Phase II Trial of TRAstuzumab deruxtecaN in firSt-line Treatment of HER2-positive Locally advanCEd or Metastatic Breast caNcer (MBC) Patients Considered Resistant to Trastuzumab + Pertuzumab + Taxane Due to Early Relapse."TRANSCENDER Study"
Phase: PHASE2
Conditions: Locally Advanced Breast Cancer, Metastatic Breast Cancer
Sponsor: Spanish Breast Cancer Research Group

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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Protocol GEICAM/2021-08  
“Phase II trial of TRAstuzumab deruxtecaN in firSt-line treatment of HER2-
positive locally advanCEd or metastatic breast caNcer (MBC) patients 
considered resistant to trastuzumab + pertuzumab + taxane Due to Early 
Relapse.” 
“TRANSCENDER Study” 
SPONSOR:  
GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama) 
Avenida de los Pirineos 7, planta 1ª, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid), Spain 
Phone: 0034 916 592 870 
 
Fax: 0034 916 510 406 
Email: geicam@geicam.org 
 
CHIEF INVESTIGATORS: 
Dr. Miguel Martín. H. General Universitario Gregorio Marañón. Madrid, Spain. 
Dr. Sonia Servitja. H. del Mar. Barcelona, Spain. 
 
Sponsor Study Code: GEICAM/2021-08  
EU CT Number: 2023-503627-26-00 
Protocol reviewed by FECMA (Spanish Federation of Breast Cancer Patients)  
Financed by: AstraZeneca Pharmaceutical Spain 
CONFIDENTIAL  
The information and data included in this protocol contain secrets and privileged or confidential information which is the property of 
GEICAM. No one is authorized to make this information public without the written permission of GEICAM. These limitations shall 
also be applied to all the information considered to be privileged or confidential and provided in the future. This material can be 
disclosed and used by its equipment and collaborators as necessary for conducting the clinical trial. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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Protocol Number: GEICAM/2021-08  
Protocol Tittle: Phase II trial of trastuzumab deruxtecan in first-line treatment HER2-positive 
locally advanced or metastatic breast cancer (MBC) patients considered resistant to trastuzumab + 
pertuzumab + taxane due to early relapse. “TRANSCENDER Study” 
EU CT Number: 2023-503627-26-00 
Version: 2.1 
Version Date: 06-Jun-2024 
 
__________________________________________                      _____________________ 
Chief Investigator: Dr. Miguel Martín                                             Date (dd/mmm/yyyy) 
 
__________________________________________                     _____________________ 
Chief Investigator: Dr. Sonia Servitja                                              Date (dd/mmm/yyyy) 
 
_________________________________________                       _____________________ 
Medical Monitor: Dr. Eva Carrasco                                                 Date (dd/mmm/yyyy) 
 
__________________________________________                      _____________________ 
Statistician: Mª José Escudero                                                          Date (dd/mmm/yyyy) 
 
__________________________________________                      _____________________ 
Translational Monitor: Rosalía Caballero                                         Date (dd/mmm/yyyy) 
 
__________________________________________                      _____________________ 
Project Manager: Sara Benito                                                           Date (dd/mmm/yyyy) 
 
 

 
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SUMMARY OF THE STUDY PROTOCOL 
Study Title: Phase II trial of trastuzumab deruxtecan in first-line treatment HER2-positive locally 
advanced or metastatic breast cancer (MBC) patients considered resistant to trastuzumab + 
pertuzumab + taxane due to early relapse. “TRANSCENDER Study” 
Sponsor Study Code: GEICAM/2021-08 
Sponsor: GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)   
Indication: Human Epidermal Growth Factor Receptor 2 (HER2)-positive locally advanced or 
MBC patients who have not received prior chemotherapy or HER2 targeted therapy for advanced 
disease and with a disease-free interval (DFI) of <12 months from the end of prior (neo) adjuvant 
anti-HER2 therapy. 
Countries and approximate number of sites: The trial is expected to be run in Spain in 
approximately 19 sites. 
Number of patients: approximately 41 patients will be enrolled in the study. 
Study Rationale: 
The HER2-positive breast cancer subtype (that represents around 20% of all breast cancers) was 
classically associated with poor prognosis. However, new therapeutic advances (particularly 
targeted therapies) have significantly increased the cure rate of patients in early stages. In the 
metastatic setting, anti-HER2 targeted therapies have significantly improved overall survival (OS) 
with good quality of life, however there is still a substantial group of patients who die, and therefore 
additional drugs need to be investigated.  
In early, locally advanced or inflammatory HER2-positive breast cancer, neoadjuvant/preoperative 
chemotherapy in combination with trastuzumab and pertuzumab is standard of care in patients with 
tumors ≥T2 and/or ≥N1, based on the results of several studies. For patients who have received 
neoadjuvant chemotherapy plus HER2-targeted therapy, the risk of disease recurrence or death is 
higher in patients with residual invasive disease at surgery than the risk in patients with a 
pathological complete response (pCR). 
Recently, T-DM1 has been approved for the adjuvant treatment for patients with HER2-positive 
early BC who have residual invasive disease following neoadjuvant trastuzumab and chemotherapy 
based on results of the KATHERINE study. 
In patients not receiving neoadjuvant chemotherapy, the use of adjuvant trastuzumab in HER2-
positive early-stage BC improves patient outcomes as demonstrated in several large, randomized 
trials. In addition, the results of the APHINITY study led to the approval of the double blockage 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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with trastuzumab plus pertuzumab in combination with chemotherapy in the adjuvant setting of 
patients with node positive disease. 
At disease relapse, the current standard of care for patients with HER2-positive MBC consists of 
treatment with pertuzumab plus trastuzumab plus a taxane as first-line treatment based on the 
CLEOPATRA data, followed by trastuzumab-emtansine (T-DM1) in second line, based on the 
EMILIA data. Recently, results reported in the phase 3 DESTINYBreast-03 trial will probably 
change clinical practice in the second line setting, with trastuzumab deruxtecan (T-DXd) showing 
much better results compared to T-DM1.  
The CLEOPATRA study included patients with late recurrences (more than 12 months from the 
completion of all therapy and the diagnosis of metastatic disease), so no data of the combination of 
trastuzumab plus pertuzumab plus a taxane in first line in patients recurring earlier are available 
from this study. For T-DM1, the EMILIA trial included some patients in first line, only those 
relapsing within the first 6 months after completing adjuvant treatment. Besides, a retrospective 
real-world cohort of early-relapsing patients demonstrated PFS and OS superiority of trastuzumab 
pertuzumab and chemotherapy over T-DM1 in patients with relapses between 6 and 12 months and 
even in the first 6 months. 
Thus, currently there is not enough data concerning the better strategy in patients with relapse 
within one year after completing adjuvant treatment, especially in those that have previously 
received prior trastuzumab and pertuzumab in early stage. 
There is an ongoing study exploring T-DXd with or without pertuzumab versus taxane plus 
trastuzumab plus pertuzumab in HER2-positive MBC, the DESTINY-Breast09 study 
(NCT04784715), but again, patients with a short disease-free interval will not be included in the 
study. 
Based on all of these it is quite reasonable to study the use of T-DXd in early relapse breast cancer 
patients that have previously received trastuzumab and pertuzumab and or T-DM1 in early stage. 
Study Treatment: 
Dose/Route/Regimen 
Eligible patients will be enrolled and treated with: 
✓ Trastuzumab Deruxtecan 5.4 mg/kg IV every 3 weeks. 
The T-DXd dose will be recalculated in the event that patients experience body weight variations 
greater than 10% during the treatment period. 
All patients enrolled will receive study therapy until radiographic or symptomatic progressive 
disease, unacceptable toxicity or withdraw of the informed consent, whatever occurs first. 
Study Design and Treatment: 

 
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Study Design 
This is a national, multicenter single arm phase II clinical trial to study the efficacy, safety and 
tolerability of the administration of T-DXd in HER2-positive locally advanced or MBC patients 
resistant to trastuzumab plus pertuzumab plus taxane due to early relapse. 
Forty-one evaluable patients will be enrolled in the study and treated with T-DXd according to the 
following study design: 
 
Figure 1: Study design 
  
 
 
Primary Objective: 
• To evaluate the antitumor activity of T-DXd in the first-line treatment of HER2-positive 
breast cancer patients resistant to trastuzumab-pertuzumab based therapy. 
Primary Endpoint: 
• Objective Response Rate (ORR) is defined as the rate of complete response (CR) plus 
partial response (PR) based on the investigator’s assessment using the Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1., out of the patients who received at least 1 
dose of treatment. 
Secondary Objectives: 
• To assess other efficacy measures.  

 
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• To evaluate safety and tolerability in all patients enrolled in the study. 
• To evaluate health-related quality of life (HRQoL).  
Secondary Endpoints: 
• Other efficacy endpoints: 
o Progression-Free Survival (PFS) is defined as the time from the date of enrollment to 
the date of disease progression, based on the investigator’s assessment using RECIST 
version 1.1., or death from any cause, whichever occurs first.  
o Overall Survival (OS) is defined as the time from the date of enrollment to the date of 
death from any cause. 
o Time to treatment response (TTR) is defined as the time from the date of enrollment to 
the date of first documentation of objective tumor response (CR or PR). 
o Duration of response (DoR) is defined as the time from the date of first documentation 
of objective tumor response (CR or PR) to the date of first documented progressive 
disease based on the investigator’s assessment using RECIST version 1.1., or death 
from any cause, whichever occurs first.   
• Safety: Incidence and severity of Adverse Events (AEs) and clinical lab abnormalities. AEs 
grades will be defined by the National Cancer Institute Common Terminology Criteria for 
AEs (NCI-CTCAE) version 5.0. AE terms will be coded according to the MedDRA 
dictionary. 
• Tolerability: Incidence of T-DXd dose modifications, discontinuations due to AEs, number 
of administered cycles, dose intensity, etc. 
• Changes (mean score) and time to deterioration on EORTC QLQ-C30 Global Health 
Status/QoL from baseline. 
Exploratory Objectives: 
• To assess other efficacy measures  
• To assess T-DXd efficacy according to HER2-expression and HER2 spatial distribution. 
• To explore T-DXd efficacy based on the intrinsic tumor subtypes and evaluate if patients 
with HER2-Enriched intrinsic tumor subtype benefit most from T-DXd. 
• To improve the understanding of the mechanism of action and resistance to T-DXd in 
HER2-positive advanced breast cancer patients. Explore, among others, disease-related 
inflammatory, immune, or microenvironment-related biomarkers and their correlation with 
the study treatment, and other potential parameters of clinical utility in blood and tumor 
samples. 

 
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• To explore the possibility of monitoring response to T-DXd by using longitudinal ctDNA 
assessment. 
• To improve the understanding of molecular mechanisms of the metastatic breast cancer.  
Exploratory Endpoints: 
• PFS2 and PFS3: are defined as the time from the date of enrollment to the date of disease 
progression to the second and third lines of therapy, respectively. 
• Investigate the predictive value of HER2 expression levels and HER2 spatial distribution 
in baseline tumors.  
• Intrinsic molecular subtypes of breast cancer. 
• Genomic profiles and molecular biomarkers (e.g. PIK3CA mutations, tumor infiltrated 
lymphocytes, PD-1, PD-L1, gH2AX, CD3, CD4, CD8, CD68, FoxP3, CK/SOX10), 
analyzed in tumor tissue and blood samples, associated with treatment response or 
resistance, and the outcome of patients. Biological samples of patients considered as 
‘exceptional responders’ or as ‘rapid progressors’ based on the clinical follow-up could be 
subjected to deeper molecular characterization. 
• ctDNA alterations related to response or resistance to treatment.  
• Explore tumor subtypes and other biological subgroups, defined by biomarkers involved in 
immune response, proliferation, cell cycle regulation, DNA-repair, apoptosis, signal 
transduction pathways and oncogenic dependency, among others. 
Study population and main inclusion and exclusion criteria: 
HER2-positive locally advanced or MBC patients who have not received prior chemotherapy or 
HER2 targeted therapy for advanced disease and with a Disease-Free Interval (DFI) of <12 months 
from the end of prior (neo)adjuvant anti-HER2 therapy. 
Inclusion Criteria:  
Patients are eligible to be enrolled in the study only if they meet all of the following criteria: 
1. Written and signed informed consent obtained prior to any study-specific procedure. 
2. Male or female patients of at least 18 years of age. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1. 
4. Life expectancy ≥ 12 weeks. 
5. Recurrent breast cancer that is unresectable locally advanced or metastatic. 
6. Pathologically documented HER2-positive status by local laboratory determination, 
preferably on the most recent available FFPE tumor sample, according to the American 
Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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international guidelines valid at the time of the assay. In case of discordance in HER2 
status in different biopsies, the result from the most recent biopsy will be used. 
7. Pathologically documented Hormone Receptor (HR)-positive or -negative by local 
laboratory determination, preferably on the most recent available FFPE tumor sample, 
and according to ASCO/CAP international guidelines valid at the time of the assay. In 
case of discordance in HR status in different biopsies, the result from the most recent 
biopsy will be used. 
8. Prior anti-HER2 based therapy (with trastuzumab plus pertuzumab plus taxane with or 
without trastuzumab-emtansine [T-DM1]) in the (neo)adjuvant setting with a relapse 
while on therapy or within 12 months from the end of last anti-HER2 therapy. 
9. Measurable disease assessed by the investigator based on RECIST version 1.1. 
10. Left ventricular ejection fraction (LVEF) ≥ 50% measured by multiple-gated acquisition 
scan (MUGA) or echocardiogram (ECHO).  
11. Adequate organ and marrow function defined as follows: 
a. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/L). 
b. Platelet count ≥ 100,000/mm3 (100x109/L). 
c. Hemoglobin ≥ 9g/dL (90g/L). 
d. Creatinine clearance ≥ 30 mL/min as calculated using the standard method for the 
institution. 
e. Total serum bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the 
presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or 
liver metastases at baseline. 
f. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3.0 x 
ULN (< 5.0 × ULN in participants with liver metastases). 
g. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN if bone or liver metastases 
are present). 
h. Serum albumin ≥ 2.5 g/dL 
12. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 
1.5 x ULN. 
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests 
and other study procedures. 
14. Negative serum pregnancy test with a sensitivity of at least 25 mIU/mL (unless permanent 
previous sterilization procedure such as bilateral salpingectomy, bilateral oophorectomy, 
or complete hysterectomy) for premenopausal women, and for women who have 
experienced menopause onset < 12 months prior to first dose of therapy. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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Exclusion Criteria:   
Patients will be excluded from the study if they meet any of the following criteria: 
1. Prior chemotherapy or HER2-targeted therapy for locally advanced or MBC (one prior 
endocrine therapy regimen for MBC without concurrent anti-HER2 therapy or radiotherapy 
is allowed). 
2. Ineligible for treatment with T-DXd. 
3. Any substance abuse or other medical conditions that, in the investigator's opinion, may 
interfere with patient's participation or study results. 
4. Patients with spinal cord compression, leptomeningeal disease or clinically active central 
nervous system (CNS) metastases. Participants with clinically inactive brain metastases or 
treated brain metastases that are no longer symptomatic, and no needing corticosteroids or 
anticonvulsants may be enrolled in the study.  
5. Active or prior documented interstitial lung disease (ILD)/pneumonitis or suspected 
ILD/pneumonitis that cannot be ruled out by imaging at screening. 
6. Lung criteria: 
a. 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 enrollment, severe asthma, severe Chronic obstructive 
pulmonary disease (COPD), restrictive lung disease, pleural effusion etc.). 
b. 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 electronic Case Report Form (eCRF) for patients who are 
enrolled in the study.   
c. Prior pneumonectomy. 
7. Medical history of myocardial infarction within 6 months before registration, symptomatic 
congestive heart failure (CHF), troponin levels consistent with myocardial infarction as 
defined according to American College of Cardiologists (ACC) guidelines, unstable angina, 
or serious cardiac arrhythmia requiring treatment. QT interval corrected using Fridericia’s 
formula (QTcF) > 470 msec (females) or > 450 msec (males) based on average of the 
screening triplicate 12-lead ECG.  
8. History of active primary immunodeficiency, known Human Immunodeficiency Virus 
(HIV), active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV). 
9. Patients who received before treatment starts: 

 
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a. Any investigational agent within 4 weeks.  
b. Chemotherapy within a period of time that is shorter than the cycle duration used 
for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicine or < 1 
week for weekly chemotherapy). 
c. Targeted therapy (e.g., antibodies): up to 4 weeks prior to starting study treatment. 
d. Endocrine therapy: tamoxifen or aromatase inhibitor within 2 weeks prior to starting 
study treatment. 
e. Radiotherapy within 2 weeks prior to starting study treatment. Patients who received 
prior radiotherapy to >25% of bone marrow are not eligible regardless of when it 
was administered. 
f. Major surgery or other anti-cancer therapy not previously specified within 4 weeks 
prior to starting study treatment. 
In any case, resolution of all acute toxic effects of prior anti-cancer therapy or surgical 
procedures to NCI-CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicities not 
considered a safety risk for the patient at investigator´s discretion) is mandatory.Patients 
may be enrolled with chronic, stable grade 2 toxicities (defined as no worsening to > grade 
2 for at least 3 months prior to enrollment and managed with standard of care treatment) 
that the investigator deems related to previous anticancer therapy, such as: chemotherapy-
induced 
neuropathy 
or 
fatigue 
and 
immunotherapy-induced 
toxicities 
(e.g. 
endocrinopathies as hypothyroidism/hyperthyroidism, type 1 diabetes, hypoglycemia, 
adrenal insufficiency, adrenalitis and skin hypopigmentation [vitiligo]). 
10. Have a diagnosis of any other malignancy within 3 years prior to inclusion, except for 
adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other 
solid tumors curatively treated and contralateral breast cancer. 
11. Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd. 
12. Prior treatment with T-DXd or allergic reaction to trastuzumab. 
13. Patient is pregnant or breastfeeding or planning to become pregnant within the projected 
duration of the trial, starting at screening and through 7 months after the last dose of the 
study treatment. Male patients whose partners plan to become pregnant within the duration 
of the trial, starting at screening and through 4 months after the last dose of the study 
treatment.  
✓ For premenopausal women it is necessary an agreement to remain complete 
abstinent or use single or combined non-hormonal contraceptive methods that result 
in a failure rate of < 1% per year during the treatment period and for at least 7 months 
after the last dose of study treatment. 

 
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▪ Examples of non-hormonal contraceptive methods with a failure rate of < 
1% per year include bilateral tubal litigation, male sterilization, and certain 
intrauterine devices (provided coils are copper banded). 
▪ Alternative, two methods (e.g. two barrier methods such as a condom and a 
cervical cap or combined with estrogen and progestogen) may be combined 
to achieve a failure rate of < 1% per year. Barrier methods must always be 
supplemented with the use of a spermicide. 
Female patients must not donate, or retrieve for their own use, ova from the time of 
enrollment and throughout the study treatment period, and for at least 7 months after 
the final study drug administration. They should refrain from breastfeeding 
throughout this time. Preservation of ova may be considered prior to enrollment in 
this study. 
✓ For men it is necessary an agreement to remain complete abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and to refrain from 
donating sperm during the same period, as defined below with female partners of 
childbearing potential or pregnant female partners, men must remain abstinent or 
use a condom during the treatment period and for at least 4 months after the last 
dose of study treatment to avoid exposing the embryo.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of 
the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
14. Uncontrolled intercurrent illness including uncontrolled infection requiring intravenous 
(IV) antibiotics, antivirals, or antifungals. 
15. Has substance abuse or any other medical/psychological conditions that may, in the opinion 
of the investigator, interfere with the patient’s participation in the clinical study or 
evaluation of the clinical study results. 
Justification of Sample size determination  
Assuming an ORR of 35%, and to achieve a precision of ±15% using two-sided 95% normal 
asymptotic Confidence Interval (CI) for a single proportion, we will need to enroll 39 evaluable 
patients. 
With a drop-out rate of 5% we will need 41 patients to be enrolled in the study. 
Statistical Analyses: 

 
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For descriptive analyses, frequencies, percentages and 95% CI of interest will be calculated for 
categorical variables wherever possible. For continuous variables, standard descriptive statistics, 
such as total number of observations, number of available data, mean, standard deviation, 
minimum, percentile 25, median, percentile 75 and maximum will be calculated. 
Percentage and two-sided 95% CI will be calculated for the primary endpoint (ORR).  
Kaplan-Meier Method will be used to estimate the survival functions, median time to events and 
probabilities of occurrence of an event at a certain time point (PFS, OS, TTR, DOR, PFS2, PFS3). 
Cox Proportional Hazards Regression Model could be used to estimate the hazard ratio and assess 
the association between the different risk factors and survival times. 
Study Duration: 
The start date of the study is the date of the first site activation. Recruitment period will occur 
during approximately 24 months from the first patient in.  
The end date of the study is the date of the last visit of the last patient (LPLV), including follow-
up. The duration of the study will be approximately 68 months from the first patient in. 
Performing exploratory objectives will be independent of the date of the end of the study. 
 
 

 
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Table of Contents  
Section 
Page 
1. 
Introduction .......................................................................................... 22 
1.1. 
Overview of Breast Cancer ............................................................. 22 
1.2. 
HER2 overexpression in BC ........................................................... 22 
1.3.  Treatment options for HER2-positive Metastatic BC (MBC) 
patients ............................................................................................ 22 
1.4. 
Overview of Trastuzumab deruxtecan ............................................ 24 
1.4.1 
Preclinical Data ....................................................................... 24 
1.4.2 
Human Pharmacokinetic (PK) Data ....................................... 24 
1.4.3 
QTc Evaluation Data .............................................................. 25 
1.4.4 
Trastuzumab deruxtecan Dose Rationale ............................... 25 
1.4.5 
Trastuzumab deruxtecan data in HER2-positive Breast 
Cancer ..................................................................................... 26 
1.5.  Study Rationale ............................................................................... 26 
2. 
Objectives ............................................................................................. 29 
2.1. 
Primary Objective ........................................................................... 29 
2.2.  Primary Endpoint ............................................................................ 29 
2.3. 
Secondary Objectives ...................................................................... 29 
2.4.  Secondary Endpoints ....................................................................... 29 
2.5.  Exploratory Objectives .................................................................... 30 
2.6.  Exploratory Endpoints .................................................................... 30 
3. 
Investigational Plan .............................................................................. 31 
3.1. 
Study Design ................................................................................... 31 
3.2. 
Duration of the study ....................................................................... 32 
4. 
Study Population .................................................................................. 33 
4.1. 
Inclusion Criteria ............................................................................. 33 
4.2. 
Exclusion Criteria ............................................................................ 34 
4.3. 
Discontinuations .............................................................................. 34 
4.3.1. 
Discontinuation of Study Treatment ....................................... 37 
4.3.2. 
Discontinuation of Study Sites ............................................... 38 
4.3.3. 
Discontinuation of Study ........................................................ 38 
4.4. 
Menopausal status definitions and contraception ........................... 38 
5. 
Treatment ............................................................................................. 39 
5.1. 
Treatments Administered ................................................................ 39 
5.2. 
Materials and Supplies .................................................................... 39 

 
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5.2.1.  
Storage, preparation and administration of trastuzumab 
deruxtecan ............................................................................... 39 
5.2.1.1. 
Packaging and storage ....................................................... 39 
5.2.1.2. 
Preparation ........................................................................ 40 
5.2.1.3. 
Administration .................................................................. 40 
5.2.2. 
Accountability ......................................................................... 40 
5.3. 
Method of Assigning a Patient to a Treatment ................................ 41 
5.4. 
Special Treatment Considerations. Dose Adjustments of Study 
Treatment ........................................................................................ 41 
5.4.1.  
Dose Interruptions and Reductions ......................................... 42 
5.5. 
Medication Errors and Overdose .................................................... 51 
5.6. 
General Concomitant Medication and Supportive Care 
Guidelines ....................................................................................... 51 
5.6.1. 
Prohibited Medications ........................................................... 51 
5.6.2. 
Medications Not Recommended ............................................. 52 
5.6.3. 
Permitted Medications ............................................................ 53 
5.7. 
Treatment Compliance .................................................................... 54 
6. 
Efficacy and Safety Evaluations, Sample Collection and Testing 
(Standard Laboratory Testing) and Appropriateness of Assessments . 55 
6.1. 
Efficacy Assessments ...................................................................... 55 
6.2. 
Safety Assessments ......................................................................... 56 
6.2.1. 
Timing of Assessments ........................................................... 56 
6.2.2. 
Definitions .............................................................................. 57 
6.2.3 
Management, Timing and Assessment of Adverse Events..... 60 
6.2.4. 
Management, Timing and Assessment of 
SAEs/AESIs/pregnancies........................................................ 63 
6.2.5. 
Management, Timing and Assessment of SUSARs ............... 66 
6.3. 
Other Assessments .......................................................................... 67 
6.3.1. 
Biomarker Assessments .......................................................... 67 
6.3.2 
Patient Reported Outcomes .................................................... 69 
7. 
Data Quality Assurance ........................................................................ 70 
7.1. 
Data Management and Registries file ............................................. 70 
8. 
Sample Size and Statistical Methods ................................................... 72 
8.1. 
Determination of Sample Size ........................................................ 72 
8.1.1. 
Sample Size determination ..................................................... 72 
8.2. 
Statistical and Analytical Plans ....................................................... 72 
8.2.1. 
General Considerations ........................................................... 72 

 
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8.2.1.1. 
Patient Populations ............................................................ 72 
8.2.2. 
Patient Disposition .................................................................. 73 
8.2.3. 
Patient Characteristics............................................................. 73 
8.2.4. 
Concomitant Therapy ............................................................. 73 
8.2.5. 
Treatment Compliance ............................................................ 73 
8.2.6. 
Efficacy Analyses ................................................................... 74 
8.2.6.1. 
Analyses of Primary Endpoint .......................................... 74 
8.2.6.2. 
Analysis of Secondary Endpoints ..................................... 74 
8.2.7. 
Safety Analyses....................................................................... 76 
8.2.8. 
Other Analyses ........................................................................ 76 
8.2.8.1. 
Biomarker Analyses .......................................................... 76 
8.2.8.2.  
Patient Reported Outcomes ............................................... 77 
8.2.9. 
Subgroup Analyses ................................................................. 78 
9. 
Informed Consent, Confidentiality, Responsibility Insurance and 
Regulatory Considerations ................................................................... 79 
9.1. 
Informed Consent ............................................................................ 79 
9.2. 
Respect of Confidentiality ............................................................... 79 
9.3. 
Data Protection ................................................................................ 79 
9.3.1. Personal Data Processed ............................................................... 80 
9.3.2. Arrangements to Comply with Data Protection Laws .................. 80 
9.3.3. Measures to Protect Personal Data ............................................... 80 
9.4. 
Insurance and Compensation for Injury .......................................... 81 
9.5. 
Regulatory Considerations .............................................................. 82 
9.5.1. 
Investigator Information ......................................................... 82 
9.5.2. 
Protocol Signatures ................................................................. 82 
10. Practical Considerations ....................................................................... 83 
10.1.  Monitoring, Audit and Inspections ................................................ 83 
10.5.  Use of the Information and Publication ......................................... 84 
10.5.1 
Clinical Trial Registration ...................................................... 84 
10.5.2 
Clinical Trial Results Disclosure ............................................ 84 
10.6.  Ethics Committees and/or IRBs ..................................................... 84 
11. References ............................................................................................ 86 
Protocol Attachment 1. Study Schedule ....................................................... 89 
Protocol Attachment 2. Eastern Cooperative Oncology Group 
Performance Status ............................................................................... 93 
Protocol Attachment 3. Adverse event (AE) non defined in NCI-CTCAE .. 94 

 
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Protocol Attachment 4. Adverse Events / Serious Adverse Events 
Assessment Guide ................................................................................ 95 
Protocol Attachment 5. QoL Questionnaire ................................................. 96 

 
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Abbreviations and Definitions  
ACC 
American College of Cardiologists 
AE 
Adverse Event 
AEMPS 
Spanish Agency for Medicines and Health Products 
AESI 
Adverse Event of Special Interest 
ALT/ALAT (SGPT) 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
AR 
Adverse Reaction 
AST/ASAT (SGOT) 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BC 
Breast Cancer 
cDNA 
Circulating free DNA 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CNS 
Central Nervous System 
Compliance 
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements. 
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT Scan 
Computed Tomography Scan 
DNA 
Deoxyribonucleic Acid 
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form (sometimes referred to as Clinical Report Form). An 
electronic form for recording study participants’ data during a clinical study, as 
required by the protocol. 
ECG 
Electrocardiogram 

 
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ECOG 
Eastern Cooperative Oncology Group 
End of Study (Trial) 
The end of study (trial) is the date of the last visit or last scheduled procedure shown 
in the Study Schedule for the last active patient in the study (to be modified according 
to the definition of end of study in the protocol) 
Enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned a registration number and treatment.  
Screen 
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial.  Patients 
screened into a trial are those who sign the informed consent document directly or 
through their legally acceptable representatives. 
ER 
Estrogen Receptor 
EC/IRB 
Ethics Committee/Institutional review board:  A board or committee (institutional, 
regional, or national) composed of medical professional and nonmedical members 
whose responsibility is to verify that the safety, welfare, and human rights of the 
patients participating in a clinical trial are protected. 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GEICAM 
Fundación Grupo Español de Investigación en Cáncer de Mama 
G-CSF 
Granulocyte Colony-Stimulating Factor 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus  
HER2 
Human Epidermal Growth Factor Receptor 2 
Hb 
Hemoglobin 
HR 
Hormone Receptor  
HRQoL 
Health-related quality of life 
ICD 
Informed Consent Document  
IHC 
Immunohistochemistry 

 
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ILD 
Interstitial Lung Disease  
IMP 
Investigational Medicinal Product 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator. 
ISH 
In Situ Hybridization 
ITT 
Intent To Treat 
IV 
Intravenous 
Legal Representative 
An individual, judicial, or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical trial. 
MBC 
Metastatic Breast Cancer 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
NCI 
National Cancer Institute 
NSAI 
Non-Steroidal Aromatase Inhibitor 
OR 
Objective Response 
OS 
Overall Survival 
Patient 
A subject with a defined disease. 
PD 
Progressive Disease or Pharmacodynamic depending on the context 
PFS 
Progression-Free Survival 
PgR 
Progesterone Receptor 
PK 
Pharmacokinetic 
PR 
Partial Response 
PS 
Perfomance Status 
RANKL 
Receptor Activator of Nuclear Factor Kappa-B Ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response Rate 

 
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SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T-DXd 
Trastuzumab deruxtecan 
TTP 
Time To Progression 
ULN 
Upper Limit of Normal 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Phase II trial of TRAstuzumab deruxtecaN in firSt-line treatment of HER2-
positive locally advanCEd or metastatic breast caNcer (MBC) patients 
resistant to trastuzumab + pertuzumab + taxane Due to Early Relapse 
“TRANSCENDER Study” 
 

 
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1. Introduction 
1.1. 
Overview of Breast Cancer 
Breast cancer is the most common form of cancer and the second leading cause of cancer-related 
death in women in Spain, the United States and worldwide. In the last 30 years, the female breast 
cancer death rate has experienced a decline by 41% because of screening programs and treatment 
improvements. Because of those improvements, long-term survival can be achieved1. However, 
still many of the patients diagnosed with a breast cancer will present with a metastatic disease at 
diagnosis or will eventually develop it in spite of all therapeutic efforts. Metastatic disease is 
incurable in a vast majority of patients; consequently, nowadays the primary goal of treatment in 
these patients is to extend life and palliate potential symptoms. Thus, further research is needed 
in order to improve metastatic breast cancer outcomes.  
1.2. 
HER2 overexpression in BC  
The epidermal growth factor receptor family was discovered in the 1960s, and includes four 
different members: ErbB1 or EGFR, ErbB2 or HER2/neu, ErbB3, and ErbB4. The structure of 
these receptors consists of an extracellular domain, a juxtamembrane domain and an intracellular 
domain. The intracellular domain is made of two parts: a tyrosine kinase domain and a carboxyl 
terminal domain. The binding of the ligand to the extracellular domain promotes dimerization of 
this receptor with other members of the EGFR family2.  
Up to 20-25% of breast cancers overexpress the Human Epidermal Growth Factor Receptor 2 
(HER2) 3,4 Tumors that overexpress HER2 are usually more aggressive than hormone receptor 
(HR)-positive, HER2-negative breast cancer, and traditionally have been associated with poorer 
outcomes. However, therapeutic developments in the form of targeted therapies have 
dramatically changed outcomes in this particular type of breast cancer. Thus, targeted therapies 
have increased curation rates in early disease5,6 and prolonged survival in advance disease, as 
well as granting patients a better quality of life7-10. 
1.3.  Treatment options for HER2-positive Metastatic BC (MBC) patients 
As previously stated, the introduction of HER2-targeted therapy using either antibody-based 
therapy or a small molecule tyrosine kinase inhibitor (TKI) has led to significant and ongoing 
improvements in disease-free survival (DFS), progression-free survival (PFS), and OS in both 
the adjuvant and metastatic settings.  
Nowadays, patients with HER2-positive disease who are diagnosed as metastatic or who relapse 
1 year after completing adjuvant treatment, the combination of a taxane plus trastuzumab and 
pertuzumab (THP) is the standard of treatment, based on the CLEOPATRA study9. It was a phase 
III trial for HER2-positive MBC patients naive to previous chemotherapy or biological therapy 

 
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for metastatic disease. Patients could have received chemotherapy with or without trastuzumab 
in the neoadjuvant or adjuvant settings as long as there was a minimum 12-month interval 
between completion of all therapy and metastatic disease diagnosis. Patients were treated with 
trastuzumab and docetaxel and were randomly assigned to receive pertuzumab or placebo. The 
study had a potential limitation, since patients who received adjuvant or neoadjuvant trastuzumab 
was also small, because trastuzumab was not widely available for this indication during the 
recruitment of the trial. The study met its primary endpoint in terms of OS and PFS, and the 
combination of taxane plus trastuzumab and pertuzumab was established as the first line option. 
In the second-line setting, ado-trastuzumab emtansine (T-DM1) demonstrated an improvement 
in progression-free survival (PFS) and OS in comparison with lapatinib/capecitabine in the 
EMILIA trial8. The study was a phase 3 randomized, open-label, international trial involving 
patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who 
were previously treated with trastuzumab and a taxane. Patients had progressed during or after 
the most recent treatment for locally advanced or metastatic disease or within 6 months after 
treatment for early-stage disease. They were randomized to receive either T-DM1 or lapatinib 
plus capecitabine. Based on the results of this study, T-DM1 was stablished as the standard of 
care in second line. 
For the third line and beyond, treatment options included combinations of an anti-HER2 therapy 
such as trastuzumab, lapatinib or neratinib in combination with cytotoxic therapy. But recently 
two new drugs have shown better results in this setting, tucatinib and trastuzumab deruxtecan (T-
DXd). 
Tucatinib is a potent, highly selective, small-molecule kinase inhibitor of HER2. Its efficacy was 
tested in HER2CLIMB11. It was an international, randomized, double-blind trial in which 612 
patients with pretreated (prior trastuzumab, pertuzumab and T-DM1) HER2-positive MBC (with 
or without active/stable brain metastases) were randomized to receive capecitabine plus 
trastuzumab plus tucatinib or capecitabine plus trastuzumab plus placebo. PFS at 1 year was 
33.1% in the investigational arm in contrast to 12.3% in the control arm (Hazard Ratio 0.54; 
p<0.001), with a median PFS of 7.8 vs 5.6 months, respectively. OS at 2 years was 44.9% in the 
tucatinib arm and 26.6% in placebo arm.  Consequently, tucatinib has been approved by the FDA 
and EMA in patients that have received at least two prior anti-HER2 treatment regimens since 
2020. 
T-DXd is a next generation antibody-drug conjugate composed of a monoclonal anti-HER2 
antibody and a topoisomerase I inhibitor (DX-8951f). T-DXd has been granted approval by the 
FDA and EMA, and in Europe it is indicated as monotherapy for the treatment of adult patients 
with unresectable or metastatic HER2-positive breast cancer who have received two or more 
prior anti-HER2 based regimens (for more information about T-DXd see Section 1.4).  

 
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1.4. 
Overview of Trastuzumab deruxtecan 
T-DXd is a HER2-targeted antibody and topoisomerase I inhibitor conjugate. T-DXd is 
composed of a recombinant humanized anti-HER2 immunoglobulin G1 (IgG1) monoclonal 
antibody (mAb) that has the same amino acid sequence of trastuzumab, covalently conjugated to 
a drug-linker, deruxtecan. The released drug, DXd, inhibits topoisomerase I and leads to 
apoptosis of the target cells. 
1.4.1 
Preclinical Data 
The information in this section is taken from the Investigator Brochure (IB)12. Refer to this 
document for further details on the preclinical data.  
The pharmacokinetics and drug metabolism of T-DXd were investigated in cynomolgus monkeys 
to support toxicology studies and to support ongoing and planning clinical studies.  
1.4.2 
Human Pharmacokinetic (PK) Data 
The information in this section is taken from the IB12. Refer to this document for further details 
on the human PK data. 
The clinical pharmacology of T-DXd has been analyzed in a majority of completed clinical 
studies. 
The clinical pharmacology of T-DXd has been well characterized with concentrations of all 3 
analyte components of the ADC (ie, intact T-DXd, total anti-HER2 antibody, and released drug, 
DXd). 
Pharmacokinetic (PK) parameters for T-DXd and total anti-HER2 antibody were comparable. 
Serum concentrations of DXd gradually increased and reached peak concentrations with longer 
median time to maximum serum concentration (Tmax; approximately 6 hours) compared to T-
DXd (approximately 2 hours). On a molar basis, the T-DXd Cmax and trough concentrations 
across the 5.4 mg/kg to 7.4 mg/kg doses were approximately 50-fold to 53-fold and 69-fold to 
94-fold higher, respectively, than those for DXd, demonstrating in vivo stability of the ADC. 
The exposure of T-DXd, total anti-HER2 antibody, and DXd increased in a dose-related manner, 
with T-DXd exposure proportional to dose in the 3.2 mg/kg to 8.0 mg/kg dose range. In the 0.8 
mg/kg to 8.0 mg/kg dose range, the maximum serum concentration (Cmax) increased 
proportional to dose, while the area under the serum concentration-time curve (AUC) for T- DXd 
and total anti-HER2 antibody increased slightly more than proportional to dose. Exposures 
(Cmax and AUC) for DXd increased proportional to dose in the 0.8 mg/kg to 8.0 mg/kg dose 
range. 
PK data from the Dose Expansion part of the Study DS8201-A-J101, as of 01 Feb 2019 showed 
that the T-DXd, total anti-HER2 antibody, and DXd exposures were similar between HER2-

 
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positive and HER2-low breast cancer. The T-DXd and total anti-HER2 antibody exposures 
appeared to be numerically lower in HER2-positive gastric/gastroesophageal junction (GEJ) 
cancer than in breast cancer. DXd exposures were consistent across all tumor types evaluated. 
PK data as of 21 Mar 2019 showed that PK parameters were comparable for FL DP2 and Lyo-
DP following administration of 5.4 mg/kg of T-DXd (DS8201-A-U201 [DESTINY-Breast01]). 
The mean accumulation ratio for area under the plasma concentration-time curve during dosing 
interval (AUCtau) at Cycle 3 was 1.35 for T-DXd, 1.36 for total anti-HER2 antibody, and 1.09 
for DXd (DS8201-A-J102). 
The administration of T-DXd together with OATP1B, CYP3A y gp-P inhibitors did not produced 
a clinically significant increase in the concentration of T-DXd or DXd (approximately 10-20%).  
1.4.3 
QTc Evaluation Data 
QTc evaluation was performed in non clinical and clinical studies. In cynomolgus monkeys 
during the IV administration of 3 doses of T-DXd over a 6-week period, 1 female was euthanized 
moribund at 78.8 mg/kg, the highest dose level tested. At this dose level electrocardiogram 
(ECG) abnormalities (shortened PR interval and QTc prolongation) were found. 
DS8201-A-J102 was a Phase 1, multicenter, open-label, multiple-dose study of T-DXd designed 
to assess the effect on the QTc interval and PK after multiple dosing in subjects with HER2 
overexpressing metastatic and/or unresectable breast cancer. A total of 51 subjects received T-
DXd in this study. The DCO date for the primary analysis occurred after all subjects had 
completed at least 3 cycles. T-DXd 6.4 mg/kg administration was not associated with a clinically 
meaningful (change from baseline >10 milliseconds) prolongation of QT interval corrected for 
heart rate by Fridericia’s formula (QTcF) in subjects with unresectable and/or metastatic HER2 
overexpressing BC. The upper bound of the 90% CI for change in QTcF at the observed mean 
Cmax for each analyte (T-DXd and DXd) in the linear model of concentration vs change in QTcF 
for Cycles 1 and 3 was under 10 milliseconds. 
1.4.4 
Trastuzumab deruxtecan Dose Rationale 
The DESTINY-Breast01 is a phase 2 multicenter trial evaluating T-DXd in previously treated 
HER2-positive breast cancer patients. The first part of the study consisted of 2 cohorts for PK 
and a dose-finding, respectively.  
In the PK stage in part 1 of the study, the dose of T-DXd that was administered was 5.4 mg per 
kilogram in 22 patients, 6.4 mg/kg in 22 patients, and 7.4 mg/kg in 21 patients. The resulting PK 
profiles were analyzed in conjunction with those from the phase 1 study, DS8201-A-J101; 5.4 
mg/kg and 6.4 mg/kg were chosen for the dose-finding stage. 
In the part 1 dose-finding stage, an additional 28 and 26 patients (who were not enrolled during 
the PK stage) received 5.4 mg/kg and 6.4 mg/kg, respectively. Exposure-efficacy modeling 

 
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showed a significant relationship between exposure and response rate and a trend for longer 
progression-free survival at higher doses. Similarly, exposure-safety modeling showed a 
significant relationship between exposure and key adverse events (AEs), including interstitial 
lung disease. On the basis of the balance of safety and efficacy, a dose of 5.4 mg/kg was 
recommended13. 
1.4.5 
Trastuzumab deruxtecan data in HER2-positive Breast Cancer 
As of 08 Jun 2023, T-DXd is being evaluated in 34 clinical studies (20 monotherapy studies and 
14 combination therapy studies). 
Sixteen studies are complete, and 18 studies are ongoing (16 studies in breast cancer; 24 in phase 
I/II and 10 in phase III). 
The 2 most important studies in HER2-positive breast cancer are the DESTINY-Breast01 and 
DESTINY-Breast03. 
As described before, the DESTINY-Breast01 is a phase 2 multicenter trial evaluating T-DXd in 
previously treated HER2-positive breast cancer patients. The first part of the study established a 
dose of 5.4 mg/kg. The second part evaluated the safety and efficacy of T-DXd at the 
recommended dose in patients who had progressive disease while on or after receiving T-DM1 
and in patients who discontinued T-DM1 for other reasons. Overall, 184 patients received the 
recommended dose of 5.4 mg/kg. The observed response rate was 60.9% (112/184), including 
6.0% complete response and 54.9% partial response rates. Disease control rate resulted in 97.3% 
of patients. Median duration of response was 14.8. months, and median PFS was 16.4 months13,14. 
The DESTINY-Breast03 is a phase 3, multicenter, open-label, randomized trial comparing the 
efficacy and safety of T-DXd and T-DM1 in patients with HER2-positive metastatic breast 
cancer previously treated with trastuzumab and a taxane. Among the 524 included patients, the 
proportion who were alive without disease progression at 12 months was 75.8% with T-DXd and 
34.1% with T-DM1 (hazard ratio, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The proportion of 
patients who were alive at 12 months was 94.1% with T-DXd and 85.9% with T-DM1 (hazard 
ratio, 0.55; 95% CI, 0.36 to 0.86; prespecified P-value significance boundary not reached). The 
overall response was 79.7% of patients receiving T-DXd and 34.2% of those receiving T-DM1. 
The incidence of drug-related AEs of any grade was 98.1% with T-DXd and 86.6% with T-DM1, 
and the incidence of drug related AEs of grade 3 or 4 was 45.1% and 39.8%, respectively. 
Interstitial lung disease or pneumonitis occurred in 10.5% of patients in the T-DXd group and in 
1.9% of those in the T-DM1 group; none of these events were of grade 4 or 515,16. 
1.5.  Study Rationale 
The HER2-positive breast cancer subtype (that represents around 20% of all breast cancers) was 
classically associated with poor prognosis however, new therapeutic advances (particularly 

 
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targeted therapies) have significantly increased the cure rate of patients in early stages. In the 
metastatic setting, anti-HER2 targeted therapies have significantly improved overall survival 
(OS) with good quality of life, however there is still a substantial group of patients who die, and 
therefore additional drugs need to be investigated.  
In 
early, 
locally 
advanced 
or 
inflammatory 
HER2-positive 
breast 
cancer, 
neoadjuvant/preoperative chemotherapy in combination with trastuzumab and pertuzumab is 
standard of care in patients with tumors ≥T2 and/or ≥N1, based on the results of several studies 
17,18. For patients who have received neoadjuvant chemotherapy plus HER2-targeted therapy, the 
risk of disease recurrence or death is higher in patients with residual invasive disease at surgery 
than the risk in patients with a pCR19-21.  
Recently, T-DM1 has been approved for the adjuvant treatment for patients with HER2-positive 
early BC who have residual invasive disease following neoadjuvant trastuzumab and 
chemotherapy based on results of the KATHERINE study22. 
In patients not receiving neoadjuvant chemotherapy, the use of adjuvant trastuzumab in HER2-
positive early-stage BC improves patient outcomes as demonstrated in several large, randomized 
trials23-25. In addition the results of the APHINITY study led to the approval of the double 
blockage with trastuzumab plus pertuzumab in combination with chemotherapy in the adjuvant 
setting of patients with node positive disease26. 
At disease relapse, the current standard of care for patients with HER2-positive MBC consists of 
treatment with pertuzumab plus trastuzumab plus a taxane as first-line treatment based on the 
CLEOPATRA data, followed by trastuzumab-emtansine (T-DM1) in second line, based on the 
EMILIA data. Recently, results reported in the phase 3 DESTINYBreast-03 trial15-16 will 
probably change clinical practice regarding second line setting, with T-DXd showing much better 
results compared to T-DM1.  
The CLEOPATRA study included patients with late recurrences (more than 12 months from the 
completion of all therapy and the diagnosis of metastatic disease), so no data of the combination 
of trastuzumab plus pertuzumab plus a taxane in first line in patients recurring earlier are 
available from this study. For T-DM1, the EMILIA trial included some patients in first line, only 
those relapsing within the first 6 months after completing adjuvant treatment. Besides, a 
retrospective real-world cohort of early-relapsing patients demonstrated PFS and OS superiority 
of trastuzumab pertuzumab and chemotherapy over T-DM1 in patients with relapses between 6 
and 12 months and even in the first 6 months27.  
Thus, currently there is not enough data concerning the better strategy in patients with relapse 
within one year after completing adjuvant treatment, especially in those that have previously 
received prior trastuzumab and pertuzumab in early stage. 

 
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There is an ongoing study exploring T-DXd with or without pertuzumab versus taxane plus 
trastuzumab plus pertuzumab in HER2-positive MBC, the DESTINY-Breast09 study 
(NCT04784715), but again, patients with a short disease-free interval will not be included in the 
study. 
Based on all of these it is quite reasonable to study the use of T-DXd in early relapse breast 
cancer patients that have previously received trastuzumab and pertuzumab and or T-DM1 in early 
stage. 
 
 

 
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2. Objectives 
2.1. 
Primary Objective 
• To evaluate the antitumor activity of T-DXd in the first-line treatment of HER2-positive 
breast cancer patients resistant to trastuzumab-pertuzumab based therapy. 
2.2.  Primary Endpoint 
• Objective Response Rate (ORR) is defined as the rate of complete response (CR) plus 
partial response (PR) based on the investigator’s assessment using the Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1., out of the patients who 
received at least 1 dose of treatment. 
2.3. 
Secondary Objectives 
• To assess other efficacy measures.  
• To evaluate safety and tolerability in all patients enrolled in the study. 
• To evaluate health-related quality of life (HRQoL). 
2.4.  Secondary Endpoints 
• Other efficacy endpoints: 
o Progression-Free Survival (PFS) is defined as the time from the date of enrollment 
to the date of disease progression, based on the investigator’s assessment using 
RECIST version 1.1., or death from any cause, whichever occurs first.  
o Overall Survival (OS) is defined as the time from the date of enrollment to the date 
of death from any cause. 
o Time to treatment response (TTR) is defined as the time from the date of enrollment 
to the date of first documentation of objective tumor response (CR or PR). 
o Duration of response (DoR) is defined as the time from the date of first 
documentation of objective tumor response (CR or PR) to the date of first 
documented progressive disease based on the investigator’s assessment using 
RECIST version 1.1., or death from any cause, whichever occurs first.   
• Safety: Incidence and severity of Adverse Events (AEs) and clinical lab abnormalities. 
AEs grades will be defined by the National Cancer Institute Common Terminology 
Criteria for AEs (NCI-CTCAE) version 5.0. AE terms will be coded according to the 
MedDRA dictionary. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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• Tolerability: Incidence of T-DXd dose modifications, discontinuations due to AEs, 
number of administered cycles, dose intensity, etc. 
• Changes (mean score) and time to deterioration on EORTC QLQ-C30 Global Health 
Status/QoL from baseline. 
2.5.  Exploratory Objectives 
• To assess other efficacy measures.  
• To assess T-DXd efficacy according to HER2-expression and HER2 spatial distribution. 
• To explore T-DXd efficacy based on the intrinsic tumor subtypes, and evaluate if patients 
with HER2-Enriched intrinsic tumor subtype benefit most from T-DXd. 
• To improve the understanding of the mechanism of action and resistance to T-DXd in 
HER2-positive advanced breast cancer patients. Explore, among others, disease-related 
inflammatory, immune, or microenvironment-related biomarkers and their correlation 
with the study treatment, and other potential parameters of clinical utility in blood and 
tumor samples. 
• To explore the possibility of monitoring response to T-DXd by using longitudinal ctDNA 
assessment. 
To improve the understanding of molecular mechanisms of the metastatic breast cancer. 
2.6.  Exploratory Endpoints 
• PFS2 and PFS3 are defined as the time from the date of enrollment to the date of disease 
progression to the second and third lines of therapy, respectively. 
• Investigate the predictive value of HER2 expression levels and HER2 spatial distribution 
in baseline tumors.  
• Intrinsic molecular subtypes of breast cancer. 
• Genomic profiles and molecular biomarkers (e.g. PIK3CA mutations, tumor infiltrated 
lymphocytes, PD-1, PD-L1, gH2AX, CD3, CD4, CD8, CD68, FoxP3, CK/SOX10), 
analyzed in tumor tissue and blood samples, associated with treatment response or 
resistance, and the outcome of patients. Biological samples of patients considered as 
‘exceptional responders’ or as ‘rapid progressors’ based on the clinical follow-up could 
be subjected to deeper molecular characterization. 
• ctDNA alterations related to response or resistance to treatment.  
• Explore tumor subtypes and other biological subgroups, defined by biomarkers involved 
in immune response, proliferation, cell cycle regulation, DNA-repair, apoptosis, signal 
transduction pathways and oncogenic dependency, among others. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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3. 
Investigational Plan 
3.1. 
Study Design 
This is a national, multicenter single arm phase II clinical trial to study the efficacy, safety and 
tolerability of the administration of T-DXd in HER2-positive locally advanced or metastatic 
breast cancer (MBC) patients considered resistant to trastuzumab plus pertuzumab plus taxane 
due to early relapse (< 12 months from last anti-HER2 adjuvant therapy). 
Forty-one evaluable patients will be enrolled in the study and treated with T-DXd according to 
the following study design: 
 
Figure 1. Study Design 
  
 
Patients will continue to receive their assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever 
occurs first.  
For safety reasons all patients will have a visit 30 (±5) days after finishing treatment with the 
study treatment. This post-treatment visit must be performed before starting any new anticancer 
therapy. In case the beginning of a new therapy cannot be delayed as per the investigator’s 
judgment, the safety visit may be performed in advance and always before starting the new 
anticancer therapy. 
After progression, all patients will be followed until death or data cut-off date for secondary 
objectives or withdrawal of the informed consent. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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In order to perform exploratory biomarker analysis, pre-treatment tumor and sequential blood 
samples (at baseline, every three cycles and at the end of treatment [EOT]/PD) will be obtained.  
3.2. 
Duration of the study  
The start date of study is the date of the first site activation. 
It is estimated that the accrual will be completed in approximately 24 months.  
Patients will be treated till disease progression with an estimated median PFS of 18 months. After 
progression, all patients will be followed until death or data cut-off date for secondary objectives, 
assumed to be approximately 36 months, to estimate OS. The end date of study is the date of the 
last visit of the last patient (LPLV) including follow up. 
According to what is outlined above, the duration of the study will be approximately 68 months 
(5.7 years) from the first patient in. 
Performing exploratory objectives will be independent of the date of the end of the study. 
 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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4. 
Study Population 
4.1. 
Inclusion Criteria 
Patients are eligible to be enrolled in the study only if they meet all of the following criteria: 
1. Written and signed informed consent obtained prior to any study-specific procedure. 
2. Male or female patients of at least 18 years of age. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1. 
4. Life expectancy ≥ 12 weeks. 
5. Recurrent breast cancer that is unresectable locally advanced or metastatic. 
6. Pathologically documented HER2-positive status by local laboratory determination, 
preferably on the most recent available FFPE tumor sample, according to the American 
Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 
international guidelines valid at the time of the assay. In case of discordance in HER2 
status in different biopsies, the result from the most recent biopsy will be used. 
7. Pathologically documented Hormone Receptor (HR)-positive or -negative by local 
laboratory determination, preferably on the most recent available FFPE tumor sample, 
and according to ASCO/CAP international guidelines valid at the time of the assay. In 
case of discordance in HR status in different biopsies, the result from the most recent 
biopsy will be used. 
8. Prior anti-HER2 based therapy (with trastuzumab plus pertuzumab plus taxane with or 
without trastuzumab-emtansine [T-DM1]) in the (neo)adjuvant setting with a relapse 
while on therapy or within 12 months from the end of last anti-HER2 therapy. 
9. Measurable disease assessed by the investigator based on RECIST version 1.1. 
10. Left ventricular ejection fraction (LVEF) ≥ 50% measured by multiple-gated 
acquisition scan (MUGA) or echocardiogram (ECHO).  
11. Adequate organ and marrow function defined as follows: 
a. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/L). 
b. Platelet count ≥ 100,000/mm3 (100x109/L). 
c. Hemoglobin ≥ 9g/dL (90g/L). 
d. Creatinine clearance ≥ 30 mL/min as calculated using the standard method for the 
institution. 
e. Total serum bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the 
presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) 
or liver metastases at baseline. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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f. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3.0 x 
ULN (< 5.0 × ULN in participants with liver metastases). 
g. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN if bone or liver metastases 
are present). 
h. Serum albumin ≥ 2.5 g/dL 
12. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) 
≤ 1.5 x ULN. 
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests 
and other study procedures. 
14. Negative serum pregnancy test with a sensitivity of at least 25 mIU/mL (unless 
permanent previous sterilization procedure such as bilateral salpingectomy, bilateral 
oophorectomy, or complete hysterectomy) for premenopausal women, and for women 
who have experienced menopause onset < 12 months prior to first dose of therapy. 
 
4.2. 
Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Prior chemotherapy or HER2-targeted therapy for locally advanced or MBC (one prior 
endocrine therapy regimen for MBC without concurrent anti-HER2 therapy or 
radiotherapy is allowed). 
2. Ineligible for treatment with T-DXd. 
3. Any substance abuse or other medical conditions that, in the investigator's opinion, may 
interfere with patient's participation or study results. 
4. Patients with spinal cord compression, leptomeningeal disease or clinically active central 
nervous system (CNS) metastases. Participants with clinically inactive brain metastases 
or treated brain metastases that are no longer symptomatic, and no needing corticosteroids 
or anticonvulsants may be enrolled in the study.  
5. Active or prior documented interstitial lung disease (ILD)/pneumonitis or suspected 
ILD/pneumonitis that cannot be ruled out by imaging at screening. 
6. Lung criteria: 
a. 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 enrollment, severe asthma, severe Chronic obstructive 
pulmonary disease (COPD), restrictive lung disease, pleural effusion etc.). 
b. 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 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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should be recorded in the electronic Case Report Form (eCRF) for patients who 
are enrolled in the study.   
c. Prior pneumonectomy. 
7. Medical history of myocardial infarction within 6 months before registration, 
symptomatic congestive heart failure (CHF), troponin levels consistent with myocardial 
infarction as defined according to American College of Cardiologists (ACC) guidelines, 
unstable angina, or serious cardiac arrhythmia requiring treatment. QT interval corrected 
using Fridericia’s formula (QTcF) > 470 msec (females) or > 450 msec (males) based on 
average of the screening triplicate 12-lead ECG.  
8. History of active primary immunodeficiency, known Human Immunodeficiency Virus 
(HIV), active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV). 
9. Patients who received before treatment starts: 
d. Any investigational agent within 4 weeks.  
e. Chemotherapy within a period of time that is shorter than the cycle duration used 
for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicine or < 
1 week for weekly chemotherapy). 
f. Targeted therapy (e.g., antibodies): up to 4 weeks prior to starting study treatment. 
g. Endocrine therapy: tamoxifen or aromatase inhibitor within 2 weeks prior to 
starting study treatment. 
h. Radiotherapy within 2 weeks prior to starting study treatment. Patients who 
received prior radiotherapy to >25% of bone marrow are not eligible regardless 
of when it was administered. 
i. Major surgery or other anti-cancer therapy not previously specified within 4 
weeks prior to starting study treatment. 
In any case, resolution of all acute toxic effects of prior anti-cancer therapy or surgical 
procedures to NCI-CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicities not 
considered a safety risk for the patient at investigator´s discretion) is mandatory.Patients 
may be enrolled with chronic, stable grade 2 toxicities (defined as no worsening to > 
grade 2 for at least 3 months prior to enrollment and managed with standard of care 
treatment) that the investigator deems related to previous anticancer therapy, such as: 
chemotherapy-induced neuropathy or fatigue and immunotherapy-induced toxicities (e.g. 
endocrinopathies as hypothyroidism/hyperthyroidism, type 1 diabetes, hypoglycemia, 
adrenal insufficiency, adrenalitis and skin hypopigmentation [vitiligo]). 
10. Have a diagnosis of any other malignancy within 3 years prior to inclusion, except for 
adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other 
solid tumors curatively treated and contralateral breast cancer. 
11. Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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12. Prior treatment with T-DXd or allergic reaction to trastuzumab. 
13. Patient is pregnant or breastfeeding or planning to become pregnant within the projected 
duration of the trial, starting at screening and through 7 months after the last dose of the 
study treatment. Male patients whose partners plan to become pregnant within the 
duration of the trial, starting at screening and through 4 months after the last dose of the 
study treatment.  
✓ For premenopausal women it is necessary an agreement to remain complete 
abstinent or use single or combined non-hormonal contraceptive methods that 
result in a failure rate of < 1% per year during the treatment period and for at least 
7 months after the last dose of study treatment. 
▪ Examples of non-hormonal contraceptive methods with a failure rate of < 
1% per year include bilateral tubal litigation, male sterilization, and certain 
intrauterine devices (provided coils are copper banded). 
▪ Alternative, two methods (e.g. two barrier methods such as a condom and 
a cervical cap or combined with estrogen and progestogen) may be 
combined to achieve a failure rate of < 1% per year. Barrier methods must 
always be supplemented with the use of a spermicide. 
Female patients must not donate, or retrieve for their own use, ova from the time 
of enrollment and throughout the study treatment period, and for at least 7 months 
after the final study drug administration. They should refrain from breastfeeding 
throughout this time. Preservation of ova may be considered prior to enrollment 
in this study. 
✓ For men it is necessary an agreement to remain complete abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and to refrain from 
donating sperm during the same period, as defined below with female partners of 
childbearing potential or pregnant female partners, men must remain abstinent or 
use a condom during the treatment period and for at least 4 months after the last 
dose of study treatment to avoid exposing the embryo.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
14. Uncontrolled intercurrent illness including uncontrolled infection requiring intravenous 
(IV) antibiotics, antivirals, or antifungals. 
Has substance abuse or any other medical/psychological conditions that may, in the opinion of 
the investigator, interfere with the patient’s participation in the clinical study or evaluation of 
the clinical study results. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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4.3. 
Discontinuations 
4.3.1. 
Discontinuation of Study Treatment 
The criteria for enrollment must be followed explicitly. If a patient who does not meet enrollment 
criteria is inadvertently enrolled, that patient should be discontinued from the study treatment, 
but can be allowed to continue in the study in order to provide the follow-up data needed for the 
analysis of the entire population. An exception may be granted if the patient, in the opinion of 
the investigator, is having benefit from the study treatment. In these rare cases, the investigator 
must obtain documented approval from GEICAM to allow the patient to continue to receive the 
study treatment. 
Patients can be discontinued from the study therapy in the following circumstances: 
• 
Patient’s own request. 
• 
Unacceptable toxicity as defined in the protocol. 
• 
Tumor progression as defined in the protocol. 
• 
Any clinical AE, laboratory abnormality or inter-current illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of 
the patient. 
• 
Pregnancy: 
✓ Instruct to contact the investigator or study staff immediately if they suspect they 
might be pregnant. 
✓ The investigator must immediately notify GEICAM if a study patient or the female 
partner of a male patient becomes pregnant. 
• 
Termination of the study by GEICAM. 
• 
Physician’s decision, including need of other anti-cancer therapy, not specified in the 
protocol.  
• 
If the patient is non-compliant with study procedures.  
• 
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g. infectious disease) illness. 
• 
Death 
All permanent treatment discontinuation should be recorded by the Investigator in the electronic 
Case Report Form (eCRF) when considered as confirmed. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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4.3.2. 
Discontinuation of Study Sites 
Study Site participation may be discontinued if GEICAM, the investigator or the Ethics 
Committee/Institutional Review Board (EC/IRB) of the study site judges it necessary for any 
reason.  
4.3.3. 
Discontinuation of Study 
The study may be discontinued by GEICAM if this is medically reasonable and consistent with 
applicable regulations of Good Clinical Practice (GCP). Stopping the study for medical reasons 
may be required if patients experienced adverse reactions under the treatment with the study 
treatment or if new information about the safety or effectiveness of the study treatment justifies 
it. 
4.4. 
Menopausal status definitions and contraception 
For the purpose of this study, a woman is considered of childbearing potential (WOCBP), i.e. 
fertile, following menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy.  
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a post-menopausal state in women not using hormonal contraception or hormone 
replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
For the purpose of this study, a man is considered fertile after puberty unless permanently sterile 
by bilateral orchidectomy. 
Patients of childbearing potential must agree to avoid becoming pregnant while receiving study 
drug and for 7 months after the last dose of study treatment to avoid exposing the embryo. 
If there is any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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5. Treatment 
5.1. 
Treatments Administered 
All patients enrolled will be treated with the following: 
✓ Trastuzumab deruxtecan 5.4 mg/kg IV every 3 weeks (± 3 days). 
The subject’s weight at baseline will be used to calculate the initial dose. If during the course of 
treatment the subject’s weight changes by ± 10% of the baseline weight, the subject’s dose will 
be recalculated based on the subject’s updated weight. 
Patients will receive T-DXd until unacceptable toxicity, progressive disease (PD), informed 
consent withdrawal, or other discontinuation criterion is met.  
5.2. 
Materials and Supplies 
T-DXd used in this trial will be named as study treatment throughout the protocol.  
T-DXd will be provided to the study sites by GEICAM with the appropriate label for clinical 
trial use for the purpose of this study.  
5.2.1.  
Storage, preparation and administration of trastuzumab deruxtecan 
Investigators and site staff are reminded to continuously monitor refrigerator storage 
temperatures and ensure that thermometers are working correctly as required for proper storage 
of study treatment. These include thermometers for the refrigerator storage.  
Storage area temperature conditions must be monitored and recorded daily. A daily temperature 
log will also be kept at the study site. 
Any issue or deviation that affect the storage conditions or handling of the study treatment must 
be reported to the Sponsor for its information. 
For T-DXd provided by the Sponsor, any temperature excursions must be reported immediately 
to GEICAM and documented. Once a deviation is identified, the study treatment MUST be 
quarantined and not used until GEICAM provides documentation of permission to use the study 
treatment product.  
T-DXd should be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements. Returned study treatment provided by the Sponsor should be stored 
separately from study treatment that needs to be dispensed. 
5.2.1.1. 
Packaging and storage 
T-DXd will be supplied by AstraZeneca as a 100 mg/vial lyophilized powder for concentrate for 
solution for infusion in a single-use glass vial. It is supplied in carton containing 1 vial and should 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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be stored in their original container protected from light at 2°C–8ºC. Storage conditions and the 
expiry date are indicated on the primary and secondary package label. T-DXd must be stored in 
its original packaging at controlled refrigerator and protected from moisture. The investigator or 
designee must confirm that appropriate temperature conditions have been maintained during the 
transit for the received T-DXd and that any discrepancies are reported and resolved before its 
use. 
Please refer to the current version of the T-DXd IB and/or Pharmacy Manual for further details 
on the use, handling, and storage of the study drug. 
5.2.1.2. 
Preparation 
Dilution for dose solution preparation must occur under appropriate aseptic conditions, as the 
study drug contains no preservatives.  
Reconstitute each 100 mg vial using a sterile syringe to slowly inject 5 mL of water for injections 
in each vial to obtain a final concentration of 20mg/ml. 
Dose solutions should be prepared in a 100 mL IV infusion bag containing sterile 5% aqueous 
glucose solution. The infusion bag is constructed with product contacting materials of polyvinyl 
chloride (PVC), polyethylene (PE), or polyolefin (PO) composed of PE and polypropylene (PP). 
Slowly add the required volume of drug product to the IV bag and gently mix by slowly rotating 
the bag without shaking. 
The solution for infusion should be used immediately to limit product degradation and microbial 
growth in case of potential accidental contamination. If not used immediately, the dose solution 
may be stored at 2°C–8°C for 24 hours or at ambient temperature ≤25°C for 4 hours. This time 
includes storage and time for administration for infusion. If the dose solution is stored at 2°C-
8°C, it should be removed from refrigeration and allowed to reach room temperature prior to 
administration. 
5.2.1.3. 
Administration 
In the first infusion T-DXd should be infused over 90 minutes. 
In the subsequent infusions T-DXd should be infused over 30 minutes if the previous infusion 
was well tolerated without an infusion-related reaction. 
5.2.2. 
Accountability 
It is the responsibility of the investigator to ensure that a current record of T-DXd disposition is 
maintained at each study site where study treatment provided by GEICAM are inventoried and 
disposed.  

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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A drug dispensing log, including records of T-DXd received from GEICAM and T-DXd 
administered to the patients, will be provided and kept at the study site. GEICAM will provide 
forms to facilitate inventory control if the staff at the investigational site does not have an 
established system that meets these requirements. Records or logs must comply with applicable 
regulations and guidelines.  
T-DXd provided by GEICAM will be preferably destroyed at each participating site. The site 
must obtain written authorization from GEICAM before it is destroyed, and this destruction must 
be documented on the appropriate form. 
5.3. 
Method of Assigning a Patient to a Treatment 
All patients who meet all criteria for enrollment will be registered to receive T-DXd. 
Patients will be screened by one of the investigators prior to study entry. An explanation of the 
study and discussion of the expected side effects and presentation of the informed consent 
document (ICD) will take place. Eligible and consented patients will be screened and then 
enrolled into the study.  
All patients screened in the study, will be included in a Patient Screening Log maintained at each 
site and at the GEICAM central office. 
No patients can be enrolled and receive study treatment until the patient has been screened in the 
study. All eligibility criteria must be met at the time of enrollment. There will be no exceptions. 
Any question should be addressed with GEICAM prior to enrollment. An eligibility checklist 
must be completed and signed by the Principal Investigator or Sub-Investigator before enrolling 
each patient to confirm all inclusion/exclusion criteria. This eligibility checklist should be filed 
with the study documentation. Once the eligibility checklist is completed, the study personnel at 
the site will enroll the patient through the eCRF and the system will send the unique enrollment 
number of the patient. This enrollment number should be used on all documentation and 
correspondence with the GEICAM central office. Only after the confirmation of enrollment by 
the system, the patient can receive the study treatment. All patients enrolled in the study will be 
registered in a Patient Enrollment and Identification Log that will be only maintained at the site. 
Study treatment must be administered within 7 days from enrollment.  
5.4. 
Special Treatment Considerations. Dose Adjustments of Study 
Treatment 
All dose modifications should be based on the worst preceding toxicity.  
Every effort should be made to administer study treatment at the planned dose and schedule. 
However, in the event of significant treatment-related toxicity, administration of study treatment 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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may need to be adjusted as described in the following sections. Depending on the nature of the 
toxicity observed, dose adjustments may be required for T-DXd. 
All dose modifications/adjustments must be clearly documented in the patient's source notes and 
the appropriate section of the eCRF.  
5.4.1.  
Dose Interruptions and Reductions 
In the event of significant treatment-related toxicity, T-DXd dosing may be interrupted or 
delayed and/or reduced. Patients are to be instructed to notify Investigators at the first occurrence 
of any adverse sign or symptom. 
T-DXd recommended dose modifications for treatment related toxicities requiring treatment 
interruption/delay/reduction or persisting despite optimal medical treatment are described in 
Tables 1 and 2. 
Table 1. Dose Reduction Levels of T-DXd 
Dose Level 
T-DXd 
Starting dose 
5.4 mg/kg 
-1 
4.4 mg/kg 
-2 
3.2 mg/kg 
 
Table 2. Dose Modifications of T-DXd 
Worst toxicity NCI-CTCAE v 5.0 
Grade (unless otherwise specified) 
Management Guidelines for T-DXd 
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 patients 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 
Administration of T-DXd should be interrupted and 
symptomatic treatment started (e.g. antihistamines, NSAIDs, 
narcotics, IV fluids). 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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anti-inflammatory drugs (NSAIDs), 
narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 hrs) 
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 T-DXd should be discontinued immediately 
and permanently. 
Urgent intervention indicated. Antihistamines, corticosteroids, 
epinephrine, bronchodilators, vasopressors, intravenous fluid 
therapy, oxygen inhalation etc., should be administered. 
Hematologic Toxicity: if supportive therapy fails (as clinically indicated and according to local practice), 
consider additional toxicity management guidelines as below. For any grade 4 hematological toxicity with 
significant clinical symptoms that does not resolve with treatment within 4 weeks, resuming T-DXd may be 
possible if the toxicity resolves, in consultation with GEICAM. 
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, then reduce dose 1 level 
Febrile Neutropenia  
(absolute neutrophil count < 1 x 109/L, fever 
> 38.3°C or a sustained temperature of ≥ 38 
°C for more than one hour) 
Delay dose until resolved, then reduce 1 dose level 
Lymphocyte Count Decreased 
Grade 1 to Grade 3  
No dose modification 
Grade 4 (< 0.2 x 109/L) 
Delay dose until resolved to ≤ Grade 2: 
- If resolved in ≤ 14 days from day of onset, maintain dose 
- If resolved in > 14 days from day of onset, reduce dose 1 
level 
Anemia 
Grade 3 (Hemoglobin [Hb] <8.0 g/dL); 
transfusion indicated 
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4 (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 patient from study treatment 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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Decrease in Left ventricle ejection fraction 
(LVEF) 10-20% (absolute value), but LVEF 
> 45% 
Continue treatment with T-DXd 
LVEF 40% to ≤ 45% and decrease is < 10% 
(absolute value) from baseline 
Continue treatment with T-DXd 
Repeat LVEF assessment within 3 weeks 
LVEF 40% to ≤ 45% and decrease is 10-
20% (absolute value) from baseline 
Interrupt T-DXd dosing 
Repeat LVEF assessment within 3 weeks: 
- If LVEF has not recovered to within 10% (absolute value) 
from baseline, discontinue permanently T-DXd 
- If LVEF recovers to within 10% from baseline, resume 
treatment with T-DXd at the same dose 
LVEF < 40% or > 20% (absolute value) 
drop from baseline 
Interrupt T-DXd dosing 
Repeat LVEF assessment within 3 weeks: 
- If LVEF < 40% or > 20% drop from baseline is confirmed, 
discontinue permanently T-DXd 
- If not confirmed, follow the rules described above 
Electrocardiogram QTc Prolonged 
Grade 3 (average QTc > 500 ms or >60 ms 
change from baseline) 
Delay dose until resolved to ≤ Grade 1 (corrected QT ≤ 480 ms), 
determine if another medication the patient 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 T-
DXd, reduce dose 1 level 
Grade 4  
(Torsade de pointes or polymorphic 
ventricular tachycardia or signs/symptoms 
of serious arrhythmia) 
Discontinue permanently T-DXd 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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Pulmonary Toxicity 
Any evidence of ILD/pneumonitis should be promptly 
investigated. If a subject develops radiographic changes 
potentially consistent with ILD/pneumonitis or develops new or 
worsening pulmonary or other related signs/symptoms such as 
dyspnea, cough or fever, rule out ILD/pneumonitis. 
If the AE is confirmed to have an etiology other than 
ILD/pneumonitis, follow the management guidance outlined in 
other AEs in this table. 
If the AE is suspected to be ILD/pneumonitis, treatment with T-
DXd should be interrupted pending further evaluations. 
Evaluations should include: 
- High resolution computer tomography (CT) Scan 
- Pulmonologist consultation (Infectious Disease consultation 
as clinically indicated) 
- Bronchoscopy and bronchoalveolar lavage if clinically 
indicated and feasible 
- Pulmonary function tests including forced vital capacity, 
carbon monoxide diffusing capacity and pulse oximetry 
(SpO2) 
- Clinical laboratory test 
- Arterial blood gases if clinically indicated 
- Blood culture, blood cell count, differential white 
blood cell count, C-reactive protein, COVID-19 test 
- One blood sample collection for PK analysis as soon 
as ILD/pneumonitis is suspected, if feasible 
Other tests could be considered, as needed (e.g., PCP screening, 
beta-D-glucan test, BAL) in all patients with suspected 
ILD/pneumonitis as part of the ILD diagnosis of exclusion 
especially in patients with 1 or more of the following risk 
factors: lymphopenia, long-term/intermittent steroid use, brain 
metastases, and chronic lung diseases). 
If the AE is confirmed to be  ILD/pneumonitis, follow the 
ILD/pneumonitis management guidance as outlined below. 
 
 All events of ILD/pneumonitis, regardless of severity or 
seriousness, will be followed until resolution including after T-
DXd discontinuation. 
Grade 1 
The administration of T-DXd must be interrupted for any 
ILD/pneumonitis events regardless of grade. 
- Monitor and closely follow-up in 2 to 7 days for onset of 
clinical symptoms and pulse oximetry. 
- Consider follow-up imaging in 1-2 weeks (or as clinically 
indicated). 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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- Consider starting systemic corticosteroids (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 (unless the 
patient is asymptomatic) 
T-DXd 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 has not resolved 
within 18 weeks (126 days) from the last infusion, T-DXd 
should be permanently discontinued. 
Grade 2 
Permanently discontinue T-DXd. 
- Promptly start and treat with systemic corticosteroids (e.g., 
at least 1mg/kg/day prednisone or equivalent) for at least 14 
days 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 corticosteroids (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. 
Grade 3 or 4 
Permanently discontinue T-DXd. 
- 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 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 T-DXd until resolved to ≤ Grade 1: 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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- 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 
Permanently discontinue T-DXd 
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) 
Permanently discontinue T-DXd 
Hepatic Toxicity 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) with simultaneous total blood 
bilirubin (TBL) increased (see section 5.4.1.1) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
Grade 2 (>3.0 - 5.0 x ULN if baseline was 
normal; >3.0 - 5.0 x baseline if baseline was 
abnormal) 
No action  
Grade 3 (>5.0 - 20.0 x ULN if baseline was 
normal; >5.0 - 20.0 x baseline if baseline 
was abnormal) 
In patients without liver metastases and 
patients with liver metastases and baseline 
level ≤ 3 x ULN 
Repeat testing within 3 days. Delay dose until resolved to ≤ 
Grade 1 if baseline was normal, 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 patients 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) 
Permanently discontinue T-DXd 
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, repeat testing within 3 days. 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: 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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- If resolved in ≤ 7 days from day of onset, reduce dose 1 
level 
- If resolved in > 7 days from day of onset, permanently 
discontinue T-DXd   
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, permanently 
discontinue T-DXd 
Grade 4 (>10.0 x ULN if baseline was 
normal; >10.0 x baseline if baseline was 
abnormal) 
Permanently discontinue T-DXd 
Blood Alkaline Phosphatase Increased 
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 
Permanently discontinue T-DXd 
Other AEs 
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 
Permanently discontinue T-DXd 
Once the dose of T-DXd has been reduced for a given patient because of toxicity, all subsequent 
cycles should be administered at that lower dose level unless further dose reduction is required. 
If toxicity continues after 2 dose reductions, then the patient will be withdrawn from study 
treatment. T-DXd dose re-escalation is not allowed in the study. 
Dose can be interrupted for up to 28 days from the planned date of administration. If a patient is 
assessed as requiring a dose delay longer than 28 days, the patient will be withdrawn from the 
study (except for Grade 1 ILD/pneumonitis for which a 126 delay is permitted). 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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5.4.1.1. Follow-up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with total bilirubin increase may be indicative of 
potential DILI and should be considered as clinically important events. 
In general, any increase of serum aminotransferases to > 3 x upper limit of normal (ULN) should 
be followed by repeat testing within 48 to 72 hours. 
If total bilirubin is elevated > 2 x ULN, fractionation into direct and indirect bilirubin is required. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and total 
bilirubin value; patients meeting any of the following criteria will require further follow-up as 
outlined below: 
• For patients with normal ALT and AST and total bilirubin value at baseline: AST or ALT 
≥ 3.0 x ULN combined with total bilirubin ≥ 2.0 x ULN. 
• For patients with elevated AST or ALT or total bilirubin value at baseline: AST or ALT 
≥ 2 x baseline AND > 3.0 x ULN OR AST or ALT ≥ 8.0 x ULN, combined with total 
bilirubin ≥ 2 x baseline AND ≥ 2.0 x ULN or ≥ 3.0 x ULN in case of Gilbert´s syndrome. 
Medical review needs to ensure that liver test elevations are not caused by cholestasis. 
Cholestasis is defined as ALP elevation > 2.0 x ULN with R value (see note below) < 2 in patients 
without bone metastasis.  
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic 
(R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. 
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat liver function testing as soon as possible, preferably within 48 hours 
from the awareness of the abnormal results. The evaluation should include laboratory tests, 
detailed history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
Upon presentation: 
• Perform comprehensive medical history including cardiac disease, blood transfusions, 
i.v. drug abuse, travel, work, alcohol intake, and full clinical examination for evidence of 
acute or chronic liver disease, cardiac disease, and infection etc. 
• History of concomitant drug use (including nonprescription medications and herbal and 
dietary supplement preparations), alcohol use, recreational drug use, special diets, and 
chemicals exposed to within one month of the onset of the liver injury. 
• Exclude other causes of liver disease. 
Patient monitoring: 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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• Repeat liver chemistry tests within 48-72 hours. 
• Retest frequency can decrease to weekly or less if abnormalities stabilize, drug has been 
discontinued, and the patient is asymptomatic. 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered, and their role clarified before the diagnosis of DILI is confirmed (see Table 3). Liver 
biopsy has limited value in the diagnosis of DILI as histopathological findings in DILI can 
resemble many other liver conditions. However, biopsy can be useful to establish an alternative 
diagnosis especially if other tests are inconclusive. 
If DILI confirmed: permanently discontinue. 
If DILI unlikely - interrupt treatment. Consider alternative causes of liver disease (see Table 3) 
Treat identified cause according to institutional guidelines. If resolved, reduce by one dose level. 
Re-administration of study treatment should be considered only if the investigator assesses 
benefit to outweigh the risk. Any decision regarding re-administration of study drug/s and dose 
regimen should be discussed with the Sponsor. 
Table 3. Alternative causes of liver disease 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBsAg, IgM anti-HBc, HBV 
DNA; anti-HCV, HCV RNA, IgM & IgG 
anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; 
IgM & IgG anti-EBV 
Autoimmune hepatitis 
ANA & ASMA titers, total IgM, IgG, IgE, 
IgA 
Alcoholic hepatitis 
Ethanol history, gammaGT, MCV, CD-
transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic CHF, 
hypotension, 
hypoxia, 
hepatic 
venous 
occlusion. Ultrasound or MRI. 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease 
Caeruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
Following appropriate causality assessments, as outlined above, the causality of the drug is estimated as “probable” 
i.e. > 50% likely, if it appears greater than all other causes combined. The term “drug-induced” indicates probably 
caused by the drug, not by something else, and only such a case can be considered a DILI case and should be reported 
as an SAE. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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5.5. 
Medication Errors and Overdose 
Medication errors may result in this study from the administration or consumption of the wrong 
drug, by the wrong patient, at the wrong time or at the wrong dosage strength. Such medication 
errors occurring to a study participant are to be captured on the AE page of the eCRFs and on the 
SAE form when appropriate. In the event of medication dosing error, GEICAM should be 
notified immediately.  
Medication errors are reportable irrespective of the presence of an associated AE/SAE, including: 
✓ Medication errors involving patient exposure to the product; 
✓ Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating patient. 
Whether or not the medication error is accompanied by an AE, as determined by the Investigator, 
the medication error and, if applicable, any associated AE(s) is captured on the AE eCRF page 
(refer to Management, Timing and Assessment of Adverse Events section for further details). 
5.6. 
General Concomitant Medication and Supportive Care Guidelines 
Patients must be instructed not to take any additional medication (over-the-counter or other 
products) during the study without prior consultation with the investigator. Any medications 
including herbal supplements, vitamins, or treatment taken by the patient from 28 days prior to 
the start of study treatment and up to 30 days following the last dose of study treatment and the 
reason for their administration must be recorded on the eCRF.  
Routine postoperative care, such as dressing changes, suture removal, drain removal, or venous 
access (central or peripheral), does not need to be recorded. Anesthetics used for any surgical 
procedures performed during the patient’s participation in the study can be recorded as 
“unspecified anesthesia” on the concomitant treatment records; it is not necessary to list the 
specific anesthetics. Palliative and supportive care for cancer-related symptoms will be offered 
to all patients in this study. 
5.6.1. 
Prohibited Medications 
The following treatments are prohibited throughout the duration of the active treatment phase: 
✓ Anticancer agents: No additional investigational or commercial anticancer agents such 
as chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or 
endocrine therapy will be permitted during the active treatment phase. In general, any 
drugs containing “for the treatment of breast cancer” on the product insert are not 
permitted on study. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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✓ Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (eg, 
raloxifene) are prohibited during the active treatment phase. 
✓ Any concurrent radiotherapy (except palliative radiotherapy as specified under Section 
5.6.3.) is prohibited throughout the duration of the active treatment phase of the study. 
Patients requiring this procedure will be discontinued from the active treatment phase and 
will enter the follow-up phase. This radiotherapy will be considered an alternative cancer 
therapy. 
✓ Chronic immunosuppressive therapies (IV or oral) withing 14 days prior to first study 
dose including corticosteroids or other immunosuppressive medications (methotrexate, 
azathioprine, and tumor necrosis factor- alpha blockers). IV or oral corticosteroids may 
be used only for: short-term courses (< 2 weeks) of low to moderate dose (<10mg 
prednisolone per day or equivalent); long-term, alternate-day treatment with short-acting 
preparations maintenance physiologic doses (replacement therapy). A temporary period 
of corticosteroid treatment will be allowed for different indications after discussion with 
the sponsor (e.g., chronic obstructive pulmonary disease, radiation, nausea, etc.). 
Patient’s with bronchopulmonary disorders who require intermittent use of 
bronchodilators (such as albuterol) will not be excluded from this study.  
The use of immunosuppressive medications for the management of T-DXd related AEs, 
as antiemetic prophylaxis (see Section 5.6.3) or in patients with hypersensitivity reactions 
to radiographic contrast agents is acceptable.  
Topical administration (skin or eyes), or by aerosol, or by intra-articular, bursal, or tendon 
injection prevention is permitted.  
✓ Chloroquine or hydroxychloroquine is not allowed during the study treatment. If 
treatment with them is absolutely required for SARS-CoV-2 (i.e. COVID-19), T-DXd 
must be interrupted and a wash-out period of more than 14 days will be required before 
restarting T-DXd. 
5.6.2. 
Medications Not Recommended 
The following treatments are not recommended throughout the duration of the active treatment 
phase. Alternative therapies should be considered whenever possible. If usage of the following 
treatments is deemed necessary, consultation and agreement with GEICAM is required prior to 
treatment initiation.  
✓ The use of herbal medicine is not recommended during the active treatment phase. 
✓ Patients must avoid using tanning lights and booths and should cover their skin and use 
sunscreen when in the sun (or exposed to UV radiation) as possible. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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5.6.3. 
Permitted Medications 
The following treatments are permitted throughout the duration of the active treatment phase:  
✓ Standard therapies for pre-existing medical conditions, medical and/or surgical 
complications, and palliation. Any medication intended solely for supportive care (eg, 
analgesics, antidiarrheals, antidepressants) may also be used at the investigator’s 
discretion. All medications should be recorded.  
✓ Bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) 
inhibitors for the treatment of osteoporosis or management of existing bone metastases 
may be continued for patients who are receiving them. However, the need to initiate or 
increase the dose of these therapies during the study will be considered as indicative of 
disease progression leading to the discontinuation of patient from the active treatment 
phase unless disease progression can be completely ruled out and the exact reason for the 
use of these therapies clearly documented in the patient’s source documentation. 
✓ Hematopoietic growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage colony stimulating factor [GM-CSF]): Primary prophylactic use 
of granulocyte-colony stimulating factors is not permitted but they may be used to treat 
treatment-emergent neutropenia as indicated by the current American Society of Clinical 
Oncology (ASCO) guideline. If neutropenic complications are observed in a cycle in 
which primary prophylaxis with CSFs was not received, secondary prophylaxis may be 
given at the discretion of the investigator, but only if dose reduction or delay are not 
considered to be a reasonable alternative. 
✓ Palliative radiotherapy is permitted for the treatment of painful bony lesions provided 
that the lesions were known to be present at the time of study entry and the investigator 
clearly documents that the need for palliative radiotherapy is not indicative of disease 
progression. For patients with bone involvement, it is suggested to administer palliative 
radiotherapy before study initiation if possible and clinically appropriate (eg, lesions at 
risk for spontaneous micro-factures or painful lesions). The dates on which palliative 
radiotherapy is administered should be recorded in concomitant medication. It is not 
required to hold T-DXd during palliative radiotherapy. 
Areas that have received palliative radiotherapy cannot be used to assess response to 
study treatment. 
✓ COVID-19 vaccination. Regarding the vaccination against COVID-19, national 
guidelines should be followed. 
✓ Hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy). 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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✓ Antiemetics. 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 corticosteroids (e.g. dexamethasone) 
should be considered and administered in accordance with the prescribing information or 
institutional guidelines. 
5.7. 
Treatment Compliance 
Patients will be treated with T-DXd at the site by the investigator or designee, under medical 
supervision. The date and start and end time of each dose administered at the site will be recorded 
in the source documents and in the eCRF. 
In case of infusion interruption, the times of infusion stop and restart will be recorded. If an 
incomplete dose is administered, the amount of drug infused will be calculated and entered in the 
eCRF. 
The dose of study treatment and study patient identification will be confirmed at the time of each 
dosing by a member of the study site personnel.  

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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6. 
Efficacy and Safety Evaluations, Sample Collection and Testing 
(Standard Laboratory Testing) and Appropriateness of Assessments 
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule, Protocol Attachment 1. 
6.1. 
Efficacy Assessments 
Tumor response will be assessed using RECIST 1.1. Tumor assessment should be performed 
during the screening period; however, if a patient has a valid image test performed up to 28 days 
before the date of enrollment it is not required to repeat it.  
Tumor assessment during the screening period should consist of clinical exam and of anatomical 
imaging consisting of:  
✓ Contrast enhanced (unless clinically contraindicated) CT scan or MRI of the chest, 
abdomen and pelvis (CAP). A positron emission tomography (PET)-CT scan will be 
accepted if the CT scan meets the RECIST version 1.1. requirements for tumor lesion 
evaluation. 
✓ Bone scan is mandatory if the patient has bone disease or if there is any suspicion of bone 
metastases. A PET scan will be also accepted to assess the already known or newly-
suspected bone metastatic disease. Any suspicious abnormalities (i.e., hotspots) identified 
on the bone or PET scan at screening must be confirmed by X-ray, CT scan with bone 
window or MRI. Additional bone scans will be performed only to confirm a complete 
response (CR) in patients with bone lesions identified at screening, or whenever clinically 
or biochemically bone progression or newly diagnosed bone disease is suspected.  
✓ Brain CT scan with IV contrast or MRI is mandatory if the patient has previously known 
CNS metastases or if there is any suspicion of CNS metastases. 
✓ CT scan or MRI of any other sites of disease as clinically indicated. 
✓ Clinical assessment of superficial disease by callipers which will include colour 
photographs of all superficial metastatic lesions including a ruler to estimate the size of 
the lesion. When lesions can be evaluated by both a clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective. 
All measurable and evaluable lesions should be assessed at the screening visit and re-assessed at 
each subsequent tumor evaluation and documented in the eCRF. Tumor assessments will be 
performed at screening, every 9 weeks (±7days) and after the third tumor evaluation every 12 
weeks (±7days) until radiographically and/or clinically (i.e., for photographed or palpable 
lesions) documented PD as per RECIST version 1.1., withdrawal of consent, start of new 
anticancer treatment, death, or study termination, whichever occurs first. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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Tumor assessment will be continued in patients that discontinue treatment without disease 
progression per RECIST version 1.1. until death, disease progression, start of new anticancer 
therapy, patient’s consent withdrawal, or study termination, whichever occurs first, every 12 
weeks (± 7 days) from the last tumor assessment and bone scans (if applicable) as stated above.  
The same radiographic procedures and technique must be used throughout the study for each 
patient.  
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.  
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as the primary data source. 
Patients discontinuing the tumor assessments for the primary endpoint will enter a follow-up 
period during which further treatments, date of progressions to the following two additional lines 
of therapy and survival information will be collected. Data collection will happen every 6 months 
(± 14 days) from the last tumor assessment. The follow-up period will conclude at the time of 
the final OS analysis.  
6.2. 
Safety Assessments  
Investigators are responsible for monitoring the safety of patients who have been enrolled in this 
study and for alerting GEICAM of any event that seems unusual. 
The investigator is responsible for appropriate medical care of patients during the study. 
The investigator remains responsible for following, through an appropriate health-care option, 
AEs that are serious or that caused the patient to discontinue before completing the study. The 
patient should be followed until the event is resolved or explained. Frequency of follow-up 
evaluation is left to the discretion of the investigator. 
During the course of the study, all patients enrolled in the trial must be evaluated according to 
the schedule outlined in the flow charts and described below. The results of the evaluation will 
be recorded in the eCRF pages until the patients are not followed anymore. 
6.2.1. 
Timing of Assessments 
All assessments to be performed at screening and during the study are specified in the Study 
Schedule, Protocol Attachment 1.  
Vital signs assessments will include blood pressure, pulse and body temperature.  

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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Measurement of LVEF by MUGA or ECHO will be performed at screening and at the times 
specified in the Study Schedule. The same method of LVEF assessment, ECHO or MUGA, must 
be used throughout the study, and to the extent possible, at the same institution. Triplicate 12-
lead ECGs will be obtained at screening (it is recommended to record the triplicate ECGs 2-4 
minutes apart) and at the times specified in the Study Schedule. Parameters will be measured, 
including RR, PR, QT intervals, and QRS duration. 
The following safety laboratory assessments will be performed by the local laboratories, at 
screening and at the times specified in the Study Schedule: 
• Hematology: hemoglobin, white blood cells (WBC), absolute neutrophils count (ANC), 
lymphocytes, platelet count. 
• Blood Chemistry: alkaline phosphatase, ALT, AST, total bilirubin, serum creatinine, 
creatinine clearance (if required), sodium, potassium, total calcium, blood urea nitrogen 
(BUN) (or urea), albumin. 
• Troponin Test. 
• Coagulation testing: International Normalized Ratio (INR)] and activated PTT (aPTT). 
• Pregnancy test (only applicable to premenopausal patients): serum test (with a sensitivity 
of at least 25 mIU/mL) prior to enrollment, and urine (or serum) test during the active 
treatment phase and at the post-treatment visit (30 [±5] days from the last study treatment 
dose). Any positive urine test must immediately be confirmed by a serum test. 
• Ophthalmologic assessments: visual acuity testing, slit lamp examination, and 
fundoscopy. 
• Viral serology (in case of suspicion): HIV, HBV serology [HBsAg, anti-HBsAg] and 
HCV (anti-HCV). In patients with a positive anti-HCV, HCV RNA detection and 
quantification by PCR will be additionally performed.  
All AEs (and their relatedness to the study treatment) occurring during the study will be 
documented in the eCRF. AEs will be graded according to NCI-CTCAE version 5.0 
6.2.2. 
Definitions 
The safety definitions are described in the Table 4. 
Table 4: Safety definitions  
Concept 
Definition 
Adverse Event (AE) 
Any new untoward medical occurrence or worsening of a pre-
existing medical condition in a patient or clinical investigation 
subject administered an investigational (medicinal) product and 

 
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that does not necessarily have a causal relationship with this 
treatment.  
An AE can therefore be any unfavorable and unintended sign, 
symptom or disease temporally associated with the use of 
investigational product, whether or not considered related to the 
investigational product.  
Laboratory and vital signs abnormalities should be reported as 
AE only in case they lead to an action on study treatment, need 
a new concomitant medication/procedure, lead to an action on 
concomitant medication/procedure or if they are serious.  
 
Special situations (SS) 
and Overdose 
The following events will be considered Special Situations (SS) 
and they have to be documented as AE in the eCRF: medication 
error, drug misuse, drug abuse and overdose (whether accidental 
or intentional). 
If a SS results in an AE, the AE must be recorded separately in 
the eCRF and if it fulfills seriousness criteria, it must be reported 
as a SAE. 
An overdose (accidental or intentional) of the study treatment is 
an event suspected by the investigator defined as an 
administration of an amount of T-DXd that is 10% higher than is 
normally used for a given cycle.  
Adverse Reaction (AR) 
A response to a medicinal product which is noxious and 
unintended. 
The determination of the possible relation with the study 
treatment is responsibility of the principal investigator of the site 
or the person designated by him. 
Investigators should use their knowledge of the patient, the 
circumstances surrounding the event, and an evaluation of any 
potential alternative causes to determine whether an AE is 
considered related to the study treatment as follows: 
o Related (probable, possible): there is a temporal 
relationship between the onset of the AE and the 
administration of the study treatment, the AE cannot be 
explained by the patient’s clinical state, intercurrent 

 
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illness or concomitant therapies; and/or the AE follows a 
known pattern of response to the study treatment; and/or 
the AE abates or resolves upon discontinuation of the 
study treatment or dose reduction and, if applicable, 
reappears upon re-challenge. 
o Not related (unlikely): An AE will be considered as 
related unless it fulfills the following criterion: the AE 
has an etiology other than the study treatment (i.e. 
preexisting medical condition, underlying disease, 
intercurrent illness, or concomitant medications); and/or 
has no temporal relationship to administration of the 
study treatment.    
All expected ARs of T-DXd are listed in the section 6.9 of the 
IB. If the nature or the severity of an AR is not consistent with 
the applicable product information, the AR is defined as 
unexpected. The basis for the decision is the current version of 
the corresponding reference document that has been submitted 
and approved by the competent authority and the ethics 
committees. 
Serious AE (SAE) and 
Serious AR (SAR) 
Any AE or AR that, at any dose: 
o is fatal (results in death), 
o initial or prolonged inpatient hospitalization, 
o a life-threatening experience (that is, immediate risk of 
dying, defined as an event in which the patient was at risk 
of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it 
were more severe), 
o persistent or significant disability/incapacity, 
o congenital anomaly/birth defect or 
o an important medical event, defined as a medical event 
that may not be immediately life-threatening or result in 
death or hospitalization but, based on appropriate 
medical and scientific judgment, may jeopardize the 
patient or may require intervention (eg. medical, 
surgical) to prevent one of the other serious outcomes 
listed above.  

 
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Do not confuse the concept “serious”, described before, with 
“severe” which refers to the intensity of the AE or AR 
(minor/mild/severe). 
Second primary malignancy is also considered a SAE and must 
be reported to GEICAM according to Section 6.2.4. 
Management, Timing and Assessment of SAEs/pregnancies. 
Accountability criteria 
The causality assessment of a SAE is made by the investigator 
as described in the AR section. However, the sponsor will 
perform a causality assessment of SAEs based on the 
information reported by the investigators. The causality 
assessment reported by the investigator will not be downgraded 
by the sponsor. Causality assessment of both the investigator and 
the sponsor will be recorded in the case file into the GEICAM’s 
safety database. 
Sponsor will classify the reported SAEs as “Related” or “Not 
Related” according to the method described in the section 
“Adverse Reaction (AR)”. 
Suspected Unexpected 
SAR (SUSAR) 
Any SAR whose nature, intensity or consequences do not 
correspond with the Reference Safety Information for the 
investigational product.  
6.2.3 
Management, Timing and Assessment of Adverse Events 
AE Classification  
 
AEs should be classified following version 5.0 of the NCI-
CTCAE. A copy can be downloaded in the NCI web site: 
http://evs.nci.nih.gov/ftp1/CTCAE. The investigators team must 
have access to the NCI-CTCAE version 5.0.  
The AE not included in the NCI-CTCAE will be classified as 
described on Protocol Attachment 3. 
Wherever possible the reporting Investigator will use the 
clinical, rather than the laboratory term (e.g., anemia versus low 
hemoglobin value). 
Procedure to notify an 
AE to GEICAM 
The site must notify to GEICAM, through eCRF, the following 
events: 
o All AEs that occur after signed ICD.  

 
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o Preexisting conditions that get worse during the study.  
o The evaluation of the possible relationship of each AE to 
the study treatment or protocol procedure.  
o The circumstances and data that causes the suspension of 
the treatment of a patient due to an AE. 
o The signs or symptoms of disease progression will not be 
recorded as AEs, unless the investigator believes they 
could have been caused by the study treatment.   
o The events leading to the clinical outcome of death from 
disease progression will not be recorded as AEs in the 
eCRF, unless the investigator believes they could have 
been caused by the study treatment or when the death 
occurred during the active treatment phase of the study 
and within 30 days following the last treatment 
administration, in this case it has to be reported as SAE 
in the eCRF and a SAE form will be notified to the 
Pharmacovigilance Department of GEICAM.  
Timing and assessment 
of AE/SAE (see Protocol 
Attachment 4) 
The site personnel will report on the eCRF the information of the 
AE in the following periods: 
• Baseline (after the patient signs the ICD and before 
study treatment administration): study site personnel 
will note the occurrence and nature of each patient´s 
medical condition(s) and preexisting conditions in the 
appropriate section of the eCRF. If a patient never 
receives study treatment but experiences an AE/SAE 
after the ICD is signed, ONLY events the investigator 
believes may have been caused by a protocol procedure 
will be reported to GEICAM via eCRF and SAE form (if 
applicable). 
• During treatment with the study treatment: during the 
study treatment administration, site personnel will record 
any change in the condition(s) and the occurrence and 
nature of any AE/SAE. An NCI-CTCAE grade rating 
will be assigned to every AE/SAE experienced. 
• 30-day (±5 days) post-treatment follow-up period: 
each patient will have a 30-day post-treatment follow-up 
evaluation approximately 30 days following the 

 
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discontinuation of study treatment. Patients should be 
closely followed for study treatment AEs in order to 
detect delayed toxicity. If study treatment-related 
toxicity is present beyond 30 days post-treatment, 
patients must be followed until it resolves or improved to 
baseline, the relationship is reassessed as unrelated, the 
investigator confirms that no further improvement can be 
expected, another therapy is initiated, or death. 
• Long-Term Follow-up Period (after the 30-day post-
discontinuation/post-treatment): ongoing SAEs, and 
new SAEs thought to be related to study treatment or 
protocol procedures should be documented on the eCRF 
and 
immediately 
reported 
to 
the 
GEICAM 
Pharmacovigilance Department as described in the 
Section 6.2.4. If the study has been closed, the 
notification has to be reported only to the GEICAM 
Pharmacovigilance Department as described in the 
Section 6.2.4. 
• SAES related with study treatment should be collected 
and analyzed until they are solved or until the toxicity is 
considered irreversible. 
Adverse Events of 
Special Interest (AESI)  
AESIs for this study are as follows: 
• Interstitial 
lung 
disease 
(ILD)/pneumonitis 
is 
considered an important identified risk based on a 
comprehensive cumulative review of potential interstitial 
lung disease (ILD)/pneumonitis cases from: the available 
safety data from the T-DXd clinical development 
program, 
available 
data 
from 
recent 
epidemiology/literature, biological plausibility, and 
safety information from drugs of similar class. Refer to 
the current IB for a summary of preliminary clinical 
study data. 
• LVEF decrease in association with T-DXd is considered 
an 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. 

 
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• Hepatic AEs events which meet the potential DILI 
criteria defined as:  
o an elevated ALT or AST ≥ 3.0 x ULN combined 
with total bilirubin ≥ 2.0 x ULN (in patients with 
normal ALT, AST and bilirubin at baseline) 
o an elevated AST or ALT ≥ 2 x baseline AND > 
3.0 x ULN OR AST or ALT ≥ 8.0 x ULN, 
combined with total bilirubin ≥ 2 x baseline AND 
≥ 2.0 x ULN or ≥ 3.0 x ULN in case of Gilbert´s 
syndrome (for patients with elevated AST, ALT 
or total bilirubin at baseline). 
AESIs should be documented on the eCRF and immediately 
reported to the GEICAM Pharmacovigilance Department as 
described in the Section 6.2.4.  
6.2.4. 
Management, Timing and Assessment of SAEs/AESIs/pregnancies 
Timing of SAEs/AESIs 
(see Protocol Attachment 
4) 
All SAEs/AESIs (either spontaneously or during the trial visits) 
will be collected since the patient signs the ICD. 
All the SAEs/AESIs must be documented in the medical record 
of the patient and in the eCRF. A follow up of all the 
SAEs/AESIs should be done until they are solved or until the 
toxicity is considered irreversible.  
Pregnancies 
Patients must be instructed to immediately inform the 
investigator if she or his partner (in case of a male patient) 
becomes pregnant while the patient is enrolled in this study and 
up to one month after EOT. 
If a patient becomes pregnant while enrolled in this study, it must 
be reported in the Pregnancy Form and sent to the GEICAM 
Pharmacovigilance Unit within 24 hours of becoming aware of 
it. 
If the female partner of a male patient becomes pregnant while 
he is enrolled in this study, it must be reported as soon as possible 
to the GEICAM Pharmacovigilance Department in the 
Pregnancy Form, and always after obtaining the corresponding 
Informed Consent from the pregnant woman. 

 
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The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications and 
documented in the Pregnancy Form. 
All infants born after fetal exposure must be followed for the first 
12 months after delivery. 
SAEs which do not need 
to be notified to the 
Pharmacovigilance 
Department of GEICAM  
The following events are not considered SAEs: 
o A visit to the emergency room or other hospital 
department lasting less than 24 hours that does not result 
in admission (unless considered an “important medical 
event” or a life-threatening event). 
o Elective surgery planned before signing consent. 
o Hospitalization which is due solely to a planned study 
visit and without prolongation. 
o Routine health assessment requiring admission for 
baseline/trending 
of 
health 
status 
(eg. 
routine 
colonoscopy). 
o Medical/surgical admission for purpose other than 
remedying ill health state that was planned before study 
entry. Appropriate documentation is required in these 
cases. 
o Admission encountered for another life circumstance 
that carries no bearing on health status and requires no 
medical/surgical intervention (eg. lack of housing, 
economic 
inadequacy, 
caregiver 
respite, 
family 
circumstances, administrative). 
o SAEs related to progression of the malignancy during the 
study (including signs and symptoms of progression), 
should not be reported as SAE, except when the outcome 
is fatal and death occurs during the active treatment 
phase of the study or within 30 days after the last 
treatment administration, in this case it must be reported 
as SAE to the Pharmacovigilance Department of 
GEICAM. 
o An overnight stay in the hospital that is only due to 
transportation, 
organization, 
or 
accommodation 
problems and without medical background.  

 
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The rest of SAEs must be notified as described below. 
Procedure to notify a 
SAE or AESI to the 
Pharmacovigilance 
Department of GEICAM 
The SAEs and AESIs must be notified to the Pharmacovigilance 
Department of GEICAM. A member of the investigator team 
must complete and sign the GEICAM SAE notification form 
which will be sent by fax/mail, immediately and always within 
the 24 hours of knowledge of the SAE: 
Pharmacovigilance Department of GEICAM  
Fax: +34 917 371 619  
farmacovigilancia@geicam.org  
GEICAM will review the received form and, if necessary, will 
ask more information to the investigator. 
When additional information is obtained about the SAEs, or this 
is solved or is improbable it will change, a follow-up report must 
be also completed and sent by fax/mail, immediately and always 
within the 24 hours of knowledge to the Pharmacovigilance 
Department of GEICAM. 
If GEICAM suspects that the SAE could be a SUSAR, the 
investigator should give the follow up information requested. 
GEICAM will report all SAEs immediately to the Chief 
Investigator for assessment.  
All SAEs will be followed-up by the investigator until 
satisfactory resolution.  
Annually all SARs will be reported at the Study Development 
Safety Update Report (DSUR) to the competent authorities and 
the leading ethics committee, including all SUSARs. 
Death on Study 
Any death occurring during the active treatment phase of the 
study and within 30 days of the last treatment administration 
must be reported as SAE to GEICAM as the sponsor within 24 
hours, regardless of the relationship to study treatment, and must 
be reported on the death report form and AE sections of the 
eCRF.  
The cause of death should be documented (cancer-related, 
treatment-related, cancer- and treatment-unrelated). Autopsy 
reports should be collected whenever possible and sent to 
GEICAM.  

 
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Deaths that occur due to tumor progression do not have to be 
reported as a SAE unless they occur before EOT (+30 days).  
Deaths after the end of study which are considered to be related 
to study treatment have to be reported as SAEs.  
To the extent feasible sufficient information including relevant 
laboratory values, ECGs, scans, biopsies or autopsy results must 
be provided by the investigator in the SAE narrative (even if 
investigator determines the SAE is not related) so as to permit an 
independent causality assessment by a Competent Authority. 
6.2.5. 
Management, Timing and Assessment of SUSARs 
Expedited Notification of 
SUSAR to the Competent 
Authorities  
The Pharmacovigilance Department of GEICAM or its designee 
is responsible to notify to each of the competent authorities  of 
the participating countries, all the SUSARs collected in the 
study, following the procedures shown in the current legislation.  
Timing of notification  
The deadline for reporting a SUSAR shall be 15 calendar days 
from when GEICAM or its designee becomes aware of it. When 
suspected SUSAR caused the death of the patient or endangered 
her/his life, GEICAM or its designee will send the information 
within 7 calendar days from the date on which it becomes aware. 
Expedited reporting of 
other relevant safety 
information 
GEICAM or its designee will also notify, expeditiously, all the 
information that could modify the balance benefit/risk of the 
investigational 
product, 
or 
determine 
changes 
in 
its 
administration pattern or in the study performance, such as: 
o A qualitative change or an increase in the percentage of 
occurrence of the SAR expected, which are considered 
clinically significant. 
o The SUSAR occurring after completion of the study and 
reported by the investigator to the sponsor.  
o New events related to the conduct of a trial or the 
development of an IMP likely to affect the safety of 
patients, such as: 
✓ SAE that could be related with the study 
procedure and could modify the conduct of the 
trial. 

 
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✓ A significant risk to patients such as lack of 
efficacy in a drug used to treat a life-threatening 
illness. 
✓ A major safety finding from a newly completed 
animal study (such as carcinogenicity). 
✓ A temporary halt of a trial for safety reasons if the 
trial is conducted with the same investigational 
medicinal products in another country and if this 
information is known by GEICAM. 
✓ Any 
recommendation 
from 
the 
chief 
investigators that is relevant to the safety of 
patients (if applicable). 
This relevant information shall be notified as soon as possible 
and no later than 15 days after GEICAM or its designee becomes 
aware of it. Additional information will also be notified as 
quickly as possible.  
Development Safety 
Update Report (DSUR) 
The DSUR that includes the SAEs, SAR and SUSARs collected 
during the study will be sent by GEICAM or its designee to the 
Competent Authorities and EC/IRB at the time established by 
the current legislation. 
Notification to 
investigators 
GEICAM or its designee will communicate to the investigators 
any safety information that may affect the safety of trial patients, 
as soon as possible.  
Information on SUSAR occurred during the study will be sent to 
investigators every 6 months, in aggregate, in a list along with a 
brief analysis of the data provided.  
They will be also informed, throughout the entire study, of any 
safety aspect that impacts the performance on the clinical trial or 
the product development, including the interruption or 
modification in the development program due to safety-related 
issues.  
6.3. 
Other Assessments  
6.3.1. 
Biomarker Assessments 
Biomarkers will be analyzed centrally in an exploratory fashion to investigate possible 
associations with resistance/sensitivity to T-DXd in advanced HER2-positive patients. 

 
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We will explore the predictive value of HER2 expression by immunohistochemistry (IHC) and 
in situ hybridization (ISH) analysis in pre-treatment tumors, and the HER2 spatial distribution 
by artificial intelligence (AI) using weakly supervised and clustering algorithms on HER2-
positive slides images at baseline. Additionally, we will explore the correlation of HER2 by 
IHC/ISH with ERBB2 mRNA levels.  
We will evaluate the predictive value of intrinsic molecular breast cancer subtypes in pre-
treatment tumors.  
We will assess intratumoral and stromal TILs and PD-L1 expression on pre-treatment tumor 
samples; the immune profiling in tumors (e.g. CD3, CD4, CD8, CD68, FoxP3, CK/SOX10) and 
in PBMCs (MDSC, Tregs and other immune subpopulations), and the expression pattern of pro- 
and anti-inflammatory cytokines in sequential blood samples. Protein profiling could be 
performed in baseline tumors, and in plasma and/or on circulating PBMCs at baseline, on 
treatment and at PD.  
RNA profiling and genomic analysis in tumors and circulating PBMCs may be assessed.  
Additionally, we could explore response dynamics, tumor tracking, tumor mutational burden, 
and clonal diversity during study treatment and at PD, based on genomic and molecular profiling 
in tumor and blood samples. 
Biomarkers may be assessed depending on emerging data.  
The following samples will be collected: 
• Tumor Tissue: Investigators will be encouraged to send the most recent pre-treatment 
tumor tissue sample, preferably from a metastatic lesion. However, if this is not possible, 
archived tissue samples either from primary tumor or metastasis will be acceptable. 
• Blood samples: Whole blood and plasma samples will be collected at the following 
timepoints: 
- 
at baseline (within 7 days before treatment initiation), 
- 
during study treatment, every 3 cycles on Day 1 (pre-dose) until treatment 
discontinuation for any reason, and  
- 
at the study treatment discontinuation, collected at the post-treatment visit (30 [±5] 
days from the last study treatment administration). If a patient ends the study 
treatment due to a reason other than disease progression, an additional sample must 
be collected once progression is documented (even if that patient has initiated another 
treatment). 

 
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Detailed instructions for the collection, handling and shipment of samples are outlined in the 
Sample Management Manual that will be available to the investigator and will be distributed at 
the time of site activation.  
Biological sample leftovers from the study will be included, subject to the patient consent, in the 
GEICAM Biobank located currently at the Hospital Universitario Fundación Jiménez Díaz in 
Madrid (Spain), whose owner is GEICAM and is an authorized not for profit institution, which 
meets all the technical, legal, and ethical requirements for managing, storing and using biological 
samples. 
6.3.2 
Patient Reported Outcomes 
Patient reported outcomes of health-related quality of life will be assessed using the EORTC 
QLQ-C30 (see attachment 5). 
The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional 
subscales (physical, role, cognitive emotional, and social functioning), three multi-item symptom 
scales (fatigue, nausea/vomiting, and pain), a global health/quality of life (QOL) subscale, and 
six single items assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite, 
diarrhea, constipation, 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. For functional and global QOL scales, higher scores represent a 
better level of functioning and are converted to a 0 to 100 scale. For symptom-oriented scales, a 
higher score represents more severe symptoms. 
Patients will complete EORTC-QLQ-C30: 
• 
at baseline (within 7 days before treatment initiation), 
• 
during study treatment, every 3 cycles (- 3 days) until treatment discontinuation, and 
• 
at the post-treatment visit (30 [±5] days from the last study treatment dose) or before if 
the patient is starting a new treatment.  
Completed questionnaires are always considered source document and must be filed accordingly. 
Patients must complete these instruments in clinic (cannot be taken home) prior to having any 
discussion of their progress with healthcare personnel at the site. Interviewer administration in 
clinic may be used under special circumstances (eg, patient forgot their glasses or feels too ill). 
The instruments will be given to the patient in the appropriate language for the site.  

 
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7. 
Data Quality Assurance 
To ensure accurate, complete and reliable data, GEICAM or its designee will do the following: 
• Provide instructional material to the study sites, as appropriate. 
• Perform a start-up training session to instruct the investigators and study 
coordinators. This session will give instructions on the protocol, the completion 
of the eCRFs, and study procedures. 
• Make periodic visits to the study site to review study progress, investigator and 
patient compliance with the clinical trial protocol requirements and any emergent 
problems. 
• Be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax. 
• Review and evaluate eCRF data and use standard computer edits to detect errors 
in data collection. Concurrent manual review of part of the data can be performed 
and ad hoc queries will be generated within the eCRF and followed-up for 
resolution. 
• Conduct a quality review of the database.  
• Verify the quality of the data. 
To ensure the safety of participants in the study and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study. If requested, the 
investigator will provide GEICAM, applicable regulatory agencies, and applicable ethical review 
boards with direct access to original source documents. 
7.1. 
Data Management and Registries file 
Data for this study will be recorded in an eCRF with web access, designed, created and 
maintained by GEICAM using Oracle Clinical®. Data will be transcribed by the site staff from 
the source documents into the eCRF. The eCRF will never be considered as source data for this 
trial. 
This eCRF meets the FDA’s Title 21 Code of Federal Regulations (CFR) Part 11, ensuring the 
validation of the system, the traceability and the audit trail, the retention, protection, 
reproducibility and recovery of trial data, control of access to information and electronic 
signature, among others. 

 
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Visit data should be entered into the eCRFs within 7 business days. Each eCRF should be 
completed by the investigator or delegate as stated in the Site Delegation List.  
Electronic queries will be raised if data is unclear or missing. GEICAM will perform a data 
review and additional requests can be sent through the eCRF, which the investigator is obliged 
to respond to by modifying or clarifying the data questioned. The requests with their responses 
will be managed through the eCRF. 
If a correction is made, the corrected information will be entered into the eCRF, superseding the 
initial information. An audit trail allows you to identify the modification. 
 
 
  

 
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8. Sample Size and Statistical Methods 
8.1. 
Determination of Sample Size 
8.1.1. 
Sample Size determination  
The primary endpoint of the study is to estimate the ORR.  
Assuming an ORR of 35%  (considering the results of response rates obtained with T-DM1 from 
published studies) 28 and to achieve a precision of ±15% using two-sided 95% normal asymptotic 
CI for a single proportion, we will need to include 39 evaluable patients. 
With a drop-out rate of 5% we will need 41 patients to be enrolled in the study. 
8.2. 
Statistical and Analytical Plans 
8.2.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of GEICAM. The interpretation of 
study results will be the responsibility of the principal investigator of the study.   
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained by 
GEICAM. This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment. 
All analysis will be performed using the SAS Enterprise Guide 7.1 version. 
8.2.1.1. 
Patient Populations 
Intent to treat population (ITT): the ITT population will include all patients who are enrolled 
in the study.  
Efficacy population: is a subset of the ITT population that have measurable disease, have 
received at least one dose of study treatment and completed the study without major protocol 
deviations which are considered to have a significant impact on results. 
The efficacy population will be the primary population for the primary endpoint analysis. A 
sensitivity analysis will be performed using the ITT population. 
Safety population: will include all patients enrolled in the study who received at least one dose 
of study treatment. This population is for the safety analysis.  
QoL population: a subset of the safety population with available QoL questionnaires (the 
baseline and at least one more). 

 
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8.2.2. 
Patient Disposition 
A detailed description of patient disposition will be provided. It will include: 
• summary of patients screened and by site 
• total number of patients screened 
• total number of patients enrolled 
• total number of patients treated 
• summary of reasons for patients enrolled, but not treated. 
A detailed summary of reasons for patient discontinuation from study treatment will be provided. 
A summary of all identified important protocol violations will be provided. 
8.2.3. 
Patient Characteristics 
Patient characteristics will include a summary of the following: 
• patient demographics 
• Disease characteristics (at diagnosis and at study entry) 
• preexisting conditions/secondary conditions 
• prior therapy 
Other patient characteristics will be summarized as deemed appropriate. 
Standard descriptive statistics, such as the mean, median, range and proportion, will be used to 
summarize the patient sample and to estimate parameters of interest. Ninety-five percent 
confidence intervals will be provided for estimates of interest where possible.  
8.2.4. 
Concomitant Therapy  
A summary of concomitant therapies will be generated in the safety population.  
8.2.5. 
Treatment Compliance  
Treatment information will be collected at each dose administration. The estimate of percent 
compliance will be given by: 
    Percent Compliance =       Actual dose administered per week 
    x   100 
 
 
 
 
     Dose expected to be administered per week 
No minimal level of compliance will be defined for patient inclusion in efficacy analyses. To be 
considered compliant patients should have received at least 80% of the planned number of doses. 
Exploratory analysis of the impact of compliance on selected efficacy endpoints may be 
performed if deemed necessary. 

 
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A summary of the incidence of T-DXd dose modifications and interruptions due to AEs, the 
number of administered cycles and dose intensity will be generated. 
8.2.6. 
Efficacy Analyses 
8.2.6.1. 
Analyses of Primary Endpoint 
The primary endpoint is the Objective response rate (ORR). ORR is defined as the rate of 
complete response (CR) plus partial response (PR) out of the efficacy population.  
A patient will be considered to have achieved an OR if the patient has a CR or PR according to 
RECIST v.1.1. definitions. Otherwise, the patient will be considered as nonresponder in the ORR 
analysis. Additionally, patients with inadequate data for tumor assessment (eg, no baseline 
assessment or no followup assessments) will be considered as nonresponders in the ORR 
analysis. The best response through the treatment will be recorded. 
ORR will be calculated by dividing the number of patients with objective response (CR or PR) 
by the efficacy population.  
Objective Response Rate =                 Number of CRs + PRs                       
    
  Efficacy population  
The ORR will be reported, including a 95% CI using the Clopper-Pearson method. 
A sensitivity analysis will be performed using the ITT population. 
8.2.6.2. 
Analysis of Secondary Endpoints 
The secondary efficacy endpoints are: 
Progression-Free survival (PFS): is defined as the time from the date of enrollment to the date 
of disease progression, based on the investigator’s assessment using RECIST version 1.1., or 
death from any cause, whichever occurs first. PFS data will be censored on the date of the last 
tumor assessment on study for patients who do not have objective tumor progression and who 
have not died due to any cause while on study. Additionally, patients who start a new anti-cancer 
therapy prior to documented PD will be censored at the date of the last tumor assessment prior 
to the start of the new therapy.  
PFS analysis will be performed in the safety population. 
PFS will be assessed using the Kaplan-Meier method. The median event time and 95% CI will 
be estimated if reached. 
Overall Survival (OS): is defined as the time from the date of enrollment to the date of death 
from any cause. OS data will be censored on the last date the patient is known to be alive.  
OS analysis will be performed in the safety population. 

 
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OS will be assessed using the Kaplan-Meier method. The median event time and 95% CI will be 
estimated if reached. 
Time to Treatment Response (TTR): TTR: is defined as the time from the date of enrollment 
to the date of first documentation of objective tumor response (CR or PR). 
TTR analysis will be performed in the efficacy population in patients with an OR. 
TTR will be assessed using the Kaplan-Meier method. The median event time and 95% CI will 
be estimated.  
Duration of Response (DOR): is defined as the time from the date of first documentation of 
objective tumor response (CR or PR) to the date of first documented progressive disease based 
on the investigator’s assessment using RECIST version 1.1, or death from any cause, whichever 
occurs first. DOR will be censored on the date of the last tumor assessment on study for patients 
who do not have objective tumor progression and who have not died due to any cause while on 
study. Additionally, patients who start a new anti-cancer therapy prior to documented PD will be 
censored at the date of the last tumor assessment prior to the start of the new therapy.  
DOR analysis will be performed in the efficacy population in patients with an OR.  
DOR will be estimated using Kaplan-Meier methods. The median event time and 95% CI will 
be estimated if reached.    
Additional sensitivity analyses of all this endpoints will be outlined in the SAP if required. 
8.2.6.3. 
Analysis of Exploratory Endpoints 
PFS2: is defined as the time from the date of enrollment to the date of disease progression to the 
second line of therapy. PFS2 data will be censored on the last date in which the patient was 
known not to have tumor progression or death due to any cause within the second line of therapy. 
Additionally, patients who start a third line therapy prior to progression to the second line will 
be censored at the date of the start of the third line therapy.  
PFS2 will be performed in the safety population. 
PFS2 will be assessed using the Kaplan-Meier method. The median event time and 95% CI will 
be estimated if reached. 
PFS3: is defined as the time from the date of enrollment to the date of disease progression to the 
third line of therapy. PFS3 data will be censored on the last date in which the patient was known 
not to have tumor progression or death due to any cause within the third line of therapy. 
Additionally, patients who start a fourth line therapy prior to progression to the third line will be 
censored at the date of the start of the fourth line therapy.  
PFS3 will be performed in the safety population. 

 
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PFS3 will be assessed using the Kaplan-Meier method. The median event time and 95% CI will 
be estimated if reached. 
Additional sensitivity analyses of these 2 endpoints will be outlined in the SAP if required. 
8.2.7. 
Safety Analyses 
The toxicity and tolerability of study treatments will be evaluated in the safety population. Safety 
analyses will include summaries of the incidence of AEs by maximum NCI-CTCAE grade (v5.0; 
NCI 2019) and SAEs that occur during the study treatment period or within 30 days of the last 
dose of study treatment, regardless of causality and according to the relationship to study 
treatment as assessed by the investigator. Additionally, the following safety-related outcomes 
will be summarized: 
• study treatment discontinuations due to AEs. 
• deaths 
• hospitalizations and transfusions  
• use of key concomitant medications or growth factors. 
Analyses for data with discrete dates, for example, deaths, transfusions, and concomitant 
medications, will be done through 30 days after each patient’s last dose of study treatment.    
AEs and SAEs will be presented in frequency tables by grade. Hematological and clinical 
biochemistry toxicities will be assessed from laboratory test parameters. The safety analysis will 
be performed in the safety population.  
8.2.8. 
Other Analyses 
8.2.8.1. 
Biomarker Analyses 
Biomarkers will be analized in an exploratory fashion as described in the Exploratory Statistical 
Analysis Guide (ESAG) to investigate possible associations with resistance/sensitivity to T-DXd 
in advanced HER2-positive patients. 
The biomarker analysis will make use of descriptive statistical methods. Some of the proposed 
biomarkers are categorical variables (mutations, tumor subtypes, ...), and others are continuous 
variables (HER2 expression, gene expression, genetic signatures, ... ).  
Categorical variables will be summarized by numbers and proportions. In all possible cases, the 
95% confidence intervals will be calculated. If appropriate, a chi-squared test will be used to test 
group differences. 
For continuous variables, descriptive statistics including the mean, standard deviation, median, 
minimum, and maximum values, will be provided. Continuous biomarkers can be categorized 

 
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using standard cutoffs, if exist, or the median can be used to establish two groups, high and low 
expression of genes or signatures, for example. 
To analyze the relationship between biomarkers and ORR, we will take into account whether 
they are continuous or categorical, using the statistical techniques specified below. If applicable, 
parametric test (analysis of variance or t test) or non-parametric testing, such as Wilcoxon’s rank-
sum test or Kruskal–Wallis test for continuous variables, and the Pearson χ2-test or Fisher exact 
test for categorical variables will be used to test group differences. All test performed will be 
two-sided and carried out with a 5% α-error rate without correction for multiplicity. 
The Kaplan-Meier limit-product method will be used to estimate the secondary and exploratory 
endpoints: PFS, OS, TTR, DOR, PFS2, PFS3, calculating separate curves for each of the groups 
of biomarkers defined as categorical. The comparison of those endpoints between groups of 
biomarkers will be performed using the Log-Rank test. The Kaplan-Meier survival curves will 
be presented graphically. Median (PFS, OS, TTR, DOR, PFS2, PFS3) with the 95% confidence 
interval will be reported. Cox regression models will be used to estimate unadjusted and adjusted 
hazard ratio and its 95% confidence interval, for evaluate the relation between the continuous 
and categorial biomarkers with the different endpoints. The Wald test will be used to establish 
the prognostic importance of each variable. Univariate and multivariate analyses could be carried 
out to explore the influence of the selected variables (include the specific clinical characteristics 
for each study) in PFS, OS, TTR, DOR, PFS2, PFS3. Any additional sensitivity analyses will be 
outlined in specific SAPs. 
8.2.8.2.  Patient Reported Outcomes 
Patient reported outcomes of health-related quality of life will be assessed using the QLQ-C30 
questionnaire and analized on the QoL population.  
Published scoring manuals and guidelines will be used to generate scale scores and handle 
missing data. Descriptive statistics for actual values will be tabulated at each scheduled time 
point. 
QoL variables and method for analysis:  
• Change from baseline in the global health status score (GHS) and each scale of the 
EORTC QLQ-C30 questionnaire. It will be presented at each scheduled time point for 
the GHS score and each of the functionals and symptoms scales from the QLQ-C30 
questionnaires. Longitudinal analysis of scores will be performed using linear mixed 
models. 
• Time to deterioration (TTD) in QoL: is defined as the time from the date of enrollment 
to the date of first detection of a deterioration event. A deterioration event is defined as 
an increase of ≥ minimally important difference (MID) from baseline for the EORTC 
QLQ-C30 symptom scales and a decrease of ≥ MID from baseline for the EORTC QLQ-

 
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C30 functional scales and GHS scale. It will be assessed using the Kaplan-Meier. Method. 
The median event time and 95% CI for the median will be estimated if reached. TTD will 
be censored at the date of the last QoL assessment prior to the start of a new therapy. 
 
Detailed methodology will be documented in the SAP of the study. 
8.2.9. 
Subgroup Analyses  
Exploratory subgroup analysis may be performed if deemed appropriate. 

 
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9. 
Informed Consent, Confidentiality, Responsibility Insurance and 
Regulatory Considerations 
9.1. 
Informed Consent 
The investigator is responsible for ensuring that the patient understands the risks and benefits of 
participating in the study, including answering any questions the patient may have throughout 
the study and sharing any new information that may be relevant to the patient's willingness to 
continue his or her participation in the trial in a timely manner. 
The ICD will be used to explain the risks and benefits of study participation to the patient in 
simple terms before the patient is screened into the study, and to document that the patient is 
satisfied with his or her understanding of the risks and benefits of participating in the study and 
desires to participate in the study. 
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative. This includes obtaining the appropriate signatures and dates on the ICD prior 
to the performance of any protocol procedures and prior to the administration of study treatment.   
As used in this protocol, the term "informed consent" includes all consent and assent given by 
patients or their legal representatives. 
If new safety information results in significant changes in the risk/benefit assessment, the consent 
form should be reviewed and updated if necessary. All patients (including those already being 
treated) should be informed of the new information, given a copy of the revised form and give 
their consent to continue in the study.  
9.2. 
Respect of Confidentiality 
The investigator will be responsible for preserving the suitable information about each patient (for 
example, name, address, telephone number, social security number and study identification) so that 
the competent authorities can have access to said information if necessary. These records must be 
confidentially preserved for the time indicated by the legislation. 
The investigators and GEICAM and its designee will maintain the confidentiality of all patients 
participating in the study, according to Good Clinical Practice and local legislation. 
9.3. 
Data Protection 
This clinical trial will be held in accordance and in compliance with local current legislation. 
Any treatment of personal data that is held within the clinical trial, for Sponsor, Principal 
Investigator, Site, and / or any other participant in the clinical trial, especially as far as informed 
consent, shall conform to the provisions of Organic Law 3/2018, of December 5, Protection of 

 
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Personal Data and Guarantee of Digital Rights, Regulation (EU) 2016/679 of the European 
Parliament and of the Council of 27 April 2016 (GDPR) and any other rules in the matter.  
9.3.1. Personal Data Processed  
When a patient participates in the study, his/her personal data is processed. Processing operations 
includes the collection, storage, analysis, transmission and any other use of the personal data. 
Personal data includes information that identifies the patient directly (such as his/her name, 
address, telephone number, or health insurance number, etc) and information that could lead to 
an indirect identification (such as information relating to the patient's state of health, information 
about the patient's biological samples and the results of analyses performed on these, the patient’s 
medical treatments and his/her response to medical treatments, etc). 
9.3.2. Arrangements to Comply with Data Protection Laws   
GEICAM is the data controller of the processing of patient’s encoded data collected for the 
purposes of the Study. The investigators and the sites are also data controllers of the patient's 
unencoded data collected for their own purposes, if any.  
9.3.3. Measures to Protect Personal Data   
All personal data are treated in accordance with data protection laws, including the GDPR. 
Personal data must be encoded at the study site before any transmission to a third party. The 
principle of data encoding entails that if a patient participates in the study, a code will be assigned 
to him/her. The code will replace all directly or indirectly identifying data on documents used for 
data collection or biological samples collected for the study.  
Data unencoded will be kept only in the study sites’ medical records. 
Individuals accessing the unencoded personal data at the study site are subject to professional 
secrecy, and/or to confidentiality agreements. In addition, a limited number of the Sponsor's 
employees, or its contractual partners, ethics committees and regulatory authorities may consult 
the personal data and these persons are bound by an obligation of confidentiality.  
If a transfer of personal data to a third country is needed, the data controller will put in place the 
appropriate measures equivalent to the measures required by the Spanish and the European data 
privacy laws to protect patients privacy.  
If a patient wishes to exercise his/her rights relating to data about him/her, or if the patient wishes 
to know more about the measures to protect his/her personal data, he/she can send a request to the 
investigator or to the data protection officer of the study site. The investigator or the data protection 
officer (DPO) of the study site can contact the DPO of any of the data controller at 
incidencia.lopd@geicam.org. 

 
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Personal data related to the study is stored on secured servers. These servers protect data against 
loss, destruction, access, modification or dissemination by unauthorised persons. Only a limited 
and controlled number of persons are authorized to access the data.  
All the personal data transferred over internet are submitted in coded form. Secure Socket Layer 
(SSL) encryption is used for the transmission of data. 
To ensure compliance with GDPR and taking into account the state of the art, the nature, the scope, 
the context and the purposes of the processing to be carried out, the data controller shall apply 
appropriate technical and organizational measures to ensure a level of security appropriate to the 
risk. Some of the measures that may be considered are: 
✓ Identification, dissemination and documentation of the functions and duties of personnel 
with access to the data. 
✓ Definition and implementation of a procedure to identify and authenticate users. 
✓ Definition and implementation of a data access control procedure. 
✓ Definition and implementation of a procedure for recording incidents and data breach.  
✓ Definition and implementation of a system of verification of user accesses to data. 
✓ Definition and implementation of a backup procedure. 
✓ Definition of the criteria for filing media and the devices for their storage. 
✓ Definition and implementation of regular checks on the Company, testing, assessing and 
evaluating the effectiveness of technical and organizational measures, in order to ensure 
the security of the processing. 
✓ Implementation of firewalls, antivirus and spyware in the servers containing personal data. 
✓ Appointment of a Security Officer(s) or Data Protection Officer, as appropriate. 
In case of a data security breach occurs, the data controller will assess the risk for individuals’ 
privacy, the measures to be implemented in order to mitigate the risk, minimizing its consequences 
and preventing any repeat in the future, as well as they will assess, depending on its severity, the 
need of notifying the correspondent data protection authority and/or the individuals concerned.   
9.4. 
Insurance and Compensation for Injury 
GEICAM shall ensure that the trial patients are compensated for any damage suffered as a result 
of the trial. 
GEICAM has hired an insurance policy covering the damage, as well as any liability that might 
be incurred by the sponsor, principal investigator and members of the investigator team, 
including contracted clinical investigators, and the hospital or site where the clinical trial is 
conducted, according to applicable legislation. 

 
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9.5. 
Regulatory Considerations 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with good clinical practices and the applicable 
laws and regulations. Each investigator will conduct the study according to applicable local or 
regional regulatory requirements and align his or her conduct in accordance with the 
“Responsibilities of the Investigator”. The principles of Helsinki are addressed through the protocol 
and through appendices containing requirements for informed consent and investigator 
responsibilities. 
9.5.1. 
Investigator Information 
Physicians who take care of breast cancer patients will participate as investigators in this clinical 
trial. 
If investigators are added after the study has been approved by the Sponsor, an EC/IRB, or a 
regulatory agency, these additions will not be considered changes to the protocol. 
9.5.2. 
Protocol Signatures 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to GEICAM. 

 
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10. Practical Considerations 
10.1.  Monitoring, Audit and Inspections 
Onsite or remote monitoring visits to the study site will be made periodically during the study 
and according to the Monitoring Plan Document to ensure that all aspects of the protocol are 
followed. During the visits to the site, the monitor must review the original records of the patients, 
the records of medication stocks and document preservation according to the Monitoring Plan 
Document. The monitor must evaluate the study procedures and discuss the possible problems 
with the investigator. During the course of the study, audit visits can be carried out in the 
participating sites. The investigator will allow direct access to the source documents/data for the 
tasks of monitoring, audit, reviewed by the EC/IRB and the inspection by the Competent 
Authorities, and should inform the site monitor immediately if contacted by a Competent 
Authority about an inspection at the study site. 
10.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with GEICAM or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will 
be no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria. 
10.3.  Preservation of Study Documentation 
The copies of all the relevant information will be preserved by the investigator for a period of at 
least 25 years after the end of the study, according to current legislation. 
10.4.  Protocol Modification 
Once it has been authorized by the EC/IRB and the competent authority any protocol 
modification must be documented by writing, in the form of an amendment. 
The amendments must be duly identified, by its chronological order number, dated and signed 
by GEICAM and the Chief investigator. 
The protocol amendments considered as substantial must be notified to the EC/IRBs involved in 
the trial and to the competent authority. The authorization of the involved EC/IRBs and/or the 
competent authority will be necessary before their application. 
After reading the protocol amendment, each principal investigator will sign the protocol 
amendment signature page and send a copy of the signed page to GEICAM. 

 
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10.5.  Use of the Information and Publication 
All the information concerning the study treatment provided by GEICAM in relation to this study, 
and not previously published, is considered to be confidential information with property right of 
GEICAM. This information comprises the basic information about the product, the clinical 
protocol, the work forms where appropriate, the eCRFs, the assessment methods, the technical 
methodology and the basic scientific data. This confidential information will be the property of 
GEICAM, it must not be disclosed to third parties without the prior written consent of GEICAM 
and it must not be used other than for the purposes of the study. 
The information developed during the practice of this clinical study is also considered to be 
confidential. This information can be disclosed to the extent considered necessary by GEICAM.  
To allow the use of the information derived from this study and to ensure the compliance with the 
current rules, the investigator is obliged to provide GEICAM with all the results of examinations 
and all the data developed in this study. Except in that required by law, the information obtained 
during the study can only be provided to the doctors and to the competent authorities by GEICAM. 
GEICAM commits to comply with current legislation relating to studies, which establishes the 
obligation to publish the results, both positive and negative, in conferences and journals, with the 
reference that EC/IRB approved the study, and its funding source. The list of authors will be 
developed in accordance with the GEICAM SOPs (standard operating procedures).  
10.5.1 
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, GEICAM will, at a minimum register 
interventional clinical trials sponsored by GEICAM anywhere in the world on ClinicalTrials.gov 
or other publicly accessible websites (European Union Clinical Trials Register and national clinical 
trials public website [if applicable]), as required by GEICAM Policy/SOPs and local health 
authorities.  
10.5.2 
Clinical Trial Results Disclosure 
GEICAM will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by GEICAM Policy/SOPs and applicable local laws and/or regulations. 
10.6.  Ethics Committees and/or IRBs 
GEICAM or its designee or the Investigator will supply relevant documents for submission to 
the respective EC/IRB for the protocol’s review and approval. This protocol, the IB/Summary of 
Product Characteristics (SmPC), a copy of the ICD, and, if applicable, patient recruitment 
materials and/or advertisements and other documents required by all applicable laws and 

 
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regulations, will be submitted to a central or local EC/IRB for approval. The EC/IRB’s written 
approval of the protocol and patient informed consent must be obtained and submitted to 
GEICAM or designee before commencement of the study (ie, before shipment of the sponsor-
supplied study treatment or study specific screening activity). GEICAM or its designee will 
notify the site once GEICAM or its designee has confirmed the adequacy of site regulatory 
documentation and, when applicable, GEICAM or its designee has received permission from 
competent authority to begin the trial. Until the site receives notification, no protocol activities, 
including screening, may occur. 
As per applicable regulatory requirements, GEICAM or its designee or the Investigator will submit 
the required reports of the progress of the study to the EC/IRB and will communicate the possible 
SAE, the life-threatening AEs and deaths. At the end of the study, GEICAM or its designee or the 
Investigator must inform the EC/IRB of trial closure. Al these notifications will be performed 
according to the applicable regulatory requirements. 
 

 
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11. References 
1. 
American 
Cancer 
Society. 
Cancer 
facts 
& 
figures 
2021. 
Available 
at: 
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-
figures/2021/cancer-facts-and-figures-2021.pdf. Accessed: March 10th, 2022. 
 2.Ceresa BP, Peterson JL. Cell and molecular biology of epidermal growth factor receptor. Int Rev Cell Mol Biol. 
2014;313:145–78. 
3. Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor 
and HER2 status. J Natl Cancer Inst. 2014 Apr 28;106(5):dju055. doi: 10.1093/jnci/dju055. PMID: 24777111; 
PMCID: PMC4580552. 
4. Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ hybridization and 
correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clinical breast cancer. 
2004;5(1):63-9. 
5. Gianni L, Dafni U, Gelber RD, et al. Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab 
for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a 
randomised controlled trial. Lancet Oncol. 2011 Mar;12(3):236-44. doi: 10.1016/S1470-2045(11)70033-X. Epub 
2011 Feb 25. PMID: 21354370. 
6. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive 
breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. doi: 10.1056/NEJMoa052122. PMID: 16236738. 
7. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for 
metastatic breast cancer that overexpresses HER2. N Engl J Med.. 2001;344(11):783-92. 
8. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J 
Med. 2012;367(19):1783-91. 
9. Swain SM, Baselga J, Kim SB, et al. CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in 
HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513. 
PMID: 25693012; PMCID: PMC5584549. 
10. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. 
N Engl J Med. 2006;355(26):2733-43. 
11. Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic 
Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. doi: 10.1056/NEJMoa1914609. Epub 2019 Dec 11. 
Erratum in: N Engl J Med. 2020 Feb 6;382(6):586. PMID: 31825569. 
12. Trastuzumab deruxtecan Investigator Brochure. V10.0 dated 10Oct2023. 
13. Modi S, Saura C, Yamashita T, et al. DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously 
Treated HER2-Positive Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):610-621. doi: 10.1056/NEJMoa1914510. 
Epub 2019 Dec 11. PMID: 31825192; PMCID: PMC7458671. 

 
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14. Dunton K, Vondeling G, Hancock E, et al. Methods for Estimating Long-Term Outcomes for Trastuzumab 
Deruxtecan in HER2-Positive Unresectable or Metastatic Breast Cancer After Two or More Anti-HER2 Therapies. 
Target Oncol. 2022 Nov 7. doi: 10.1007/s11523-022-00923-9. Epub ahead of print. PMID: 36342619. 
15. Cortes J, Kim S, Chung W. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients 
(Pts) with HER2þ metastatic breast cancer (mBC): results of the randomized phase III DESTINY- Breast03 study. 
Ann Oncol. 2021;32(suppl 5):S1283-S1346. 
16. Cortés J, Kim SB, Chung WP, et al. DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus 
Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24;386(12):1143-1154. doi: 
10.1056/NEJMoa2115022. PMID: 35320644. 
17. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women 
with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, 
open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. doi: 10.1016/S1470-2045(11)70336-9. Epub 2011 
Dec 6. PMID: 22153890. 
18. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant 
anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast 
cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. doi: 
10.1093/annonc/mdt182. Epub 2013 May 22. PMID: 23704196. 
19. Untch M, Fasching PA, Konecny GE, et al. Pathologic complete response after neoadjuvant chemotherapy plus 
trastuzumab predicts favorable survival in human epidermal growth factor receptor 2.overexpressing breast cancer: 
results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 2011; 29: 3351-7. 
20. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast 
cancer: the CTNeoBC pooled analysis. Lancet 2014; 384: 164-72. 
21. Spring LM, Fell G, Arfe A, al. Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on 
Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis. Clin Cancer Res. 2020 Jun 
15;26(12):2838–48. 
22. von Minckwitz G, Huang C, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive 
Breast Cancer. N Engl J Med. 2019; 380:617.628. 
23. Romond E, Perez E, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast 
cancer. N Engl J Med. 2005; 353:1673.1684. 
24. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-
positive breast cancer. N Engl J Med. 2005; 353:1659-1672. 
25. Slamon, D, Eiermann, W., Robert, N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J 
Med. 2011; 365:1273-1283. 
26. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-
Positive Breast Cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. doi: 10.1056/NEJMoa1703643. Epub 2017 Jun 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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5. Erratum in: N Engl J Med. 2017 Aug 17;377(7):702. Erratum in: N Engl J Med. 2018 Oct 18;379(16):1585. 
PMID: 28581356; PMCID: PMC5538020. 
27. Schettini F, Conte B, Buono G, et al. T-DM1 versus pertuzumab, tras- tuzumab and a taxane as first-line therapy 
of early-relapsed HER2- positive metastatic breast cancer: an Italian multicenter observational study. ESMO Open. 
2021;6(2):100099.28. Dzimitrowicz H, Berger M, Vargo C, et al. T-DM1 Activity in Metastatic Human Epidermal 
Growth Factor Receptor 2-Positive Breast Cancers That Received Prior Therapy With Trastuzumab and Pertuzumab. 
J Clin Oncol. 2016 Oct 10;34(29):3511-3517. doi: 10.1200/JCO.2016.67.3624. PMID: 27298406; PMCID: 
PMC6075965.

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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Protocol Attachment 1. Study Schedule 
 
Study Schedule of Events and Timelines. 
GEICAM/2021-08 (TRANSCENDER) 
During Study Treatment. 
All visits ± 3 days of scheduled 
treatment day 
Post-
treatment 30  
(±5) days 
from the last 
study 
treatment 
dose 
After study treatment termination 
 
Cycle 
Screening 
 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
PFS/DOR  
Follow-up Period  
(12 weeks ± 7 days) 
PFS2/PFS
3/OS 
Follow-up 
Period (6 
months 
±14 days) 
Day of cycle 
 
REGISTRATION 
1 
1 
1  
 
 
 
Procedure/Laboratory/ 
Diagnostic Test 
Within 28 days 
 
 
 
 
 
 
ICD for Entry (before any 
study specific tests)a 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical and surgical history 
and demographicsb 
X 
 
 
 
 
 
 
Physical examinationc 
X 
X 
X 
X 
X 
 
 
ECOG PS 
X 
X 
X 
X 
X 
 
 
Hematologyd 
X 
X 
X 
X 
X 
 
 
Blood Chemistrye 
X 
X 
X 
X 
X 
 
 
Troponin 
X 
 
 
 
 
 
 
Coagulationf 
X 
 
 
 
 
 
 
Viral serologyg 
X 
 
 
 
 
 
 
Pregnancy Testh 
X 
X 
X 
X 
X 
 
 

 
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Ophthalmologic assessmenti 
X 
 
 
 
X 
 
 
ECHO or MUGAj 
X 
 
 
X 
X 
 
 
Triplicate 12-lead ECGk 
X 
 
X 
X 
 
 
 
QoL Questionnairesl 
 
X 
 
Every 3 
cycles 
X 
 
 
Concomitant medications 
X 
X 
 
AEs and SAESm 
X 
X 
Only related SAEs 
Study Treatment 
  
T-DXd 5.4 mg/kg IV every 3 weeks. 
 
 
 
Tumor Assessmentn 
X 
Every 9 weeks (±7 days) from the start of treatment. 
X 
 
Date of death  
 
 
 
 
 
 
Xo 
Translational Research 
  
  
Blood samples for biomarker 
analysisp 
 
 
X (Day 1) 
 
Every 3 
cycles (Day1) 
At study 
treatment 
discontinuatio
n and at PD  
 
 
Tumor tissue for Biomarker 
analysisq 
X 
 
 
 
 
 
 
 
 
Study Schedule of Events and Timelines. Protocol GEICAM/2021-08 (TRANSCENDER) 
a 
Signed, written informed consent (approved by the EC/IRB) obtained prior to any study specific procedure. 
b 
Includes local laboratory ER/PgR/HER2 expression levels and methods used to assess them, previous treatments. Sex, Race and Age  
c 
Physical examination includes measurements of height (screening only), weight, blood pressure, pulse rate and body temperature. The T-DXd dose will be 
recalculated in the event that patients experience body weight variations greater than 10% during the treatment period. 
d 
Hemoglobin, white blood cells (WBC), absolute neutrophils count (ANC), lymphocytes and platelet count. Cycle 1 analysis will not be necessary if the 
screening analysis is performed within 14 days of the treatment initiation. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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e 
Alkaline phosphatase, ALT, AST, total bilirubin, serum creatinine, creatinine clearance (if required) sodium, potassium, total calcium, blood urea nitrogen 
(BUN) (or urea), albumin. Cycle 1 analysis will not be necessary if the screening analysis is performed within 14 days of the treatment initiation. 
f 
Coagulation includes International Normalized Ratio (INR) and activated PTT (aPTT).  
g 
Viral serology: HIV, HBV serology [HBsAg, anti-HBsAg] and HCV (anti-HCV). In patients with a positive anti-HCV, HCV RNA detection and 
quantification by PCR will be additionally performed. 
h 
Pregnancy test (only applicable to premenopausal patients): serum test within 7 days prior to enrollment. During the active treatment phase, a urine (or serum) 
test must be performed within 72 hours before each cycle and at the post-treatment visit (30 [±5] days from the last study treatment dose). Any positive urine 
test must immediately be confirmed by a serum test. 
i 
Ophthalmologic assessments include visual acuity testing, slit lamp examination, and fundoscopy. This assessment will be performed at screening and at the 
post-treatment visit (30 [±5] days from the last study treatment dose). 
j 
Perform an ECHO or MUGA scan assessment (note: the same test must be used for the patient throughout the study) every 4 cycles (±7 days) (Cycle 5, 9, 
13…) and at the post-treatment visit (30 [±5] days from the last study treatment dose). 
k 
Triplicate 12-lead ECGs will be performed at screening and before each cycle. 
l 
EORTC QLQ-C30 must be completed before other assessments are performed or study drug is administered: 
- at baseline (within 7 days before treatment initiation), 
- during study treatment, every 3 cycles (- 3 days) until treatment discontinuation, and 
- at the post-treatment visit (30 [±5] days from the last study treatment dose) or before if the patient is starting a new treatment.  
 
m 
After ICD signature, but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention will be collected. AEs to be monitored 
continuously during the treatment period. All AEs occurring during the study and until the treatment discontinuation visit 30 days after the last study medication 
to be recorded with grading according to NCI-CTCAE version 5.0, thereafter all study treatment-related SAEs should continue to be collected. 
n 
Tumor assessment should be performed during the screening period; however, if a patient has a valid image test performed up to 28 days before the date of 
the study treatment initiation it is not required to repeat it. Disease assessment for all patients will include: 
✓ Contrast enhanced (unless clinically contraindicated) CT scan or MRI of the chest, abdomen and pelvis (CAP). A positron emission tomography (PET)-
CT scan will be accepted if the CT scan meets the RECIST version 1.1. requirements for tumor lesion evaluation.  
✓ Bone scan is mandatory if the patient has bone disease or if there is any suspicion of bone metastases. A PET scan will be also accepted to assess the 
already known or newly suspected bone metastatic disease. Any suspicious abnormalities (i.e., hotspots) identified on the bone or PET scan at baseline 
must be confirmed by X-ray, CT scan with bone window or MRI. Additional bone scans will be performed only to confirm a complete response (CR) in 
patients with bone lesions identified at baseline, or whenever clinically or biochemically bone progression or newly diagnosed bone disease is suspected.  
✓ Brain CT scan with IV contrast or MRI is mandatory if the patient has previously known CNS metastases or if there is any suspicion of CNS metastases. 
✓ CT scan or MRI scan of any other sites of disease as clinically indicated. 
✓ Clinical assessment of superficial disease by calipers which will include color photographs of all superficial metastatic lesions including a ruler to estimate 
the size of the lesion. When lesions can be evaluated by both a clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective.  

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-00 
 
 
 
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All measurable and evaluable lesions should be assessed at the screening visit and re-assessed at each subsequent tumor evaluation and documented in the 
eCRF. Tumor assessments will be performed at screening, every 9 weeks (±7days) and after the third tumor evaluation every 12 weeks (±7days) until 
radiographically and/or clinically (i.e., for photographed or palpable lesions) documented PD as per RECIST version 1.1., withdrawal of consent, start of new 
anticancer treatment, death, or study termination, whichever occurs first. 
Tumor assessment will be continued in patients that discontinue treatment without disease progression per RECIST version 1.1. until death, disease 
progression, start of new anticancer therapy, patient’s consent withdrawal, or study termination, whichever occurs first, every 12 weeks (± 7 days) from the 
last tumor assessment and bone scans (if applicable) as stated above.  
o 
Patients will be followed until death, loss to follow-up, withdrawal of consent or study termination by GEICAM. After progression, tumor assessments will 
be performed according to the standard medical practice. All treatments received by the patient after progression as well as the dates of disease progression 
to the second and third lines and death will be collected in the eCRF, to calculate PFS2, PFS3 and OS respectively.   
p 
 
Whole blood and plasma samples for biomarker analysis will be collected: 
- at baseline (within 7 days before treatment initiation),  
- during study treatment, every 3 cycles on Day 1 (pre-dose) until treatment discontinuation for any reason, and  
- at the study treatment discontinuation, collected at the post-treatment visit (30 [±5] days from the last study treatment administration). If a patient ends the 
study treatment due to a reason other than disease progression, an additional sample must be collected once progression is documented (even if that patient 
has initiated another treatment). 
q 
Investigators will be encouraged to send the most recent pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue sample, preferably from a 
metastatic lesion, for retrospective biomarker assessments. However, if this is not possible, archived tissue samples from primary tumor will be acceptable. 
Samples will be sent to the sponsor-designated central laboratories.  
 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-
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Protocol Attachment 2. Eastern Cooperative Oncology Group 
Performance Status 
ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light 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 
 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 1982. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
5(6):649-65. 
 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-
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Protocol Attachment 3. Adverse event (AE) non defined in NCI-CTCAE 
CTC Grade 
Equivalent to: 
Definition 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate 
Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
Grade 3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
Grade 4 
Life-
threatening / 
disabling 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death 
Death related to AE. 
 
Activities of Daily Living (ADL)  
*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. 
 
 
                            

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-
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Protocol Attachment 4. Adverse Events / Serious Adverse Events 
Assessment Guide 
Time 
After ICD 
Before Study 
Treatment 
During Therapy 
30-Day (±5 days)  
Post-treatment  
Follow-up Period 
Long-Term  
Follow-up Period 
Events to 
Collect  
AE/SAEs 
 
New/Ongoing AE/SAEs 
 
New/Ongoing SAEs 
 
 
Related to 
Procedures 
Regardless of Relatedness to 
Study Treatment or Procedures 
Related to Study 
Treatment or Procedures 
Abbreviations:  AE = adverse event, ICD = informed consent document, SAE = serious adverse event. 

 
GEICAM/2021-08 (TRANSCENDER)                                                     EU CT number: 2023-503627-26-
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Protocol Attachment 5. QoL Questionnaire 
In a separate document