, Nancy E. 
Davidson, Elizabeth Tan-Chiu, et al. 2005. “Trastuzumab plus Adjuvant Chemotherapy for 
Operable HER2-Positive Breast Cancer.” The New England Journal of Medicine 353 (16): 1673–
84. https://doi.org/10.1056/NEJMoa052122. 
Schouten, Leo J., Joost Rutten, Hans A. M. Huveneers, and Albert Twijnstra. 2002. “Incidence of 
Brain Metastases in a Cohort of Patients with Carcinoma of the Breast, Colon, Kidney, and Lung 
and Melanoma.” Cancer 94 (10): 2698–2705. 
Scott, Brian J, and Santosh Kesari. 2013. “Leptomeningeal Metastases in Breast Cancer.” 
American 
Journal 
of 
Cancer 
Research 
3 
(2): 
117–26. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623833/. 
Shitara, Kohei, Yung-Jue Bang, Hyun Cheol Chung, Hiroshi Yabusaki, Satoru Iwasa, Daisuke 
Sakai, Kei Muro, et al. 2019. “A Phase II, Multicenter, Open-Label Study of [Fam-] Trastuzumab 
Deruxtecan (DS-8201a) in Subjects with HER2-Expressing Gastric Cancer.” Journal of Clinical 
Oncology 
37 
(4_suppl): 
TPS180–TPS180. 
https://doi.org/10.1200/JCO.2019.37.4_suppl.TPS180. 
Stemmler, Hans-Joachim, Manfred Schmitt, Amina Willems, Helga Bernhard, Nadia Harbeck, and 
Volker Heinemann. 2007. “Ratio of Trastuzumab Levels in Serum and Cerebrospinal Fluid Is 
Altered in HER2-Positive Breast Cancer Patients with Brain Metastases and Impairment of Blood-
Brain 
Barrier.” 
Anti-Cancer 
Drugs 
18 
(1): 
23–28. 


 
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https://doi.org/10.1097/01.cad.0000236313.50833.ee. 
Verma, Sunil, David Miles, Luca Gianni, Ian E. Krop, Manfred Welslau, José Baselga, Mark 
Pegram, et al. 2012. “Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer.” New 
England Journal of Medicine 367 (19): 1783–91. https://doi.org/10.1056/NEJMoa1209124. 
Weil, Robert J., Diane C. Palmieri, Julie L. Bronder, Andreas M. Stark, and Patricia S. Steeg. 
2005. “Breast Cancer Metastasis to the Central Nervous System.” The American Journal of 
Pathology 167 (4): 913–20. https://doi.org/10.1016/S0002-9440(10)61180-7. 
Yardley, D. A., D. Tripathy, A. M. Brufsky, H. S. Rugo, P. A. Kaufman, M. Mayer, J. Magidson, B. 
Yoo, C. Quah, and M. Ulcickas Yood. 2014. “Long-Term Survivor Characteristics in HER2-
Positive Metastatic Breast Cancer from RegistHER.” British Journal of Cancer 110 (11): 2756–
64. https://doi.org/10.1038/bjc.2014.174. 
Zagouri, Flora, Theodoros N. Sergentanis, Rupert Bartsch, Anna S. Berghoff, Dimosthenis 
Chrysikos, Evandro de Azambuja, Meletios-Athanassios Dimopoulos, and Matthias Preusser. 
2013. “Intrathecal Administration of Trastuzumab for the Treatment of Meningeal Carcinomatosis 
in HER2-Positive Metastatic Breast Cancer: A Systematic Review and Pooled Analysis.” Breast 
Cancer Research and Treatment 139 (1): 13–22. https://doi.org/10.1007/s10549-013-2525-y. 
 
 


 
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14 
Appendices 
14.1 
Appendix 1. Schedule of Assessments and Study Procedures 
Study Period 
Screening Period 
Treatment Period* 
 
Post-Treatment Follow-
Up Period 
Day 
-28 to -1 
-14 to -1 
Cycle 1 Day 1 
Cycle X Day 1 
Within 40 days (± 7 days) 
after last dose of study 
treatment 
(EoT) 
Follow-up every 12 
weeks (± 14 days)19 
Informed Consent Form1 
X 
 
 
 
 
 
HER2 status2 
X 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
Physical examination  
 
X 
X 
X 
X 
 
ECOG performance status 
 
X 
X 
X 
X 
 
Weight and vital signs4 
 
X 
X 
X 
X 
 
Concomitant medication 
reporting5 
 
X 
X 
X 
X 
 
AE reporting6 
 
X 
X 
X 
X 
 
12-lead ECG7 
 
X 
X7 
X7 
X7 
 
ECHO or MUGA scan8 
X 
 
 
X8 
X 
 
Troponin9 
 
X 
 
 
X 
 
Ophthalmologic 
assessments10 
X 
 
 
 
X 
 
pSO211 
 
X 
X 
X 
X 
 
Tumor assessments12 
X 
 
 
X12 
X12 
 
Tumor samples 
(for exploratory study)13 
X 
(if feasible) 
 
 
 
At the time of progression 
(if feasible) 
 
Blood samples (for 
exploratory study)14 
X 
 
 
X 
At the time of progression 
 
Hematology15 
 
X 
X 
X 
X 
 
Chemistry15 
 
X 
X 
X 
X 
 


 
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Study Period 
Screening Period 
Treatment Period* 
 
Post-Treatment Follow-
Up Period 
Day 
-28 to -1 
-14 to -1 
Cycle 1 Day 1 
Cycle X Day 1 
Within 40 days (± 7 days) 
after last dose of study 
treatment 
(EoT) 
Follow-up every 12 
weeks (± 14 days)19 
INR/PT and aPTT 15 
 
X 
 
 
X 
 
Urinalysis 
 
X 
 
 
 
 
Pregnancy test16 
 
X 
X 
X 
X16 
 
Viral serology17 
 
X 
 
 
 
 
Trastuzumab deruxtecan (DS-
8201a) administration 
 
 
X 
X 
 
 
Review patient diary 
 
 
X 
X 
 
 
PRO assessments18 
 
X 
X 
X 
X 
X 
Survival status 
 
 
 
 
X 
X 
Post-study anticancer therapy 
 
 
 
 
X 
X 
AEs = Adverse events; aPTT = Activated partial thromboplastin time; ECG = Electrocardiogram; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EoT = End of Treatment; HER2 = Human Epidermal Growth Factor Receptor 2; INR = International normalized ratio; MUGA = Multiple-
Gated Acquisition; PRO QOL: Patient reported outcome-Quality of life; PT = Prothrombin time. 
* All visits must occur within ± 2 working days. Assessments scheduled for Days 1 each cycle must be performed within 48 hours prior to study treatment 
administration, respectively, unless otherwise indicated in the schedule of assessments, in order to confirm to the patient if treatment can be followed up. 
 
1. 
Informed Consent Form: Signed written Informed Consent Form obtained prior to any trial-specific procedure. 
2. 
HER2 status: Local confirmation of HER2-positive status. 
3. 
Medical history: Complete medical history and demographics (including age, gender, and ethnic origin). All medications taken in the last 28 days prior to 
enrolment will be collected. 
4. 
Weight and vital signs: Weight, height (only at screening), respiratory rate, blood pressure measurements (systolic and diastolic), pulse rate, and body 
temperature (oral, axillary, or tympanic temperature). Vital signs should be measured at screening (within 14 days), before and after the end of the infusion 
on Day 1 of cycle 1 to 3 and only before infusion on Day 1 of subsequent cycles. 


 
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5. 
Concomitant medication reporting: Relevant concomitant medication will be recorded at screening and on an ongoing basis. 
6. 
AE reporting: All AEs occurring during the trial and until 30 days after treatment discontinuation visit (EoT visit) have to be recorded with grading according 
to the NCI–CTCAE v.5.0 criteria. 
7. 
12-lead ECG: ECGs (will be taken in triplicate, in close succession, while in a supine/semi-recumbent position) to be collected at screening (within 14 
days before enrollment). Subsequent ECGs will be performed in triplicate in close succession. If an abnormality is noted, ECG will be taken. ECGs will be 
taken at every 4th cycle while in a supine/semirecumbent position. 
8. 
ECHO or MUGA scan: LVEF assessment will be performed at screening (within 28 days before enrollment), Cycle 5 Day 1, and on Day 1 of every four 
cycles (±7 days) thereafter (e.g., Cycles 9, 13, 17, etc.) while on treatment, and at the EoT visit Note: the same test must be used for the subject throughout 
the study 
9. 
Troponin: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. Subjects may also have local troponin testing 
as clinically indicated during the treatment phase based on subject reported cardiac symptoms . If ECG is abnormal, follow institutional guidelines. If troponin 
levels are above the upper limit of normal and below the level of myocardial infarction as defined by the manufacturer (CTCAE Grade 1) at baseline, no 
repeat testing is required if the troponin level is not Grade 3. 
10. 
Ophthalmologic assessments: They will include visual acuity testing, slit lamp examination and fundoscopy will be performed at screening (within 28 
days before enrollment), at EoT and if patient present sign or symptoms of ophthalmologic problems.  
11. 
pSO2: pulse oximetry will be performed at screening (within 14 days) and on Day 1, of every cycle, and until the safety follow-up visit 40 days after last 
dose. During Cycle 1, pulse oximetry will be assessed on Day 1 prior and after infusion of trastuzumab deruxtecan, on Day 8 and Day 15. On Day 1 pre-
dose measurements will be taken thereafter.  
12. 
Tumor assessments: Baseline assessments of the chest, abdomen, and pelvis (preferably CT or MRI in case of contrast allergy) must be performed no 
more than 28 days before the first dose of study treatment. Post-baseline assessments will be performed every 6 weeks (± 3 working days) from the first 
dose of study treatment for the first 6 months of treatment and every 9 weeks (± 5 working days) thereafter using the same imaging method and where 


 
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possible obtained at the same institution for an individual patient as used during screening until progression disease or EoS. Bone scans will be only 
performed at baseline and every 24 weeks (± 7 working days) for patients with bone lesions identified at baseline, unless clinically or biochemically 
suspected bone progression. If a bone scan was performed > 28 days but ≤ 60 days prior to start of study treatment, the bone scan does not need to be 
repeated. Brain imaging (MRI) will be performed within 28 days prior to the first administration of study medication and during the trial should be performed 
every 6 weeks [± 3 working days] from the first dose of study treatment for the first 6 months, and, thereafter, every 9 weeks [± 5 working days]) unless 
clinically suspected brain progression. Patients who discontinue treatment without evidence of disease progression will be followed every nine weeks (± 5 
days) for tumor assessments until documented progression, elective withdrawal from the study, the start of new anti-cancer treatment, or study completion 
or termination.Note: For patients included in the study cohort 5, axis MRI and spinal tap for CSF collection must also be performed, at baseline, every 3 
weeks for 12 weeks (corresponding to the first 5 cycles of treatment), every 6 weeks thereafter, and at the time of treatment progression or study termination. 
13. 
Tumor samples (for exploratory study): A tissue sample should be provided at baseline (if feasible) from breast primary tumor or metastases amenable 
to biopsy (at sites of locoregional recurrence [skin, chest wall, breast or lymph nodes], or distant recurrence [bone, liver, lung or abdomen]) that will be 
obtained between progression to the prior regimen and inclusion in the study. Patients for whom tissue sample cannot be obtained (e.g., non-measurable 
disease, inaccessible tumor or subject safety concern) may submit an archived metastatic tumor specimen only upon agreement from the Sponsor. If 
feasible, an additional tissue sample should be collected at the end of treatment visit for patients who discontinue treatment due to disease progression 
14. 
Blood samples (for exploratory study): Blood samples are required for all patients at the time of inclusion, after two cycles of study treatment, and upon 
progression or study termination. 
15. 
Hematology/chemistry: Cycle 1 Day 1 hematology and chemistry panel assessments are not required if the screening hematology and chemistry panel 
was performed at screening within 48 hours prior to start of study treatment. On cycle 1, hematology, chemistry assessment must be repeated on day 8 
and day 15.Coagulation assessment INR/PT and PTT/aPTT only in screening (within 14 days) and EoT. 
16. 
Pregnancy test: A serum pregnancy test at screening to confirm eligibility in the trial and within one week prior to start of study medication (with result 
available prior to dosing). This assessment does not need to be repeated at Cycle 1 Day 1 if it was performed at screening within 48 hours prior to start of 


 
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study treatment. Thereafter, repeat pregnancy tests (urine or serum test per institutional guideline) before infusion of each cycle and at end of treatment. A 
serum test should be performed to confirm any positive urine pregnancy test during the trial.  
17. 
Viral serology: Human Immunodeficiency Virus, Hepatitis B surface Antigen (HBsAg), total Hepatitis B core Antibody (HBcAb), Hepatitis C Virus antibody; 
additional tests for Hepatitis B Virus DNA or Hepatitis C Virus RNA will be required within 14 days before enrollment to confirm eligibility. Patients positive 
for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA 
18. 
PRO Assessments: The EORTC-QLQ-C30 and the EORTC-QLQ-BR23 questionnaires will be completed at baseline, Day 1 of cycles 2-4, then on Day 
1 of every other subsequent cycle starting with cycle 6 (e.g. cycles 6, 8, 10, etc.), End of Treatment visit and during follow-up period until start of 
anticancer therapy. 
19. 
Follow-up every 12 weeks: After study treatment discontinuation, post-treatment follow-up (including survival status and post-study anticancer therapy 
evaluation) will be collected every 12 weeks (± 14 days) from the last dose of study treatment up to the end of study visit. Telephone contact is 
acceptable. 


 
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14.2 
Appendix 2. Response Evaluation Criteria According to RANO-BM Criteria (Lin et al. 
2015) 
 
Measurable disease is deﬁned as a contrast-enhancing lesion that can be accurately 
measured in at least one dimension, with a minimum size of 10 mm, and is visible on two or more 
axial slices that are preferably 5 mm or less apart with 0 mm skip (and ideally ≤1·5 mm apart with 
0 mm skip). 
Additionally, although the longest diameter in the plane of measurement is to be recorded, the 
diameter perpendicular to the longest diameter in the plane of measurement should be at least 5 
mm for the lesion to be considered measurable. 
Measurement of a tumor around a cyst or surgical cavity is a particularly diﬃcult challenge. 
Generally, such lesions should be considered non-measurable unless there is a nodular 
component that measures 10 mm or more in longest diameter and 5 mm or more in the 
perpendicular plane. 
Non-measurable disease includes all other lesions, including lesions with longest dimension 
less than 10 mm, lesions with borders that cannot be reproducibly measured, dural metastases, 
bony skull metastases, cystic-only lesions, and leptomeningeal disease. 
 
Response assessment 
Target lesions 
• 
Complete response: Disappearance of all central nervous system (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 response: 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. 
• 
Progressive disease: 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. 
• 
Stable disease: 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. 
Non-target lesions 


 
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Non-target lesions should be assessed qualitatively at each of the timepoints speciﬁed in the 
protocol.  
• 
Complete response: Requires all of the following: disappearance of all enhancing CNS non-
target lesions, no new CNS lesions.  
• 
Non-complete response or non-progressive disease: Persistence of one or more non-target 
CNS lesion or lesions. 
• 
Progressive disease: 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 tumor-related non-enhancing (T2/FLAIR) CNS lesions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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14.3 
Appendix 3. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law. 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law (HL). It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates in reviewing and assessing of cases meeting PHL criteria to agree 
whether HL criteria are met. HL criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the IMP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
AE and SAE according to the outcome of the review and assessment in line with standard safety 
reporting processes. 
 
Definition 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal 
(ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study following the start 
of study medication irrespective of an increase in Alkaline Phosphatase (ALP). 
 
 
Hy’s Law (HL) 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the IMP, 
can be found to explain the combination of increases (e.g., elevated ALP indicating cholestasis, 
viral hepatitis, another drug). Therefore, if increases are reasonably explainable as due to 
cholestasis other than drug liver injury, then reporting is not necessary 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. within 
one cycle) the elevation in TBL, but there is no specified timeframe within which the elevations in 
transaminases and TBL must occur. 
 


 
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Identification of Potential HY’S law cases 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
• ALT ≥ 3xULN; 
• AST ≥ 3xULN; 
• TBL ≥ 2xULN. 
Note: There are different processes for the identification of potential Hy’s law cases depending 
on whether central or local laboratories are being used. 
 
When a patient meets any of the identification criteria, in isolation or in combination, the 
Investigator will immediately: 
• Notify the Sponsor’s representative (or designee’s); 
• Request a repeat of the test (new blood draw) by the local laboratory; 
• Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result. 
 
When the identification criteria are met from local laboratory results the Investigator will without 
delay: 
• Determine whether the patient meets PHL criteria (see 2. Definition within this Appendix) by 
reviewing laboratory reports from all previous visits. 
 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• Notify the Sponsor’s representative (or designee’s); 
• Promptly enter the laboratory data into the laboratory CRF. 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’ (66): 
https://www.fda.gov/media/116737/download 


 
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14.4 
14.4 Appendix 4. Instructions related to Severe acute respiratory syndrome 
coronavirus 2 (SARS-COV-2) 
 
Inclusion criteria 
1. 
Has adequate treatment washout period before randomization/enrollment, defined as: 
• 
Chloroquine/Hydroxychloroquine: > 14 days 
 
Prior and Concomitant Medications 
 
The following core safety protocol restrictions (italicized below) are applicable to all Phase 1-3 
clinical study protocols developed on or after the PSR effective date, regardless of indication. 
Contact your GCL and CSPV representatives for protocol-specific safety restrictions that may 
differ from the core minimum restrictions presented hereafter. 
 
Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during the study 
treatment. If treatment with chloroquine or hydroxychloroquine treatment is absolutely required 
for SARS-CoV-2 (ie COVID-19), study treatment must be interrupted. If chloroquine or 
hydroxychloroquine is administered, then a wash-out period of no less than >14 days is required 
before restarting study treatment. 
 
Dose modification criteria for suspected or confirmed SARS-CoV-2 
All confirmed or suspected SARS-CoV-2 infection events must be recorded in the eCRF. Dose 
modifications will be based on the worst CTCAE grade. All interruptions or modifications must 
be recorded on the AE and drug administration eCRFs. Please use CTCAE v5.0 general 
grading criteria to evaluate COVID-19. 
 
 Dose modification criteria  
If SARS-CoV-2 infection is suspected, interrupt trastuzumab deruxtecan and rule out SARS-
CoV-2 per local guidance. 
 
! 
If SARS-CoV-2 is ruled out, follow dose modification and management guidelines as 
outlined in the CE protocol template. 
! 
If SARS-CoV-2 is confirmed or diagnosis is suspected after evaluation, follow dose 
modification as outlined below and manage SARS-CoV-2 per local guidance until 
recovery of SARS-CoV-2. SARS-CoV-2 recovery is defined as no signs/symptoms 


 
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SARS-CoV-2, at least 1 negative RT-PCR test result*,and nearly or completely resolved 
chest CT findings. Then follow below dose modifications: 
 
SARS-CoV-2 Dose Modification Criteria 
SARS-CoV-2 Worst Toxicity NCI-CTCAE 
Version 5.0 Grade (unless otherwise specified) 
Schedule Modification for trastuzumab 
deruxtecan 
Grade 1 
Resume study drug at the same dosea 
Grade 2 
Resume study drug at the same dose if chest CT 
findings are completely resolveda 
Reduce by 1 dose level if chest CT findings are 
nearly resolved 
Grade 3 
Reduce by 1 dose level if chest CT findings are 
completely resolved 
Discontinue study drug if chest CT findings are 
not completely resolved 
Grade 4 
Discontinue study drug 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); CT = 
computed tomography 
a Closely monitor signs/symptoms after resuming study treatment, initially with a phone call 
every 3 days for the first week, and then with a weekly phone call thereafter, for a total of 6 
weeks. 
 
• 
In addition to the recommendations outlined in the table above, Investigators may 
consider dose modifications of the study drug according to the subject’s condition and 
after discussion with the study Medical Monitor or designee. 
• 
If an event is suspected to be drug related ILD/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline.  
* If PCR testing is not available, the subject must not have any sign/symptoms for at least 2 
weeks, in addition to meeting the requirement for chest CT imaging. 

SAP_001.pdf: 
CONFIDENTIAL INFORMATION 
 
Statistical Analysis Plan (SAP) 
 
FINAL Version 3.0 
15th February 2024 
 
EudraCT Number 
2019-001739-29 
Protocol Number 
MedOPP243 (DEBBRAH) 
Protocol Version Date 
V5.0, 18-JAN-2022 
Title 
 
A Multicenter, Open-Label, Single-Arm, Multicohort 
Phase II Clinical Trial of Trastuzumab Deruxtecan (DS-
8201a) in Human Epidermal Growth Factor Receptor 2 
(HER2)-Positive Advanced Breast Cancer with Brain 
Metastases and/or Leptomeningeal Carcinomatosis. 
DS-8201a for trEatment of aBc, BRain mets, And 
Her2[+] disease 
–The DEBBRAH Study– 
Sponsor 
 
MEDSIR 
Torre Glòries. Av. Diagonal, 211 
Planta 27. 08018 Barcelona 
 
 
 
 
 
 
 
 
Performed by: 
 
Avenida Meridiana 350, 9 D 
08027 Barcelona (Spain) 
www.sail-biometria.com
STATISTICAL ANALYSIS PLAN (SAP) 
           


 Study Code: 2019-001739-29 (MedOPP243)                                                                 Statistical Analysis Plan 
 February 15, 2024                                                        2                                                                      Final 
 
Signature Page 
 
 
EudraCT Number: 
2019-001739-29 
Protocol Number: 
MedOPP243 
 
 
Written by:  
Signature:  
                            ___________________________ 
Date:  
                            ___________________________ 
Biostatistician  
SAIL S.L.L. 
Barcelona, Spain 
 
 
Sponsor Signature: 
The undersigned hereby declare that they have examined the Statistical Analysis Plan document 
and agree to its form and content.  
Represented by: 
 
Signature: 
__________________________ 
Date: 
__________________________ 
Name: 
__________________________ 
Title: 
__________________________ 
 
__________________________ 
Date: 
__________________________ 
Name: 
__________________________ 
Title: 
__________________________ 
 
 
 
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

 



 Study Code: 2019-001739-29 (MedOPP243)                                                                 Statistical Analysis Plan 
 February 15, 2024                                                        3                                                                      Final 
 
SAP Revision History: 
 
Version 
Number 
Date 
Changes 
1.0 
08th February 2021 
New 
2.0 
11th June 2021 
Changes according to protocol version 4.0, 30 Dec 
2020 
3.0 
15th February 2024 
Changes according to protocol version 5.0, 18 Jan 
2022 
 
 
 
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 Study Code: 2019-001739-29 (MedOPP243)                                                                 Statistical Analysis Plan 
 February 15, 2024                                                        4                                                                      Final 
LIST OF ABBREVIATIONS 
 
Abbreviation Definition 
ABC Advanced Breast Cancer 
AE Adverse Event 
AESI Adverse Event of Special Interest 
ARO Academic Research Organization  
ATC Anatomical Therapeutic Chemical 
BC Breast Cancer 
BM Brain Metastases 
BPM Beats Per Minute 
CB Clinical Benefit 
CBR Clinical Benefit Rate 
CI Confidence Interval 
CNS Central nervous Nervous System 
CPMP Committee for proprietary Proprietary medicinal Medicinal productsProducts 
CR  Complete Response 
CSF Cerebrospinal Fluid 
CT Computed Tomography 
CTCAE Common Terminology Criteria for Adverse Events 
DOR Duration of Response 
ECG Electrocardiogram  
ECOG Eastern Cooperative Oncology Group  
ECRF electronic Case Report Form 
EOS End of Study 
EOT End of Treatment 
ER Endocrine Receptors 
EUDRACT European Clinical Trials Database 
FAS Full Analysis Set 
HER2 Human Epidermal Growth Factor Receptor 2 
HR Hazard Ratio 
IQR Interquartile Range 
LMC Leptomeningeal Carcinomatosis 
LVEF Left Ventricular Ejection Fraction 
MBC Metastatic Breast Cancer 
MEDDRA Medical Dictionary for Regulatory Activities 
MRI Magnetic Resonance Imaging 
MTD Maximum Tolerated Dose 
NCI National Cancer Institute 
ORR Overall Response Rate 
OS Overall Survival 
PD Progression Disease 
PFS Progression-Free Survival 
PP Per Protocol set 
PR Partial Response 
PRO Patient Reported Outcomes 
PT Preferred Term 
RANO-BM Response Assessment in Neuro-Oncology Brain Metastases criteria 
RD Recommended Dose 
RDI Relative Dose Intensity 
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Abbreviation Definition 
RECIST Response Evaluation Criteria in Solid Tumors 
RNA Ribonucleic Acid 
RR Relative Risk 
RS Recurrence Score 
SAE Serious Adverse Event  
SAIL SAIL S.L.L. 
SAP Statistical Analysis Plan  
SAS Statistical Analysis Software 
SC Steering Committee 
SD Stable Disease / Standard Deviation 
SI International System of Units 
SOC System Organ Class 
SRS Stereotactic Radiosurgery 
TEAE Treatment emergent adverse event 
TLF Tables, listings and figures 
TTP Time To Progression 
TTR Time To Response 
UMVUE Uniformly Minimum Variance Unbiased Estimator 
WBRT Whole Brain Radiation Therapy 
WHO World Health Organization 
 
 
 
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 Study Code: 2019-001739-29 (MedOPP243)                                                                 Statistical Analysis Plan 
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TABLE OF CONTENTS 
1 
INTRODUCTION ______________________________________________ 9 
1.1 
General ___________________________________________________________ 9 
1.2 
Type of Study ______________________________________________________ 9 
1.3 
Study Design _______________________________________________________ 9 
1.4 
Study Flow Chart ___________________________________________________ 10 
1.5 
Sample Size _______________________________________________________ 12 
2 
STUDY OBJECTIVES __________________________________________ 13 
2.1 
Cohort 1 __________________________________________________________ 13 
2.1.1 
Primary Objective _________________________________________________ 13 
2.1.2 
Secondary Objectives ______________________________________________ 13 
2.1.3 
Exploratory Objectives _____________________________________________ 13 
2.2 
Cohorts 2, 3 and 4 __________________________________________________ 14 
2.2.1 
Primary Objective _________________________________________________ 14 
2.2.2 
Secondary Objectives ______________________________________________ 14 
2.2.3 
Exploratory Objectives _____________________________________________ 14 
2.3 
Cohort 5 __________________________________________________________ 14 
2.3.1 
Primary Objective _________________________________________________ 14 
2.3.2 
Secondary Objectives ______________________________________________ 14 
2.3.3 
Exploratory Objectives _____________________________________________ 15 
3 
DEFINITION OF ENDPOINTS ___________________________________ 15 
3.1 
Cohort 1 __________________________________________________________ 15 
3.1.1 
Primary Endpoint _________________________________________________ 15 
3.1.2 
Secondary Endpoints ______________________________________________ 15 
3.1.3 
Safety Endpoints _________________________________________________ 16 
3.1.4 
Exploratory Endpoints _____________________________________________ 16 
3.2 
Cohorts 2, 3 and 4 __________________________________________________ 16 
3.2.1 
Primary Endpoint _________________________________________________ 16 
3.2.2 
Secondary Endpoints ______________________________________________ 16 
3.2.3 
Safety Endpoints _________________________________________________ 17 
3.2.4 
Exploratory Endpoints _____________________________________________ 17 
3.3 
Cohort 5 __________________________________________________________ 17 
3.3.1 
Primary Endpoint _________________________________________________ 17 
3.3.2 
Secondary Endpoints ______________________________________________ 17 
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3.3.3 
Safety Endpoints _________________________________________________ 18 
3.3.4 
Exploratory Endpoints _____________________________________________ 18 
4 
ANALYSIS SETS _____________________________________________ 18 
5 
STATISTICAL METHODS _______________________________________ 18 
5.1 
General Methodology ________________________________________________ 18 
5.2 
Subject Disposition _________________________________________________ 19 
5.3 
Baseline Characteristics ______________________________________________ 20 
5.4 
Response Evaluation Criteria __________________________________________ 21 
5.4.1 
RANO-BM Criteria _________________________________________________ 21 
5.4.2 
RECIST v.1.1 Criteria ______________________________________________ 22 
5.5 
Response Efficacy Definitions _________________________________________ 22 
5.5.1 
Primary Efficacy Endpoint Definitions _________________________________ 23 
5.5.2 
Secondary Efficacy Endpoints Definitions ______________________________ 23 
5.6 
Efficacy Analysis ___________________________________________________ 24 
5.6.1 
Primary Efficacy Analysis ___________________________________________ 24 
5.6.2 
Decision Rules and Adjustment of Alpha for Primary Endpoint _____________ 25 
5.6.3 
Secondary Efficacy Analysis _________________________________________ 25 
5.6.4 
Handling of Missing Efficacy Data ____________________________________ 26 
5.6.5 
Estimands _______________________________________________________ 27 
5.6.6 
Exploratory Analysis _______________________________________________ 29 
5.7 
Safety Analysis _____________________________________________________ 29 
5.7.1 
Duration and Extent of Exposure ____________________________________ 30 
5.7.2 
Concomitant Medications ___________________________________________ 30 
5.7.3 
Dose Delays, Reductions and Discontinuations __________________________ 31 
5.7.4 
Adverse Events __________________________________________________ 31 
5.7.5 
Clinical Laboratory Parameters ______________________________________ 33 
5.7.6 
Vital Signs ______________________________________________________ 33 
5.7.7 
Physical Examination ______________________________________________ 33 
5.8 
Interim Analysis ____________________________________________________ 34 
5.8.1 
Futility Interim Analyses in Cohort 1 __________________________________ 34 
5.8.2 
Feasibility Interim Analyses _________________________________________ 34 
5.9 
Changes of Analysis from Protocol _____________________________________ 35 
5.10 
Deviations from SAP ________________________________________________ 35 
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 February 15, 2024                                                        8                                                                      Final 
6 
BIBLIOGRAPHY _____________________________________________ 36 
7 
APPENDIX _________________________________________________ 37 
7.1 
Appendix 1 – Codes _________________________________________________ 37 
7.1.1 
R Code - UMVUE _________________________________________________ 37 
7.1.2 
SAS Code - Stochastic Binomial Exact Test _____________________________ 40 
7.1.3 
R Code - Maximum Likelihood Method for Exponential Distribution __________ 40 
7.2 
Appendix 2 - List of Tables, Listings, Figures _____________________________ 40 
 
 
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 Study Code: 2019-001739-29 (MedOPP243)                                                                 Statistical Analysis Plan 
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1 
INTRODUCTION 
1.1 General 
The purpose of this statistical analysis plan (SAP) is to provide a protocol specific description of the 
statistical analysis that will be performed to produce an integrated clinical/statistical report. 
This SAP is based upon the following study documents: 
- 
Protocol version Date: version 4.0, 30 Dec 2020 
- 
eCRF release version date: version 5.0, 06-Nov-2020 
1.2 Type of Study 
This is a multicenter, international, open-label, single-arm, multicohort, two-stage optimal Simon’s design, 
phase II clinical trial. 
1.3 Study Design 
This is a multicenter, open-label, single-arm, multicohort, two-stage optimal Simon’s design, phase II 
clinical trial that is designed to evaluate the safety, tolerability, and efficacy of trastuzumab deruxtecan 
(DS-8201a) for pretreated patients with unresectable locally advanced or metastatic HER2-positive or 
HER2-low expressing BC with untreated or treated BMs or LMC. 
Patients will be assigned to one of the following five study cohorts: 
• 
Cohort 1 (N=8): HER2-positive BC with non-progressing BM (after WBRT and/or SRS and/or 
surgery) 
• 
Cohort 2 (N=10): HER2-positive or HER2-low BC with asymptomatic, untreated BMs 
• 
Cohort 3 (N=7): HER2-positive BC with progressing BMs after local treatment 
• 
Cohort 4 (N=7): HER2-low expressing BC with progressing BMs after local treatment 
• 
Cohort 5 (N=7): HER2-positive or HER2-low expressing BC with LMC 
Enrolment will start for all cohorts at the same time. 
A futility interim analysis has been planned in cohorts 1, after the recruitment of 4 patients. At the interim 
analysis, if the number of patients achieving the primary endpoint is equal or less than futility boundary 
in each cohort, the accrual in the cohort must be stopped. The stopping rules for each cohort are: 
• 
Cohort 1: All 4 patients with progressive disease or death at 16 weeks. 
Additionally, a feasibility interim analysis has been planned in each cohort. At the halfway point of the 
recruitment period, the Steering Committee will evaluate if the accrual objective for the first stage was 
achieved in each study cohorts (4, 5, 3, 3 and 3 patients for cohorts 1, 2, 3, 4 and 5, respectively). If this 
accrual objective has not achieved in a cohort, the Steering Committee will propose a corrective action 
plan or finalize the study in this cohort. 
For estimation of PFS, TTR, ORR, DOR, CBR, OS, 12-week CNS disease stabilization, and best percentage 
of change in target tumor lesions, tumor assessment will be based on RANO-BM criteria and on RECIST 
v.1.1 criteria for estimation in non-target tumor lesions (Brain MRI and chest/pelvis and abdomen CT) 
(see Appendix 1) and will be performed every six weeks (± 3 days) for the first six months and, thereafter, 
every nine weeks (± 5 days) until disease progression. If patient interrupts treatment without confirmation 
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on disease progression, tumor assessment will continue until event is confirmed unless patient starts new 
anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. 
Tumor assessments will be performed on the specified schedule regardless of treatment delays. 
In addition, for patients allocated in the study cohort 5, CSF analysis will be performed at base line, every 
three weeks for 12 weeks (corresponding to the first 5 cycles of treatment) and every six weeks thereafter 
and at the time of disease progression, treatment discontinuation, the start of new anti-cancer treatment, 
withdrawal of consent, death, or the end of the study, whichever occurs first. 
Bone scans will be only performed every 24 weeks (± 7 days) for patients with bone lesions identified at 
baseline, unless clinically or biochemically suspected bone progression. 
Safety assessments will include the incidence, nature, and severity of AEs and laboratory abnormalities 
graded per the NCI-CTCAE v.5.0. Laboratory safety assessments will include the regular monitoring of 
hematology, blood chemistry, coagulation, and pregnancy test (see Appendix 1 of the protocol). 
To perform exploratory studies, patients must have consented to provide sufficient newly obtained tumor 
biopsy tissue except for patients for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or 
subject safety concern) that may submit an archived metastatic tumor specimen only upon agreement 
from the Sponsor. Patients will also be given the option of providing a tissue biopsy sample obtained at 
disease progression for exploratory analyses; this decision will not affect overall study eligibility. 
Furthermore, patients have agreed to give blood samples (liquid biopsy) at the time of inclusion, after two 
cycles of study treatment, and upon progression or study termination. Moreover, patient allocated in the 
study cohort 5, must have consented to provide CSF samples for their analysis at baseline, every three 
weeks for 12 weeks (corresponding to the first 5 cycles of treatment) and every six weeks thereafter and 
at the time of disease progression or study termination. 
 
1.4 Study Flow Chart 
Summary of study assessments is reported in Appendix 1 (schedule of Assessments) of the protocol. 
Study Period 
Screening Period 
Treatment Period* 
EoT 
Post-Treatment 
Follow-Up Period 
Day 
-28 to -1 
-14 to -1 
Cycle 1 
Day 1 
Cycle X 
Day 1 
Within 40 days (± 7 
days) after last dose 
of study treatment 
Follow-up every 
12 weeks 
(±14 days)19 
Informed Consent Form1 
X 
 
 
 
 
 
HER2 status2 
X 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
Physical examination  
 
X 
X 
X 
X 
 
ECOG performance status 
 
X 
X 
X 
X 
 
Weight and vital signs4 
 
X 
X 
X 
X 
 
Concomitant medication 
reporting5 
 
X 
X 
X 
X 
 
AE reporting6 
 
X 
X 
X 
X 
 
12-lead ECG7 
 
X 
X7 
X7 
X7 
 
ECHO or MUGA scan8 
X 
 
 
X8 
 
 
Troponin9 
 
X 
 
 
X 
 
Ophthalmologic 
assessments10 
X 
 
 
 
X 
 
pSO211 
 
X 
X 
X 
X 
 
Tumor assessments12 
X 
 
 
X12 
X12 
 
Tumor samples 
(for exploratory study)13 
X 
(if feasible) 
 
 
 
At the time of 
progression 
(if feasible) 
 
Blood samples (for 
exploratory study)14 
X 
 
 
X 
At the time of 
progression 
 
Hematology 
 
X 
X 
X 
X 
 
Chemistry15 
 
X 
X 
X 
X15 
 
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Study Period 
Screening Period 
Treatment Period* 
EoT 
Post-Treatment 
Follow-Up Period 
Day 
-28 to -1 
-14 to -1 
Cycle 1 
Day 1 
Cycle X 
Day 1 
Within 40 days (± 7 
days) after last dose 
of study treatment 
Follow-up every 
12 weeks 
(±14 days)19 
INR/PT and aPTT  
 
X 
X 
X 
X 
 
Urinalysis 
 
X 
 
 
 
 
Pregnancy test16 
 
X 
X 
X 
X16 
 
Viral serology17 
 
X 
 
 
 
 
Trastuzumab deruxtecan 
(DS-8201a) 
administration 
 
 
X 
X 
 
 
Review patient diary 
 
 
X 
X 
 
 
PRO assessments18 
 
X 
X 
X 
X 
X 
Survival status 
 
 
 
 
X 
X 
Post-study anticancer 
therapy 
 
 
 
 
X 
X 
AEs = Adverse events; aPTT = Activated partial thromboplastin time; ECG = Electrocardiogram; ECHO = Echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EoT = End of Treatment; HER2 = Human Epidermal Growth Factor Receptor 2; INR = International normalized 
ratio; MUGA = Multiple-Gated Acquisition; PRO QOL: Patient reported outcome-Quality of life; PT = Prothrombin time. 
* All visits must occur within ± 2 working days. Assessments scheduled for Days 1 each cycle must be performed within 48 hours prior to study 
treatment administration, respectively, unless otherwise indicated in the schedule of assessments, to confirm to the patient if treatment can be 
followed up. 
1. Informed Consent Form: Signed written Informed Consent Form obtained prior to any trial-specific procedure. 
2. HER2 status: Local confirmation of HER2-positive status. 
3. Medical history: Complete medical history and demographics (including age, gender, and ethnic origin). All medications taken in the last 
28 days prior to enrolment will be collected. 
4. Weight and vital signs: Weight, height (only at screening), respiratory rate, blood pressure measurements (systolic and diastolic), pulse 
rate, and body temperature (oral, axillary, or tympanic temperature). Vital signs should be measured before and after the end of the infusion 
on Day 1 of cycle 1 to 3 and only before infusion on Day 1 of subsequent cycles. 
5. Concomitant medication reporting: Relevant concomitant medication will be recorded at screening and on an ongoing basis. 
6. AE reporting: All AEs occurring during the trial and until 30 days after treatment discontinuation visit (EoT visit) have to be recorded with 
grading according to the NCI–CTCAE v.5.0 criteria. 
7. 12-lead ECG: ECGs (will be taken in triplicate, in close succession, while in a supine/semi-recumbent position) to be collected at screening 
(within 14 days before enrollment). Subsequent ECGs will be performed in triplicate in close succession if an abnormality is noted. ECGs will 
be taken at every 4th cycle. 
8. ECHO or MUGA scan: LVEF assessment will be performed at screening (within 28 days before enrollment), Cycle 5 Day 1, and on Day 1 of 
every four cycles (±7 days) thereafter (e.g., Cycles 9, 13, 17, etc.) while on treatment, and at the EoT visit. Note: the same test must be 
used for the subject throughout the study. 
9. Troponin: 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. Subjects may also have 
local troponin testing as clinically indicated during the treatment phase based on subject reported cardiac symptoms. If ECG is abnormal, 
follow institutional guidelines. If troponin levels are above the upper limit of normal and below the level of myocardial infarction as defined 
by the manufacturer (CTCAE Grade 1) at baseline, no repeat testing is required if the troponin level is not Grade 3. 
10. Ophthalmologic assessments: They will include visual acuity testing, slit lamp examination and fundoscopy will be performed at screening 
(within 28 days before enrollment), at EoT and if patient present sign or symptoms of ophthalmologic problems. 
11. pSO2: pulse oximetry will be performed on Day 1, of every cycle, and until the safety follow-up visit 40 days after last dose.  During Cycle 1, 
pulse oximetry will be assessed on Day 1 prior and after infusion of trastuzumab deruxtecan, on Day 8 and Day 15. On Day 1 pre-dose 
measurements will be taken thereafter. 
12. Tumor assessments: Baseline assessments of the chest, abdomen, and pelvis (preferably CT or MRI in case of contrast allergy) must be 
performed no more than 28 days before the first dose of study treatment. Post-baseline assessments will be performed every 6 weeks (± 3 
working days) from the first dose of study treatment for the first 6 months of treatment and every 9 weeks (± 5 working days) thereafter 
using the same imaging method and where possible obtained at the same institution for an individual patient as used during screening until 
progression disease or EoS. Bone scans will be only performed every 24 weeks (± 7 working days) for patients with bone lesions identified 
at baseline, unless clinically or biochemically suspected bone progression. If a bone scan was performed > 28 days but ≤ 60 days prior to 
start of study treatment, the bone scan does not need to be repeated. Brain imaging (MRI) during the trial should be performed every 6 
weeks [± 3 working days] from the first dose of study treatment for the first 6 months, and, thereafter, every 9 weeks [± 5 working days]) 
unless clinically suspected brain progression. Patients who discontinue treatment without evidence of disease progression will be followed 
every nine weeks (± 5 days) for tumor assessments until documented progression, elective withdrawal from the study, the start of new anti-
cancer treatment, or study completion or termination. Note: For patients included in the study cohort 5, axis MRI and spinal tap for CSF 
collection must also be performed, at baseline, every 3 weeks for 12 weeks (corresponding to the first 5 cycles of treatment), every 6 weeks 
thereafter, and at the time of treatment progression or study termination. 
13. Tumor samples (for exploratory study): A tissue sample should be provided at baseline (if feasible) from breast primary tumor or 
metastases amenable to biopsy (at sites of locoregional recurrence [skin, chest wall, breast or lymph nodes], or distant recurrence [bone, 
liver, lung or abdomen]) that will be obtained between progression to the prior regimen and inclusion in the study. Patients for whom tissue 
sample cannot be obtained (e.g., non-measurable disease, inaccessible tumor or subject safety concern) may submit an archived metastatic 
tumor specimen only upon agreement from the Sponsor. If feasible, an additional tissue sample should be collected at the end of treatment 
visit for patients who discontinue treatment due to disease progression. 
14. Blood samples (for exploratory study): Blood samples are required for all patients at the time of inclusion, after two cycles of study 
treatment, and upon progression or study termination. 
15. Hematology/chemistry: Cycle 1 Day 1 hematology and chemistry panel assessments are not required if the screening hematology and 
chemistry panel was performed at screening within 48 hours prior to start of study treatment. On cycle 1, hematology, chemistry and 
coagulation assessment must be repeated on day 8 and day 15. 
16. Pregnancy test: A serum pregnancy test at screening to confirm eligibility in the trial and within one week prior to start of study medication 
(with result available prior to dosing). This assessment does not need to be repeated at Cycle 1 Day 1 if it was performed at screening within 
48 hours prior to start of study treatment. Thereafter, repeat pregnancy tests (urine or serum test per institutional guideline) before infusion 
of each cycle and at end of treatment. A serum test should be performed to confirm any positive urine pregnancy test during the trial. 
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17. Viral serology: Human Immunodeficiency Virus, Hepatitis B surface Antigen (HBsAg), total Hepatitis B core Antibody (HBcAb), Hepatitis C 
Virus antibody; additional tests for Hepatitis B Virus DNA or Hepatitis C Virus RNA will be required within 28 days before enrollment to confirm 
eligibility. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 
18. PRO Assessments: The EORTC-QLQ-C30 and the EORTC-QLQ-BR23 questionnaires will be completed at baseline, Day 1 of cycles 2-4, then 
on Day 1 of every other subsequent cycle starting with cycle 6 (e.g., cycles 6, 8, 10, etc.), End of Treatment visit and during follow-up period 
until start of anticancer therapy. 
 
 
1.5 Sample Size 
A maximum of 39 patients with pretreated unresectable locally advanced or metastatic HER2-positive or 
HER2-low expressing patients will be recruited following the five study cohorts: 
Cohort 1: N = 8 
Cohort 2: N = 10 
Cohort 3: N = 7 
Cohort 4: N = 7 
Cohort 5: N = 7 
The sample size calculations were described in the protocol using the following wording: 
The primary endpoint for this study in the cohort of patients with stable BMs (cohort 1) is the PFS at 16 weeks. The 
primary endpoint for this study in the cohorts of patients with untreated or progression BMs (cohorts 2 to 4) is the 
best ORR-IC. The primary endpoint for this study, in the cohorts of patients with LMC (cohort 5) is the OS. 
The trial uses a two-stage optimal Simon’s design for the cohort 1, a one-stage A’Hern design for the cohorts 2 to 4, 
and a one-stage survival design for the cohort 5. The analysis in the cohort 1 will be one-sided, based on stochastic 
ordering of uniformly minimum variance unbiased estimator (UMVUE). The analyses in the cohorts 2 to 4 will be one-
sided, based on stochastic binomial exact test. The sample size for the LMC cohort was based on a one arm time-
to-event design. The analysis will be based on maximum likelihood exponential test. 
The local type I and II errors for all designs will be 0.05 and 0.2, respectively. 
• 
Cohort 1 
We hypothesized that excluding a rate of patients without PFS events ≤5% while targeting an improvement of 
patients without PFS events to ≥40% would be an optimal approach to evaluation of the study strategy. Non 
evaluable patients enrolled in the initial stage can be replaced. We will accrual 4 patients in the first stage. We will 
stop this cohort if all 4 patients progressed at 16 weeks. Otherwise, 4 additional patients will be accrued for a total 
of 8. At least 2 patients without progressive disease at 6 months among 8 patients enrolled will be adequate to justify 
the investigation of this strategy in further clinical trials. 
• 
Cohort 2 
We hypothesized that excluding an ORR-IC ≤5% while targeting an improvement of the ORR to ≥40% would be an 
optimal approach to evaluation of the study strategy. At least 3 patients with overall response among 10 patients 
will be adequate to justify the investigation of this strategy in further clinical trials. 
• 
Cohort 3 
We hypothesized that excluding an ORR-IC ≤5% while targeting an improvement of the ORR to ≥40% would be an 
optimal approach to evaluation of the study strategy. At least 2 patients with overall response among 7 patients will 
be adequate to justify the investigation of this strategy in further clinical trials. 
• 
Cohort 4 
We hypothesized that excluding an ORR-IC ≤5% while targeting an improvement of the ORR to ≥40% would be an 
optimal approach to evaluation of the study strategy. At least 2 patients with overall response among 7 patients will 
be adequate to justify the investigation of this strategy in further clinical trials. 
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• 
Cohort 5 
The one-sided maximum likelihood exponential test has an 80% power to detect a 4-month increase in median OS 
over a 2-months median OS. We scheduled an 18-month accrual period and 6-month of follow-up period. At least 3 
patients will be accrued in the first stage to evaluate the feasibility of this cohort. A total of 7 patients will be accrued 
in this cohort. 
Stopping boundary based on accrual: 
At the halfway point of the recruitment period, the steering committee will evaluate if the accrual objective for the 
first stage was achieved in every study cohorts (4, 5, 3, 3 and 3 patients for cohorts 1, 2, 3, 4 and 5, respectively). 
If this accrual objective has not achieved in a cohort, the Steering Committee will propose a corrective action plan 
or finalize the study in this cohort. 
2 
STUDY OBJECTIVES 
2.1 Cohort 1 
2.1.1 
Primary Objective 
• 
To assess efficacy –defined as 16 weeks PFS per Response Assessment in Neuro-Oncology Brain 
Metastases (RANO-BM) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of trastuzumab 
deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic HER2-
positive BC with non-progressing BM (after WBRT and/or SRS and or surgery). 
2.1.2 
Secondary Objectives 
• 
To assess efficacy –defined as PFS, ORR, CBR, time to response (TTR), duration of response (DOR), 
and best percentage of change in tumor burden per RANO-BM (for IC lesions) and RECIST 1.1 
(extracranial lesions and overall lesions)–after treatment with trastuzumab deruxtecan (DS-8201a) in 
this population. 
• 
To assess OS in this population. 
• 
To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) in this population by NCI-
CTCAE v.5.0. 
2.1.3 
Exploratory Objectives 
• 
To assess patient 
using the 
and its 
this population. 
• 
To evaluate predictive or prognostic biomarkers (plasma and/or tissue and/or CSF) associated with 
disease activity status or response to treatment in this population. 
• 
To identify possible mechanisms of resistance to study treatments through the comparative analysis 
of potential biomarkers from paired pre-treatment and post-progression tumor and/or blood and/or 
CSF samples from this population. 
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2.2 Cohorts 2, 3 and 4 
2.2.1 
Primary Objective 
• 
To assess efficacy -defined as intracranial overall response rate (ORR-IC) per RANO-BM of trastuzumab 
deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic BC: 
- 
Cohort 2: HER2-positive or HER2-low expressing with untreated BMs 
- 
Cohort 3: HER2-positive with progressing BMs after local treatment 
- 
Cohort 4: HER2-low expressing with progressing BMs after local treatment. 
2.2.2 
Secondary Objectives 
• 
To assess efficacy –defined as PFS, CBR, TTR, DOR, and best percentage of change in tumor burden 
per RANO-BM (for IC lesions) and RECIST 1.1 (for extracranial lesions and overall lesions); and ORR 
per RECIST 1.1 (for extracranial lesions and overall lesions). 
• 
Time to WBR and/or SRS (only for cohort 2), defined as the time from the treatment initiation to time 
of CNS disease progression that requires treatment with WBR and/or SRS, and determined locally by 
the investigator through the use of RANO-BM and RECIST 1.1 criteria. 
• 
To assess OS. 
• 
To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) by NCI-CTCAE v.5.0. 
2.2.3 
Exploratory Objectives 
• 
To assess 
using the 
and its 
in study cohorts 
2, 3, and 4. 
• 
To evaluate predictive or prognostic biomarkers (plasma and/or tissue and/or CSF) associated with 
disease activity status or response to treatment in study cohorts 2, 3, and 4. 
• 
To identify possible mechanisms of resistance to study treatments through the comparative analysis 
of potential biomarkers from paired pre-treatment and post-progression tumor and/or blood and/or 
CSF samples from patients of study cohorts 2, 3, and 4. 
2.3 Cohort 5 
2.3.1 
Primary Objective 
• 
To assess efficacy –defined as OS– of trastuzumab deruxtecan (DS-8201a) in patients with pretreated 
unresectable locally advanced or metastatic HER2-positive or HER2-low expressing BC with LMC. 
2.3.2 
Secondary Objectives 
• 
To assess efficacy -defined as PFS, ORR, CBR, TTR, DOR, and best percentage of change in tumor 
burden per RANO-BM (IC lesions) and RECIST 1.1 (extracranial lesions and overall lesions). 
• 
To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) by NCI-CTCAE v.5.0. 
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2.3.3 
Exploratory Objectives 
• 
To assess 
using the 
and i
, 
in this population. 
• 
To evaluate predictive or prognostic biomarkers (plasma and/or tissue and/or CSF) associated with 
disease activity status or response to treatment in this population. 
• 
To identify possible mechanisms of resistance to study treatments through the comparative analysis 
of potential biomarkers from paired pre-treatment and post-progression tumor and/or blood and/or 
CSF samples from this population. 
3 
DEFINITION OF ENDPOINTS 
3.1 Cohort 1 
3.1.1 
Primary Endpoint 
• 
16 weeks-PFS, defined as the period of time from treatment initiation to the first occurrence of disease 
progression or death from any cause, whichever occurs first. Progression will be determined locally by 
the investigator through the use of Response Assessment in Neuro- Oncology Brain Metastases (RANO-
BM) criteria (IC lesions) and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and 
extracranial) lesions. 
3.1.2 
Secondary Endpoints 
• 
PFS defined as the period of time from treatment initiation to the first occurrence of disease 
progression or death from any cause, whichever occurs first. Progression will be determined locally by 
the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both 
extracranial lesions and overall (IC and extracranial) lesions. 
• 
ORR, defined as a CR or PR, determined locally by the investigator through the use of RANO-BM criteria 
for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) 
lesions. 
• 
CBR, defined as an objective response (CR or PR), or stable disease (SD) for at least 24 weeks, 
determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST 
criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. 
• 
TTR, defined as the time from the treatment initiation to time of the first objective tumor response 
observed for patients who achieved a CR or PR, determined locally by the investigator through the use 
of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
• 
DOR, defined as the time from the first occurrence of a documented objective response to disease 
progression or death from any cause, whichever occurs first, determined locally by the investigator 
through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial 
lesions and overall (IC and extracranial) lesions. 
• 
OS, defined as the time from treatment initiation to death from any cause. Patients without 
documented death at the time of the final analysis will be censored at the date of the last follow-up. 
• 
Maximum Tumor Shrinkage, best percentage of change from baseline in the size of tumors, defined 
as the biggest decrease, or smallest increase if no decrease will be observed and determined locally 
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by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
3.1.3 
Safety Endpoints 
• 
Patient safety and AEs will be evaluated using the NCI-CTCAE v.5.0.  
All AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of 
the treatment. 
3.1.4 
Exploratory Endpoints 
• 
Overall change from baseline in 
, 
and 
; Time to 
in 
; Time to 
in 
; Time to 
. 
• 
Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical 
characteristics (e.g., baseline features) and outcome (e.g., duration of 
). 
3.2 Cohorts 2, 3 and 4 
3.2.1 
Primary Endpoint 
• 
ORR-IC, defined as a complete response (CR) or partial response (PR), and determined locally by the 
investigator through the use of RANO-BM criteria. 
3.2.2 
Secondary Endpoints 
• 
PFS, defined as the period of time from treatment initiation to the first occurrence of disease 
progression or death from any cause, whichever occurs first. Progression will be determined locally 
per RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
• 
ORR, defined as a CR or PR, determined locally by the investigator through the use of RECIST criteria 
v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. 
• 
CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, and determined locally 
by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for 
both extracranial lesions and overall (IC and extracranial) lesions. 
• 
TTR, defined as the time from the treatment initiation to time of the first objective tumor response 
(tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, determined locally by 
the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both 
extracranial lesions and overall (IC and extracranial) lesions. 
• 
DOR, defined as the time from the first occurrence of a documented objective response to disease 
progression or death from any cause, whichever occurs first, determined locally by the investigator 
though the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1. for both extracranial 
lesions and overall (IC and extracranial) lesions. 
• 
OS, defined as the time from treatment initiation to death from any cause. Patients without 
documented death at the time of the final analysis will be censored at the date of the last follow-up. 
• 
Maximum Tumor Shrinkage, best percentage of change from baseline in the size of tumor lesions, 
defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined 
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locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 
for both extracranial lesions and overall (IC and extracranial) lesions. 
• 
Only cohort 2: Time to WBRT and/or SRS, defined as the time from treatment initiation to CNS disease 
progression that requires treatment with WBRT and/or SRS, according RANO-BM and RECIST 1.1 
criteria. 
3.2.3 
Safety Endpoints 
• 
Patient safety and AEs will be evaluated using the NCI-CTCAE v.5.0.  
All AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of 
the treatment. 
3.2.4 
Exploratory Endpoints 
• 
Overall change from baseline in 
, 
and 
; Time to 
in 
; Time to 
in 
; Time to 
. 
• 
Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical 
characteristics (e.g., baseline features) and outcome (e.g., duration of 
). 
3.3 Cohort 5 
3.3.1 
Primary Endpoint 
• 
OS, defined as the time from treatment initiation to death from any cause. 
Patients without documented death at the time of the final analysis will be censored at the date of the 
last follow-up. 
3.3.2 
Secondary Endpoints 
• 
ORR, defined as a CR or PR, determined locally by the investigator through the use of RANO-BM criteria 
for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) 
lesions. 
• 
CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, determined locally by 
the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both 
extracranial lesions and overall (IC and extracranial) lesions. 
• 
PFS, defined as the period of time from treatment initiation to the first occurrence of disease 
progression or death from any cause, whichever occurs first during at least first 12 months. Progression 
will be determined locally by the investigator through the use of RANO-BM criteria for IC lesions and 
RECIST criteria v.1.1 for both extracranial lesions and overall (ICand extracranial) lesions. 
• 
TTR, defined as the time from the treatment initiation to time of the first objective tumor response 
observed for patients who achieved a CR or PR, determined locally by the investigator through the use 
of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall 
(IC and extracranial) lesions. 
• 
DOR, defined as the time from the first occurrence of a documented objective response to disease 
progression or death from any cause, whichever occurs first, determined locally by the investigator 
through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial 
lesions and overall (IC and extracranial) lesions. 
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• 
Maximum Tumor Shrinkage, best percentage of change from baseline in the size of tumor lesions, 
defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined 
locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 
for both extracranial lesions and overall (IC and extracranial) lesions. 
 
3.3.3 
Safety Endpoints 
• 
Patient safety and AEs will be evaluated using the NCI-CTCAE v.5.0.  
All AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of 
the treatment. 
3.3.4 
Exploratory Endpoints 
• 
Overall change from 
, 
and 
; Time to 
in 
L; Time to 
in 
; Time to 
. 
• 
Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical 
characteristics (e.g., baseline features) and outcome (e.g., duration of 
). 
4 
ANALYSIS SETS 
The following sets will be analyzed: 
• 
Screening: Patients who were present at the screening visit. 
• 
Safety and FAS (Full Analysis Set) Set: The safety/FAS set includes patients who received at least 
one dose of study treatment. 
Efficacy and Safety endpoints will be analyzed on the Safety/FAS set. 
• 
Exploratory Analysis Set: Exploratory analyses will be performed on those patients in the safety 
set who consented to participate in the exploratory research program and were evaluable for 
exploratory endpoints. 
Exploratory analysis will be performed on exploratory evaluable set. 
5 
STATISTICAL METHODS 
5.1 General Methodology 
Definition of baseline: For each safety or efficacy parameter, the last valid assessment made before first 
study drug administration will be used as the baseline for all analyses of that safety or efficacy parameter 
unless otherwise specified. 
Continuous data will be summarized in terms of the number of observations, mean, standard deviation 
(SD), median, minimum, maximum, and first and third quartiles, unless otherwise stated. Where data are 
collected over time, both the observed data and change from baseline will be summarized at each time 
point. 
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean, median, and first and third quartiles will be reported to one more 
decimal place than the raw data recorded in the database. The SD will be reported to two more decimal 
places than the raw data recorded in the database. In general, the maximum number of decimal places 
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reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the relevant 
time point (n), frequency counts and percentages. Changes from baseline in categorical data will be 
summarized using shift tables where appropriate. 
Percentages will be presented to one decimal place. A percentage of 100% will be reported as 100%. 
Percentages will not be presented for zero counts. Unless otherwise stated, percentages will be calculated 
using n as the denominator, for frequency tables not assessed by time point the set will be used as 
denominator. If sample sizes are small, the data displays will show the percentages, but any textual report 
(e.g., clinical study report) will describe frequencies only. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places. However, 
if a p-value is only presented to four decimal places (by SAS) it will not be rounded again but will be 
presented to four decimal places. P-values less than 0.0001 will be presented as “<0.0001”. 
Confidence intervals will be presented to one more decimal place than the raw data. A two-sided 
significance level of 5% will be used for confidence intervals. 
For binary endpoints, the 95% confidence intervals (CIs) will be constructed based on an exact binary 
distribution. 
For time to event endpoints the Kaplan-Meier method will be applied. Number and proportion of events, 
median survival time and survival rates, with corresponding 95%Cl will be calculated. 
All scores and change from baseline will be summarized in terms of the number of observations, mean, 
standard deviation, 95%CI of mean, median, range and interquartile range. We will examine the residuals 
to assess model assumptions. 
All report outputs will be produced using SAS® version 9.4 version in a secure and validated environment. 
All report outputs will be provided to the Sponsor in a single Microsoft Word document. 
5.2 Subject Disposition 
Descriptive statistics will be provided for the following: 
• 
Overall number of subjects in the screening set, the number of patients eligible to participate in the 
study, and number of screen failures. 
• 
Number and percent of subjects in each of the analysis sets.  
• 
Number and percent of subjects excluded from each of the analysis sets along with reason for 
exclusion. 
• 
Listing of subjects excluded from each of the analysis sets along with reason for exclusion. 
• 
Study termination: 
- 
Number and percent of subjects who completed the study. 
- 
Frequency of premature termination reasons. 
- 
Listing of all dropouts along with reason for termination, dose level and time of termination. 
• 
Follow-up time (months), defined as the time from start dose until the last available follow-up date. 
• 
Follow-up Dates: 
- 
Database cut-off date. 
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- 
Start date of treatment dose of the first patient. 
- 
Start date of treatment dose of the last patient. 
- 
End date of treatment dose of the last patient. 
- 
End date of follow-up of the last patient. 
No statistical tests are planned for these data. 
5.3 Baseline Characteristics 
Baseline characteristics will be provided by arm and overall, for the Safety/FAS set. 
Descriptive statistics, including number of subjects, mean, standard deviation (SD), median and range for 
continuous variables and frequency and percent for categorical variables will be provided. 
Baseline Characteristics: 
o Demographic characteristics 
o Oncological history 
o Medical history 
o History of Breast Cancer 
o Previous early disease treatment 
o Previous advanced/metastatic disease treatment 
o HER2 and HR status 
o Physical examination 
o ECOG 
o Vital Signs 
o 12-lead electrocardiogram 
o LVEF Evaluation 
o Tumor assessment 
o Prior concomitant medication 
No statistical tests are planned for these data. 
A by-subject listing of all demographic and other baseline characteristics will be provided. 
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5.4 Response Evaluation Criteria 
Lesions will be classified as target and non-target at baseline, in accordance with RANO-BM criteria (for 
CNS lesions) and RECIST v.1.1 criteria (in case of non-CNS lesions). 
5.4.1 
RANO-BM Criteria 
Overall response evaluation according to RANO-BM Criteria (Lin et al. 2015) will be obtained from CNS 
target lesion response, CNS non-target lesion response, CNS new lesions, corticosteroids, clinical status 
as follows: 
 
CNS Target lesions: 
- 
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. 
- 
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. 
- 
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. 
- 
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. 
CNS Non-target lesions: 
- 
CR: Requires all the following: disappearance of all enhancing CNS non-target lesions, no new CNS 
lesions. 
- 
Non-CR or non-PD: Persistence of one or more non-target CNS lesion or lesions. 
- 
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 
tumor-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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5.4.2 
RECIST v.1.1 Criteria 
Overall response according RECIST v1.1 will be obtained from target lesion response, non-target lesion 
response and new lesions, as follows: 
Target Lesions 
Non-target Lesions 
New Lesions Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
5.5 Response Efficacy Definitions 
- 
Best Overall Response, defined as the best overall response recorded from the start of the study 
treatment until 35 days after last dose administration date and confirmation of response is not 
required. 
o When CR or PR is the best response across all time points, then best overall response will be 
CR or PR respectively.  
o When SD is the best response for ≥ 24 weeks the best overall response will be SD ≥ 24 w.  
o When SD is the best response for < 24 weeks the best overall response will be SD < 24 w. 
o When non-target disease only and Non-CR/Non-PD is the best response for ≥ 24 weeks the 
best overall response will be SD ≥ 24 w.  
o When non-target disease only and Non-CR/Non-PD is the best response for < 24 weeks the 
best overall response will be SD < 24 w.  
o When PD is the best response across all time points, best overall response will be PD. 
o When there is no evaluable tumor assessments best overall response will be NE. 
- 
PFS is defined as the time from start dose until death by any cause or objective tumor progression or 
clinical disease progression. Patients with no progression or death will be censored at the date of their 
last evaluable imaging previous 35 days after last dose administration date. Censoring rules are 
specified below: 
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Situation 
Date of progression or censoring 
Outcome 
Progression documented 
between scheduled visits  
Earliest of: 
• Date of assessment by investigator (if progression is 
based on clinical criteria); 
or 
• Date of assessment showing new lesion (if progression 
is based on new lesion); 
or 
• Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions). 
Progressed  
Death before first progression 
disease (PD) assessment 
Date of death. 
Progressed  
Death between adequate 
assessment visits  
Date of death. 
Progressed  
No progression 
Date of last radiological assessment of measured 
lesions. 
Censored 
Treatment discontinuation for 
undocumented progression  
Date of last radiological assessment of measured 
lesions. 
Censored 
Treatment discontinuation for 
toxicity or other reason 
Date of last radiological assessment of measured 
lesions. 
Censored 
Death or progression after 
more than one missed visit 
Date of last radiological assessment of measured 
lesions. 
Censored 
 
5.5.1 
Primary Efficacy Endpoint Definitions 
The primary endpoint for this study, in the cohort of patients with stable BMs (cohort 1) is the PFS at 16 
weeks. PFS is defined as the number of patients without PD or death at 16 weeks (non- PFS event) divided 
by the number of patients in the analysis set. Progression will be assessed based on local Investigator’s 
assessment according RANO-BM criteria (for IC lesions) and RECIST criteria v.1.1 for both extracranial 
lesions and overall (IC and extracranial) lesions. We will consider a patient as PFS event if accomplish any 
of both criteria for progression or die from any cause in absence of documented progressive disease. 
The primary endpoint for this study, in the cohorts of patients with untreated or progression BMs (cohorts 
2 to 4) is the best ORR-IC. The ORR-IC is defined as the number of patients with CR or PR divided by the 
number of patients in the analysis set. Best overall response will be assessed based on local Investigator’s 
assessment according RANO-BM criteria. We will consider a patient as responder if accomplish the criteria 
at the same tumor evaluation. Patients without tumor response evaluation will be considered as no 
responder. 
The primary endpoint for this study, in the cohorts of patients with LMC (cohort 5) is the OS. OS is defined 
as the time from treatment initiation to death from any cause. Patients without documented death at the 
time of the final analysis will be censored at the date of the last follow-up. 
5.5.2 
Secondary Efficacy Endpoints Definitions 
The secondary efficacy variables are PFS, ORR, DOR, TTR, OS and Maximum Tumor reduction: 
- 
ORR in cohort 1 to 4, as defined in secondary endpoint section. 
- 
OS in cohorts 1 to 4, as defined in secondary endpoint section. 
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- 
PFS in cohorts 2 to 4, as defined in secondary endpoint section. 
- 
PFS in cohorts 2 to 4, defined as time to event outcome. PFS is defined as the period of time from 
treatment initiation to the first occurrence of disease progression or death from any cause, whichever 
occurs first. Progression will be determined locally per RANO-BM criteria for IC lesions and RECIST 
criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. We will consider a 
patient as PFS event if accomplish any of both criteria for progression or die from any cause in absence 
of documented progressive disease. 
- 
CBR in cohorts 1 to 4, CBR is defined as an objective response (CR or PR), or SD for at least 24 weeks, 
and determined locally by the investigator through the use of RANO-BM criteria for IC lesions and 
RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. 
- 
TTR in Study cohort 1. TTR, defined as the time from the treatment initiation to time of the first 
objective tumor response observed for patients who achieved a CR or PR, determined locally by the 
investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both 
extracranial lesions and overall (IC and extracranial) lesions. 
- 
TTR in study cohorts 2 to 4. TTR defined as the time from the treatment initiation to time of the first 
objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or 
PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and 
RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions. 
- 
DOR in study cohorts 1 to 4, DOR is defined as the time from the first occurrence of a documented 
objective response to disease progression or death from any cause, whichever occurs first, as 
determined locally by the Investigator through the use of RANO-BM criteria for IC lesiosn and RECIST 
v.1.1 criteria, for both extracranial lesions and overall (IC and extracranial) lesions. In case of the 
patient first reaching PR and later CR, the duration of CR will be measured and reported separately, 
starting from the date when first documented, and ending when a progressive disease is diagnosed, 
or the patient dies. 
- 
Best percentage of change from baseline in the size of tumor lesions, defined as the biggest decrease, 
or smallest increase if no decrease will be observed, and determined locally by the investigator through 
the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and 
overall (IC and extracranial) lesions. 
- 
Maximum tumor reduction in study cohorts 1 to 4. Maximum tumor reduction is defined as the biggest 
decrease, or smallest increase if no decrease will be observed, as determined locally by the Investigator 
through the use of RANO-BM criteria. 
5.6 Efficacy Analysis 
5.6.1 
Primary Efficacy Analysis 
All primary efficacy analyses will be analyzed at feasibility interim (see section 5.8.2) and final analysis.  
PFS at week 16 in cohort 1 will be calculated with UMVUE method (1). The p-value and 95% confidence 
will be calculated based on Koyama and Chen, 2017 (2). We will use the functions published on the R 
library “OneArmPhaseTwoStudy” November 13, 2017 (3). The R codes of these functions are described in 
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appendix 7.1.1 Additionally, the 95% exact (Pearson-Clopper) confidence intervals and p-value under 
exact binomial test will be reported. 
In cohorts 2, 3, and 4 the ORR-IC with its 95% exact (Pearson-Clopper) confidence intervals and p-value 
under exact binomial test will be reported. At final analysis it will be declared positive if the null hypothesis 
(H0: ORR-IC ≤5%) is beyond the lower boundary of the confidence interval. The one-sided p-value will 
be obtained based on exact binomial test at a nominal alpha level of 0.025. The SAS code is described in 
appendix 7.1.2. 
For overall survival (OS) in cohort 5 the p-value will be obtained from one-sided maximum likelihood 
exponential test. The R code function is described in appendix 7.1.3 Additionally, the number and 
proportion of events, median survival time and survival rates, with corresponding 95% CI, by Kaplan-
Meier method will be reported. 
5.6.2 
Decision Rules and Adjustment of Alpha for Primary Endpoint 
The study would be defined as positive at final analysis in the study cohort 1 if the rate of patients without 
PFS events in the trastuzumab deruxtecan (DS-8201a) arm is statistically significantly greater (p<0.05) 
than expected under the null hypothesis (H0: % of pts without PFS events ≤ 5%). The analysis will be 
one-sided, based on stochastic ordering of UMVUE. 
The UMVUE for the response rate, the p-value and the 95% confidence intervals will be calculated using 
the functions published on R library “OneArmPhaseTwoStudy” November 13, 2017 (3). The R codes of 
these functions are described in appendix section 7.1. 
The study would be defined as positive at final analysis in the study cohorts 2, 3 and 4, if the ORR-IC 
in the trastuzumab deruxtecan (DS-8201a) arm is statistically significantly greater (p<0.05) than expected 
under the null hypothesis (H0: ORR-I-IC ≤ 5%). The analysis will be one-sided, based on binomial exact 
test. 
The study would be defined as positive at final analysis in the study cohort 5, if the median overall 
survival in the DS-8310a arm is statistically significantly greater (p<0.05) than expected under the null 
hypothesis (H0: median OS ≤ 2 months). The analysis will be based on the one-sided maximum likelihood 
exponential test. 
5.6.3 
Secondary Efficacy Analysis 
Secondary efficacy analyses will be reported in the FAS set and separately by each cohort.  
For binary endpoints, the number and proportion of patients with response with the 95% Pearson-Clopper 
CI will be calculated. 
For time to event endpoints the Kaplan-Meier method will be applied. Number and proportion of events, 
median survival time and survival rates, with corresponding 95%Cl, will be calculated. 
Maximum tumor shrinkage will be described with the median, range, mean, standard deviation, and 
interquartile range. Waterfall plots describing the percentage of change in target tumor lesions will be 
provided. 
For all tests, we will use two-sided p-values with alpha ≤ 0.05 level of significance. P-values emerging 
from these analyses will not be interpreted in a confirmative sense; they will be considered of descriptive 
nature only. 
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5.6.4 
Handling of Missing Efficacy Data 
Study variables could be missing for patients who withdrawn from the trial or for specific visits. We will 
report reasons for withdrawal.  
Patient with missing in response outcomes (ORR and CBR or without PFS events at 6 months) will be 
considered as no responders, or last observation will be carried forward (maximum tumor reduction). 
Patients without any post-baseline assessment will be considered as non-responders or without clinical 
benefit. 
For the analysis of maximum tumor shrinkage only observed cases will be used. 
The analysis of timed endpoints is based on a Kaplan-Meier method (PFS, ORR, CBR, TTR, DOR, and OS), 
therefore, not affected by patient withdrawals (as they are censored) provided that dropping out is 
unrelated to prognosis. 
For PFS, TTR and DOR, patients without a date of disease progression or death will be analyzed as 
censored observations on the date of last tumor assessment. If no post-baseline tumor assessment is 
available, patients will be censored at the date of treatment initiation + 1 day. Data for patients with an 
event who missed two or more scheduled assessments immediately prior to the event will be censored at 
the last tumor assessment prior to the missed visits. 
For OS, patients who are not reported as having died will be analyzed as censored observations on the 
date they were last known to be alive. If no post-baseline data are available, OS will be censored at the 
date of treatment initiation + 1 day.  
The other variables will be managed with simple imputations methods (last observation carried forward). 
The effect that any missing data might have on results will be assessed via sensitivity analysis. 
 
 
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5.6.5 
Estimands 
Estimands for the study are defined in the table 1: 
Table 1. Estimands 
Estimand 
Population 
Variable 
Intercurrent event strategy 
Summary measure 
Primary 
Cohort 1 
Full Analysis 
Set 
PFS at 
week 16 
- Patient with no progression or death 
at week 16 will considered as non-PFS 
at week 16. 
- Patients without any post-baseline 
assessment will be considered as non-
PFS. 
The 95% CI and p-value by 
UMVUE method. 
Sensitivity 
to Primary 
Cohort 1 
Full Analysis 
Set 
PFS at 
week 16 
- Patient with no progression or death 
at week 16 will considered as non-PFS 
at week 16. 
- Patients without any post-baseline 
assessment will be considered as non-
PFS. 
The 95% Pearson-Clopper CI 
and p-value under exact 
binomial test. 
Primary 
Cohort 
2,3,4 
Full Analysis 
Set 
ORR 
- Patient with missing ORR outcomes 
will be considered as no responders. 
- Patients without any post-baseline 
assessment will be considered as non-
responders. 
The 95% Pearson-Clopper CI 
and p-value under exact 
binomial test. 
Primary 
Cohort 5 
Full Analysis 
Set 
OS 
- Patients who are not reported as 
having died will be analyzed as 
censored observations on the date 
they were last known to be alive. 
- If no post-baseline tumor assessment 
is available, patients will be censored 
at the date of treatment initiation + 1 
day. 
Kaplan-Meier plot, number 
and proportion of events, 
median survival time, 1- and 
2-year survival rates with 
corresponding 95% Cl 
Secondary 
1 
Full Analysis 
Set 
by cohorts 2 
to 5 
PFS 
- Patients with no progression or death 
will be censored at the date of their 
last evaluable imaging previous 35 
days after last dose administration 
date. 
- If no post-baseline tumor assessment 
is available, patients will be censored 
at the date of treatment initiation + 1 
day. 
- Data for patients with an event who 
missed two or more scheduled 
assessments immediately prior to the 
event will be censored at the last 
tumor assessment prior to the missed 
visits. 
Kaplan-Meier plot, number 
and proportion of events, 
median survival time with 
corresponding 95% Cl. 
Secondary 
2 
Full Analysis 
Set 
by cohorts 
PFS at 
week 16 
- Patients with no progression or death 
will be censored at the date of their 
last evaluable imaging previous 35 
days after last dose administration 
date. 
- PFS time irrespective of start of new 
therapies will be considered. 
- If no post-baseline tumor assessment 
is available, patients will be censored 
at the date of treatment initiation + 1 
day. 
- Data for patients with an event who 
missed two or more scheduled 
assessments immediately prior to the 
event will be censored at the last 
tumor assessment prior to the missed 
visits. 
Kaplan-Meier plot, week 16 
survival rates with 
corresponding 95% Cl. 
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 February 15, 2024                                                        28                                                                      Final 
Estimand 
Population 
Variable 
Intercurrent event strategy 
Summary measure 
Secondary 
3 
Full Analysis 
Set 
by cohorts 
PFS at 
week 24 
- Patients with no progression or death 
will be censored at the date of their 
last evaluable imaging previous 35 
days after last dose administration 
date. 
- PFS time irrespective of start of new 
therapies will be considered. 
- If no post-baseline tumor assessment 
is available, patients will be censored 
at the date of treatment initiation + 1 
day. 
- Data for patients with an event who 
missed two or more scheduled 
assessments immediately prior to the 
event will be censored at the last 
tumor assessment prior to the missed 
visits. 
Kaplan-Meier plot, week 24 
survival rates with 
corresponding 95% Cl. 
Secondary 
4 
Full Analysis 
Set 
by cohorts 
ORR 
- Patient with missing ORR outcomes 
will considered as no responders. 
- Patients without any post-baseline 
assessment will be considered as non-
responders. 
The 95% Pearson-Clopper CI 
and p-value under exact 
binomial test. 
Secondary 
5 
Full Analysis 
Set 
by cohorts 
CBR 
- Patient with missing CBR outcomes 
will consider as non-clinical benefit. 
- Patients without any post-baseline 
assessment will be considered as non-
clinical benefit. 
The 95% Pearson-Clopper CI 
and p-value under exact 
binomial test. 
Secondary 
6 
Full Analysis 
Set 
by cohorts 
OS 
- Patients who are not reported as 
having died will be analyzed as 
censored observations on the date 
they were last known to be alive. 
- If no post-baseline tumor assessment 
is available, patients will be censored 
at the date of treatment initiation + 1 
day. 
Kaplan-Meier plot, number 
and proportion of events, 
median survival time, 1- and 
2-year survival rates with 
corresponding 95% Cl 
Secondary 
7 
Full Analysis 
Set 
by cohorts 
DOR 
- Patients with no progression or death 
will be censored at the date of their 
last evaluable imaging previous 35 
days after last dose administration 
date. 
- If no post-response tumor 
assessment is available, patients will 
be censored at the date of treatment 
response + 1 day. 
- Data for patients with an event who 
missed two or more scheduled 
assessments immediately prior to the 
event will be censored at the last 
tumor assessment prior to the missed 
visits. 
Kaplan-Meier plot, number 
and proportion of events, 
median survival time, 1- and 
2-year survival rates with 
corresponding 95% Cl 
Secondary 
8 
Full Analysis 
Set 
by cohorts 
TTR 
- Patients with no response will be 
censored at the date of their last 
evaluable imaging previous 35 days 
after last dose administration date. 
Kaplan-Meier plot, number 
and proportion of events, 
median survival time, 1- and 
2-year survival rates with 
corresponding 95% Cl 
Secondary 
9 
Full Analysis 
Set 
by cohorts 
Maximum 
Tumor 
Shrinkage 
Only observed cases will be used 
Median, range, mean, 
standard deviation, and 
interquartile range. 
Waterfall plots describing the 
percentage of change in 
target tumor lesions 
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 February 15, 2024                                                        29                                                                      Final 
Estimand 
Population 
Variable 
Intercurrent event strategy 
Summary measure 
Secondary 
10 
Cohort 2 
Full Analysis 
Set 
Only Cohort 
2 
Time to 
WBRT/SR
S 
- Patients with no progression 
(according RANO-BM criteria) will be 
censored at the date of their last 
evaluable imaging previous 35 days 
after last dose administration date. 
- Patients with no WBRT and/or SRS 
treatment will be censored at the date 
of their last evaluable imaging previous 
35 days after last dose administration 
date. 
- If no post-baseline tumor assessment 
is available, patients will be censored 
at the date of treatment initiation + 1 
day. 
- Data for patients with an event who 
missed two or more scheduled 
assessments immediately prior to the 
event will be censored at the last 
tumor assessment prior to the missed 
visits. 
Kaplan-Meier plot, number 
and proportion of events, 
median survival time, 1- and 
2-year survival rates with 
corresponding 95% Cl 
 
5.6.6 
Exploratory Analysis 
These statistical analyses will be exploratory. Therefore, no pre-specified analyses are detailed in the SAP. 
Exploratory analyses will be performed on the exploratory analysis set. 
Changes in biomarkers will be evaluated on a 
level regarding their association with treatment. 
Baseline and post-treatment values of quantitative biomarkers will be described with 
, 
, 
and 
in 
(
, 
…). Baseline and 
post-treatment values of categorical biomarkers (
, 
, and 
…) will be described with frequency and percentage. 
Change from baseline between values of quantitative biomarkers will be analyzed with 
and 
differences. The corresponding 95% confidence intervals, applicable test statistics and p-values will be 
presented. P-values and 95%CI for 
differences will be based on paired 
. P-values for ranks 
will be based on 
. The 95%CI for 
difference will be based on 
. Change from baseline between percentage of categorical biomarkers will be analyzed 
with 
t. 
Markers will be evaluated on a 
level regarding their change over potential for prediction of the 
clinical endpoints (
. Biomarker and response correlations with clinical covariates will be 
investigated. It will be checked whether covariates can improve the prediction and whether there is an 
interaction with the biomarkers. Further 
techniques (e.g., 
) will be evaluated to study combinations of markers. 
Techniques to control false discovery rate and overfitting (cross-validation) will be also considered. 
Analysis will be performed on exploratory analysis set. 
5.7 Safety Analysis 
All safety tables will list or summarize subjects by cohort on the entire Safety set. These safety assessments 
will be subjected to clinical review and summarized by appropriate descriptive statistics. 
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5.7.1 
Duration and Extent of Exposure 
Duration and extent of exposure will be based on the safety set. 
The following parameters will be calculated: 
• 
b: “Actual Cycle Duration” is the treatment duration for a cycle per CRF. It is the length of time (days) 
between actual and next cycle start date dose. At the last cycle is the difference between start and 
stop date dose.  
• 
c: “Actual Cycle Dose Days” is the number of days with dose administration in the cycle, considering 
the interruptions. 
• 
d: “Actual Total Dose per Cycle” is the total dose a patient took in a cycle, considering interruptions 
and reductions. 
• 
e: “Intended Daily Dose per Cycle” is equal to 60 mg/m2 every 2 weeks. 
• 
f: “Intended Cycle Duration” is equal to 14 days +/- 2 days.  
 
• 
g: “Intended Cycle Dose Days” is equal to 1 day for all cycles. 
• 
A: “Total number of cycles”. 
• 
B: “Treatment Duration” = Sum over all cycles of (b). 
• 
C: “Days on drug” = Sum over all cycles of (c). 
• 
D: “Total Actual Total Dose” = Sum over all cycles of (d). 
• 
E: “Mean Intended Daily Dose” = Mean over all cycles of (e). 
• 
F: “Total Intended Duration” = Sum over all cycles of (f). 
• 
G: “Total Intended Dose Days” = Sum over all cycles of (g). 
• 
H: “Intended Total Dose” = G*E  
• 
I: “Actual Average Daily Dose on Dose Days” = D/C 
• 
J: “Ratio for Dose Interruption” = C/G 
• 
K: “Ratio for Cycle Duration” = F/B 
• 
L: “Actual Average Daily Dose Intensity” = I*J*K 
• 
M: “Relative Dose Intensity (RDI)” = L/E*100 
The treatment duration (days), number of cycles, and Treatment compliance (%) will be summarized in 
terms of the number of observations, mean, standard deviation (SD), median, minimum and maximum, 
to each cohort. 
Extent of exposure measured as RDI will be described with median, interquartile range (IQR) and range. 
The RDI will be dichotomized in different cutoffs (≥50%, ≥70%, ≥80%, ≥90%, ≥100%) and described 
with frequencies and percentages.  
5.7.2 
Concomitant Medications 
The number and percent of unique patients taking concomitant medications will be summarized by 
therapeutic classification, coded term and dose level. Elective surgeries/procedures performed during the 
study will be presented in a listing. 
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The following are conventions that will be used to classify individual medications as prior and/or 
concomitant: 
- 
Medications with stop dates prior to start dose will be considered prior. 
- 
Medications with missing stop dates or stop dates the day of or after start dose will be considered 
concomitant, regardless of start date. Additionally, if the start date is prior to start dose or missing, 
the medication will also be considered prior. 
Frequencies and by-subject listing of all prior and concomitant medications will be provided, containing 
variables listed on Prior/Concomitant Assessment eCRF, their corresponding categories (Prior or 
Concomitant), and WHO Anatomical Therapeutic Chemical (ATC) level 2 and preferred term if applicable. 
5.7.3 
Dose Delays, Reductions and Discontinuations 
The following summaries will be provided by cohort: 
o Subjects with at least one dose delay. 
o Subjects with at least one dose delay due to adverse event. 
o Subjects with at least one dose reduction. 
o Subjects with at least one dose reduction due to adverse event. 
o Subjects with permanently dose discontinuation. 
o Subjects with permanently dose discontinuation due to adverse event. 
5.7.4 
Adverse Events 
All AEs will be recorded on the eCRF “Adverse Events” page and will be coded using the current version 
of MedDRA® to give a system organ class (SOC) and preferred term (PT) for each event. All adverse 
event safety data will be updated to the version of MedDRA that is current at the time of the database 
lock and statistical analyses. Adverse events will be coded with grades defined according to CTCAE V5.0 
criteria. 
Treatment-emergent AEs (i.e., those events occur after the first study medication administration and were 
not present at baseline or worsened in severity following the start of treatment) will be tabulated. The 
TEAE will be tabulated according to intensity and causality. If intensity of an AE or causality of an AE to 
the study medication is missing, a worst-case scenario will prevail (severe in intensity or probably related 
will be assumed). In the summary tables the number of subjects with events and the number of events 
will be presented. 
The onset date of an AE will be compared to the date of first dose of study drug to determine whether 
the AE is treatment emergent. Adverse events with an onset date on or after the date of first dose of 
study drug will be classified as treatment emergent. 
All deaths and SAEs, regardless of cause, from treatment start until 28 days after final dose of treatment. 
Non-fatal AEs occurring after treatment start regardless of cause, up until 28 days after final dose of 
treatment or until start of new anti-cancer treatment, whichever is first. Disease progression is not 
considered a treatment emergent adverse event unless the patient dies of disease prior to 28 days after 
discontinuation of treatment. Events that are continuations of baseline abnormalities are considered 
treatment emergent adverse events only if there is an increase in grade over baseline, or if there is an 
increase following a decrease during the study. 
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Treatment emergent adverse events with cause possibly, probably, or definitely related to treatment as 
judged by the investigator. Events that are continuation of baseline abnormalities are not considered 
treatment related unless there is an increase in grade, or if there is an increase following a decrease, and 
the increase is judged by the investigator to be due to treatment. 
Descriptive statistics will be used to characterize the profiles of treatment-related AEs, treatment-related 
deaths, SAEs, treatment-related delays, dose reductions, and/or treatment discontinuations. All AEs will 
be graded according to the current version of the NCI-CTCAE v.5.0 and the Medical Dictionary for 
Regulatory Activities (MedDRA). 
AEs will be graded according to the NCI-CTCAE v.5.0. Additionally, treatment compliance, in particular 
dose reduction requirements, skipped doses and/or cycle delays due to AEs, will be described. 
The following summaries will be provided: 
- 
Summary of Adverse Events 
o Subjects with at least one Adverse Event (AE) 
o Subjects with at least one Treatment Emergent AE (TEAE) 
o Subjects with at least one related study drug TEAE 
o Subjects with at least one grade 3 or 4 or 5 TEAE 
o Subjects with at least one related grade 3 or 4 or 5 TEAE 
o Subjects with at least one serious TEAE 
o Subjects with at least one related serious TEAE 
o Subjects with at least one non-serious TEAE 
o Subjects with at least one Adverse Event of Special Interest (AESI) 
o Deaths due to TEAE 
o Subjects with TEAE leading to Discontinuation of Study Treatment 
o Subjects dropped out due to AE 
- 
Summary by SOC and PT of the number and percentage of subjects reporting each: 
o Treatment Emergent Adverse Events 
o Treatment Emergent Adverse Events by Treatment and Haematologic 
o Treatment Emergent Adverse Event Related to Study Drug 
o Related Treatment Emergent Adverse Event by Treatment and Haematologic 
o AESI Treatment Emergent Adverse Events 
o Treatment Emergent Adverse Events with Grade 3 or 4 or 5 
o Related Treatment-Emergent Adverse Event with Grade 3 or 4 or 5 
o Serious Treatment Emergent Adverse Event 
o Serious and Related Treatment Emergent Adverse Event 
o Treatment Emergent Adverse Event by Maximum Severity 
o Treatment Emergent Adverse Event Leading to Discontinuation of Study Drug 
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 February 15, 2024                                                        33                                                                      Final 
5.7.5 
Clinical Laboratory Parameters 
The following summaries will be produced for all hematology and biochemistry laboratory parameters: 
- 
Shift tables of low, normal, high distribution (n; %) with respect normal ranges of center, at each post-
baseline cycle by baseline (cycle 1 day 1) distribution. 
- 
Shift tables of low, normal, high distribution (n; %) of clinically significant at each post-baseline cycle 
comparing with baseline (cycle 1 day 1) distribution. 
- 
The value distribution will be displayed using a serial box plot at each cycle, for each treatment arm. 
5.7.6 
Vital Signs 
The following summaries will be produced for all vital sign’s parameters: 
- 
Shift tables of low, normal, high distribution (n; %) at each post-baseline cycle by baseline (cycle 1 
day 1) distribution. 
5.7.7 
Physical Examination 
The following summaries will be produced for all physical examination’s parameters: 
- 
Shift tables of low, normal, high distribution (n; %) at each post-baseline cycle by baseline (cycle 1 
day 1) distribution. 
 
 
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 February 15, 2024                                                        34                                                                      Final 
5.8 Interim Analysis 
5.8.1 
Futility Interim Analyses in Cohort 1 
A futility interim analysis has been planned in cohort 1. The recruitment will not be stopped during the 
interim analysis. However, after the interim analysis, if the number of patients achieving the primary 
endpoint is equal or less than futility boundary in each cohort, the accrual in the cohort must be stopped. 
The stopping rule is: 
Cohort 1: All 4 patients with progressive disease or death at 16 weeks. 
5.8.2 
Feasibility Interim Analyses 
At the halfway point of the recruitment period, the steering committee will evaluate if the accrual objective 
for the first stage was achieved in each study cohorts (4, 5, 3, 3 and 3 patients for cohorts 1, 2, 3, 4 and 
5, respectively). 
If this accrual objective has not achieved in a cohort, the Steering Committee will propose a corrective 
action plan or finalize the study in this cohort. 
Interim analyses report will summarize descriptively the following results by cohort on the Safety/FAS set. 
• 
Subject disposition 
• 
Baseline characteristics 
• 
Efficacy analysis 
• 
PFS events at 16 weeks 
• 
Median PFS 
• 
Unconfirmed tumor response according RECIST v.1.1 Criteria 
• 
Maximum Tumor Shrinkage 
• 
Unconfirmed Tumor Response according RANO-BM Criteria 
• 
Waterfall Plot 
• 
DOR 
• 
TTR 
• 
Median OS 
• 
Safety analysis 
• 
TEAEs 
• 
AESIs 
• 
Serious TEAEs 
• 
Dose delays, reductions, and discontinuations 
No statistical tests are planned for these data. 
 
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 February 15, 2024                                                        35                                                                      Final 
5.9 Changes of Analysis from Protocol 
In section 3.1, the method for calculating the primary endpoint of cohort 1 is specified in greater detail. 
We have included the analyses of maximum Tumor Shrinkage in all lesions as secondary endpoint. 
 
5.10 Deviations from SAP 
Any deviations from the original statistical plan will be described and justified in the final clinical study 
report. 
 
 
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 February 15, 2024                                                        36                                                                      Final 
6 
BIBLIOGRAPHY 
1.- Jung S-H (2015). Statistical issues for design and analysis of single-arm multi-stage phase II cancer 
clinical trials. Contemp Clin Trials. May;42:9–17). DOI: 10.1016/j.cct.2015.02.007 
2.- Koyama T and Chen H (2008). Proper inference from Simon’s two-stage designs. Statistics in Medicine, 
Jul 20; 27(16): 3145–3154. DOI: 10.1002/sim.3123 
3.- Kieser M, et all (2017). OneArmPhaseTwoStudy: An R Package for Planning, Conducting, and Analysing 
Single-Arm Phase II Studies. Nov, 81(8). DOI:10.18637/jss.v081.i08 
 
 
 
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 February 15, 2024                                                        37                                                                      Final 
7 
APPENDIX 
7.1 Appendix 1 – Codes 
All report outputs will be produced using SAS® version 9.4 (TS1M5) version in a secure and validated 
environment. 
7.1.1 
R Code - UMVUE 
- 
The UMVUE of the overall response rate, based on function “get_UMVUE_GMS”: 
 
k<- Total number of responders in the study; 
r1<-Futility boundary at interim analysis (number of events); 
n1<-Accrued patients at first stage; 
n2<-Accrued patients at second stage; 
n<-Overall patients accrued in the two stages of the study; 
p0<-Expected response rate; 
 
get_UMVUE_GMS <-function (k, r1, n1, n)  
{ 
    stopifnot(class(k) == "numeric" | class(k) == "integer",  
        k >= 0) 
    stopifnot(class(r1) == "numeric", r1 >= 0) 
    stopifnot(class(n1) == "numeric", n1 >= 0, n1 > r1) 
    stopifnot(class(n) == "numeric", n >= 0, n > n1) 
    umvue <- numeric(0) 
    if (k <= r1) { 
        umvue <- k/n1 
    } 
    else { 
        upper_boundry_dividend <- min(k - 1, n1 - 1) 
        lower_boundry_dividend <- max(r1, k - 1 - n + n1) 
        upper_boundry_divisor <- min(k, n1) 
        lower_boundry_divisor <- max(r1 + 1, k - n + n1) 
        i_upper <- lower_boundry_dividend:upper_boundry_dividend 
        i_lower <- lower_boundry_divisor:upper_boundry_divisor 
        umvue <- sum(choose(n1 - 1, i_upper) * choose(n - n1,  
            k - 1 - i_upper))/sum(choose(n1, i_lower) * choose(n -  
            n1, k - i_lower)) 
    } 
    umvue } 
 
 
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- 
Calculation of p-value based on function “get_p_KC“: 
 
k<- Total number of responders in the study; 
r1<-Futility boundary at interim analysis (number of events); 
n1<-Accrued patients at first stage; 
n2<-Accrued patients at second stage; 
n<-Overall patients accrued in the two stages of the study; 
p0<-Expected response rate; 
 
get_p_KC<- function(k, r1, n1, n, p0)  
{ 
    stopifnot(class(k) == "numeric" | class(k) == "integer",  
        k >= 0) 
    stopifnot(class(r1) == "numeric", r1 >= 0) 
    stopifnot(class(n1) == "numeric", n1 >= 0, n1 > r1) 
    stopifnot(class(n) == "numeric", n >= 0, n > n1) 
    stopifnot(class(p0) == "numeric", p0 >= 0, p0 <= 1) 
    p <- numeric(0) 
    if (k > r1) { 
        k1 <- (r1 + 1):n1 
        k2 <- k - k1 
        n2 <- n - n1 
        p <- sum(dbinom(k1, n1, p0) * (1 - pbinom(k2 - 1, n2,  
            p0))) 
    } 
    else { 
        p <- 1 - pbinom(k - 1, n1, p0) 
    } 
    p 
} 
 
 
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 Study Code: 2019-001739-29 (MedOPP243)                                                                 Statistical Analysis Plan 
 February 15, 2024                                                        39                                                                      Final 
- 
Calculation of 95% confidence intervals for response based on function “get_CI”: 
 
k<- Total number of responders in the study; 
r1<-Futility boundary at interim analysis (number of events); 
n1<-Accrued patients at first stage; 
n2<-Accrued patients at second stage; 
n<-Overall patients accrued in the two stages of the study; 
p0<-Expected response rate; 
alpha= overall significance level the trial was planned for; 
precision= gives the precision (in decimal numbers) to which the confidence interval should 
be calculated (should be less than 10). 
 
get_CI<- function (k, r1, n1, n, alpha = 0.05, precision = 4)  
{ 
    stopifnot(class(k) == "numeric" | class(k) == "integer",  
        k >= 0) 
    stopifnot(class(r1) == "numeric", r1 >= 0) 
    stopifnot(class(n1) == "numeric", n1 >= 0, n1 > r1) 
    stopifnot(class(n) == "numeric", n >= 0, n > n1) 
    stopifnot(class(alpha) == "numeric", alpha > 0, alpha <=  
        1) 
    stopifnot(class(precision) == "numeric", precision >= 0,  
        precision < 10) 
    stopifnot(k > r1, precision > 1) 
    eff <- seq(0, 1, 0.01) 
    tmp <- sapply(eff, function(bla) get_p_KC(k = k, r1 = r1,  
        n1 = n1, n = n, p0 = bla)) 
    index_low <- which(tmp >= alpha)[1] 
    index_high <- which(tmp >= (1 - alpha))[1] - 1 
    if (precision > 2) { 
        eff_low <- seq(eff[index_low - 1], eff[index_low], (1/(10^(3)))) 
        eff_high <- seq(eff[index_high], eff[index_high + 1],  
            (1/(10^(3)))) 
        for (i in 2:(precision)) { 
            if (i > 2) { 
                eff_low <- seq(eff_low[index_low - 1], eff_low[index_low],  
                  (1/(10^(i + 1)))) 
                eff_high <- seq(eff_high[index_high], eff_high[index_high +  
                  1], (1/(10^(i + 1)))) 
            } 
            tmp_low <- sapply(eff_low, function(bla) get_p_KC(k = k,  
                r1 = r1, n1 = n1, n = n, p0 = bla)) 
            tmp_high <- sapply(eff_high, function(bla) get_p_KC(k = k,  
                r1 = r1, n1 = n1, n = n, p0 = bla)) 
            index_low <- which(tmp_low >= alpha)[1] 
            index_high <- which(tmp_high >= (1 - alpha))[1] -  
                1 
        } 
        result <- data.frame(CI_low = eff_low[index_low], CI_high = eff_high[index_high]) 
    } 
    else { 
        result <- data.frame(CI_low = eff[index_low], CI_high = eff[index_high]) 
    } 
    result 
} 
 
 
 
 
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 Study Code: 2019-001739-29 (MedOPP243)                                                                 Statistical Analysis Plan 
 February 15, 2024                                                        40                                                                      Final 
7.1.2 
SAS Code - Stochastic Binomial Exact Test 
ORR 
The number and proportion of patients with CNS-ORR, with its 95% exact (Pearson-Clopper) confidence 
intervals will be calculated.  
proc freq data=ITT; 
  tables CNSORR / binomial(exact p=.05) alpha=.025; 
  title 'CNS-ORR (FAS)'; 
run; 
 
7.1.3 
R Code - Maximum Likelihood Method for Exponential Distribution 
- 
Calculation of p-value: 
 
######Maximum likelihood for exponential distribution, superiority. 
mOSobs = observed median overall survival (OS). 
mOS0 = null hypothesis (H0) of median overall survival. 
HRobs = observed Hazard Rate (HR) = -log(0.5)/mOSobs 
HR0 = H0 of HR = -log(0.5)/mOS0 
Ev = events at the end of study 
log() = natural logarithm in R 
pnorm = The pnorm function is used to calculate the cumulative distribution function of the normal 
distribution. 
Formula: 
p-value = pnorm(sqrt(Ev)*(log(HRobs)-log(HR0))) 
 
 
 
7.2 Appendix 2 - List of Tables, Listings, Figures 
A complete list of tables, listings and figures (TLFs) will be given in a separate document which can be 
updated without updating the SAP. The list will serve as a reference for both the Sponsor, the trial 
statistician and the statistical programmer and includes the totality of statistical output to be produced. 
All output will be headed with an appropriate heading specifying the study ID and abbreviated study title. 
All output will be dated and have page numbers in the form 'Page [x / y]' where x denotes the current 
page within an output and y the total number of pages of that output. 
All statistical output will identify the underlying analysis sets and indicate the number of patients/events 
in this set (N) and the number of patient/events actuals contributing to the output (n). All statistical output 
will be presented per treatment (if applicable). 
All patient listings will contain additionally to the patient identification the analysis set and the treatment.  
 
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