A Single-arm Phase II Trial to Evaluate the Safety and Efficacy of the Antibody-Drug Conjugate (ADC) SYD985 in Patients With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Endometrial Carcinoma Who Previously Progressed on or After First Line Platinum-based Chemotherapy
Phase: PHASE2
Conditions: Endometrial Cancer
Sponsor: Byondis B.V.

 
A single-arm phase II trial to evaluate the safety and efficacy of the antibody-drug conjugate 
SYD985 in patients with HER2-expressing recurrent, advanced or metastatic endometrial 
carcinoma who previously progressed on or after first line platinum-based chemotherapy 
 
NCT04205630 
 
Version 3.0, dated 30 September 2020 
 
 

 
 
 Document number (version): Form.NL03.78820 (3.0) 
 
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Clinical Trial Protocol SYD985.003 
 
 
Protocol title: 
A single-arm phase II trial to evaluate the safety and efficacy of the antibody-drug conjugate 
SYD985 in patients with HER2-expressing recurrent, advanced or metastatic endometrial 
carcinoma who previously progressed on or after first line platinum-based chemotherapy 
 
 
 
  
Protocol Number:  
 
 
SYD985.003 
Development phase:  
 
Phase II 
Drug product code: 
 
 
SYD985  
Drug substance: 
 
 
Trastuzumab vc-seco-DUBA  
INN = [vic-]trastuzumab duocarmazine 
EudraCT Number: 
 
 
2019-002888-10 
IND Number:  
 
 
146672 
Protocol Version: 
 
 
3.0 
Protocol Date:  
 
 
30 September 2020 
Document Number:  
 
CSP.NL03.78820 
 
Author(s): 
 
 
 
Byondis BV: 
Maaike Hendriks, Clinical Project Leader 
Norbert Koper, VP Clinical Development 
 
 
 
 
 
This document includes confidential and privileged information (including trade secrets) 
which is property of Byondis BV. It is not allowed to make this information public without 
prior written permission of Byondis BV. This document may be disclosed to and used by 
the staff that conducts the clinical trial at a clinical investigational site. 
Protocol Template Version 3.0 (Form.NL03.39605) 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
1. 
Protocol synopsis 
Title of study 
A single-arm phase II trial to evaluate the safety and efficacy of the antibody-drug conjugate 
SYD985 in patients with HER2-expressing recurrent, advanced or metastatic endometrial carcinoma 
who previously progressed on or after first line platinum-based chemotherapy 
 
Objectives 
The primary objective of this study is: 
• To evaluate the objective tumour response rate (ORR) of SYD985;  
The secondary objectives of this study are to evaluate for SYD985: 
• Progression-free survival (PFS); 
• Overall survival (OS);  
• Safety. 
 
Study design 
 This is an open-label, single-arm study in patients with Human Epidermal growth factor Receptor 2 
(HER2)-expressing recurrent, advanced or metastatic endometrial carcinoma. HER2-expression is 
defined as a 1+, 2+ or 3+ score on immunohistochemistry (IHC) or positive by in situ hybridization 
(ISH). Inclusion of patients with HER2 1+/2+, ISH negative tumours will be limited to a maximum 
of 50% of the total sample size. Eligible patients for this study should have progressed on or after 
first line platinum-based chemotherapy. Patients who have had two or more lines of chemotherapy 
for advanced/metastatic disease are not eligible. 
 
Eligible patients will receive SYD985 every three weeks (Q3W) until disease progression (PD) or 
unacceptable toxicity. During the first treatment cycle, patients will have to visit the clinical site 
weekly for safety assessments, followed by one visit in subsequent cycles. Patients who have stopped 
study treatment for other reasons than PD (e.g. due to toxicity) will continue their tumour evaluations 
in an observation period until disease progression or start of a new anticancer therapy. 
Duration of patient treatment and participation: 
After a screening period of maximally 28 days, patients who are eligible will be treated until disease 
progression or unacceptable toxicity. A safety follow-up visit is planned 30 days after the treatment 
discontinuation visit after which patients may move into an observation period and/or survival 
follow-up.  
 
Study population 
The study population will consist of patients complying with the following in- and exclusion criteria: 
 
 
 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
Inclusion criteria 
1. Female patients, age ≥18 years at the time of signing main informed consent; 
2. Patients with histologically confirmed recurrent, advanced or metastatic endometrial carcinoma 
(including endometrioid, mucinous, serous, squamous, clear-cell, undifferentiated or mixed 
carcinoma or carcinosarcoma);  
3. Eligible patients should have progressed on or after one prior systemic platinum-based 
chemotherapy regimen for endometrial cancer. Patients who have had two or more lines of 
chemotherapy  are not eligible. 
Note: 
– Patients may have received up to one additional line of chemotherapy if given in the 
neoadjuvant or adjuvant setting provided that such treatment was completed more than 6 
months prior to the current tumour recurrence or progression; 
– No more than one line of non-cytotoxic systemic cancer therapy (such as immunotherapy, 
trastuzumab or protein kinase inhibitors) is allowed; 
Note: there is no restriction regarding to the lines of prior hormonal therapy. 
4. HER2 tumour expression defined as a 1+, 2+ or 3+ score on IHC or positive by ISH as 
determined by the central laboratory on most recent available/obtained tumour material; 
5. At least one measurable cancer lesion as defined by the Response Evaluation Criteria for Solid 
Tumours (RECIST version 1.1); 
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 
7. Adequate organ function, evidenced by the following (local) laboratory results:  
– Absolute neutrophil count ≥ 1.5 x 109/L; 
– Platelet count ≥ 100 x 109/L; 
– Hemoglobin ≥ 9.0 g/dL or 5.6 mmol/L; 
– Total bilirubin ≤ 1.5 x the upper limit of normal (ULN);  
– Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN (or ≤ 
5.0 x ULN in the presence of liver metastases); 
– Serum creatinine ≤ 1.5 x ULN; 
8. For women of childbearing potential highly effective contraception must be used during the study 
and up to at least 6 months after last study treatment. This is not required in case the patient or 
sole partner is surgically sterilized or in case the patient truly abstains from sexual activity; 
 
Exclusion criteria 
1. Having been treated with:  
a. Any HER2-targeting antibody-drug conjugate (ADC) therapy; 
b. Anthracycline treatment within 8 weeks prior to start IMP treatment;      
c. Other anticancer therapy including chemotherapy, immunotherapy, or investigational 
agents within 4 weeks prior to start IMP treatment or 5 times the half-life of the therapy, 
whichever is shorter; 
d. Radiotherapy within 4 weeks prior to start IMP treatment, or within 1 week prior to start 
IMP treatment for palliative care (as long as the lungs were not exposed);  
e. Hormone therapy within 1 week prior to start IMP treatment; 
The patient must have sufficiently recovered from any treatment-related toxicities to CTCAE 
Grade ≤ 1 (except for toxicities not considered a safety risk for the patient at the investigator’s 
discretion); 
2. History of infusion-related reactions and/or hypersensitivity to trastuzumab or excipients of 
the study drug which led to permanent discontinuation of the treatment; 
3. History or presence of keratitis; 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
4. Severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary, or 
metabolic disease) at screening; 
5. Left ventricular ejection fraction (LVEF) < 50% as assessed by either echocardiography or 
multigated acquisition (MUGA) scan at screening, or a history of clinically significant 
decrease in LVEF during previous treatment with trastuzumab leading to permanent 
discontinuation of treatment;  
6. History (within 6 months prior to start IMP treatment) or presence of clinically significant 
cardiovascular disease such as unstable angina, congestive heart failure (CHF), myocardial 
infarction, uncontrolled hypertension, or cardiac arrhythmia requiring medication; 
7. Symptomatic brain metastases, brain metastases requiring steroids to manage symptoms, or 
treatment for brain metastases within 8 weeks prior to start IMP treatment; 
8. History or presence of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan; 
9. Known active Hepatitis B, C or E infection; 
10. Major surgery within 4 weeks prior to start IMP treatment; 
11. Pregnancy or lactation; 
12. Other condition, which in the opinion of the investigator, would compromise the safety of the 
patient or the patient's ability to complete the study. 
 
Study medication, mode of administration:  
 
SYD985, [vic-]trastuzumab duocarmazine, Byondis BV, The Netherlands 
SYD985 is an ADC comprised of Byondis’ HER2-targeting monoclonal IgG1 antibody trastuzumab 
covalently bound to a linker-drug. The linker-drug contains a cleavable linker and the prodrug seco-
duocarmycin-hydroxybenzamide-azaindole (seco-DUBA). The linker can be cleaved by proteases 
in the tumour at the dipeptide valine-citrulline (vc) motif, which releases the active DNA-alkylating 
toxin (DUBA).  
Drug product vials contain 80 mg sterile lyophilized SYD985 which should be reconstituted prior to 
use with 8.0 mL sterile water for injection to yield a solution of 10 mg/mL. The calculated amount 
of solution should be added to an infusion bag containing 0.9% sodium chloride without other 
additives. SYD985 is to be administered intravenously over 60 minutes for the first infusion, 
subsequent infusions can be given over 30 minutes. 
 
Study assessments and procedures (see also flowchart) 
The informed consent form (ICF) must be signed before any study-related procedure is performed. 
The pre-screening HER2 testing-ICF should be used to allow the central analysis of HER2 
expression on most recent available tumour material from a potentially eligible patient. A fresh 
tumour biopsy should be performed if no adequate tumour tissue is available. In case the HER2 
tumour expression does not comply with the inclusion criterion, the patient cannot participate. Before 
continuing with full screening the Main-ICF should be signed.  
 
Safety assessments will include physical examination, ECOG performance status, vital signs, weight 
assessment, electrocardiography (ECG), LVEF measurements by echocardiography or MUGA scan, 
laboratory measurements, pulmonary function testing (PFT), ophthalmological examination and 
adverse event (AE) reporting. Blood samples for blood chemistry and haematology will be measured 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
by the local laboratory. In addition, genetic analysis will be performed by a central laboratory on 
most recent available tumour tissue and a blood sample, to explore the correlation between 
biomarkers and tumour response and/or toxicity. The patient will be requested to sign the Genetic 
tumour analysis-ICF for this purpose. 
 
Patients will be clinically and radiologically (CT or MRI scan) evaluated for tumour response at 
screening and subsequently during treatment every 6 weeks for the first 24 weeks and every 12 weeks 
thereafter. Tumour responses will be assessed locally by the investigator/radiologist using RECIST 
(version 1.1). In addition, scans will be collected and stored at a central imaging lab, for potential 
central analysis at a later stage. Patients who have stopped study treatment for other reasons than PD 
(e.g. due to toxicity) will continue their tumour evaluations in an observation period until disease 
progression or start of a new anticancer therapy.  
 
After a treatment discontinuation visit patients will be contacted to follow up on clinical disease 
progression, unresolved AEs and new anticancer therapies. After the last study related visit (either 
30-day follow up or observation period) patients will be contacted every 3 months to collect overall 
survival data. 
 
Number of patients and study sites 
Approximately 60 patients will be recruited in up to 35-40 participating clinical sites located in 
Europe, USA and Asia-Pacific. Inclusion of patients with HER2 1+/2+, ISH negative tumours will 
be limited to a maximum of 50% of the total sample size. This study is of explorative nature; 60 
patients should provide for sufficient safety information and for an ORR estimate with acceptable 
confidence interval for future decision-making. 
 
Estimated clinical study period 
First patient First Visit: Q2 2020 
Last Patient First Visit: Q3 2021 
Study completion for primary endpoint: Q2 2022 
 
 
 
 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
1.1. 
Study flowchart – assessments and procedures 
 
 
Screening 
Treatment Phase 
Treatment 
discontinua
tion16 
Follow-up 
17 
Observation 
phase18 
Survival 
Follow up20 
Cycle 12 
Cycle 2 
onwards 
Visit day 
Day 
-28 to -1 Day 13 Day 8 Day 15 
Day 13 
 
30 days 
after 
treatment 
discont. 
visit 
To coincide 
with tumour 
evaluation 
schedule 
Every 3 
months 
after last 
contact 
Visit window (days) 
 
 
± 1  
± 1 
± 3 
 
± 7 
 
± 14 
Informed consent1 
✓ 
 
 
 
 
 
 
 
 
Demographics 
✓ 
 
 
 
 
 
 
 
 
Medical history 
✓ 
 
 
 
 
 
 
 
 
In/exclusion criteria 
✓ 
✓ 
 
 
 
 
 
 
 
Physical examination 
✓ 
✓ 
 
 
✓ 
✓ 
 
 
 
Vital signs4 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
Weight, height (only at 
screening) 
✓ 
✓5 
 
 
✓5 
✓ 
 
 
 
ECOG performance status 
✓ 
✓ 
 
 
✓ 
✓ 
 
 
 
PFTs6 
✓ 
When clinically indicated 
 
 
 
HER2 assessment7 
✓ 
 
 
 
 
 
 
 
 
Genetic tumour analysis8 
including blood sample 
 
 
 
 
Cycle 2 
 
 
 
 
Haematology / blood 
chemistry  
✓ 
✓9 
✓ 
✓ 
✓9 
✓ 
 
 
 
Pregnancy test10 
✓ 
✓ 
 
 
✓ 
✓ 
 
 
 
LVEF11,12 
✓ 
 
 
 
✓ 
+ every 4th 
cycle 
✓ 
 
 
 
ECG13 
✓ 
✓ 
 
 
✓ 
+ every 4th 
cycle 
✓ 
 
 
 
Ophthalmological 
examination11 
✓ 
 
 
 
✓ 
+ every 2nd 
cycle 
✓ 
 
 
 
Tumour evaluation14 
✓ 
Every 6 weeks for first 24 wks,  
thereafter every 12 wks 
✓ 
 
✓19 
 
Study drug 
administration15 
 
✓ 
 
 
✓ 
 
 
 
 
(S)AEs 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
Previous and concomitant 
medication 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
Survival information  
 
 
 
 
 
 
 
✓ 
✓ 
 
General note: in case assessments show abnormal results that warrant more extensive monitoring for safety, 
additional visits and assessments should be considered. 
 
1 
Following signing the main study ICF an eligible patient should be treated within 28 days. In addition to the main ICF separate informed 
consent forms are available for determination of the HER2 tumour status and for genetic tumour analysis; 
2 
A cycle is defined as 21 days (3 weeks); 
3 
Day 1 assessments are to be done prior to study drug administration unless otherwise stated; 
4 
Vital signs should include assessment of blood pressure, heart rate, body temperature and oxygen saturation by pulse oximetry;  
5 
Weight should always be measured prior to SYD985 administration on the Day 1 visits. However, weight measured up to 7 days before 
the Day 1 visit can be used for the preparation of the infusion bag; 
6 
Pulmonary Function Testing (PFTs) should be done at baseline and whenever clinically indicated, according to local hospital standard; 
7 
Archived tumour material should be submitted for central analysis of HER2 status by IHC and ISH. HER2 status should be available 
before start IMP treatment. If there is no archival tumour material available a biopsy should be performed to obtain tumour material; 
8 
Genetic tumour analysis will be performed by a central laboratory. Most recent available tumour tissue should be sent to the central lab 
together with a blood sample taken on the Cycle 2 Day 1 visit to determine the germline DNA; 

 
 
 
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                                                                             30 Sep 2020  
9 
Blood sampling for haematology/chemistry should be done as closely as possible to the start of the new cycle, but may be done up to 3 
days before. Results from the local laboratory should be available before the start of the new cycle to determine if the patient can continue 
or not. If the screening assessment is done within 5 days before the first study drug administration, analysis does not need to be repeated 
at the day of first administration;   
10 Pregnancy tests (serum test at screening and serum or urinary tests during treatment and at treatment discontinuation) will be performed 
to exclude pregnancy in women with childbearing potential, and may be done up to 3 days before the start of the new cycle. If the screening 
assessment is done within 5 days before the first study drug administration, analysis does not need to be repeated at the day of first 
administration; 
11 LVEF assessment as well as ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up 
time, and pachymetry) should be done as closely as possible to the start of the indicated cycle, but may be done up to 7 days before. Results 
should be available before the start of the indicated cycle to determine whether the patient can continue; 
12 LVEF should be measured by echocardiogram or MUGA scan according to routine local clinical practice, however the method should 
remain the same per patient. If LVEF is below 50% the next assessment should be performed before the start of the next cycle as indicated 
in the dose modification Section 9.6.1.3 of the protocol; Assessments should be done at cycle 2 and every 4th cycle, meaning cycle 2, 6, 
10 etc. 
13 12-lead ECGs should be recorded in triplicate; Assessments should be done at cycle 1 and 2 and every 4th cycle, meaning cycle 1, 2, 6, 10 
etc. 
14 Tumour evaluation includes systemic use of clinical, radiological (e.g. CT or MRI) and other methods (if deemed necessary). For tumour 
measurements, a CT or MRI scan should be performed every 6 weeks (± 3 days) for the first 24 weeks and every 12 weeks (± 7 days) 
thereafter, independent of dosing delays. If tumour evaluation falls at the Day 1 of a cycle (in case there are no treatment delays), it can 
also be performed up to 7 days prior to the Day 1 visit, but should always be done prior to IMP infusion. The methodology and imaging 
levels should remain the same at baseline and subsequent evaluations for a given patient. Additionally, scans should be provided to the 
central imaging lab for collection and storage;  
15 Administration of SYD985 in a 21-days regimen (± 3 days) until disease progression or unacceptable toxicity. No recalculation of the 
SYD985 dose in mg is needed if the weight at the day of administration has changed < 5% compared to the weight at Cycle 1 Day 1. 
Concomitant prophylactic lubricating eye drops should be prescribed to patients, to be used 3 times a day or as needed; 
16 The treatment discontinuation visit should occur at the time study treatment is discontinued for any reason. Tumour evaluation at the 
discontinuation visit is required for patients who discontinue study treatment before first scheduled in-treatment tumour assessment (week 
6) and for patients whose previous tumour assessment did not demonstrate PD and was done more than 21 days prior to the treatment 
discontinuation period. For patients who continue into the Observation Phase there is no need to perform a tumour evaluation at the 
discontinuation visit, they should maintain the same tumour evaluation schedule as during the Treatment Phase; 
17 If a follow-up visit is not possible, the patient should be contacted by telephone; 
18 The Observation Phase is for any patient that discontinued study treatment for reasons other than PD (e.g. toxicity). Patients stay in the 
Observation Phase until the time of PD or the start of a new anticancer treatment; 
19 Tumour imaging for the Observation Visits should be maintained by the same schedule that was initiated during the Treatment Phase; 
20 Every 3 months (±14 days) following the last visit/contact (i.e. 30-day follow up visit or final observation phase visit) patient should be 
contacted for survival until death, lost to follow-up or consent withdrawal, whichever comes first. During this follow-up only survival 
information and initiation of new anticancer medication should be documented.  
 
 
 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
2. 
Sponsor information and responsibilities 
A current version of all contact information for functions involved in the clinical study conduct 
and emergency contacts will be maintained in the Trial Master File (TMF) and Investigator Site 
File (ISF). The protocol will therefore not be amended for changes in e.g. responsibilities, 
contact information details as presented below. 
 
 
Sponsor: 
 
Byondis BV 
Microweg 22 
6545 CM Nijmegen 
The Netherlands 
 
Clinical Project Leader 
Telephone number: 
E-Mail: 
 
Maaike Hendriks 
+31 24 372 7966  
Maaike.Hendriks@byondis.com 
 
CRO (clinical services): 
 
 
 
 
PSI CRO AG 
Baarerstrasse 113a 
6300 Zug 
Switzerland  
 
EDC services 
Medidata 
Medidata Solutions 
350 Hudson Street, 9th Floor,  
New York, NY 10014 
USA 
IMP logistics:  
 
 
 
 
 
 
 
ALMAC Clinical Services 
ALMAC Group 
9 Charlestown Road 
Seagoe Industrial Estate, Craigavon 
BT63 5PW 
United Kingdom 
 
 
Central Image Vendor: 
 
(collect and hold scans, potential 
RECIST evaluation) 
Bioclinica 
Imaging Core Lab and Cardiac Safety Princeton 
Office 
211 Carnegie Center Drive 
Princeton, NJ 08540 
USA 
Central laboratory  
(for HER2 tumour expression):  
 
 
Targos Molecular Pathology 
Germaniastrasse 7 
D-34119 Kassel 
Germany 
  

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
Central laboratory  
(for genetic tumour analysis) 
Tempus Labs 
600 West Chicago Ave, Suite 510 
Chicago, IL 60654 
USA 
 
 
 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
  
3. 
Table of contents 
1. 
Protocol synopsis 
2 
1.1. 
Study flowchart – assessments and procedures 
6 
2. 
Sponsor information and responsibilities 
8 
3. 
Table of contents 
10 
4. 
List of abbreviations 
13 
5. 
Introduction 
15 
5.1. 
Therapeutic background and study rationale 
15 
5.2. 
Patient population rationale 
16 
5.3. 
Dosage rationale 
16 
5.4. 
Primary endpoint rationale 
16 
5.5. 
Safety considerations 
17 
5.6. 
Benefit-risk assessment 
19 
6. 
Objective(s) 
19 
6.1. 
Efficacy objectives 
19 
6.1.1. 
Primary objectives 
19 
6.1.2. 
Secondary objectives 
19 
6.1.3. 
Other objectives 
19 
7. 
Study design 
19 
8. 
Study population 
20 
8.1. 
Eligibility criteria 
20 
8.1.1. 
Inclusion criteria 
20 
8.1.2. 
Exclusion criteria 
21 
8.2. 
Screen failures and re-screening 
22 
9. 
Study medication and dosing instructions 
22 
9.1. 
Description of study drug 
22 
9.2. 
Labeling, packaging and storage 
22 
9.3. 
Treatment assignment 
23 
9.4. 
Treatment regimen and individual administration procedure 
23 
9.5. 
Treatment compliance and accountability 
24 
9.6. 
Dose modifications 
24 
9.7. 
Subject emergency card 
26 
10. 
Concomitant medication 
27 
10.1. 
Acceptable concomitant medication 
27 
10.2. 
Prohibited concomitant medication 
27 
10.3. 
Contraception 
28 
11. 
Study procedures and assessments 
28 
11.1. 
Obtain informed consent 
28 
11.2. 
Demographics and medical history 
29 
11.3. 
Inclusion/exclusion criteria 
29 
11.4. 
Physical examination 
29 
11.5. 
Vital signs, body weight and height 
29 

 
 
 
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11.6. 
Eastern cooperative oncology group (ECOG) performance status 
29 
11.7. 
Pulmonary Function Testing 
30 
11.8. 
Determination of HER2 tumour status 
30 
11.9. 
Genetic tumour analysis 
30 
11.10. 
Haematology and blood chemistry 
31 
11.11. 
Pregnancy test 
31 
11.12. 
LVEF assessment 
31 
11.13. 
ECG assessment 
32 
11.14. 
Ophthalmological examination 
32 
11.15. 
Tumour evaluation 
32 
11.16. 
Previous and concomitant medication 
33 
11.17. 
(Serious) adverse events 
33 
11.18. 
Visit requirements 
33 
11.18.1. 
Screening 
33 
11.18.2. 
Treatment phase 
34 
11.18.3. 
Discontinuation visit 
34 
11.18.4. 
Follow-up 
34 
11.18.5. 
Observation phase 
34 
11.18.6. 
Survival follow-up 
34 
11.19. 
Study assessments after last patient enrolled 
34 
12. 
Safety monitoring 
34 
12.1. 
Definitions 
34 
12.2. 
Adverse event monitoring 
36 
12.3. 
Adverse events documentation 
36 
12.3.1. 
Adverse events severity 
37 
12.3.2. 
Adverse events causality 
37 
12.4. 
Serious adverse events documentation 
37 
12.5. 
Reporting of serious adverse events 
38 
12.6. 
Adverse events of special interest 
38 
12.7. 
Reporting of death 
39 
12.8. 
Reporting of serious breaches 
39 
12.9. 
Reporting of pregnancies 
39 
13. 
Criteria for patient discontinuation, replacement and study termination 
40 
13.1. 
Patient discontinuation 
40 
13.2. 
Patient replacement 
41 
13.3. 
Start and end of study 
41 
14. 
Study evaluation, statistical considerations and data analysis 
41 
14.1. 
General considerations for data analysis 
41 
14.1.1. 
Missing data 
42 
14.2. 
Analysis populations 
42 
14.2.1. 
Full analysis set 
42 
14.2.2. 
Efficacy analysis set 
42 
14.3. 
Timing of analysis 
42 
14.3.1. 
Interim analysis 
42 
14.3.2. 
Main analysis 
42 
14.4. 
Demographic and baseline characteristics 
42 
14.5. 
Study endpoints 
43 

 
 
 
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14.5.1. 
Primary endpoint 
43 
14.5.2. 
Secondary endpoints 
43 
14.5.3. 
Other endpoints 
43 
14.6. 
Efficacy analysis 
43 
14.6.1. 
Primary objective 
43 
14.6.2. 
Secondary objective 
44 
14.6.3. 
Other objectives 
44 
14.7. 
Safety data analysis 
44 
14.7.1. 
Extent of exposure 
45 
14.7.2. 
Treatments 
45 
14.7.3. 
Adverse events 
45 
14.7.4. 
Clinical laboratory evaluations 
45 
14.7.5. 
ECG analyses 
45 
14.7.6. 
LVEF 
46 
14.7.7. 
Opthalmological exams 
46 
14.7.8. 
Other safety measures 
46 
14.8. 
Sample size 
46 
15. 
Study administration 
46 
15.1. 
Regulatory and ethics committee considerations 
46 
15.1.1. 
Approval by competent regulatory authority and IEC/IRB 
47 
15.1.2. 
Informed consent 
47 
15.1.3. 
Investigator reporting requirements 
47 
15.1.4. 
Amendments to study protocol 
48 
15.1.5. 
Investigator compensation 
48 
15.1.6. 
Coordinating Investigator for Clinical Study Report 
48 
15.2. 
Monitoring and quality assurance 
48 
15.2.1. 
Monitoring 
48 
15.2.2. 
Direct access to source data/documents 
49 
15.2.3. 
Quality assurance 
49 
15.3. 
Data handling and records retention 
49 
15.3.1. 
Collection of data and data management 
49 
15.3.2. 
Records retention 
50 
15.3.3. 
Information of investigators about study results 
50 
15.4. 
Publication policy and inventions 
50 
15.4.1. 
Publication 
50 
15.4.2. 
Confidentiality 
51 
15.4.3. 
Ownership and copyright 
51 
16. 
References 
51 
APPENDIX 1: Tumour evaluation criteria (based on RECIST 1.1) 
53 
APPENDIX 2: Protocol amendment I 
57 
APPENDIX 3: Protocol amendment II 
61 
 
 

 
 
 
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4. 
List of abbreviations 
 
 
ABG 
Arterial Blood Gas 
ADA 
Anti-Drug Antibody 
ADC 
Antibody-Drug Conjugate 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
ALanine aminoTransferase 
AP 
Alkaline phosphatase 
AST 
ASpartate-amino-Transferase 
ATC 
Anatomical therapeutic chemical classification system 
BUN 
Blood urea nitrogen 
CBR 
Clinical Benefit Rate 
CHF 
Congestive heart failure 
CI 
Confidence Interval 
CK 
Creatine kinase 
CR 
Complete response 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DUBA 
DUocarmycin hydroxyl Benzamide Azaindole 
ECG 
Electro Cardio Gram 
eCRF 
electronic Case Report Form  
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full Analysis Set 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transpeptidase 
HER2 
Human Epidermal growth factor Receptor 2 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form  
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry  
ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product 
INN 
International Non-proprietary Name 
IRB 
Institutional review Board 
ISF 
Investigator Site File 
ISH 
In situ hybridization  
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LDH 
Lactate DeHydrogenase 
LVEF 
Left Ventricular Ejection Fraction 

 
 
 
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MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
Multigated acquisition 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PFT 
Pulmonary Function Test 
PR 
Partial response 
Q3W 
Dosing every three weeks 
RECIST 
Response Evaluation Criteria for Solid Tumours 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SYD985 
trastuzumab vc-seco-DUBA 
TEAE 
Treatment Emergent Adverse Event 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
vc 
Valine-citrulline 
 
 
 
 
 
 

 
 
 
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5. 
Introduction 
5.1. 
Therapeutic background and study rationale 
 
Endometrial cancer is the second most common gynaecologic malignancy world-wide, with an 
estimated 380,000 new cases and 90,000 deaths in 2018.1 Metastatic disease remains non 
curable. For advanced, metastatic disease platinum-based chemotherapy is the preferred first 
treatment line.2,3 Few chemotherapy agents have been shown to produce meaningful response 
rates in the second-line setting, highlighting a need for new therapies in advanced, recurrent, 
metastatic endometrium cancer.4  
 
Human Epidermal growth factor Receptor 2 (HER2) provides critical signalling for cancer cell 
growth, survival, and proliferation.5,6 Amplification and over-expression of HER2 are 
associated with shortened survival in breast cancer.7,8 Four HER2-targeting therapies have been 
approved up to now in the EU and the US for HER2-positive breast cancer: two antibodies 
(trastuzumab and pertuzumab), antibody-drug-conjugate (ADC) (ado-trastuzumab emtansine, 
T-DM1), and a small molecule kinase inhibitor (lapatinib). 
 
According to literature on average 25-30% of patients with endometrial cancer have HER2-
positive disease.9,10,11,12. In an aggressive endometrial cancer subtype of uterine serous 
carcinoma the addition of trastuzumab to a chemotherapy combination of carboplatin/paclitaxel 
has shown increased progression-free survival (PFS) in HER2-positive patients.13  
 
Byondis developed a new HER2-targeting therapy, SYD985, which is comprised of Byondis’ 
monoclonal IgG1 antibody trastuzumab covalently bound to a linker-drug. This linker-drug 
contains a cleavable linker and the prodrug seco-DUocarmycin-hydroxyBenzamide-Azaindole 
(seco-DUBA). After binding to HER2 on the cell membrane, SYD985 undergoes receptor 
mediated internalization and the linker is cleaved in the lysosome at the dipeptide valine-
citrulline (vc) motif by proteases. Upon cleavage, two self-elimination reactions occur to 
generate the prodrug (seco-DUBA), which then spontaneously rearranges to form the active 
toxin (DUBA). The active toxin alkylates DNA resulting in DNA damage in both dividing and 
non-dividing cells, and ultimately cell death. In addition, in vitro studies showed that the active 
toxin can cross the cell membrane and kill neighbouring, HER2-negative tumour cells as a 
bystander effect (see for more details the Investigator's Brochure (IB)). 
 
Results of the first-in-human Phase I study suggest that SYD985 is efficacious and has an 
acceptable safety profile in heavily pre-treated patients with HER2-expressing metastatic 
cancer.14 In the HER2-positive breast cancer cohort an objective response was achieved by 16 
(33%, 95% CI 20.4-48.4) of 48 patients and a median PFS of 7.6 months (95% CI 4.2-10.9). 
Further investigation of SYD985 is ongoing in a phase III study comparing the efficacy and 
safety of SYD985 to physician’s choice in patients with HER2-positive unresectable locally 
advanced or metastatic breast cancer. 
 
In the endometrial cancer cohort of the Phase I study, 13 patients were enrolled and treated with 
SYD985. The objective response rate (ORR) was 39% (95% CI 13.9-68.4), with partial 
responses in 5 patients. These partial responses were observed both in patients with high- and 
low-expressing HER2 tumours. Median PFS was 4.3 months (95% CI: 2.4-9.9).14 
 

 
 
 
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The intent of this Phase II study is to further investigate the efficacy and safety of SYD985 for 
the treatment of patients with HER2-expressing recurrent, advanced or metastatic endometrial 
cancer who have progressed on first line platinum-based chemotherapy.  
 
5.2. 
Patient population rationale 
 
The patient population for this study includes patients with HER2-expressing recurrent, 
advanced or metastatic endometrial cancer who have progressed after receiving primary 
treatment with platinum-based chemotherapy. Patients may have had prior chemotherapy in the 
neoadjuvant or adjuvant setting.  
 
Few agents have been shown to produce meaningful response rates in the second-line setting 
and no HER2-targeting therapies have been approved yet for endometrial cancer while 25-30% 
of the patients overexpress the HER2-receptor. 
 
Patients who have received one previous line of HER2-targeting therapy and who have 
developed resistance to this therapy are eligible, as clinical data suggests that HER2-positive 
cancers continue to depend on HER2 at the time of progression.15,16 In addition, efficacy has 
been demonstrated in the phase I study with SYD985 in patients with breast cancer after having 
received multiple prior HER2-targeting therapies. 
 
As it is not known what minimal level of HER2-expression is required to initiate an anti-tumour 
effect with SYD985 in endometrial cancer, and considering the promising results in the phase 
I study, both patients with high- and patients with low-expressing HER2 tumours will be 
included in this study, where the patients with HER2-low tumours will not exceed more than 
50% of the total sample size.  
 
5.3. 
Dosage rationale 
 
SYD985 will be administered in a dose of 1.2 mg/kg once every three weeks. 
 
The 3-weekly interval was investigated in the dose-escalation part of the Phase I study and is 
the regimen chosen to investigate in the ongoing phase III and in this phase II trial. Dosing 
delays and reductions are allowed to reduce toxicity in an individual patient (Section 9.6).  
 
5.4. 
Primary endpoint rationale 
 
The primary endpoint of this study is to evaluate the anticancer activity of SYD985 with respect 
to ORR. 
 
ORR will be defined as the percentage of patients with a best overall response of complete 
response (CR) or a partial response (PR). This is an established measure of anti-tumour activity, 
as tumour reduction is a direct therapeutic effect whereas stable disease (SD) could reflect the 
natural history of the disease. The objective tumour response will be assessed by the 
investigators using RECIST 1.1.17  
 

 
 
 
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5.5. 
Safety considerations 
 
This section is primarily based on the clinical data from the phase I and ongoing phase III study 
with SYD985. Please refer to the SYD985 IB for further information. It should be taken into 
account that toxicity other than described in the IB may evolve. For the most up to date 
information one should always refer to the current version of the IB.  
 
The most common drug-related AEs reported in the clinical studies (>10%) are: 
• Conjunctivitis, dry eye, keratitis, lacrimation increased; 
• Fatigue; 
• Nausea, stomatitis; 
• Alopecia, skin hyperpigmentation; 
• Neutropenia, anaemia; 
• Decreased appetite; 
     
In addition, specific important safety considerations are described in more detail below. 
 
Ocular toxicity 
Ocular toxicity was commonly reported with SYD985. Patients previously reported treatment-
related ocular toxicity, including most commonly conjunctivitis, dry eye, keratitis and 
lacrimation increased. Most eye disorders were of mild or moderate intensity. The most 
common severe AEs were keratitis and conjunctivitis. In the majority of patients, the ocular 
toxicity improves and eventually recovers, but it may take several months. 
 
Ocular toxicity should be monitored prior to initiation of treatment and every other cycle by an 
ophthalmological examination (see Section 1.1). Patients with a history of keratitis are not 
eligible for this study. Specific guidelines regarding dose delays and/or reductions or 
discontinuation for severe ocular toxicity are provided in Section 9.6.1.1. 
 
Pulmonary toxicity 
Pulmonary events, including Interstitial Lung Disease (ILD)/pneumonitis, dyspnoea 
(exertional), pleural effusion and respiratory failure, have been reported with SYD985. So far 
one fatal pneumonitis event has been reported at 2.4 mg/kg in the phase I study and one possibly 
related case of fatal respiratory failure at 1.2 mg/kg in the phase III study.  
 
Caution should be exercised when a patient presents with non-specific respiratory signs and 
symptoms such as hypoxia, pleural effusion, cough, dyspnoea or radiological features on chest 
CT scan. To detect pneumonitis or other pulmonary toxicity in an early stage, tumour evaluation 
CT scans should be carefully evaluated for lung changes e.g. by means of high resolution CT. 
Infectious and disease-related aetiologies should be ruled out. Patients should be advised to 
promptly report any new or worsening respiratory symptoms.  
 
The diagnosis of ILD/pneumonitis should be made on clinical/radiological findings. 
Biomarkers for ILD/pneumonitis are exploratory and they should not be used for diagnosis or 
monitoring of drug induced ILD/pneumonitis. When evaluating ILD/pneumonitis (regardless 
of stage) it is highly recommended to include a pulmonary consult, a high resolution CT, 
pulmonary function testing (PFT), pulse oximetry and arterial blood gases (ABGs). 
 

 
 
 
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In case pneumonitis is suspected one should consider treatment with a sufficiently high dose of 
corticosteroids followed with an adequate taper period as per standard hospital protocol for 
drug-induced pneumonitis. Specific guidance for dose modifications for pneumonitis is 
described in Section 9.6.1.2. 
 
Cardiac toxicity 
Decreased left ventricular ejection fraction (LVEF) was reported as treatment-related AE in a 
small number of patients treated with SYD985. The majority of events was reported as 
recovered. No other significant cardiotoxicity has been reported with SYD985 to date. SYD985 
should be delayed or discontinued in cases of left ventricular dysfunction according to the 
guidance in Section 9.6.1.3.  
 
Infusion related reactions 
Infusion related reactions were reported for some patients treated with SYD985. All infusion 
related reactions occurred at the start of the study drug treatment, either after the first and/or 
second infusion, and SYD985 treatment was continued in all patients. The most common 
symptoms included chills/ shivering and fever that mostly recovered within 1 day.    
 
Infusion related reactions mostly occur during or immediately following the (initial) infusion. 
Infusions should be slowed or interrupted for patients experiencing infusion-related symptoms. 
 
Injection site reactions 
Injection site reaction was reported in a few patients. Infusion site extravasation was reported 
sporadically.  
 
It is recommended to avoid the use of veins over joints or in extremities with compromised 
venous or lymphatic drainage. At the end of each infusion, the line must be flushed with up to 
100 mL of sterile 0.9% sodium chloride for infusion, at the discretion of the investigator. When 
extravasation is noted, immediately stop the infusion and follow the local hospital extravasation 
protocols for vesicant drugs in consultation with the responsible physician.  
 
Haematological toxicity 
Treatment-related haematotoxicity, with neutropenia and anemia as the only treatment-related 
haematological events reported for more than 10% of patients, were mostly mild or moderate 
in intensity and only a few patients discontinued SYD985 treatment due to it (all decreased 
platelet count). Of the patients that recovered, the majority either did not require any 
intervention or recovered after delayed dosing. Dose modification for haematological events is 
described in Section 9.6.1.4.  
 
Embryo-foetal toxicity 
There are no data from the use of SYD985 in pregnant women. Although specific studies to 
assess a potential effect of SYD985 on fertility or embryonic development have not been 
conducted, it is likely that SYD985 can have an effect on fertility and is a developmental toxin 
based on the DNA reactive nature of the toxin. Therefore, pregnant and lactating women are 
not eligible to participate in clinical studies with SYD985. Participating patients must use 
highly effective methods of contraception as described in Section 10.3. In case a patient 
becomes pregnant during SYD985 treatment, she must be discontinued from the study.  
 

 
 
 
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5.6. 
Benefit-risk assessment 
 
Currently there are few to none treatment options available beyond first-line chemotherapy for 
patients with advanced or metastatic endometrial cancer that provide a clinically meaningful 
benefit.  
 
As described in Section 5.5, in previous studies SYD985 was associated with dose-related 
ocular and pulmonary toxicities. These toxicities are also commonly observed with other 
ADCs.18,19 Frequent safety assessments such as ophthalmological and physical examinations, 
haematology/biochemistry and ECG/LVEF measurements are included in the study to early 
detect and adequately monitor toxicities when they occur. Clear instructions for dose 
modifications, i.e. dose delay, reduction or discontinuation, are provided in Section 9.6 
specifically for ocular, lung, cardiac and haematological toxicity. In addition, investigators will 
be instructed to carefully evaluate the tumour evaluation scans for any lung changes. Patients 
with a history or presence of keratitis, impaired cardiac function and/or lung disease are 
excluded from the study as these patients may potentially be at higher risk to develop significant 
treatment-related toxicity.    
 
Based on the efficacy and safety data observed in the clinical phase I and III study and the 
implemented safety measures in this study, the benefit-risk assessment supports clinical 
development of SYD985 in this patient population. 
 
6. 
Objective(s) 
6.1. 
Efficacy objectives 
6.1.1. 
Primary objectives 
 
The primary objective of this study is to evaluate the ORR of SYD985. 
6.1.2. 
Secondary objectives 
 
The secondary objectives of this study are to evaluate SYD985 with respect to: 
• Progression Free Survival (PFS); 
• Overall Survival (OS); 
• Safety. 
 
6.1.3. 
Other objectives 
The other objectives of this study are as follows: 
• To describe time to response; 
• To describe duration of response; 
• To describe the clinical benefit rate (CBR);  
• To explore genomic profile/response relationships. 
 
7. 
Study design 
This is an open-label, single-arm study in patients with HER2-expressing recurrent, advanced 
or metastatic endometrial carcinoma. This is defined as a 1+, 2+ or 3+ score on 
immunohistochemistry (IHC) and/or positive by in situ hybridization (ISH). Inclusion of 

 
 
 
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patients with HER2 1+/2+, ISH negative tumours will be limited to a maximum of 50% of the 
total sample size. Eligible patients for this study should have progressed on or after first line 
platinum-based chemotherapy.  Patients who have had two or more lines of chemotherapy for 
advanced/metastatic disease are not eligible. 
 
Eligible patients will receive SYD985 1.2 mg/kg every three weeks (Q3W) until disease 
progression (PD) or unacceptable toxicity. During the first treatment cycle, patients will have 
to visit the clinical site three times for safety assessments, followed by one visit in subsequent 
cycles.  Patients who have stopped study treatment for other reasons than PD (e.g. due to 
toxicity) will continue their tumour evaluations in an observation period until disease 
progression or start of a new anticancer therapy.  
 
8. 
Study population 
The study population will consist of patients with HER2-expressing recurrent advanced or 
metastatic endometrial carcinoma. Patients should comply with all inclusion and none of the 
exclusion criteria as described below. All patients must provide their written informed consent 
before any protocol specific procedure including screening procedures, are performed. 
 
8.1. 
Eligibility criteria 
8.1.1. 
Inclusion criteria  
 
Any patient must meet the following inclusion criteria: 
 
1. Female patients, age ≥18 years at the time of signing main informed consent; 
2. Patients with histologically confirmed recurrent, advanced or metastatic endometrial 
carcinoma (including endometrioid, mucinous, serous, squamous, clear-cell, 
undifferentiated or mixed carcinoma or carcinosarcoma);  
3. Eligible patients should have progressed on or after one prior systemic platinum-based 
chemotherapy regimen for endometrial cancer. Patients who have had two or more lines 
of chemotherapy disease are not eligible. 
Note: 
– Patients may have received up to one additional line of chemotherapy if given in the 
neoadjuvant or adjuvant setting provided that such treatment was completed more than 
6 months prior to the current tumour recurrence or progression; 
– No more than one line of non-cytotoxic systemic cancer therapy (such as 
immunotherapy, trastuzumab or protein kinase inhibitors) is allowed; 
Note: there is no restriction regarding to the lines of prior hormonal therapy. 
4. HER2 tumour expression defined as a 1+, 2+ or 3+ score on IHC and/or positive by ISH 
as determined by the central lab on most recent available/obtained tumour material; 
5. At least one measurable cancer lesion as defined by the Response Evaluation Criteria for 
Solid Tumours (RECIST version 1.1); 
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 
 

 
 
 
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7. Adequate organ function, evidenced by the following (local) laboratory results:  
− Absolute neutrophil count ≥ 1.5 x 109/L; 
− Platelet count ≥ 100 x 109/L; 
– Hemoglobin ≥ 9.0 g/dL or 5.6 mmol/L; 
– Total bilirubin ≤ 1.5 x the upper limit of normal (ULN);  
– Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN 
(or ≤ 5.0 x ULN in the presence of liver metastases); 
– Serum creatinine ≤ 1.5 x ULN; 
8. For women of childbearing potential highly effective contraception must be used during 
the study and up to at least 6 months after last study treatment. This is not required in case 
the patient or sole partner is surgically sterilized or in case the patient truly abstains from 
sexual activity; 
8.1.2. 
Exclusion criteria 
 
Any patient who meets any of the exclusion criteria below must be excluded from participation 
in the study:  
 
1. Having been treated with:  
a. Any HER2-targeting ADC therapy; 
b. Anthracycline treatment within 8 weeks prior to start IMP treatment;     
c. Other anticancer therapy including chemotherapy, immunotherapy, or investigational 
agents within 4 weeks prior to start IMP treatment or 5 times the half-life of the 
therapy, whichever is shorter; 
d. Radiotherapy within 4 weeks prior to start IMP treatment, or within 1 week prior to 
start IMP treatment for palliative care (as long as the lungs were not exposed);  
e. Hormone therapy within 1 week prior to start IMP treatment; 
The patient must have sufficiently recovered from any treatment-related toxicities to NCI 
CTCAE Grade ≤1 (except for toxicities not considered a safety risk for the patient at the 
investigator’s discretion); 
2. History of infusion-related reactions and/or hypersensitivity to trastuzumab or excipients 
of the study drug which led to permanent discontinuation of the treatment; 
3. History or presence of keratitis; 
4. Severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, 
pulmonary, or metabolic disease) at screening; 
5. LVEF < 50% as assessed by either echocardiography or multigated acquisition (MUGA) 
scan at screening, or a history of clinically significant decrease in LVEF during previous 
treatment with trastuzumab leading to permanent discontinuation of treatment;   
6. History (within 6 months prior to start IMP treatment) or presence of clinically significant 
cardiovascular disease such as unstable angina, congestive heart failure (CHF), 
myocardial infarction, uncontrolled hypertension, or cardiac arrhythmia requiring 
medication; 
7. Symptomatic brain metastases, brain metastases requiring steroids to manage symptoms, 
or treatment for brain metastases within 8 weeks prior to start IMP treatment; 
8. History or presence of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. 
bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or 
evidence of active pneumonitis on screening chest CT scan; 
9. Known active Hepatitis B, C or E infection; 

 
 
 
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10. Major surgery within 4 weeks prior to start IMP treatment; 
11. Pregnancy or lactation; 
12. Other condition, which in the opinion of the investigator, would compromise the safety of 
the patient or the patient's ability to complete the study. 
 
8.2. 
Screen failures and re-screening 
 
Patients who signed the pre-screening HER2 testing-informed consent form (ICF) and/or the 
Main-ICF but failed to meet the inclusion and/or exclusion criteria are defined as pre-screen or 
screen failures. 
 
Re-screening is not allowed, a patient who failed one of the in- or exclusion criteria cannot be 
screened again at a later time point, except for HER2 tumour expression. In case the HER2 
tumour staining was unevaluable, it is allowed to send in new material for re-analysis. 
 
 
9. 
Study medication and dosing instructions 
9.1. 
Description of study drug 
 
Investigational medicinal product 
Test Product:  
SYD985: trastuzumab vc-seco-DUBA 
INN = [vic-]trastuzumab duocarmazine 
Formulation: 
Drug product vials contain 80 mg lyophilized SYD985 drug 
product which should be reconstituted prior to use with 8.0 ml of 
sterile water for injection to yield a solution of 10 mg/mL. 
Excipients: 
L-histidine, L-histidine hydrochloride monohydrate, trehalose 
dehydrate, polysorbate 20 
Manufacturer: 
Byondis BV, The Netherlands 
 
9.2. 
Labeling, packaging and storage 
SYD985 will be labelled according to Good Manufacturing Practice Annex 13. The drug labels 
are designed according to the locally applicable regulations and will generally contain the 
Sponsor name, protocol number, batch number, expiry date (where required), drug product 
name and content, route of administration, and storage conditions, as appropriate. Individual 
infusion bags will be prepared by the hospital pharmacy and will be labelled according to the 
local procedures. 
 
SYD985 should be stored in a secure, limited access location and kept out of sight and reach of 
children. The vials should be stored in the refrigerator at 2 to 8 °C (36-46 °F) and should not be 
frozen. The supplies should not be used beyond the expiry date. 
 
Reconstituted vials and prepared infusion solutions should be used immediately, or can be 
temporarily stored at 2 to 8 °C (36-46 °F) for use within 24 hours after reconstitution of the 
vial. 

 
 
 
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9.3. 
Treatment assignment 
 
When all screening data are available and patient eligibility has been confirmed by the Contract 
Research Organization (CRO)/Sponsor, the patient will be assigned SYD985 treatment as long 
as enrolment is not yet completed. A patient should start study treatment within 28 days of 
signing the Main-ICF.  
 
Enrolment of patients with a HER2-tumour status of IHC 1+, 2+ and ISH-negative or IHC 3+ 
and/or ISH-positive will be monitored and stopped when 50% (30 patients) have been enrolled 
in each sub-group. 
 
9.4. 
Treatment regimen and individual administration procedure 
 
SYD985 1.2 mg/kg will be administered once every three weeks (± 3 days) by intravenous 
infusion using an infusion set with filter as specified in the pharmacy manual.  
 
The infusion should be prepared aseptically. Slowly inject 8.0 ml sterile water for injection into 
the 80 mg SYD985 vial to yield a solution of 10 mg/mL. The vial should be swirled gently until 
completely dissolved. DO NOT SHAKE. Let the vial stand undisturbed for 5 minutes before 
further use. Inspect the solution for particulates and discoloration. The solution should be clear 
to slightly opalescent and free of visible particles. The solution should be colourless to pale 
yellow. Do not use the solution if it contains visible particles or is cloudy or discoloured. The 
reconstituted vials should preferably be used immediately but can be stored temporarily (see 
below). 
 
The volume of the SYD985 solution needed for a particular patient should be calculated based 
on the weight of the patient. The weight should always be measured prior to IMP infusion at 
the Day 1 visits. However, weight measured up to 7 days before the Day 1 visit can be used for 
the preparation of the infusion bag. If the weight at a dosing day differs more than 5% from the 
Cycle 1 Day 1 measurement the actual weight should be used for the preparation.  
 
The required volume needs to be withdrawn from the vial(s) and added to a 100 ml infusion 
bag as specified in the pharmacy manual containing 0.9% sodium chloride without other 
additives. To mix the solutions the infusion bag should be gently inverted to avoid foaming.  
 
In case the reconstituted vial and/or prepared infusion bag is not used immediately, they can be 
stored at 2 to 8 °C (36-46 °F). The prepared infusion bag must be used within 24 hours after 
reconstitution of the vial. 
 
The first infusion should be administered over 60 minutes (± 10 minutes). Following the initial 
dose, patients will be observed for at least 90 minutes after end of infusion for fever, chills, or 
other infusion-related symptoms. If prior infusions were well tolerated (without any signs or 
symptoms of infusion reactions) subsequent infusions can be given over 30 minutes (minimum 
of 25 minutes), with a minimum 30-minute observation period following the end of infusion.  
 
For each SYD985 infusion, it is recommended to avoid, if possible, the use of veins over joints 
or in the extremities with comprised venous or lymphatic drainage. At the end of every infusion, 
the infusion line must be flushed with sterile 0.9% sodium chloride solution for infusion as 

 
 
 
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indicated in the pharmacy manual, at the discretion of the investigator. In case extravasation is 
noted, the infusion should be stopped immediately and the local hospital extravasation protocol 
for vesicant drugs should be followed.  
 
Infusions may be slowed or interrupted for patients experiencing infusion-related symptoms at 
the discretion of the investigator. Infusion of SYD985 should be interrupted for patients who 
develop dyspnoea or clinically significant hypotension, but may resume at decreased infusion 
rate when sufficiently recovered. Infusions may be restarted at the full rate during the next 
cycle, provided there is adequate monitoring. Adequate premedication should be considered at 
the discretion of the investigator. Patients who experience a Grade 4 infusion-related reaction 
or a Grade 3 infusion-related reaction which does not respond to symptomatic medication 
and/or temporary interruption of infusion or infusion rate reduction should be discontinued 
from study treatment. 
 
Prophylactic lubricating eye drops should be prescribed to patients, to be used 3 times a day or 
as needed. All patients are advised not to wear contact lenses or rub their eyes during SYD985 
treatment. 
9.5. 
Treatment compliance and accountability 
 
SYD985 will be administered to the patient by trained staff of the study site. Details of 
preparation and administration will be documented in the electronic Case Report Form (eCRF). 
 
All Investigation Medicinal Product (IMP) will be tracked and accounted for at the 
investigational site following receipt, dispensing and administration to the patient, and 
ultimately including destruction or return to the Sponsor/CRO. In case of missing or damaged 
medication cartons or vials, this is to be reported to the Sponsor/CRO according to the 
instructions provided in the Pharmacy Manual. The product accountability will be fully 
documented by the investigational site. The investigational site will retain all unused study drug 
(and outer packaging) until the drug accountability has been checked by the clinical research 
associate (CRA).  
 
9.6. 
Dose modifications 
 
Patients should be assessed for toxicity prior to each dose: dosing should only occur if the 
clinical assessment and laboratory test values are acceptable. Dosing delays and reductions are 
designed to maximize treatment for those who derive clinical benefit from treatment while 
ensuring patient safety. 
 
Irrespective of the reason, if dosing is delayed, dosing should be resumed within 42 days from 
the last dose received, or the patient should discontinue treatment. On a case-by-case basis it 
can be decided to postpone dosing for a longer duration, e.g. in case the patient has clearly 
benefit from study drug treatment. Please contact the Medical Monitor for approval.  
 
Dose delays for SYD985-related toxicities, other than the ones specified below, should be 
handled as follows: 
• If significant SYD985-related toxicities have not recovered to Grade 1 or baseline, the 
next scheduled dose may be delayed for up to 42 days from the last dose received. 
“Significant” and “related” will be based on the judgement of the investigator (in 

 
 
 
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consultation with the Medical Monitor). For example, alopecia even if considered 
related would most likely not be considered to be significant. Fatigue may or may not 
be considered either related or significant. 
• In general, when the significant and related toxicity (or any other toxicity that the 
investigator chooses to delay dosing for) resolves to Grade 1 or baseline or is sufficiently 
resolved in the opinion of the investigator, the patient may resume SYD985 if the delay 
has not exceeded 42 days from the last received dose. Patients should be re-evaluated 
weekly during the delay whenever possible. If dosing resumes, the patient may receive 
SYD985 either at the same dose level as before or the dose can be reduced, at the 
discretion of the investigator. The dosing interval for subsequent cycles should remain 
every 21 days. 
• If toxicity does not resolve sufficiently within 42 days from the last dose received, the 
patient should be discontinued from study treatment and should be followed in the 
observation period for PD as described in Section 11.18.5. 
 
If a patient needs a dose reduction the dose should be reduced from 1.2 mg/kg to 0.9 mg/kg. 
Patients on the 0.9 mg/kg dose who develop an AE necessitating further dose reductions should 
be reduced to 0.6 mg/kg. Patients on the 0.6 mg/kg dose who develop an AE necessitating 
further dose reductions should be discontinued from treatment.  Dose escalation is not allowed 
after a dose reduction. 
 
Protocol requirements for specific toxicities are outlined below. 
 
9.6.1.1. 
Dose modifications for ocular toxicity 
 
Patients who experience Grade 3 (or higher) ocular toxicity should be discontinued from 
treatment. For patients who experience Grade 2 ocular toxicity, it should be considered to delay 
dosing for up to 42 days from the last received dose and appropriate treatment with eye drops, 
cream, or gel should be applied (e.g. steroid containing eye drops). If study drug is interrupted 
for Grade 2 toxicity it should resolve to Grade 1 or baseline before restarting treatment. Patients 
may continue treatment at the same dose level as before or the dose can be reduced, at the 
discretion of the investigator. Subsequent dosing delays or treatment discontinuation should be 
considered in case the ocular toxicity persists. The ocular toxicity should be monitored by an 
ophthalmologist (or qualified delegate) for recovery. 
 
9.6.1.2. 
Dose modifications for pulmonary toxicity 
 
Patients who experience ILD/pneumonitis Grade ≥ 2 will be discontinued from treatment. For 
patients who experience Grade 1 ILD/pneumonitis dosing must be delayed for up to 42 days 
from the last received dose. When the ILD/pneumonitis resolves to Grade 0 patients may 
continue treatment and a dose reduction should be considered. Reversibility or stabilisation of 
ILD/pneumonitis should be monitored and documented. If in addition to SYD985 a patient is 
receiving co-medication and develops drug-induced ILD/pneumonitis this should be considered 
related to SYD985.  
 
Caution should be exercised when a patient presents with non-specific respiratory signs and 
symptoms such as hypoxia, pleural effusion, cough, dyspnoea or radiological features on chest 
CT scan. The diagnosis of ILD/pneumonitis should be made on clinical/radiological findings. 

 
 
 
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Biomarkers for ILD/pneumonitis are exploratory and they should not be used for diagnosis or 
monitoring of drug induced ILD/pneumonitis. When evaluating ILD/pneumonitis (regardless 
of stage) it is highly recommended to include a pulmonary consult, a high resolution CT, PFTs, 
pulse oximetry and ABGs. It is recommended to delay SYD985 infusions until symptom 
improvement or until the diagnosis is clarified. It should be considered to reduce the SYD985 
dose for subsequent infusions or to discontinue treatment, at the discretion of the investigator. 
 
9.6.1.3. 
Dose modifications for cardiotoxicity 
 
Patients who develop clinically significant symptomatic cardiac disease during the study will 
be discontinued.  
 
LVEF assessments will be performed regularly during the study and declines will be handled 
as summarized in Figure 1. 
Figure 1: SYD985 dosing in relation to LVEF assessment 
 
SYD985 administration may be delayed to maximally 42 days after the last dose.  
 
9.6.1.4. 
Dose modifications for haematologic toxicity 
 
For patients who experience a Grade 3 (or higher) haematological event dosing must be delayed 
for up to 42 days from the last received dose. When the haematologic event resolves to Grade 
1 or baseline, patients may continue treatment at the same dose level as before or the dose can 
be reduced, at the discretion of the investigator.  
 
9.7. 
Subject emergency card 
 
At start of treatment patients will be handed out a Subject Emergency Card. This card indicates 
that the patient is participating in a clinical study and contains the patient number and provides 
details on the study drug that is being studied in the study. The patient is to carry the card at all 

 
 
 
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times, so that in case of a medical event, the treating medical personnel are aware of the study 
drug administration. The card also presents an emergency phone number. At the treatment 
discontinuation visit, the patient is to return the Subject Emergency Card.  
 
10. 
Concomitant medication 
10.1. 
Acceptable concomitant medication 
 
Patients are allowed to receive supportive care therapies concomitantly during the study (i.e. 
during treatment and observation phase). Concomitant medication and supportive care should 
be administered only as medically necessary during the study. Any concomitant medication 
(including herbal medication and vitamins) must be recorded in full detail (drug, dose, duration 
of treatment, reason for concomitant medication) in the eCRF. Note that the use of concomitant 
medication must relate to the documented medical history, an AE or be reported as prophylactic 
treatment.  
 
After consultation with the medical monitor, palliative radiotherapy may be allowed during the 
study for e.g. symptomatic treatment of painful bone lesions as long as the lesion is not a 
RECIST 1.1 defined target lesion and is not administered for tumour control. Study treatment 
should be held during the course of palliative radiotherapy and should be resumed no earlier 
than the next scheduled administration of study treatment. Treatment of brain metastases may 
also be allowed after consultation, unless the (symptoms of) brain metastases are classified as 
progressive disease for which the patient needs to be discontinued.   
 
Patients will not be routinely treated with an antiemetic regimen prior to SYD985 
administration. If a patient experiences grade 3 or greater nausea, diarrhoea and/or vomiting, 
medical intervention should occur, including prophylactic administration of antiemetic agents 
for subsequent infusions as indicated. Serious infusion-related events should be managed with 
supportive therapies as clinically indicated according to standard clinical practice (e.g. 
supplemental oxygen, β2-adrenergic receptor agonist, and/or corticosteroids). Reduction of the 
infusion rate and prophylactic treatment should be considered for subsequent infusions, if the 
patient continues in the study. 
 
Prophylactic lubricating eye drops should be prescribed to patients, to be used 3 times a day or 
as needed. All patients are advised not to wear contact lenses or rub their eyes during SYD985 
treatment. 
 
10.2. 
Prohibited concomitant medication 
 
Patients are prohibited to receive the following therapies during the study (i.e. during treatment, 
and observation phase, if applicable): 
• All anti-cancer therapies, including: 
o Chemotherapy; 
o HER2-targeting therapy;  
o Other anticancer therapy including immunotherapy or investigational agents; 
o Hormone therapy; 
• Radiotherapy (except for palliative care as described in Section 10.1). 
 

 
 
 
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Washout criteria apply for anticancer therapy prior to start of study treatment as described in 
exclusion criterion 1.  
 
10.3. 
Contraception 
Patients of childbearing potential must use highly effective contraception during the study, and 
up to at least 6 months after last study drug dose. For this study, methods that can achieve a 
failure rate of less than 1% per year when used consistently and correctly are considered as 
acceptable highly effective birth control methods in line with the recommendations of the 
Clinical Trial Facilitation Group.20 Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, or transdermal); 
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, or implantable); 
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS); 
• Bilateral tubal occlusion. 
 
The above contraception is not required in case the patient or sole partner of patient is surgically 
sterilized, or in case the patient truly abstains from sexual activity (when this is in line with the 
preferred and usual lifestyle of the patient).  
 
11. 
Study procedures and assessments 
The Study Flow Chart in Section 1.1 summarizes the study procedures to be performed at each 
visit. Individual study procedures are described below. For details of assessment and reporting 
of AEs, see Section 12 (Safety Monitoring). 
11.1. 
Obtain informed consent 
 
The investigator or authorized delegate will explain the study to the patient, answer all of his/her 
questions and obtain the patient’s written informed consent before performing any study-related 
procedure.  
 
The following ICFs will be available in this study: 
• Pre-screening HER2 testing-ICF; 
• Main-ICF; 
• Genetic tumour analysis-ICF; 
• Pregnancy-ICF (see Section 12.9). 
 
For potential participants, the pre-screening HER2 testing-ICF should be used to allow the 
central analysis of HER2 expression on most recently available tumour tissue and to perform a 
fresh tumour biopsy, if applicable (see also Section 11.8). When the HER2 tumour expression 
complies with the inclusion criterion and patient enrolment is still open, the patient should sign 
the Main-ICF before full screening can be started. In addition, the patient will be asked to sign 
the Genetic tumour analysis-ICF. In case a patient does not consent for this genetic tumour 
analysis, she can still participate in the study.   
 
The patient can only start study treatment when all inclusion and none of the exclusion criteria 
are met and enrolment is not yet complete. The patient should start study treatment within 28 
days of signing the Main-ICF.  

 
 
 
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11.2. 
Demographics and medical history 
 
Demographic and medical history data will be obtained by the investigator or authorized 
(medically qualified) delegate. The medical history will include at minimum the time of initial 
and metastatic cancer diagnosis, sites of metastases, prior anticancer therapies (including 
therapies in the (neo) adjuvant and/or metastatic setting) and details on the hormone receptor 
(Estrogen and/or Progestrogene receptor) status of the primary tumour and/or metastasis (if 
available). Only clinically relevant conditions should be reported on the CRF as medical 
history. 
 
11.3. 
Inclusion/exclusion criteria 
The inclusion and exclusion criteria will be reviewed by medically qualified study personnel to 
ensure that the patient qualifies for the study. The review of inclusion and exclusion criteria and 
confirmation of the patient’s eligibility will be noted in patient’s source documents and 
appropriate eCRF.  
 
11.4. 
Physical examination  
 
A complete physical examination will be performed by the investigator or a medically qualified 
delegate, which should involve abnormalities of at least head/neck, thorax, abdomen, 
extremities, skin and lymph nodes. Results of the examination should be documented in the 
patient’s medical chart and the eCRF. Abnormal findings at screening are to be reported in the 
medical history and any clinical significant findings during treatment or at discontinuation as 
AEs. 
 
11.5. 
Vital signs, body weight and height 
 
Vital signs assessments include blood pressure, heart rate, body temperature and oxygen 
saturation by pulse oximetry. Vital signs and weight should be measured at screening and at the 
time points as indicated in the flowchart (see Section 1.1). Body weight should be used to 
prepare the IMP infusion bag as described in Section 9.4. Height will be recorded only at the 
screening visit. 
 
11.6. 
Eastern cooperative oncology group (ECOG) performance status 
 
The ECOG performance status quantifies the functional status of the patient and should be 
determined by the investigator or a medically qualified delegate according Table 1.  

 
 
 
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Table 1: 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 
Death. 
 
 
11.7. 
Pulmonary Function Testing 
Pulmonary function testing should be done according to local hospital standards, and may 
include spirometry, diffusing capacity of the lungs for carbon monoxide or peripheral oxygen 
saturation. 
 
11.8. 
Determination of HER2 tumour status 
HER2 tumour status will be determined on most recent available tumour tissue. Tumour tissue 
taken from previously irradiated areas should not be used for the analysis. Formalin-fixed 
paraffin-embedded (FFPE) tumour blocks or freshly cut FFPE tissue slides should be sent to a 
central laboratory for assessment of HER2 expression by IHC and ISH, according to the 
instructions in the laboratory manual. The remaining part of the tumour block will be returned 
to the institution. If no archived tumour material is available a biopsy should be performed to 
obtain tumour material. The biopsy should be performed according to local routine clinical 
practice.  
 
A patient will be considered eligible if the central laboratory reports a HER2 expression grade 
1+, 2+ or 3+ by means of IHC analysis and/or ISH positive.  
 
In general, in case the HER2 tumour assessment was unevaluable, it is allowed to send in new 
material for re-analysis.  
 
11.9. 
Genetic tumour analysis 
 
Genetic tumour analysis will be performed by a central laboratory using a clinically validated 
next generation sequencing test. The analysis will be done on most recent available tumour 
tissue in combination with blood analysis on germline DNA. Instructions for sample handling 
and shipment will be provided in the laboratory manual. The patients’ tumour mutational profile 
will be determined, including microsatellite instability and tumour mutational burden. The 
genetic analysis will cover genes known to be involved in e.g. DNA damage repair pathways, 
apoptosis, cell cycle and senescence pathways. In addition, gene expression levels by RNA-
sequencing may be analyzed as well. 
 

 
 
 
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11.10. 
Haematology and blood chemistry 
 
Blood samples will be taken and analyzed by the local laboratory for haematology and blood 
chemistry according to local routine clinical practice. In general, the following parameters will 
be included, but it may differ slightly between local laboratories:  
 
Haematology: 
Erythrocyte counts, haematocrit, haemoglobin, mean cell volume 
(MCV), full and differential white blood cell counts (basophils, 
eosinophils, lymphocytes, monocytes, neutrophils), mean corpuscular 
haemoglobin concentration (MCHC), platelets. 
Serum biochemistry: Albumin, alkaline phosphatase (AP), ALT, AST, total and direct (i.e. 
conjugated) bilirubin, blood urea nitrogen (BUN) (i.e. urea), calcium, 
chloride, creatinine, creatine kinase (CK), GGT, glucose, inorganic 
phosphorus, LDH, magnesium, potassium, sodium, total protein, uric 
acid. 
 
Sampling should be done as indicated in the flowchart (see Section 1.1). The Day 1 samples 
should be taken as closely as possible to the start of the new cycle, but may be done up to 3 
days before. If the screening assessment is done within 5 days before the first infusion, no new 
analysis needs to be done at Cycle 1 Day 1. Results of the local laboratory should be available 
before the start of the new cycle to determine if the patient can continue or not. Patients with 
screening values not in line with inclusion criterion 7 are not eligible to enter the study (see 
Section 8.1). For dose modifications or treatment discontinuations based on abnormal 
laboratory values, see Section 9.6. Clinically relevant laboratory values occurring during the 
study should be recorded as AEs, preferably as a diagnosis or symptom. 
 
The Sponsor should be provided with a copy of the local laboratory’s certification and a 
tabulation of the normal ranges and units of each parameter collected in the eCRF. The 
investigator is responsible for reviewing all laboratory reports for patients in the study and 
evaluating any abnormalities for clinical significance. 
 
11.11. 
Pregnancy test 
 
To exclude pregnancy in women of childbearing potential, a serum pregnancy test should be 
performed at screening and a serum or urine pregnancy test during treatment. 
 
In the event a patient becomes pregnant during the study, treatment is to be discontinued. The 
outcome of the pregnancy should be followed up according to the procedures described in 
Section 12.9. 
 
11.12. 
LVEF assessment 
 
LVEF should be measured by echocardiogram or MUGA scan according to the routine local 
clinical practice. Although both echo and MUGA can be used, the method must remain the 
same per patient from screening onwards. Results of the examinations should be documented 
in the patient’s medical chart and the eCRF.  
 

 
 
 
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If LVEF is below 50% the next assessment should be performed during the next cycle as 
indicated in the dose modification Section 9.6.1.3. 
 
The Day 1 examinations should be performed as closely as possible to the start of the new cycle, 
but may be done up to 7 days before. Results should be available before the start of the new 
cycle. Any clinically relevant findings should be reported as an AE. 
 
11.13. 
ECG assessment 
 
Standard 12-lead ECG should be recorded in supine position after the patients being 5 minutes 
at rest.  
ECGs should be recorded in triplicate for at least 3 seconds with approximately a 3-7 minutes’ 
gap between each of the triplicate readings. ECGs should be obtained before study drug 
administration for all patients.  
 
Evaluation should be done by the investigator or qualified delegate and any clinically 
significant abnormalities during treatment should be reported as AEs. Key parameters, 
including the QT/QTc interval, will be recorded in the CRF. Printouts of the ECGs should be 
retained for each patient. 
 
11.14. 
Ophthalmological examination 
An ophthalmologist (or qualified delegate) should perform the eye examination, which should 
at least include a slit lamp exam, corneal sensitivity testing, fluorescence tear film break-up 
time, and pachymetry. Details of the findings should be recorded in the patient’s medical chart 
and the CRF. Abnormal findings at screening are to be reported in the medical history and any 
clinically significant findings during treatment or at discontinuation as AEs. 
 
The Day 1 examinations should be performed as closely as possible to the start of the new cycle, 
but may be done up to 7 days before. Results should be available before the start of the new 
cycle.  
 
11.15. 
Tumour evaluation 
 
Measurable and non-measurable lesions must be documented at screening (within 28 days of 
start study treatment) and must be re-assessed at each subsequent tumour evaluation. Tumour 
response will be assessed locally according to RECIST version 1.1 until disease progression 
(for details see Appendix 1).  
 
Scans will be collected and stored by a central imaging laboratory. Independent and blinded 
assessment of these scans may be initiated at a later point in time when deemed necessary. 
  
Patients must have at least one measurable cancer lesion that is evaluable per RECIST v1.1 (see 
Appendix 1) to be eligible for the study. 
 
The assessment technique used at screening should be used throughout the study. Technical 
imaging parameters are defined in the imaging manual. All images are to be submitted to the 

 
 
 
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central imaging centre. Preferably the same investigator/radiologist should assess all tumour 
responses for each patient. 
 
CT or MRI scans that were performed before a patient signed the “Main”-ICF may be used to 
provide screening tumour status as long as they were performed within 28 days prior to start 
IMP treatment, at the same hospital, with the same technique or machine and preferably by the 
same individual as those for the tumour assessments during the study. This should be 
documented in the study files at the site. 
 
Tumour evaluations will be performed every 6 weeks (± 3 days) after the date of start IMP 
treatment, for the first 24 weeks and every 12 weeks (± 7 days) thereafter. The timing of the 
tumour assessments is independent of dosing delays. If tumour evaluation falls at the Day 1 of 
a cycle (in case there are no treatment delays), it can also be performed up to 7 days prior to the 
Day 1 visit, but should always be done prior to IMP infusion. 
 If a tumour assessment has to be performed earlier or later, subsequent assessments should be 
conducted according to the original schedule based on the date of start IMP treatment. 
 
Tumour evaluation at the discontinuation visit is required for patients who discontinue study 
treatment before first scheduled in-treatment tumour assessment (week 6) and for patients 
whose previous tumour assessment did not demonstrate PD and was done more than 21 days 
prior to the treatment discontinuation period. For patients who continue into the Observation 
Phase as described in Section 11.18.5 there is no need to perform tumour evaluation at the 
discontinuation visit, they should maintain the same tumour evaluation schedule as during the 
Treatment Phase. 
 
In cases where there is suspicion of progression before the next scheduled assessment, an 
unscheduled CT or MRI scan is to be performed, if possible.  
 
11.16. 
Previous and concomitant medication 
 
Information on all prior received anticancer therapies must be recorded in the eCRF and 
reviewed in view of the required wash-out period as defined in the exclusion criteria. Other pre-
treatment medication and concomitant medication used between 14 days prior to signing the 
Main-ICF till the treatment discontinuation visit should be recorded in the CRF. The use of 
concomitant medication must relate to the documented medical history, an AE or be reported 
as prophylactic treatment. For details on allowed and not-allowed concomitant medication, see 
Section 10. 
 
11.17. 
(Serious) adverse events 
 
For details of assessment and reporting of AEs, see Section 12. 
 
11.18. 
Visit requirements 
11.18.1. 
Screening 
 
Visit requirements are outlined in the study flowchart in Section 1.1. Specific procedure-related 
details are provided above in Section 11. 

 
 
 
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Maximally 28 days before start IMP treatment, potential patients will be evaluated to determine 
eligibility with the in- and exclusion criteria as described in Section 8.1. 
 
11.18.2. 
Treatment phase 
 
Visit requirements are outlined in the study flowchart in Section 1.1. Specific procedure-related 
details are provided above in Section 11. Visits are based on a 21-day cycle (± 3 days).  
 
11.18.3. 
Discontinuation visit 
 
The treatment discontinuation visit should occur at the time study treatment is discontinued for 
any reason (e.g. due to PD, unacceptable toxicity or withdrawal of consent).  
 
11.18.4. 
Follow-up 
A follow-up visit should be scheduled 30 days after the treatment discontinuation visit. In case 
a visit is not possible, the patient should be contacted by telephone. During this visit/contact, 
additional information on (S)AEs that were ongoing at the previous visit will be collected, as 
well as information on new (S)AEs and concomitant medication used since that visit.   
 
11.18.5. 
Observation phase 
Patients who discontinue study treatment for reasons other than PD (e.g. toxicity), should 
continue into the Observation Phase of the study and continue tumour imaging according to 
their original schedule until the time of PD or start of a new anticancer therapy. 
 
11.18.6. 
Survival follow-up 
 
After the 30-day follow up visit and/or observation period a patient will be followed up for data 
on disease progression, new anticancer therapies, and survival. These survival follow-up 
contacts should continue until patient’s death, lost to follow-up, consent withdrawal or end of 
study data collection, whichever comes first. 
 
11.19. 
Study assessments after last patient enrolled 
 
Study assessments will continue as per flowchart (see Section 1.1) until all patients are enrolled 
and treated in the main study for at least 6 months or have discontinued study participation. 
Patients who are still on treatment beyond this date may continue treatment, but the frequency 
and number of study assessments may be reduced as per instructions of the Sponsor. Collected 
information, such as the toxicity profile of the study drug, will be used to justify the adapted 
assessment schedule and details will be documented appropriately. Safety assessments and 
safety reporting will continue in such a way that patient’s safety is adequately monitored and 
documented. 
 
12. 
Safety monitoring  
12.1. 
Definitions 

 
 
 
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AE 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
TEAE 
An treatment emergent adverse event is any event not present prior to the initiation of the 
treatments or any event already present that worsens in either intensity or frequency 
following exposure to the treatments. 
ADR 
An adverse drug reaction is any noxious and unintended response to a medicinal product 
related to any dose. This definition implies a reasonable possibility of a causal 
relationship between the AE and the IMP, i.e. the relationship cannot be ruled out. 
Unexpected ADR 
An adverse reaction, the nature or severity of which is not consistent with the 
risk information set out in the IB. 
SAE 
An AE that is/ results in: 
− Fatal; 
− Life-threatening; 
− Persistent or significant disability/incapacity; 
− Admission to hospital as an in-patient or prolongation of hospital stay; 
− A congenital anomaly; 
− Other important medical event. 
 
Note when assigning one of the above serious outcomes the following should be referred 
to: 
 
Life-threatening: Any adverse drug experience that places the patient, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e. it does not 
include a reaction that had it occurred in a more severe form, might have caused death. 
 
Hospitalization: Admission overnight to an acute care hospital. Procedures done in or 
visits to a clinic or outpatient facility are not considered serious AEs (SAEs). Admission 
to a rehabilitation facility, transitional care unit, or nursing home is not considered a 
hospitalization. 
 
Prolonged hospitalization: Any AE that extends a patient’s hospital stay beyond the 
normal expected time. 
 
Disability: A substantial disruption of a person’s ability to conduct normal life functions. 
 
Congenital anomaly: Intrauterine development of an organ or structure that is abnormal 
in form, structure, or position. 
 
Important medical event:  Medical and scientific judgement should be exercised in 
deciding whether expedited reporting is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalisation but may jeopardise the patient or may require intervention to prevent one 
of the other outcomes listed in the definition above. These should also usually be 
considered serious. 
SUSAR 
A suspected unexpected serious adverse reaction is a serious ADR that is not identified 
in nature or severity in the risk information set out in the IB or SmPC/PI. 
Protocol 
defined 
events of special 
interest (AESI) 
The following events are adverse events of special interest and will need to be reported 
to the CRO expeditiously, irrespective of regulatory seriousness criteria or causality: 
– 
Pneumonitis/ILD, 
– 
Keratitis grade ≥ 2, 
– 
Other ocular toxicity grade ≥ 3 
– 
LVEF decrease to < 50%. 

 
 
 
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12.2. 
Adverse event monitoring  
 
Investigators are responsible for monitoring the safety and for providing appropriate medical 
care in patients who have entered this study (i.e. from the signing of “Main-ICF” onwards). In 
addition, the investigator remains responsible for following AEs that are serious, drug-related, 
AESIs, or that caused the participant to discontinue treatment until the event has resolved or 
until the event has stabilized and determined to be persistent. 
Each patient will be carefully questioned and/or examined by the investigator or a medically 
qualified delegate to obtain information regarding AEs (including SAEs) at each visit until the 
last protocol specified visit or contact. All AEs will be reported and documented as stated 
below. 
12.3. 
Adverse events documentation 
 
AEs will be collected from signing of the Main-ICF up to the follow-up visit 30 days after 
treatment discontinuation. AEs occurring between signing the HER2 testing-ICF and the Main-
ICF do not need to be reported, unless it is related to study procedures (i.e. when a tumour 
biopsy is performed under the HER2 testing-ICF). Anticipated day-to-day fluctuations of pre-
existing conditions that do not represent a clinically significant exacerbation or worsening need 
not be considered AEs. Worsening of pre-existing conditions should be reported as a (S)AE. 
 
The investigator/designee is responsible for recording all AEs which have occurred during the 
study in the patient’s medical charts and in the eCRF, regardless of their relationship to the 
study drug. This includes AEs spontaneously reported by the patient, observed by the 
investigator/designee or elicited by general non-leading questioning, as well as clinically 
important deviations of laboratory values from normal ranges. The investigator will review this 
data and determine the severity and causality as per the definitions provided in Sections 0 and 
12.3.2.  
 
Note that by definition AEs include accidents (e.g. motor vehicle accidents) and the reasons for 
changes in concomitant medication (drug and/or dose), medical, nursing and/or pharmacy 
consultation, and admission to hospital and surgical operations. Progression of the underlying 
malignancy itself is not considered to be an AE. 
 
Planned hospital admissions and/or surgical operations/procedures for an illness or disease that 
existed before the investigational product was given or the patient was enrolled in a clinical 
study are not to be considered AEs. This needs to be documented clearly in the patient’s medical 
records. Note that any (prolongation of) hospitalization resulting from these planned admissions 
or procedures are to be recorded as SAEs. 
 
Clinical laboratory data collected during the course of the study, which exceed or drop below 
the acceptable limits for the patient population and which, based on baseline values, are 
considered by the investigator to be clinically significant, will be reported as an AE. Note that 
if clinically significant abnormal laboratory values lead to, or are associated with clinical 
symptom(s), the diagnosis should be reported as an AE rather than the abnormal laboratory 
value to allow proper coding. 
 

 
 
 
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If a patient’s participation is discontinued as a result of an AE, study site personnel must clearly 
document the circumstances and data leading to the reason for discontinuation. 
12.3.1. 
Adverse events severity 
 
The investigator should determine the severity of AEs according to the Common Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE) 
(version 
5.0) 
(see 
the 
website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). AEs that are not 
listed in the CTCAE should be graded according to Table . 
 
Table 2: Adverse Event grading (for events not listed in the CTCAE)  
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 activities of daily living. 
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 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death 
Death related to AE. 
 
12.3.2. 
Adverse events causality  
 
The investigator will determine the relationship of any AE to the study drug according to the 
following guidelines: 
 
Unlikely Related:  
 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations.  
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear. 
Probably Related: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically 
reasonable 
response 
on 
withdrawal 
(dechallenge). 
Rechallenge information is not required to fulfill this definition.  
 
If a clinical event occurred before the patient received study drug, the causality will be 
considered as Not Applicable.   
 
12.4. 
Serious adverse events documentation 
 
The following information must be provided for all SAEs:  
• Detailed patient data; 

 
 
 
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• Exact documentation of the event; 
• Exact description of the temporal sequence to the therapy course; 
• Documentation of the results of diagnostic and therapeutic measurements; 
• Details of the development and outcome including medical judgement; 
• As much other supporting data as possible which are important for the judgement 
concerning the relationship of the SAE to the study drug; 
• Critical examination of the relationship to the study drug; 
• Name of the reporter. 
 
Events solely due to the progression of underlying malignancy should not be reported as 
an SAE. Clinical symptoms of progression may be reported as AEs if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the underlying disease. In case of progression of disease, 
the patient must be discontinued from the study. 
 
All SAEs must be followed until resolved or stabilized. The investigator must obtain and 
maintain files of all pertinent medical data relating to the event. This includes medical records, 
information and medical judgments from any party who assists in the treatment and follow-up 
of the patient.  
 
12.5. 
Reporting of serious adverse events 
 
The occurrence of any SAE from signing of the Main-ICF up to the follow-up visit 30 days 
after discontinuation visit (regardless of relationship to IMP) has to be notified immediately 
(within 24 hours of the investigator or designee becoming aware of the event) to the CRO via 
the electronic data capture system. This also applies to study procedure-related SAEs that occur 
between signing the HER2 testing-ICF and Main-ICF. In case the SAE cannot be reported via 
the system, a completed serious adverse event reporting form should be send by fax to the 
Pharmacovigilance Department of …... 
 
The investigator or designee must promptly report (within 24 hours of becoming aware of the 
event) clinically significant follow-up information pertaining to the SAE to the CRO. The 
investigator is obliged to pursue and provide additional information as requested by 
Sponsor/CRO medical monitor or its designee. The final outcome of the SAE has to be reported 
in the electronic data capture system or if not available, by fax.  
 
The CRO will report all suspected unexpected serious adverse reactions (SUSARs) to the 
appropriate Regulatory Agencies, adhering to timelines for reporting outlined as per the 
(inter)national and local regulatory requirements and ICH GCP Guideline. For this study the 
Investigator’s Brochure contains the reference safety information and is to be used to assess the 
expectedness of an AE for SYD985.  
 
Investigators must report all SAEs to their Independent Ethic Committee (IEC)/ Institutional 
Review Board (IRB) according to local requirements.  
 
12.6. 
Adverse events of special interest 
 

 
 
 
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The following events are protocol defined AEs of Special Interest (AESI) and will need to be 
reported to the CRO expeditiously, irrespective of regulatory seriousness criteria or causality: 
• ILD/Pneumonitis; 
• Keratitis grade ≥ 2; 
• Other ocular toxicity grade ≥ 3; 
• LVEF decrease to < 50%. 
 
AESIs should be reported expeditiously to the CRO from start of study drug up to the follow-
up visit 30 days after treatment discontinuation, irrespective of regulatory seriousness criteria 
or causality. Initial AESIs and follow-up information should be reported to the CRO within 5 
days of the investigator becoming aware of it, with the same details as for SAEs.     
 
All AESIs must be followed until resolved or stabilized. The investigator must obtain and 
maintain files of all pertinent medical data relating to the event. This includes medical records, 
information and medical judgments from any party who assists in the treatment and follow-up 
of the patient.  
 
12.7. 
Reporting of death 
 
Deaths that occur during the protocol-specified AE reporting period (from signing of the “Main-
ICF” up to up to the follow-up visit 30 days after treatment discontinuation) that are, according 
to the investigator, due solely to the progression of underlying malignancy, should not be 
recorded as an (S)AE. Instead, date and reason of death should be documented on the 
appropriate eCRF.  Concurrent AEs should be reported as ongoing at the time of death. 
 
All other deaths that occur during the protocol-specified AE reporting period should be 
recorded on an SAE eCRF and should be reported expeditiously. During post-study survival 
follow-up, deaths due to any cause should be recorded on the appropriate eCRF. 
 
12.8. 
Reporting of serious breaches 
 
A serious breach is defined as a protocol deviation which is likely to affect to a significant 
degree: 
• The safety, physical or mental integrity of the patient in the study; or 
• The scientific value of the study. 
 
The investigator should notify the CRO in case of a suspected serious breach within 24 hours 
of becoming aware of the breach. Additionally, protocol deviations will be reviewed by the 
Sponsor / CRO during the study and suspected serious breaches will be identified. The Sponsor 
will define if the suspected serious breach is considered a serious breach. Depending on the 
nature of the breach, regulatory agencies, ethics committees and investigators will be notified 
in line with applicable laws and regulations. 
 
12.9. 
Reporting of pregnancies 
 
If a patient would become pregnant during the course of the study, the investigator or qualified 
designee must contact the CRO within 5 working days of the investigator or qualified designee 

 
 
 
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first becoming aware of, or is being notified / informed about the pregnancy. The notification 
must include a completed pregnancy reporting form. If a SAE occurs in conjunction with the 
pregnancy, then the reporting time frame for an SAE (24 hours) must be met. The anticipated 
date of birth or termination of the pregnancy should be provided at the time of the initial report. 
The patient must be followed up until birth or termination of the pregnancy and the outcome of 
the pregnancy should be forwarded to the Sponsor/CRO as soon as it is known. 
 
A patient who becomes pregnant during the study must be discontinued from treatment. 
 
13. 
Criteria for patient discontinuation, replacement and study termination 
13.1. 
Patient discontinuation 
 
Patients participating in this study have the right to withdraw from the study at any time for any 
reason. A patient must be discontinued from the study when the patient withdraws informed 
consent. From that moment onwards no new data can be collected from that patient. However, 
in the case that the patient decides to prematurely discontinue study treatment (e.g. “refuses 
treatment“) or discontinues study treatment prior to progressive disease, e.g. for toxicity or 
investigators decision, she will remain in the study and will continue all protocol-required 
follow-up visits according to the flow-chart (Section 1.1). The primary reason for study 
treatment discontinuation must be recorded in the eCRF and in the patient’s medical chart. 
 
The investigator has the right and duty to stop treatment in any case in which emerging effects 
are of such nature that the benefit-risk ratio is unacceptable to the individual patient. In addition, 
the investigator is to stop treatment of any patient with unmanageable factors that may interfere 
significantly with the study procedure and/or interpretation of the results. As an excessive rate 
of withdrawals can render the study not interpretable, unnecessary withdrawal of patients 
should be avoided.  
 
The investigator should discontinue a patient from study treatment for reasons including but 
not limited to the following: 
• Disease progression; 
• Unacceptable toxicity, including; 
o Clinically significant symptomatic cardiac disease (see Section 9.6.1.3); 
o Clinically significant drug-related toxicity requiring dose delay or interruption 
which did not resolve within 42 days from the last dose received; 
o Grade 4 infusion-related reaction or a Grade 3 infusion-related reaction which 
is not responsive to symptomatic medication and/or interruption of infusion; 
o Grade 3 (or higher) ocular toxicity; 
o Grade 2, 3 or 4 ILD/pneumonitis; 
• Pregnancy; 
• Substantial non-compliance with the requirements of the study; 
• Investigator decision based on the patient’s best interest; 
• Termination of the study by the Sponsor. 
 
Patients who discontinue from study treatment for any of the above reasons should return to the 
clinic for a treatment discontinuation and follow up visit after the last administration of study 
drug. Subsequently, these patients will continue to be followed according to protocol for disease 

 
 
 
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progression (if discontinued for other reasons than PD), unresolved AEs, new anticancer 
therapies, and survival status as detailed in Section 11.17.5 and 11.17.6.  
 
If a patient decides to completely withdraw from the study participation, the reason for 
withdrawal from the study must be recorded in the eCRF and in the patient’s medical chart. 
Discontinuation is permanent, once a patient is discontinued it is not allowed to enrol the patient 
again in the study. When a patient discontinues the study, all efforts should be made to complete 
and report clinical observations prior to withdrawal from study participation as thoroughly as 
possible. 
 
In cases where patient contact is lost, a patient should be considered lost to follow-up only after 
multiple efforts have been made to contact the patient. 
 
13.2. 
Patient replacement 
A patient that discontinues from treatment or study will not be replaced.  
 
13.3. 
Start and end of study  
 
The overall study begins when the first patient has signed the ICF. The overall study ends when 
the last patient completed the last study visit, discontinued from the study or is lost to follow-
up.  
 
The sponsor may decide to stop further recruitment in the study or at (a) particular site(s) due 
to insufficient compliance with the protocol, GCP and/or other applicable regulatory 
requirements, procedure related problems, too low recruitment speed, or any other medical, 
ethical, or business reason. Additionally, the clinical study will be stopped prematurely if the 
extent (incidence or severity) of emerging effects/clinical endpoints is such that the benefit-risk 
ratio to the study population as a whole is unacceptable. In such case, all ongoing patients will 
be requested to return to the clinic for a final follow-up visit, during which all treatment 
discontinuation assessments should be conducted. Additional safety monitoring assessments 
may also be performed, should the reason for termination of the study dictate such assessments. 
 
14. 
Study evaluation, statistical considerations and data analysis 
14.1. 
General considerations for data analysis 
 
The statistical considerations and analysis plan are summarized in this chapter. A detailed 
statistical analysis plan (SAP) will be prepared following finalization of the protocol and eCRF 
and will be finalized well in advance of database lock. Any deviations from, or additions to, the 
original analysis plan described in the protocol will be documented in the SAP and final study 
report. 
 
All study variables will be analysed using appropriate descriptive statistical methods. The 
statistical software used for analysis will be SAS® release 9.4 or higher. Continuous data will 
be summarized by their mean, standard deviation, median, minimum and maximum. 
Categorical and ordinal data will be summarized in frequency tables by their absolute frequency 
(N) and relative frequency (%). 
 

 
 
 
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As it is anticipated that accrual will be spread thinly across sites and summaries of data by site 
would be unlikely to be informative, data from all participating sites will be pooled prior to 
analysis.   
 
All data from all clinical assessments whether explicitly referred to in this statistics section or 
not, will be presented in data listings.  
 
Since the secondary endpoints are exploratory in nature, no adjustments for multiple 
comparisons will be conducted. 
 
14.1.1. 
Missing data 
 
As the duration of treatment for a given patient will depend on efficacy and tolerability, the 
duration of follow-up will vary between patients. Consequently, there will be no imputation for 
missing data.  
Handling of incomplete data required for analysis will be detailed in the SAP.  
 
14.2. 
Analysis populations 
14.2.1. 
Full analysis set 
 
The Full Analysis Set (FAS) comprises all patients who received at least 1 full dose or partial 
dose of SYD985. The FAS will be used for all listings of raw data, demographic and baseline 
characteristics, and safety analyses. Unless otherwise specified, the FAS will be the default 
analysis set used for analyses.   
 
14.2.2. 
Efficacy analysis set 
 
The efficacy analysis set consists of a subset of the FAS patients who has a baseline and at least 
one post-baseline tumour evaluation assessment. The efficacy set will be used for the efficacy 
analysis. 
 
14.3. 
Timing of analysis 
14.3.1. 
Interim analysis 
 
No formal interim analysis is planned for this study. 
 
14.3.2. 
Main analysis 
 
The primary analysis will be performed when all patients have been enrolled in the main study 
for at least 6 months or have discontinued study participation (i.e. completed the last study visit 
due to disease progression or start of a new anticancer therapy, discontinued from the study or 
lost to follow-up). All data collected after this date will be summarized and added to the final 
study report, e.g. as an appendix. 
 
14.4. 
Demographic and baseline characteristics 

 
 
 
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Assessments made at the screening visit or before infusion at Day 1 of the first treatment cycle 
(demographic characteristics, medical history, physical examinations, tumour characteristics, 
previous or concomitant medication, vital signs, etc.) will be summarized as appropriate. 
 
14.5. 
Study endpoints  
14.5.1. 
Primary endpoint 
 
The primary efficacy endpoint is ORR based on investigator assessed tumour assessment 
according to RECIST 1.1. ORR is defined as the percentage of patients with a best overall 
response of complete response (CR) or partial response (PR). The determination of tumour 
responses is described in Appendix 1. Both non-confirmed tumour responses as well as 
confirmed tumour responses (by second assessment at least 4 weeks after first assessment) will 
be used for efficacy evaluation.  
 
14.5.2. 
Secondary endpoints 
 
The secondary efficacy endpoints are: 
• 
PFS; 
• OS; 
• Safety. 
 
PFS (Investigator assessed) is defined as the time from the date of first IMP intake to the date 
of first documented investigator-assessed disease progression according to RECIST 1.1 or 
death due to any cause (whichever occurs earlier). Handling of missing values will be similar 
as described for the primary endpoint. 
 
OS is defined as the time from date of first IMP intake to date of death due to any cause. Patients 
who are alive or who are not known to have died at the time of the analysis will be censored at 
the last known date they were alive. Patients with no post-baseline information will be censored 
at the date of start IMP treatment plus 1 day.  
 
14.5.3. 
Other endpoints 
 
• To describe time to response; 
• To describe duration of response; 
• To describe the CBR;  
• To explore genomic profile/response relationships. 
 
14.6. 
Efficacy analysis 
14.6.1. 
Primary objective 
 
The primary objective of the study is to evaluate the anticancer activity of SYD985 with respect 
to ORR on the basis of investigator tumour assessment. 
 
14.6.1.1. 
Analysis 

 
 
 
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14.6.1.1.1. Objective response rate 
 
The primary efficacy endpoint is ORR, defined by RECIST 1.1. ORR will be calculated based 
on the Efficacy Analysis population. The ORR will be based on calculated responses from 
investigator lesion assessments. Proportion of patients with ORR will be presented along with 
95% CIs. Patients with unknown or missing response will be treated as non-responders, i.e. 
they will be included in the denominator when calculating the percentage. 
 
14.6.2. 
Secondary objective 
The secondary objectives of this study are to evaluate SYD985 with respect to PFS and OS. 
 
14.6.2.1. 
Analysis 
14.6.2.1.1. Investigator assessed PFS 
 
Investigator assessed PFS will be calculated based on the Efficacy Analysis population. The 
survivor distribution of PFS will be estimated using the Kaplan-Meier method. The median PFS 
along with 95% CI will be presented.  
 
14.6.2.1.2. Overall survival 
 
The analysis for OS will be based on the Efficacy Analysis population. The median duration of 
survival will be estimated using the Kaplan-Meier method.  
 
14.6.3. 
Other objectives 
 
Exploratory endpoints of this study include time to response, duration of response and clinical 
benefit rate.  
 
Time to response is the time between the date of first IMP intake until first documented 
response (CR or PR) according to RECIST 1.1.  
 
Duration of response applies to patients whose best overall response was CR or PR according 
to RECIST 1.1, the start date is the date of first documented response (CR or PR) and the end 
date is the date defined as first documented disease progression or death from any cause 
(whichever occurs first).  
 
The CBR is defined as the proportion of patients with CR, PR, or SD (SD for 24 weeks or 
longer). CR, PR and SD are defined according to RECIST 1.1. CBR will be summarized 
using descriptive statistics. These assessments will be analyzed based on the data observed in 
the FAS population and will be determined by investigator tumour assessment.  
 
If data allow, exploratory analysis or modeling techniques will be used to investigate the 
relationship between genomic profile and safety/efficacy parameters. 
 
14.7. 
Safety data analysis 
 

 
 
 
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Safety analysis will be based on the FAS population considering the sections below. Complete 
details of the safety analysis will be provided in the SAP. 
Only treatment emergent AEs (TEAEs), AEs reported to start within the in-treatment period, 
will be considered. The in-treatment period is defined as the period starting from the first dosing 
of study drug up to the follow-up visit 30 days after the treatment discontinuation visit. Events 
starting before first dosing will be presented separately.  
 
14.7.1. 
Extent of exposure 
 
The total cumulative dose, number of doses, dose intensity, and duration of exposure will be 
listed and summarized using descriptive statistics.  
 
The number of patients who had any dose modification (including dose delay, dose reduction) 
and reasons for dose modification will be listed and summarized by treatment. 
 
14.7.2. 
Treatments 
 
Concomitant medication and non-drug therapies will be listed by patient and summarized by 
ATC (Anatomical therapeutic chemical classification system) term. These summaries will 
include medications starting on or after the start of study treatment. Any pre-treatment 
medications or significant non-drug therapies ending prior to the start of study treatment will 
be listed. 
 
14.7.3. 
Adverse events 
 
AEs will be coded using the latest Medical Dictionary for Regulatory Activities (MedDRA) 
and grouped by system organ class and preferred term. AEs will be graded by the investigator 
according to the CTCAE (version 5.0) 
 
An overview table of the number (percentage) of patients with any TEAE, deaths, Serious 
TEAEs, drug-related AEs, TEAEs leading to discontinuation of treatment, and TEAEs by 
CTCAE grade will be presented. 
 
Separate summaries will be given for all drug-related TEAE, deaths, Serious TEAEs, TEAEs 
leading to discontinuation of treatment, and TEAEs by CTCAE grade.  
 
Specific protocol defined AESI have been indicated in Section 12.6. These events are grouped 
in disease categories which can include one or more safety events. Separate summaries will be 
given for all AESI categories and drug-related AESIs. 
 
14.7.4. 
Clinical laboratory evaluations 
 
Changes in laboratory data will be summarized by grade using the NCI CTCAE version 5.0. 
Changes from baseline will be presented in shift tables for the different lab assessments. 
 
14.7.5. 
ECG analyses 

 
 
 
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Standard ECGs parameters (e.g. heart rate, PR, QRS, and QT) will be summarized by scheduled 
visits. The number of patients who discontinue drug due to cardiac function will be summarized.  
 
14.7.6. 
LVEF 
 
Absolute LVEF measurements, as well as changes from baseline as a function of time, will be 
summarized by scheduled visits. In addition, the last and lowest available ejection fraction 
measurements from each patient will be summarized, along with the corresponding change 
from baseline. Further analysis will be performed if indicated by the data. 
 
The number of patients who have a LVEF decline to below 50% with an absolute decrease from 
baseline ≥ 10% points, have a LVEF decline to below 40%, or develop Grade 3 left ventricular 
dysfunction will be summarized. 
 
14.7.7. 
Opthalmological exams 
 
Results of the eye examinations, which will include a slit lamp exam, corneal sensitivity testing, 
fluorescence tear film break up time, and pachymetry, will be summarized by scheduled visits. 
 
The number of patients who develop Grade 3 (or higher) keratitis or Grade 3 conjunctivitis, or 
discontinue study drug due to ocular toxicity will be summarized. More detailed analysis may 
be performed if appropriate. 
 
14.7.8. 
Other safety measures 
 
ECOG performance status will be summarized by scheduled visits, in addition, changes from 
baseline will be presented. The results of body weight and vital signs will be summarized by 
scheduled visits.  
 
14.8. 
Sample size 
 
The primary efficacy endpoint of this study is ORR based on investigator review of tumour 
assessment. Approximately 60 patients will be recruited. Inclusion of HER2 1+/2+, ISH 
negative patients will be limited to a maximum of 50% of the total sample size. This study is 
of explorative nature; 60 patients should provide for sufficient safety information and for an 
ORR estimate with acceptable confidence interval for future decision-making. 
 
15. 
Study administration 
15.1. 
Regulatory and ethics committee considerations 
 
The Sponsor, CRO and the investigator as well as all other involved parties will ensure that the 
study is conducted in compliance with the protocol, the ethical principles that have their origin 
in the Declaration of Helsinki (Brazil, 2013), ICH Harmonised Tripartite Guideline for Good 
Clinical Practice E6, and applicable regulatory requirements.  
 

 
 
 
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15.1.1. 
Approval by competent regulatory authority and IEC/IRB 
 
The Sponsor/CRO will obtain regulatory approval from the competent authority and 
Independent Ethics Committee(s)/Institutional Review Board(s), where locally required, prior 
to study start. If any of the approved documents is amended, the Sponsor/CRO will submit these 
documents for review and subsequent approval as required. 
 
Details of the ethics review committee's composition will be made available conform local 
regulations. An annual safety/progress report will be provided by Sponsor/CRO to the 
competent regulatory authority. 
 
15.1.2. 
Informed consent 
 
The investigator and/or his/her designee will inform the patient in addition to the written patient 
information about all aspects of the patient’s study participation. The designee can be a study 
nurse to explain procedural and non-medical information on the study, but all medical 
information must be provided by a medical doctor. When a study nurse provides information 
on the study, both the investigator and the study nurse are required to sign the ICF.  
The written patient information, ICF, and any amendments to these documents must be 
approved by the competent IEC/IRB and competent regulatory authority.  
 
The investigator and/or his/her designee and the patient must sign and personally date the ICF 
prior to any study-related activities are being performed. If an authorised representative signs 
the ICF, all efforts should be made to obtain an additional signature, personally dated, from the 
patient herself. 
 
The ICF will be signed and the patient and/or the authorised representative should be provided 
with a copy of the signed ICF. The original is filed with the study documents in the Investigator 
Site File (ISF). 
 
The decision to participate in the study is entirely voluntary by the patient and/or by the 
authorised representative. The investigator and/or his/her designee must emphasise to the 
patient and/or the authorised representative that the consent to participate can be withdrawn at 
any time without penalty or loss of benefits to which the patient is otherwise entitled. 
 
15.1.3. 
Investigator reporting requirements 
 
The investigator is responsible for accuracy and completeness of all data recorded in patient’s 
medical and/or study charts and eCRFs. All data recorded in the eCRF are derived from source 
data unless specifically exempted. Source data will be defined prior to study start but consists 
in general of the information documented in the patient medical and/or study chart or from 
information documented in original records and/or certified copies. Corrections to data should 
be made in a way so that the originally recorded data is still legible and traceable. Any changes 
should be dated, initialled and explained (if necessary) by the investigator or an authorized 
member of the investigator’s study staff making the correction. The investigator will maintain 
a file of essential documents of the study as defined by the regulatory requirements, ICH GCP 
and the Sponsor/CRO (ISF).  

 
 
 
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15.1.4. 
Amendments to study protocol 
 
Amendments to the study protocol are prepared when needed and according to Standard 
Operating Procedures of the Sponsor and/or CRO. Except for administrative amendments, all 
amendments will be reviewed and approved by the competent authority and competent 
IEC/IRB prior to implementation. 
 
In the event of an emergency, the investigator may institute any medical procedures deemed 
appropriate without prior approval by the competent authority and competent IEC/IRB. 
However, all such procedures must be promptly reported to the Sponsor/CRO and the IEC/IRB.  
 
15.1.5. 
Investigator compensation 
 
Financial compensation of the investigator and/or his/her institution will be regulated in a 
financial agreement established between the Sponsor/CRO and the investigator and/or his/her 
institution. 
 
15.1.6. 
Coordinating Investigator for Clinical Study Report 
 
A Clinical Study Report (CSR) will be prepared by the Sponsor/CRO to describe the results of 
the study. One (or several) of the investigator(s) will be selected by the Sponsor to review and 
approve the final CSR in writing (i.e. coordinating investigator(s)). The Sponsor is to select the 
coordinating investigator(s) from the participating investigators using the following criteria: 
• 
Must be the Principal Investigator at a site actively enrolling patients and participating in 
the study; 
• 
Must be willing and capable of completing the necessary reviews and providing approval 
of the CSR in writing. 
 
15.2. 
Monitoring and quality assurance 
15.2.1. 
Monitoring 
 
In accordance with applicable regulations, ICH GCP Guideline, Sponsor’s and/or CRO’s 
procedures, monitors from CRO will perform the monitoring of this study. Investigational sites 
will be contacted and visited regularly by CRO staff. The investigational sites will be trained 
on all study procedures during a site initiation visit and investigator meeting (if applicable).  
 
During the study, the sites will be visited by CRO staff to review the progress of the study, 
review the data collected, conduct source data verification, perform drug accountability, 
identify issues and address their resolution. The aim of the monitoring of the study is to ensure 
that the data collected is authentic, accurate and complete, to ensure the safety of the patients 
participating in this study and that the patient’s rights are protected, and to ensure that the study 
is performed according to the approved protocol, (inter)national and local laws and all 
applicable regulations and guidelines. Monitoring will also include remote monitoring by the 
CRO/Sponsor’s staff by evaluation of the data entered in the eCRF. 
 

 
 
 
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At study end, the investigational sites will be closed at a final visit conducted by CRO staff to 
ensure availability of all necessary study documentation, return and/or destruction surplus study 
materials including study drug, and the adequate archiving of all study-related documentation 
and materials. 
 
During the whole monitoring process, the investigator agrees to allocate his/her time and the 
time of his/her staff to the monitor to resolve, discuss and address any study issues. 
 
15.2.2. 
Direct access to source data/documents 
 
The investigator agrees to allow the authorised staff from CRO/Sponsor, the auditor(s), the 
IRB/IEC and the regulatory authorities direct access to all relevant documents and source data. 
Source data, recorded in original records or certified copies, will include the patient’s medical 
and/or study charts which are maintained according to standard clinical practice, read-outs and 
photos, scans and laboratory reports.  
 
15.2.3. 
Quality assurance 
 
To ensure compliance with study protocol, ICH GCP, and applicable regulatory requirements, 
the CRO/Sponsor will conduct quality assurance audits. Regulatory agencies may also conduct 
inspections of investigational sites. Such audits and/or inspections can occur at any time during 
or after the study. If such inspection or audit occurs, the investigator and the institution agree 
to allow the auditor or inspector direct access to source data and all relevant documents and to 
allocate his/her time and the time of his/her staff to the auditor or inspector to discuss findings 
and any relevant issues. 
 
The Sponsor/CRO will evaluate processes and data that are critical to assure patient protection 
and reliability of study results throughout the study. Processes and data that will be evaluated 
with special attention will be the safety assessments, the ICF process and the primary study 
endpoint.   
15.3. 
Data handling and records retention 
15.3.1. 
Collection of data and data management 
 
All data collected for this study is to be recorded in the patient medical charts according to 
standard practice at the investigational site and according to additional requirements of the 
study. The relevant data will be transcribed from the patient’s medical chart into the eCRF. All 
data that is collected in the eCRF, including the eCRF itself, will be anonymous and will not 
reveal the patient’s name. All documents will be identified by the patient number. The eCRFs 
must be kept up-to-date so that they always reflect the latest observations on the patients 
enrolled in the study. CRFs should be signed-off by the investigator as soon as possible after 
the patient discontinued/completed the study. A monitor will review the completed eCRF. All 
source data should be kept in conformance to applicable national laws and regulations. 
 
For patients who fail screening, data are to be collected from the time the Main-informed 
consent is signed until it is determined that the patient has failed the screening. Minimal 
information should be completed on the eCRF such as patient demographics, disease 

 
 
 
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characteristics, reason for screen failure and (S)AEs. For patients who fail pre-screening, a 
subset of this data will be documented.  
 
All original laboratory reports should be available for review in each patient’s file. It is 
important that the original reports are available for review by the investigator on the evaluation 
of abnormalities for clinical significance. 
 
Data management will be performed by the CRO in accordance with the data validation and 
data management plan. 
 
15.3.2. 
Records retention 
 
Following closure of the study, the investigator agrees to maintain all site study records in a 
safe and secure location. The Sponsor/CRO will inform the investigator about the time period 
for retaining the documents. The minimum retention time will meet the strictest standards 
available to that site for the study as given by local laws or Sponsor’s standard procedures. By 
default, and if not otherwise clarified, the retention period will be at least 2 years after the last 
approval of marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. 
 
The CRO and Sponsor should be notified if the study records are moved to an offsite archive 
location. 
 
15.3.3. 
Information of investigators about study results 
 
After the CSR is completed, the Sponsor/CRO will provide the report of the study to the 
investigator. 
 
15.4. 
Publication policy and inventions 
15.4.1. 
Publication 
 
The Sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database (www.clinicaltrials.gov). In addition, upon study completion and 
finalisation of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. Individual manuscripts 
of partial/site specific data will only be approved after the overall manuscript has been accepted 
for publication. The data resulting from this study will be proprietary information of the 
Sponsor.  
 
None of the data resulting from this study will be allowed to be presented or published in any 
form, by the investigator or any other person, without the prior approval of the Sponsor. The 
investigator agrees to provide to the Sponsor 60 days prior to intended submission for 
publication or presentation, review copies of abstracts or manuscripts for publication 
(including, without limitation, slides and texts of oral or other public presentations and texts of 
any transmission through any electronic media) that report any results of the study. The Sponsor 
shall have the right to review and comment with respect to publications, abstracts, slides, and 

 
 
 
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manuscripts and the right to review and comment on the data analysis and presentation. In case 
of disagreement, efforts will be undertaken to organize a meeting to discuss and resolve any 
such issues or disagreement, but the ultimate decision remains with the Sponsor. 
 
Authorship of planned manuscripts for submission to biomedical journals shall be determined 
in accordance with the International Committee of Medical Journal Editors (ICMJE) Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals. 
 
15.4.2. 
Confidentiality 
 
A confidentiality agreement will be executed between Sponsor/CRO and an investigational site 
representative to regulate the confidentiality of all information and data provided to and/or 
generated by the investigational site. 
 
15.4.3. 
Ownership and copyright 
 
All information provided by Sponsor/CRO and all data and information generated by the sites 
as part of the study (other than patient charts) are the sole property of the Sponsor. 
 
All rights, title, and interest in any inventions, know-how or other intellectual or industrial 
property rights which are conceived or reduced to practice by the clinical site staff during the 
course of or as a result of the study are the sole property of the Sponsor. If the financial 
agreement for conduct of the study does include an ownership provision inconsistent with this 
statement, that agreement's ownership provision shall prevail. 
 
16. 
References 
(1) International 
Association 
of 
Cancer 
Registries 
(IACR). 
Retrieved 
from 
http://www.iacr.com.fr. 
 
(2) National Comprehensive Cancer Network. Endometrial Cancer (Version 3.2019). 
Retrieved from http://www.nccn.org/professionals/physicion_gls/pdf/uterine.pdf 
 
(3) Colombo N, Creautzberg C, Amant F et al. ESMO-ESGO-ESTRO consensus 
conference on endomterial cancer: diagnosis, treatment and follow-up. Annals of 
oncology 2016;27:16-41. 
 
(4) Bestvina CM, Fleming, GF. Chemotherapy for endometrial cancer in adjuvant and 
advanced disease settings. The Oncologist 2016;21:1250-1259. 
 
(5) Yarden Y, Sliwkowski M. Untangling the ErbB signalling network. Nature Reviews 
2001;2:127-137 
 
(6) Iqbal N et al. Human epidermal growth factor receptor 2 (HER2) in cancers: 
overexpression and therapeutic implications. Molecular Biology International 
2014;2014:852748. 
 
(7) Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast 
cancer: correlation of relapse and survival with amplification of the HER-2/neu 
oncogene. Science 1987;235:177-182. 
 

 
 
 
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(8) Slamon DJ, Leyland JB, 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;344:783-792. 
 
(9) Buza N, Roque D, Santin A. HER2/neu in endometrial cancer: a promising therapeutic 
target with diagnostic challenges. Arch Pathol Lab Med 2014;138:343-350. 
 
(10) Remmerie M, Janssens V. Targeted therapies in type II endometrial cancers: too little, 
but not too late. International Journal of Molecular Sciences 2018;19:2380-2402. 
 
(11) Woo JS, Apple SK, Sullivan P et al. Systematic assessment of HER2/neu in gynecologic 
neoplasms, an institutional experience. Diagnostic Pathology 2016;11:102-111. 
 
(12) Santin A, Bellone S et al. Determination of HER2/neu status in uterineserous papillary 
carcinoma:comparative analysis of immunohistochemistry and fluoresence in situ 
hybridization. Gynecologic Oncology 2005;98:24-30 
 
(13) Fader AN, Roque DM, Santin A et al. Randomized phase II trial of carboplatin-
paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that 
overexpress human epidermal growth factor receptor 2/neu. Journal of Clinical 
Oncology 2018;36(20):2044-2051. 
 
(14) Banerji U, Herpen van CML, Saura C et al. Trastuzumab duocarmazine in locally 
advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 
dose-escalation and dose-expansion study. The Lancet Oncology 2019;20(8):1124-
1135. 
 
(15)  
Rexer BN, Arteaga CL. Intrinsic and acquired resistance to HER2-targeted 
therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. 
Crit Rev Oncog. 2012;17(1):1-16. 
 
(16) Wilks S. Potential of overcoming resistance to HER2-targeted therapies through the 
PI3K/Akt/mTOR pathway. Elsevier The Breast 2015;24:548-555. 
 
(17) Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-247. 
 
(18) EMA. Summary of Product Characteristics of Kadcyla (trastuzumab emtansine). 
 
(19) Eaton JS, Miller PE et al. Ocular adverse events associated with antibody-drug 
conjugates in human clinical trials. J Ocular Pharmacological Therapy 
2015;31(10):589-604. 
 
(20) Clinical trial Facilitation Group. Recommendations related to contraception and 
pregancy 
testing 
in 
clinical 
trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
   
 
 
 

 
 
 
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APPENDIX 1: Tumour evaluation criteria (based on RECIST 1.1) 
Method of assessment 
Tumour evaluation will include systemic use of clinical, radiological, and/or other methods to 
be able to determine tumour progression. Radiological assessment of tumour burden should be 
performed by CT (preferred) or MRI scan and will follow the RECIST 1.1 criteria.16  
 
The same assessment technique must be used throughout the study for evaluating a particular 
lesion and the same investigator/radiologist should assess the tumour responses for each patient. 
 
Review of tumour response 
Tumour assessments should include an evaluation of all known and/or suspected sites of 
disease, whenever possible. Patients should have lesions selected that can be evaluated at every 
tumour assessment. Patients with non-measurable disease whose non-target lesions are not 
assessed at a follow-up visit will be considered unevaluable at that visit unless PD is assessed. 
 
Definition of measurable and non-measurable lesions 
Measurable lesions 
Measurable lesions are defined as lesions that can be accurately measured in at least one 
dimension (longest diameter is to be recorded) and have a minimum size of 10 mm when 
measured by CT scan with a CT scan slice thickness no greater than 5 mm, or have a minimum 
size of 10 mm with calliper measurements by clinical exam. If scans are used with a slice 
thickness greater than 5 mm, the minimum size of measurable lesions should be twice the slice 
thickness 
 
Measurable malignant lymph nodes need to have a minimum size of 15 mm in short axis when 
assessed by CT scan (CT scan slice thickness no greater than 5 mm).  
 
Non-measurable lesions 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis), are regarded as non-measurable. Leptomeningeal 
disease, ascites, pleural or peripheral effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, or abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques are all non-
measurable.  
 
Special considerations regarding lesion measurability 
Measurements of bone lesions, cystic lesions, and lesions previously treated with local therapy 
require special considerations: 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence 
or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT or 

 
 
 
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MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Lesions with prior local treatment: 
• Tumour lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion.  
 
Baseline documentation of target and non-target lesions 
When more than one measurable lesion is present, all lesions up to a maximum of five lesions 
in total (and a maximum of two lesions per organ), representative of all involved organs should 
be identified as target lesions. This means that for patients with only one or two involved organs, 
the maximum number of target lesions is two or four, respectively.  
 
Target lesions should be selected based on their size (lesions with the longest diameter), be 
representative of all involved organs, and should be usable for reproducible repeated 
measurements. The largest lesion may not always lend itself to reproducible measurement, in 
which circumstance the next largest lesion should be selected.  
 
Lymph nodes should be classified using the shortest axis, where a short axe of < 10 mm as 
assessed by CT scan signifies non-pathological lymph nodes. Lymph nodes with a short axis ≥ 
10 mm but < 15 mm are non-measurable, pathological lymph nodes. Only lymph nodes with a 
short axis ≥ 15 mm as assessed by CT scan can be used as measurable target lesions. 
 
A sum of the diameters for all target lesions (longest diameter for the non-nodal lesions, and 
the shortest diameter for nodal lesions) will be calculated and reported as the baseline sum 
diameters. 
 
All other lesions will automatically qualify as non-target lesions and these lesions will be 
recorded as ‘present’ at baseline. Measurement of non-target lesions is not required. 
 
Response criteria 
To determine tumour response, the sum of the diameters of the target lesions will be recorded. 
The target lesions will be evaluated as follows: 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph node 
(whether target or non-target) must have a short axis reduction to 
< 10 mm. 

 
 
 
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Partial Response (PR):  
At least 30% decrease in the sum of diameters of target lesions, 
when compared to baseline. 
Progressive Disease (PD): 
At least 20% increase in the sum of diameters of target lesions, 
compared to the smallest sum of diameters found in the study, 
including the baseline sum. In addition, the sum must also 
demonstrate an absolute increase of at least 5 mm. The 
appearance of one or more new lesions is also considered 
progression. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, when compared to the smallest sum of 
diameters while on study. 
 
Target lesions should have their actual measurements recorded at each subsequent evaluation. 
Lesions which after baseline decrease in size to less than 5 mm will be categorized as too small 
to measure (TSTM) and a default value of 5 mm will be adjudicated. 
Target nodal lesions should also have their actual measurement recorded, even when that 
measurement is below 10 mm (which would signify a normal lymph node). In the event the 
nodal lesion decreases to less than 5 mm it will be categorized as too small to measure (TSTM) 
and assigned a default value of 5 mm. For complete responses, the sum of the diameters of the 
target lesions may therefore be higher than zero while still qualifying for a complete response, 
due to the inclusion of lymph nodes. In order to achieve a complete response, the target nodal 
lesion must achieve a short axis < 10 mm. 
 
In addition, the non-target lesions will be evaluated as follows: 
 
Complete Response (CR): 
Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (<10 mm short axis) 
Non-CR/Non-PD:  
Persistence of one or more non-target lesions. 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions and/or the 
appearance of one or more new lesions. 
 
To achieve an unequivocal progression of non-target lesions, there must be an overall level of 
substantial worsening in these lesions, such that, even in the presence of SD or PR in the target 
lesions, the overall tumour burden has increase sufficiently to merit discontinuation of therapy. 
If a new lesion is equivocal because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
 
The patient’s overall response assignment on each assessment will depend on the findings of 
both target and non-target lesions and will also take into consideration the appearance of new 
lesions. Per tumour assessment, the evaluation of target and non-target lesions will be combined 
to give an overall response (see Tables A1 and A2). 
 
 
 
 
 
 

 
 
 
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Table A1: Evaluation of overall response in patients with measurable (± non-measurable) 
disease  
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not evaluable 
PD 
Any 
Yes or No 
PD 
Any  
PD 
Yes or No 
PD 
Any  
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease 
 
Table A2: Evaluation of overall response in patients with non-measurable disease only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, NE = unevaluable 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start IMP treatment until 30 
days after the last dose of study treatment.  
The best overall response is defined as the best response across all assessments. For example, 
a patient who has SD at first assessment, PR at second assessment, and PD on last assessment 
has a best overall response of PR. When SD is believed to be the best response, it must also 
meet the protocol specified minimum time from baseline. If the minimum time is not met, when 
SD is other-wise the best response, the patient’s best overall response depends on the 
subsequent assessments. For example, a patient who has SD at first assessment, PD at second 
assessment and does not meet the minimum duration for SD, will have a best response of PD. 
The same patient lost to follow-up after the first SD assessment would be considered 
unevaluable.     
 
To be assigned a status of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimal interval of 6 weeks.  
 
 

 
 
 
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APPENDIX 2: Protocol amendment I 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL AMENDMENT 
 
A single-arm phase II trial to evaluate the safety and efficacy of the antibody-drug conjugate 
SYD985 in patients with HER2-expressing recurrent, advanced or metastatic endometrial 
carcinoma who previously progressed on or after first line platinum-based chemotherapy. 
 
 
 
Protocol number: 
SYD985.003 
 
Development phase:  
Phase II 
 
Drug product code: 
SYD985 
 
Drug substance: 
Trastuzumab vc-seco-DUBA 
 
INN = [vic-]trastuzumab duocarmazine 
 
EudraCT Number: 
2019-002888-10 
 
IND Number: 
146672 
 
Amendment: 
Protocol Amendment I 
 
(leading to Protocol Version 2.0) 
 
Amendment date: 
27 February 2020 
 
Authors:  
Synthon Biopharmaceuticals BV: 
 
 
Maaike Hendriks, Clinical Project Leader 
 
Norbert Koper, VP Clinical Development 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Justification for the amendment 
 
This substantial amendment has been prepared on request of the regulatory authorities and due 
to additional quality review. The following changes have been included: 
• The study flowchart has been updated to include a physical examination at the start of 
every cycle; 
• The study flowchart has been updated to include pulmonary function testing at the 
baseline visit and whenever clinically indicated; 
• In/exclusion criteria in section 8.1 have been aligned with in/exclusion criteria in 
synopsis;  
• Section 9.6.1.1 dose modifications for ocular toxicity have been elaborated 
• Section 9.6.1.4 dose modifications for haematologic toxicity have been elaborated 
 
Apart from editorial changes, this has led to the following changes in the protocol text, all 
included in version 2.0 of the protocol. New text is underlined, deleted text is strikethrough. 
 
Synopsis: Study assessments and procedures 
Safety assessments will include physical examination, ECOG performance status, vital signs, 
weight assessment, electrocardiography (ECG), LVEF measurements by echocardiography or 
MUGA scan, laboratory measurements, ophthalmological examination and adverse event (AE) 
reporting. 
 
Now reads as: 
Safety assessments will include physical examination, ECOG performance status, vital signs, 
weight assessment, electrocardiography (ECG), LVEF measurements by echocardiography or 
MUGA scan, laboratory measurements, pulmonary function testing (PFT), ophthalmological 
examination and adverse event (AE) reporting. 
 
Section 1.1 Study flowchart: 
Physical examination has been added at the start of every cycle. 
Pulmonary function testing has been added to the baseline visit and when clinically 
indicated. 
The following footnote has been added: 
 
6 
Pulmonary Function Testing (PFTs) should be done at baseline and whenever clinically indicated, according to local hospital standard. 
 
 
 Section 8.1.1 Inclusion criteria: 
1. Female patients, age ≥18 years at the time of signing first informed consent; 
 
Now reads as: 
1. Female patients, age ≥18 years at the time of signing first main informed consent; 
 
 
 
 
 
 
 

 
 
 
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Section 8.1.2 Exclusion criteria: 
3. History of keratitis; 
4. Severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, 
pulmonary, or metabolic disease) at screening; 
5. LVEF < 50% as assessed by either echocardiography or multigated acquisition (MUGA) 
scan at screening, or a history of clinically significant decrease in LVEF during previous 
treatment with trastuzumab leading to permanent discontinuation of treatment;   
6. History (within 6 months prior to start IMP treatment) of clinically significant 
cardiovascular disease such as unstable angina, congestive heart failure (CHF), 
myocardial infarction, uncontrolled hypertension, or cardiac arrhythmia requiring 
medication; 
7. Symptomatic brain metastases, brain metastases requiring steroids to manage symptoms, 
or treatment for brain metastases within 8 weeks prior to start IMP treatment; 
8. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan; 
 
Now reads as: 
3. History or presence of keratitis; 
4. Severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, 
pulmonary, or metabolic disease) at screening; 
5. LVEF < 50% as assessed by either echocardiography or multigated acquisition (MUGA) 
scan at screening, or a history of clinically significant decrease in LVEF during previous 
treatment with trastuzumab leading to permanent discontinuation of treatment;   
6. History (within 6 months prior to start IMP treatment) or presence of clinically significant 
cardiovascular disease such as unstable angina, congestive heart failure (CHF), 
myocardial infarction, uncontrolled hypertension, or cardiac arrhythmia requiring 
medication; 
7. Symptomatic brain metastases, brain metastases requiring steroids to manage symptoms, 
or treatment for brain metastases within 8 weeks prior to start IMP treatment; 
8. History or presence of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. 
bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or 
evidence of active pneumonitis on screening chest CT scan; 
 
Section 9.6.1.1 Dose modifications for ocular toxicity: 
Patients who experience Grade 3 (or higher) keratitis should be discontinued from treatment. 
For patients who experience other Grade ≥ 3 ocular toxicity, dosing must be delayed for up to 
42 days from the last received dose. When the ocular toxicity resolves to Grade 2 or lower 
patients may continue treatment at the same dose level as before or the dose can be reduced, at 
the discretion of the investigator. Subsequent dosing delays or treatment discontinuation should 
be considered in case the ocular toxicity persists. The ocular toxicity should be monitored by 
an ophthalmologist (or qualified delegate) for recovery. 
 
 
 
 
 
 

 
 
 
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Now reads as: 
Patients who experience Grade 3 (or higher) keratitis ocular toxicity should be discontinued 
from treatment. For patients who experience other Grade ≥ 3 2 ocular toxicity, dosing must be 
delayed for up to 42 days from the last received dose. When the ocular toxicity resolves to 
Grade 2 or lower it should be considered to delay dosing for up to 42 days from the last received 
dose and appropriate treatment with eye drops, cream, or gel should be applied (e.g. steroid 
containing eye drops). If study drug is interrupted for Grade 2 toxicity it should resolve to Grade 
1 or baseline before restarting treatment. Patients may continue treatment at the same dose level 
as before or the dose can be reduced, at the discretion of the investigator. Subsequent dosing 
delays or treatment discontinuation should be considered in case the ocular toxicity persists. 
The ocular toxicity should be monitored by an ophthalmologist (or qualified delegate) for 
recovery. 
 
Section 9.6.1.4 Dose modifications for haematologic toxicity: 
For patients who experience a Grade 3 (or higher) haematological event it should be considered 
to delay dosing for up to 42 days from the last received dose. Patients may continue treatment 
at the same dose level as before or the dose can be reduced, at the discretion of the investigator.  
 
Now reads as: 
For patients who experience a Grade 3 (or higher) haematological event it should be considered 
to delay dosing must be delayed for up to 42 days from the last received dose. When the 
haematologic event resolves to Grade 1 or baseline, patients may continue treatment at the same 
dose level as before or the dose can be reduced, at the discretion of the investigator.  
 
Section 11.7 Pulmonary function testing has been added: 
Pulmonary function testing should be done according to local hospital standards, and may 
include spirometry, diffusing capacity of the lungs for carbon monoxide or peripheral oxygen 
saturation. 
 
 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
APPENDIX 3: Protocol amendment II 
 
 
 
CLINICAL TRIAL PROTOCOL AMENDMENT 
 
A single-arm phase II trial to evaluate the safety and efficacy of the antibody-drug conjugate 
SYD985 in patients with HER2-expressing recurrent, advanced or metastatic endometrial 
carcinoma who previously progressed on or after first line platinum-based chemotherapy. 
 
 
 
Protocol number: 
SYD985.003 
 
Development phase:  
Phase II 
 
Drug product code: 
SYD985 
 
Drug substance: 
Trastuzumab vc-seco-DUBA 
 
INN = [vic-]trastuzumab duocarmazine 
 
EudraCT Number: 
2019-002888-10 
 
IND Number: 
146672 
 
Amendment: 
Protocol Amendment II 
 
(leading to Protocol Version 3.0) 
 
Amendment date: 
30 September 2020 
 
Authors:  
Byondis BV: 
 
 
Maaike Hendriks, Clinical Project Leader 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
Justification for the amendment 
 
This substantial amendment has been prepared for the following reasons: 
• On April 15, 2020, the name of Synthon Biopharmaceuticals B.V. was changed to 
Byondis B.V. The legal entity of the company was not changed. The Clinical Study 
Protocol was updated with the new Sponsor name and logo and converted to a new 
template.  
• Inclusion criterion 3 has been reworded for clarification to assure correct and consistent 
understanding.  
• A time window is added for the pregnancy test at C1D1 to align with the allowed blood 
sampling window for haematology/chemistry. 
• Patient discontinuation criteria updated to reflect the change to Section 9.6.1.1 (Dose 
modifications for ocular toxicity) as described in Protocol Amendment I. 
 
Apart from editorial changes, this has led to the following changes in the protocol text, all 
included in version 3.0 of the protocol. New text is underlined, deleted text is strikethrough. 
 
Protocol Synopsis and Section 8.1.1: Study population/ Inclusion criteria 
3. Eligible patients should have progressed on or after first line platinum-based chemotherapy 
for advanced/metastatic endometrial cancer. Patients who have had two or more lines of 
chemotherapy for advanced/metastatic disease are not eligible, taking into account the 
following:  
– Patients may have received up to one additional line of chemotherapy if given in the 
neoadjuvant or adjuvant setting. If such treatment was completed less than 6 months 
prior to the current tumour recurrence or progression it is to be considered first-line 
treatment; 
– No more than one line of non-cytotoxic systemic cancer therapy (such as 
immunotherapy, trastuzumab or protein kinase inhibitors) is allowed. 
Note: there is no restriction regarding to the lines of prior hormonal therapy. 
 
Now reads as: 
 
3. Eligible patients should have progressed on or after first line one prior systemic platinum-
based chemotherapy regimen for advanced/metastatic endometrial cancer. Patients who 
have had two or more lines of chemotherapy for advanced/metastatic disease are not 
eligible, taking into account the following:. 
Note:  
– Patients may have received up to one additional line of chemotherapy if given in the 
neoadjuvant or adjuvant setting. If provided that such treatment was completed less 
more than 6 months prior to the current tumour recurrence or progression it is to be 
considered first-line treatment; 
– No more than one line of non-cytotoxic systemic cancer therapy (such as 
immunotherapy, trastuzumab or protein kinase inhibitors) is allowed. 
Note: there is no restriction regarding to the lines of prior hormonal therapy. 
 
 
 
 
 

 
 
 
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Clinical Study Protocol                                CONFIDENTIAL 
SYD985.003                                                          Version 3.0 
                                                                             30 Sep 2020  
Section 1.1 Study flowchart 
The following footnote has been updated: 
9. 
Pregnancy tests (serum test at screening and serum or urinary tests during treatment and at treatment discontinuation) will be performed 
to exclude pregnancy in women with childbearing potential, and may be done up to 3 days before the start of the new cycle; 
 
Now reads as: 
9. 
Pregnancy tests (serum test at screening and serum or urinary tests during treatment and at treatment discontinuation) will be performed 
to exclude pregnancy in women with childbearing potential, and may be done up to 3 days before the start of the new cycle. If the 
screening assessment is done within 5 days before the first study drug administration, analysis does not need to be repeated at the day of 
first administration; 
 
Section 13.1 Patient discontinuation: 
The investigator should discontinue a patient from study treatment for reasons including but 
not limited to the following: 
• Disease progression; 
• Unacceptable toxicity, including; 
o Clinically significant symptomatic cardiac disease (see Section 9.6.1.3); 
o Clinically significant drug-related toxicity requiring dose delay or interruption 
which did not resolve within 42 days from the last dose received; 
o Grade 4 infusion-related reaction or a Grade 3 infusion-related reaction which 
is not responsive to symptomatic medication and/or interruption of infusion; 
o Grade 3 (or higher) keratitis; 
o Grade 2, 3 or 4 ILD/pneumonitis; 
• Pregnancy; 
• Substantial non-compliance with the requirements of the study; 
• Investigator decision based on the patient’s best interest; 
• Termination of the study by the Sponsor. 
 
Now reads as: 
The investigator should discontinue a patient from study treatment for reasons including but 
not limited to the following: 
• Disease progression; 
• Unacceptable toxicity, including; 
o Clinically significant symptomatic cardiac disease (see Section 9.6.1.3); 
o Clinically significant drug-related toxicity requiring dose delay or interruption 
which did not resolve within 42 days from the last dose received; 
o Grade 4 infusion-related reaction or a Grade 3 infusion-related reaction which 
is not responsive to symptomatic medication and/or interruption of infusion; 
o Grade 3 (or higher) keratitis ocular toxicity; 
o Grade 2, 3 or 4 ILD/pneumonitis; 
• Pregnancy; 
• Substantial non-compliance with the requirements of the study; 
• Investigator decision based on the patient’s best interest; 
• Termination of the study by the Sponsor.