Clinical trial NCT03262935
Conditions: Metastatic Breast Cancer
Sponsor: Byondis B.V.
Start date: 2017-12-15; Completion date: 2022-06-30
Enrollment: 437 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to demonstrate that SYD985 \[(vic-)trastuzumab duocarmazine\] is superior to physician's choice in prolonging progression free survival.

Detailed description:
This study is designed as a randomized, active-controlled, superiority study in patients with unresectable locally advanced or metastatic HER2-positive breast cancer. The patients should have had either progression during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine treatment.

Eligible patients will be randomly assigned (2:1) to receive SYD985 or physician's choice treatment until disease progression, unacceptable toxicity or study termination by the Sponsor. During treatment, patients will have to visit the clinical site to assess efficacy, quality of life (QoL), and safety using standardized criteria.

Arms: arm 1: SYD985, every 3 weeks (Q3W) arm 2: 1. Lap/Cap
2. T/Cap
3. T/Vino
4. T/Eri
Interventions: intervention 1: (vic-)trastuzumab duocarmazine intervention 2: Physician's choice
Intervention descriptions: intervention 1: Intravenous SYD985, Q3W intervention 2: See drug label

Protocol documents:
Prot_000.pdf: 
 
 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and 
safety of the antibody-drug conjugate SYD985 to physician’s choice in patients 
with HER2-positive unrespectable locally advanced or metastatic breast cancer. 
 
 
NCT03262935 
 
 
Version 8.0, dated 18 January 2021 


 
Document number (version): CSP.NL03.57088 (8.0) 
Page 1 of 126 
 
         
Clinical Study Protocol SYD985.002 
 
Protocol title: 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the 
antibody-drug conjugate SYD985 to physician's choice in patients with HER2-positive unresectable 
locally advanced or metastatic breast cancer   
 
   
 
 
Abbreviated title: 
TULIP 
Protocol Number: 
SYD985.002 
 
Development phase: 
Phase III 
Drug product code: 
SYD985 
Drug substance: 
Trastuzumab vc-seco-DUBA  
EudraCT Number: 
2017-001994-18 
IND Number: 
131333 
Protocol Version: 
Version 8.0 
Protocol Date: 
18 January 2021 
Document Number: 
CSP.NL03.57088 
Authors Byondis BV: 
 
 
Evelyn van den Tweel, Clinical Project Leader  
Mayke Oesterholt, Clinical Project Leader 
Ellen Mommers, Clinical Project Leader 
Roel Mulder, Biostatistician  
 
 
 
 
 
This document includes confidential and privileged information and data that contain trade secrets which are 
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 study at a clinical 
investigational site. 


 Clinical Study Protocol 
SYD985.002 
TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 2 of 126 
 
1 
Protocol synopsis 
Title of study: 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the antibody-drug 
conjugate SYD985 to physician's choice in patients with HER2-positive unresectable locally advanced or 
metastatic breast cancer   
Objectives: 
The primary objective of this study is: 
• 
To demonstrate that SYD985 is superior to physician’s choice in prolonging progression-free survival 
(PFS) on the basis of the blinded independent central review of tumour assessment.  
 
The secondary objectives of this study are to compare the two treatment groups with respect to: 
• 
Overall survival (OS);  
• 
Objective response rate (ORR) on the basis of the blinded independent central review; 
• 
Investigator assessed PFS; 
• 
Patient reported outcomes for health related quality of life; 
• 
Safety and tolerability. 
Study design: 
This study is designed as a randomized, active-controlled, superiority study in patients with unresectable 
locally advanced or metastatic HER2-positive breast cancer. The patients should have had either progression 
during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease or 
progression during or after (ado-)trastuzumab emtansine treatment. 
 
Eligible patients will be randomly assigned (2:1) to receive SYD985 or physician’s choice treatment until 
disease progression, unacceptable toxicity or study termination by the Sponsor. During treatment, patients 
will have to visit the clinical site to assess efficacy, quality of life (QoL), and safety using standardized 
criteria. 
Duration of patient treatment and participation: 
After a screening period of maximally 28 days, patients who are eligible will be randomized and treated until 
disease progression or unacceptable toxicity. Upon treatment discontinuation patients should return for a 
treatment discontinuation visit 4-6 weeks after the last administration of study drug. Thereafter patients will 
be contacted to follow up on clinical disease progression, unresolved AEs, new anticancer therapies, and 
overall survival every 3 months after the treatment discontinuation visit up to death, lost to follow-up, consent 
withdrawal or end of study data collection, whichever comes first. 
Study population: 
When evaluating a patient for participation into the study the investigator should first consider which 
combination treatment would be prescribed if the patient would be randomized to the physician’s choice 
group. During this evaluation all routine clinical considerations, including treatment specific 
restrictions/contraindications as per Summary of Product Characteristics/Prescribing Information for the 
physician’s choice treatment options, should be taken into account.  Only after it is concluded that at least 
one of the four treatment options in the physician’s choice group would be an appropriate way to treat 
the patient, the patient can be considered for the study as per inclusion/exclusion criteria. 
 
 


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The study population will consist of patients with HER2-positive unresectable locally advanced or metastatic 
breast cancer complying with the following in- and exclusion criteria: 
  
Inclusion criteria 
1. Female patients, age ≥ 18 years old at the time of signing informed consent; 
2. Patients with histologically-confirmed, unresectable locally advanced or metastatic breast cancer; 
3. Patients should have had either progression during or after at least two HER2-targeting treatment 
regimens for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab 
emtansine treatment for locally advanced or metastatic disease; 
4. HER2-positive tumour status according to the ASCO-CAP guidelines (defined as a 3+ score on 
immunohistochemistry (IHC) and/or positive by in situ hybridization (ISH)) confirmed by the central 
laboratory;  
5. Patients must have measurable or non-measurable disease that is evaluable per Response Evaluation 
Criteria for Solid Tumours (RECIST version 1.1). Patients with bone-only sclerotic disease without a 
lytic component, or patients who have bone-only metastases requiring endocrine therapy or patients with 
non-visceral metastases requiring endocrine therapy, are not eligible; 
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 
7. Estimated life expectancy > 12 weeks at randomization; 
8. 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;  
– 
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;  
9. For women of childbearing potential, two methods of effective contraception must be used during the 
study and up to 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. SYD985 at any time;  
b. Anthracycline treatment within 12 weeks prior to randomization;      
c. Other anticancer therapy including chemotherapy, immunotherapy, or investigational agents within 
4 weeks prior to randomization; 
d. Radiotherapy within 2 weeks prior to randomization; 
e. Hormone therapy within 1 week prior to randomization; 
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, (ado-)trastuzumab 
emtansine or excipients of the study drug which led to permanent discontinuation of the treatment; 
3. History of keratitis; 
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 


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previous treatment with trastuzumab or (ado-)trastuzumab emtansine leading to permanent 
discontinuation of treatment; 
6. Cardiac troponin value above the ULN (local laboratory) at screening;  
7. History (within 6 months prior to randomization) of clinically significant cardiovascular disease such as 
unstable angina, congestive heart failure (CHF), myocardial infarction, uncontrolled hypertension, or 
cardiac arrhythmia requiring medication;  
8. Untreated brain metastases, symptomatic brain metastases, brain metastases requiring steroids to manage 
symptoms, or treatment for brain metastases within 8 weeks prior to randomization. Patients with prior 
treatment of brain metastases must have evidence of disease stability on baseline brain imaging as 
compared to historical brain imaging; 
9. 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; 
10. Known active Hepatitis B or C infection; 
11. Major surgery within 4 weeks prior to randomization; 
12. Pregnancy or lactation; 
13. 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: 
Investigational medicinal product: 
SYD985 (trastuzumab vc-seco-DUBA, Byondis BV, The Netherlands) 
Patients in the investigational group will be treated every three weeks (Q3W) with 1.2 mg/kg SYD985. 
SYD985 is an antibody-drug conjugate (ADC) comprised of Byondis' HER2-targeting monoclonal IgG1 
antibody trastuzumab (SYD977) covalently bound to a linker-drug (SYD980). The linker-drug contains a 
cleavable linker and the prodrug seco-duocarmycin-hydroxybenzamide-azaindole (seco-DUBA, SYD978). 
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, SYD986).  
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. SYD985 drug product vials should be 
stored at 2 to 8 °C (36-46 °F) until use.  
The calculated amount of solution should be added to an infusion bag containing 0.9% sodium chloride 
without other additives. If reconstituted vials or the prepared infusion bag is not used immediately, it can be 
stored at 2 to 8 °C (36-46 °F) for a maximum of 24 hours up to start of infusion. 
SYD985 is to be administered intravenously over 60 minutes for the first infusion, subsequent infusions can 
be given over 30 minutes. 
 
Reference therapy: Treatment of physician’s choice 
Patients in the reference group will be treated with approved systemic therapy administered as per local 
practice and according to the needs of each patient. Investigators can choose between four pre-specified 
treatment regimens:  
• 
Option 1: Lapatinib + Capecitabine 
• 
Option 2: Trastuzumab + Capecitabine 
• 
Option 3: Trastuzumab + Vinorelbine  
• 
Option 4: Trastuzumab + Eribulin 


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Study assessments and procedures (see also flowchart): 
The informed consent form (ICF) must be signed before any study-related procedure is performed. A specific 
“HER2 testing”-ICF may be used to allow the central assessment of HER2 tumour status on tumour tissue. 
 
Safety assessments will include physical examination, ECOG performance status, vital signs, weight 
assessment, electrocardiography (ECG), LVEF measurements by echocardiography or MUGA scan, 
laboratory measurements, urinalysis, ophthalmological examination, and adverse event (AE) reporting.  
 
The HER2 tumour status will be assessed by a central laboratory using IHC and ISH on archived (or fresh) 
material to determine eligibility.  
 
Blood samples will be drawn to assess pharmacokinetic parameters, anti-SYD985 antibodies, circulating 
tumour DNA (ctDNA), and serum HER2 extracellular domain (ECD) levels at a central laboratory. Blood 
samples for blood chemistry, haematology and cardiac biomarkers will be measured by the local and central 
laboratory. Urinalysis will be performed locally. 
  
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 42 weeks and every 9 weeks thereafter. Tumour 
responses will be assessed by the investigator / radiologist and by a central image analysis centre using the 
RECIST criteria (version 1.1).  
 
EORTC QLQ-C30 and breast module QLQ-BR23 questionnaires will be used on day 1 of the first 5 cycles 
and subsequently every 2nd cycle to monitor changes in the patient's QoL. 
 
Patients will be contacted to follow up on clinical disease progression, unresolved AEs, new anticancer 
therapies, and overall survival every 3 months after the treatment discontinuation visit up to death, lost to 
follow-up, consent withdrawal or end of study data collection, whichever comes first. 
Statistical methods: 
Data sets: 
The primary analysis set will include all patients who were randomized in the study (i.e. the Full Analysis 
Set (FAS)). For efficacy, patients will be analyzed according to the treatment group to which they were 
randomized. For safety, patients will be analyzed according to the actual treatment they received, regardless 
the randomization. 
 
Efficacy analysis 
Primary outcome: 
The primary PFS analysis will be performed when at least 256 PFS events have occurred, or when at least 
95% of patients have discontinued treatment, and only after all patients have been enrolled. The median time-
to-event outcomes and corresponding 95% Confidence Intervals (CIs) for each treatment group will be 
estimated using Kaplan-Meier methods. The two-sided log-rank test, stratified by the protocol-defined 
randomization factors will be used to compare time-to-event outcomes between treatment groups. Hazards 
Ratios and corresponding 95% CIs will be estimated using Cox proportional hazards models, stratified by the 
protocol defined randomization factors. Superiority of SYD985 to physician’s choice will be analyzed with 
the log-rank test at alpha 0.05.  
 
Secondary outcomes: 
• 
Overall survival (OS);  
• 
Objective response rate (ORR) on the basis of the blinded independent central review; 


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• 
Investigator assessed PFS; 
• 
Patient reported outcomes for health related quality of life. 
 
Safety analysis 
The safety profile will be assessed by evaluation of: 
• 
Incidence and severity of AEs; 
• 
Laboratory abnormalities; 
• 
Specific safety assessments (LVEF, ECG, ophthalmological exams). 
The evaluation will be performed using descriptive statistics. 
Sample size: 
In order to be able to detect a hazard ratio of 0.65 in PFS using the log-rank test, at 90% power, using a two-
sided test at a significance level of p < 0.05, a total of 256 events are required. Assuming a 9 month 
recruitment period and 10 month follow up period, a median time to progression of 4.1 months for the 
physician’s choice and assuming an average of 30% drop out in the physician’s choice group and 40% in the 
SYD985 group, a minimal number of 423 patients is required. Allocation is 2:1 resulting in 282 to be allocated 
to the SYD985 group and 141 to the physician’s choice group. 
 
Randomization will be done by a permutated block design with a fixed block size, using world region (Europe 
and Singapore/North-America), the number of prior treatment lines for locally advanced or metastatic breast 
cancer (excluding hormone therapy) (1 or 2/more than 2), and prior treatment with pertuzumab (yes/no) as 
stratification factors. 
Data Monitoring Committee: 
Safety will be monitored on an ongoing basis during the entire study by an independent external Data 
Monitoring Committee (DMC), of which the composition, roles and responsibilities will be described in a 
separate charter.  As part of their evaluation the DMC assessed the validity of the initial assumptions underlying 
the sample size estimation with regards to drop-out rates. Based on their pre-planned interim evaluation, the 
independent DMC has recommended to adjust the sample size and enrol a total of 423 patients to ensure 
sufficient power for the primary endpoint analysis.  
Number of study sites: 
The number of participating sites will be approximately 100 to ensure timely enrolment of the required 
number of patients. Sites will be located in Europe, Singapore and North-America.  
Planned clinical study period: 
First patient first visit: Q3 2017 
Last patient first visit:  H1 2020 
Last patient last visit:  H1 2021 


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1.1 
Study flowchart (assessments and procedures) 
 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
onwards 
Treatment 
disc. 
Survival 
Follow-up 
Visit day 
Day 
-28  
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day  
1 
Day  
2 
Day  
15 
Day  
1 
28-42 days 
after last 
dose of 
study 
treatment20 
Every 3 
months 
after last 
contact18 
Visit window (days) 
 
 
 
± 1 
± 1 
± 3 
± 1 
± 1 
± 3 
± 3 
 
± 3 
± 3 
 
± 14 
Informed consent1 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/exclusion criteria 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
✓ 
Examination only whenever indicated by AE review 
✓ 
 
Vital signs21 
✓ 
✓2 
 
✓ ✓ 
✓2 ✓ 
✓ 
✓2 
✓2 
 
 
✓2 
✓ 
 
Weight, Height (only at screening) 
✓ 
✓3 
 
 
 
✓3 
 
 
✓3 
✓3 
 
 
✓3 
✓ 
 
ECOG performance status 
✓ 
✓2 
 
 
 
✓2 
 
 
✓2 
✓2 
 
 
✓2 
✓ 
 
Central HER2 assessment4 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology / blood chemistry / 
Cardiac troponin6 
✓ 
✓5 
 
✓ ✓ 
✓5 
✓ 
✓ 
✓5 
✓5 
 
 
✓5 
✓ 
 
Urinalysis 
✓ 
✓5 
 
 
 
✓5 
 
 
✓5 
✓5 
 
 
✓5 
✓ 
 
Pregnancy test7 
✓ 
✓ 
 
 
 
✓ 
 
 
✓ 
✓ 
 
 
✓ 
✓ 
 
Blood sample(s) - PK8 
 
✓ 
✓ ✓ ✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Blood sample - immunogenicity9 
 
✓2 
 
 
 
✓2 
 
 
✓2 
✓2 
 
 
✓2 
✓ 
 
Blood sample - serum HER2 ECD 
 
✓2 
 
 
 
✓2 
 
 
✓2 
✓2 
 
 
✓2 
✓ 
 
Blood sample - ctDNA 
 
✓2 
 
 
 
 
 
 
 
 
 
 
 
✓ 
 
Ophthalmological examination10 
✓ 
 
 
 
 
✓ 
 
 
 
✓ 
+ every 2nd 
cycle 
 
 
 
✓ 
 


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Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
onwards 
Treatment 
disc. 
Survival 
Follow-up 
Visit day 
Day 
-28  
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day  
1 
Day  
2 
Day  
15 
Day  
1 
28-42 days 
after last 
dose of 
study 
treatment20 
Every 3 
months 
after last 
contact18 
Visit window (days) 
 
 
 
± 1 
± 1 
± 3 
± 1 
± 1 
± 3 
± 3 
 
± 3 
± 3 
 
± 14 
LVEF10, 11 
✓ 
 
 
 
 
✓ 
 
 
 
✓ 
+ every 4th 
cycle 
 
 
 
✓ 
 
ECG12 
✓ 
✓ ✓13  
 
✓ 
 
 
✓ 
✓ 
+ every 4th 
cycle 
✓13 
 
 
✓ 
 
Tumour evaluation14,15 
✓ 
Every 6 weeks after randomization during the first 42 weeks and every 9 weeks thereafter 
✓17 
 
CT or MRI of brain15 
✓ 
Per clinical indication 
Per clinical 
indication 
 
Whole body bone scan15 
✓ 
Per clinical indication 
Per clinical 
indication 
 
QoL questionnaires 
 
✓ 
 
 
 
✓ 
 
 
✓ 
✓ 
 
 
✓ 
+ every 
2nd cycle 
✓ 
 
Study drug administration16 
 
✓ 
 
 
 
✓ 
 
 
✓ 
✓ 
 
 
✓ 
 
 
(S)AEs 
✓ 
✓ ✓ ✓ ✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Previous and concomitant 
medication 
✓ 
✓ ✓ ✓ ✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓19 
Survival information  
(progression, death) 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
✓ 
General note: in case assessments show abnormal results that warrant more extensive monitoring for safety, additional visits and assessments should be considered. 
For patients on physician’s choice treatment in addition to the assessments in the flowchart guidance from the Summary of Product Characteristics/Prescribing 
Information of the specific treatments should be followed with regards to patient monitoring. 
1 
Following signing the “Study”-ICF an eligible patient should be randomized within 28 days. A “HER2 testing”-ICF may be used to assess the HER2 tumour status on archival tumour tissue to 
determine patient eligibility; 


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2 
Day 1 assessments are to be done prior to study drug administration; 
3 
Weight should be measured before the start of a new cycle, this may be done up to 7 days before the Day 1 visit; 
4 
Archived tumour material should be submitted for central analysis of HER2 status before randomization, this can be done after signing the “HER2 
testing”-ICF. If there is no archival tumour material available a biopsy should be performed to obtain tumour material, this can only be done after 
signing the “Study”-ICF. The HER2 tumour status will be assessed by a central laboratory using IHC and ISH; 
5 
Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as closely as possible to the start of the new cycle, but 
may be done up to 3 days before. Analyses should be performed at a local laboratory. Results of the local laboratory should be available before the 
start of the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and cardiac troponin 
should also be performed at the central laboratory;   
6 
Either cardiac troponin I or T (using a high sensitivity assay) can be measured as long as the same assay is used throughout the study for an 
individual patient;  
7 
Pregnancy test in women of childbearing potential: serum test at screening (between day -10 and day -1), serum or urinary tests during treatment 
(should be done on Day1 of the new cycle, but may be done up to 3 days before) and at treatment discontinuation visit; 
8 
PK samples will be taken in the SYD985 treatment group only. See for details the PK sampling scheme on page 10; 
9 
Immunogenicity samples will be taken in the SYD985 group only; 
10 Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as LVEF 
assessment 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; 
11 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 
9.5.1.1 of the protocol; 
12 12-lead ECGs should be recorded in triplicate. ECGs should be obtained before study drug administration for all patients. In addition ECGs should 
be obtained 30 minutes after the end of infusion at the day of first study drug administration in cycle 1 and cycle 4 in all patients excluding the 
patients in the Physician’s Choice group receiving the oral treatment combination lapatinib + capacitabine. The ECGs should be submitted for 
central review; 
13 ECG should be obtained 24 hours (± 2 hours) after study drug administration. The ECGs should be submitted for central review; 
14 For tumour measurements, a CT or MRI scan should be performed every 6 weeks (± 3 days) after the date of randomization for the first 42 weeks 
and every 9 weeks (± 3 days) thereafter, independent of dosing delays. The methodology and imaging levels should remain the same at baseline 
and subsequent evaluations for a given patient;  
15 The tumour measurements should be submitted for central review; 
16 Administration of SYD985 or administration of physician’s choice in a 21-days (3 weeks) regimen (± 3 days) until disease progression or 
unacceptable toxicity. For SYD985 no recalculation of the 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;  
17 Tumour evaluation at the treatment 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 visit; 
18 Patients should be followed up until death, lost to follow-up, consent withdrawal or end of study data collection, whichever comes first; 
19 During the survival follow-up only initiation of new anticancer medication should be documented. 
20 The end of treatment visit needs to be performed 28-42 days after the last dose of study drug or before new anticancer treatment is initiated, 
whichever comes first.  
21 Vital signs include blood pressure, heart rate, body temperature, and oxygen saturation by pulse oximetry.  
 
 
 


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PK blood sampling scheme for the SYD985 treatment group 
Cycle  
Day  
Sampling time*  
Cycle 1  
1  
Pre-dose  
End of infusion  
2 
24 hours (± 2h) after end of infusion 
8  
During the visit 
15  
During the visit 
Cycle 2  
1  
Pre-dose  
End of infusion  
8  
During the visit 
15  
During the visit 
Cycle 3  
1  
Pre-dose  
End of infusion  
Cycle 4  
1  
Pre-dose  
End of infusion  
2 
24 hours (± 2h) after end of infusion 
15  
During the visit 
Cycle 5 onwards  
1  
Pre-dose  
Treatment discontinuation  
During the visit 
* PK will be assessed for total SYD985 (includes SYD985 with a drug-to-antibody ratio (DAR) of ≥ 0), 
conjugated SYD985 (includes SYD985 with a DAR of ≥1), and for the free toxin (DUBA, SYD986) in cycle 
1 to 4. From cycle 5 onwards PK will be assessed for total SYD985 only. One or two spare aliquots will be 
stored for re-analysis purposes, a DAR average assay (if considered relevant and feasible), and/or other 
exploratory PK, biotransformation/metabolite identification or mode of action related assays which may turn 
out to be useful for further development of duocarmycin-based ADCs. In case PK, immunogenicity, efficacy 
and/or safety data indicate a possible development of anti-SYD985 antibodies, the Sponsor may discuss an 
intensified PK and/or immunogenicity sampling scheme with the site on a case-by-case basis. 
 
 


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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 Evelyn van den Tweel 
Telephone Number: +31 24 6795100 // +31 24 3727 907 
E-Mail: Evelyn.vandentweel@byondis.com 
Clinical Project Leader Mayke Oesterholt 
Telephone Number: +31 24 6795100 // +31 24 3727 787 
E-Mail: Mayke.Oesterholt@byondis.com 
Biostatistician Roel Mulder 
Telephone Number: +31 24 6795100  
E-Mail: Roel.Mulder@byondis.com 
 
 
Scientific Steering Committee 
(Chair): 
Nicholas Turner MD PhD 
The Royal Marsden Hospital/The Institute of Cancer 
Research 
London 
UK 
 
CRO  
(clinical services) 
Syneos Health 
De Entrée 99-197, 14th floor 
1101 HE Amsterdam 
The Netherlands 
 
 
EDC, randomization and QoL 
services 
Medidata 
Medidata Solutions 
350 Hudson Street, 9th Floor,  
New York, NY 10014 
USA 
 
 
IMP logistics:  
(for SYD985)  
ALMAC Clinical Services 
ALMAC group 
9 Charlestown Road 
Seagoe Industrial Estate, Craigavon 
BT63 5PW 
United Kingdom 


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Central Image Analysis: 
(RECIST evaluation) 
Bioclinica 
Imaging Core Lab and Cardiac Safety Princeton Office 
100 Overlook Center 
Princeton, NJ 08540 
USA 
 
 
Central ECG Centre: 
(ECG evaluation) 
ERT (Formerly BMS) 
77 Progress Parkway 
Maryland Heights, MO 63043 
USA 
 
 
Central Laboratory: 
(Safety laboratory & logistics) 
Eurofins 
Eurofins Central Laboratory, LCC 
22430 New Holland Pike, D100 
Lancaster, PA 17601 
USA 
 
 
Central Laboratory: 
(for PK SYD986, total SYD985, 
SYD985 
DAR≥1 
and 
immunogenicity) 
Analytical Biochemical Laboratory (ABL) 
W.A. Scholtenstraat 7 
9403 AJ Assen 
The Netherlands 
 
 
Central Laboratory: 
(for HER2 Tumour expression) 
Targos Molecular Pathology 
Germaniastrasse 7 
D-34119 Kassel 
Germany 
 
 
 
 
 
 
 


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3 
Table of contents 
1 
Protocol synopsis 
2 
1.1 
Study flowchart (assessments and procedures) 
7 
2 
Sponsor information and responsibilities 
11 
3 
Table of contents 
13 
4 
List of abbreviations 
17 
5 
Introduction 
20 
5.1 
Therapeutic background and study rationale 
20 
5.2 
Patient population rationale 
21 
5.3 
Dosage rationale 
21 
5.4 
Primary endpoint rationale 
21 
5.5 
Safety considerations 
22 
5.5.1 
SYD985 treatment 
22 
5.5.2 
Physician’s choice treatment 
24 
5.6 
Benefit – Risk assessment 
25 
6 
Objective(s) 
25 
6.1 
Efficacy objectives 
25 
6.1.1 
Primary objective 
25 
6.1.2 
Secondary objectives 
25 
6.1.3 
Other objectives 
25 
7 
Study design 
26 
8 
Study Population 
26 
8.1 
Eligibility Criteria 
26 
8.1.1 
Inclusion Criteria 
26 
8.1.2 
Exclusion Criteria 
27 
8.2 
Screen failures and re-screening 
28 
9 
Treatments 
29 
9.1 
Treatment assignment, randomisation and stratification 
29 
9.2 
Description of Study Drug 
29 
9.3 
Labeling, packaging and storage 
30 
9.3.1 
SYD985 treatment 
30 
9.3.2 
Physician’s choice treatment 
30 
9.4 
Treatment regimen and individual administration procedure 
30 
9.4.1 
SYD985 treatment 
30 
9.4.2 
Physician’s choice treatment 
32 
9.5 
Dose modifications 
32 
9.5.1 
SYD985 treatment 
32 
9.5.2 
Physician’s choice treatment 
34 
9.6 
Treatment Compliance and accountability 
35 
9.6.1 
SYD985 treatment 
35 
9.6.2 
Physician’s choice treatment 
35 
9.7 
Subject Emergency Card 
35 


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10 
Pretreatment and concomitant medication and non-drug therapies 
36 
11 
Study procedures and assessments 
37 
11.1 
Obtain Informed Consent 
37 
11.2 
Demographic and Medical history 
38 
11.3 
Inclusion/Exclusion criteria 
38 
11.4 
Physical examination 
38 
11.5 
Vital signs, body weight and height 
38 
11.6 
Eastern cooperative oncology group (ECOG) performance status 
39 
11.7 
Tumour material and central HER2 status assessment 
39 
11.8 
Haematology, blood chemistry, cardiac troponin, and urinalysis 
39 
11.9 
Pregnancy test 
40 
11.10 
Pharmacokinetics (PK) 
41 
11.11 
Immunogenicity 
41 
11.12 
Serum HER2 ECD levels 
41 
11.13 
Circulating tumour DNA 
42 
11.14 
Ophthalmological examination 
42 
11.15 
LVEF assessment 
42 
11.16 
ECG assessment 
42 
11.17 
Tumour evaluation 
43 
11.18 
Quality of life questionnaire 
45 
11.19 
Previous and concomitant medication 
45 
11.20 
(Serious) adverse events 
45 
11.21 
Treatment discontinuation 
45 
11.22 
Survival follow-up 
46 
12 
Safety Monitoring 
46 
12.1 
Definitions 
46 
12.2 
Adverse event monitoring 
47 
12.3 
Adverse Events Documentation 
47 
12.3.1 
Adverse Events Severity 
48 
12.3.2 
Adverse Events Causality 
49 
12.4 
Serious Adverse Events Documentation 
49 
12.5 
Reporting of Serious Adverse Events 
50 
12.6 
Adverse Events of Special Interest 
51 
12.7 
Reporting of Death 
51 
12.8 
Reporting of serious breaches 
52 
12.9 
Reporting of Pregnancies 
52 
12.10 
Data Monitoring Committee 
52 
13 
Criteria patient discontinuation, replacement and study termination 
52 
13.1 
Patient discontinuation 
52 
13.2 
Patient Completion 
53 
13.3 
Patient replacement 
54 
13.4 
Study termination 
54 
14 
Study evaluation, statistical considerations and data analysis 
54 
14.1 
General considerations for data analysis 
54 
14.2 
Analysis Populations 
55 
14.2.1 
Safety Set 
55 


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14.2.2 
Full analysis Set 
55 
14.2.3 
Per-Protocol Set 
55 
14.3 
Study endpoints 
55 
14.3.1 
Primary endpoint 
55 
14.3.2 
Secondary endpoints 
56 
14.3.3 
Other endpoints 
56 
14.4 
Demographic and baseline characteristics 
56 
14.5 
Efficacy analysis 
56 
14.5.1 
Primary objective 
56 
14.5.2 
Secondary objective 
58 
14.5.3 
Other objectives 
59 
14.6 
Safety data analysis 
60 
14.6.1 
Extent of exposure 
60 
14.6.2 
Treatments 
60 
14.6.3 
Adverse Events 
61 
14.6.4 
Clinical Laboratory Evaluations 
61 
14.6.5 
ECG analyses 
61 
14.6.6 
LVEF 
61 
14.6.7 
Ophthalmological exams 
62 
14.6.8 
Other Safety Measures 
62 
14.7 
Sample size 
62 
15 
Study administration 
62 
15.1 
Regulatory and ethics committee considerations 
62 
15.1.1 
Approval by Competent Regulatory Authority 
63 
15.1.2 
Review and Approval by Competent IRB or IEC 
63 
15.1.3 
Informed Consent 
63 
15.1.4 
Investigator Reporting Requirements 
64 
15.1.5 
Amendments to Study Protocol 
64 
15.1.6 
Investigator Compensation 
64 
15.1.7 
Coordinating Investigator for Clinical Study Report 
64 
15.2 
Monitoring and Quality Assurance 
65 
15.2.1 
Monitoring 
65 
15.2.2 
Direct Access to Source Data/Documents 
65 
15.2.3 
Quality Assurance 
65 
15.3 
Data Handling and Records Retention 
66 
15.3.1 
Collection of Data, Data Management 
66 
15.3.2 
Records Retention 
66 
15.3.3 
Information of investigators about study results 
67 
15.4 
Publication Policy and Inventions 
67 
15.4.1 
Publication 
67 
15.4.2 
Confidentiality 
67 
15.4.3 
Ownership and Copyright 
67 
16 
References 
69 
17 
Appendices 
71 
 
 


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Appendix 1 Sample Subject Emergency Card 
72 
Appendix 2 Tumour evaluation criteria (based on RECIST 1.1) 
73 
Appendix 3 Protocol Amendment I 
77 
Appendix 4 Protocol Amendment II 
83 
Appendix 5 Protocol Amendment III 
95 
Appendix 6 Protocol Amendment IV 
105 
Appendix 7 Protocol Amendment V 
112 
Appendix 8 Protocol Amendment VI 
121 
Appendix 9 Protocol Amendment VII 
125 
 
 
 


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4 
List of abbreviations 
ABGs 
Arterial Blood Gases 
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 
BMI 
Body Mass Index 
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 
cTnI 
Cardiac troponin I 
cTnT 
Cardiac troponin T 
DAR 
Drug-to-antibody ratio 
DMC 
Data Monitoring Committee 
ECD 
Extracellular domain 
ECG 
Electro Cardio Gram 
eCRF 
electronic Case Report Form  
ECOG 
Eastern Cooperative Oncology Group 
ESMO-MCBS 
European Society of Medical Oncology Magnitude of Clinical Benefit 
Scale 
EORTC 
European Organisation for Research and Treatment of Cancer 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transpeptidase 
HDL 
High Density Lipoprotein 
HER2 
Human Epidermal growth factor Receptor 2 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICF 
Informed Consent Form  
ICMJE 
International Committee of Medical Journal Editors 
ICR 
Independent central review 


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IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry  
ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal product Dossier 
IRB 
Institutional review Board 
ISF 
Investigator Site File 
ISH 
In situ hybridization  
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IXRS 
Interactive voice/web Response System 
LDL 
Low Density Lipoprotein 
LVEF 
Left Ventricular Ejection Fraction 
MAA 
Marketing Authorisation Application 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean cell volume 
MHRA 
Medicines and Health Care products Regulatory Agency 
MUGA 
Multigated acquisition 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Pharmacodynamics 
PFS 
Progression-Free Survival 
PFTs 
Pulmonary Function Tests 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PPS 
Per-Protocol Set 
PR 
Partial response 
Q3W 
Dosing every three weeks 
QoL 
Quality of life 
RBC 
Red Blood cell Count 
RECIST 
Response Evaluation Criteria for Solid Tumours 
SAE 
Serious Adverse Event 
SAF 
Safety (population) 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
SD 
Stable Disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SmPC/PI 
Summary of Product Characteristics/Prescribing Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SYD977 
Byondis’s monoclonal IgG1 antibody trastuzumab (which is similar to 
Herceptin®) 
SYD978 
a cleavable linker and the prodrug seco-duocarmycin-hydroxybenzamide-
azaindole (seco-DUBA) 


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SYD985 
trastuzumab vc-seco-DUBA 
SYD986 
DUocarmycin hydroxyBenzamide Azaindole (DUBA, active toxin) 
TEAE 
Treatment Emergent Adverse Event 
TMF 
Trial Master File 
ILN 
Upper limit of normal 
vc 
Valine-citrulline 
WBC 
White Blood cell Count 
 
 
 
 
 
 


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5 
Introduction 
5.1 
Therapeutic background and study rationale 
Advanced and metastatic breast cancer remains incurable, and an estimated 450,000 patients globally 
die from breast cancer per annum.1 Of these, approximately 15-20% are patients with Human 
Epidermal growth factor Receptor 2 (HER2) positive disease. Amplification and over-expression of 
HER2 are associated with shortened survival.2;3 The development of trastuzumab as a HER2-
targeting agent represented a paradigm shift in breast cancer from non-specific chemotherapy to a 
molecular targeted approach. However, despite the efficacy of trastuzumab, most patients develop 
progressive disease during or after trastuzumab treatment, and additional intervention is required. In 
view of the evidence that HER2 over-expression persists and remains relevant beyond progression2-4 
strategies to overcome insensitivity to treatment have involved changing the HER2-directed agent or 
switching chemotherapies in subsequent lines of treatment.5;6  
 
Four HER2-targeting therapies have been approved up to now in the EU and 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). With the 
exception of (ado-)trastuzumab emtansine these HER2-targeting treatments are used in combination 
therapy regimens in the locally advanced or metastatic setting. Sooner or later the disease progresses 
again and the patient will become refractory to that specific HER2-targeting therapy combination. 
For patients whose tumour progress on an anti-HER2 therapy (whether or not combined with 
cytotoxic or endocrine agent) it is important that additional anti-HER2 therapy is offered with 
subsequent treatment since it is beneficial to continuously keep on targeting the HER2 pathway.6  
Currently recommended first-line treatment for HER2-positive advanced or metastatic breast cancer 
is trastuzumab, pertuzumab and a taxane. If the cancer progresses during or after first-line therapy 
(ado-)trastuzumab emtansine is recommended for 2nd-line treatment. Once a patient becomes 
refractory to these agents, either as a single agent or as combination therapy, different treatment 
options are being used. Often standard chemotherapy or hormonal therapy will be combined with an 
anti-HER2 agent. There is insufficient evidence to recommend a specific regimen and in general it is 
the choice of the physician what is prescribed. 
 
Byondis developed a new HER2-targeting therapy, SYD985, which is comprised of Byondis’s 
monoclonal IgG1 antibody trastuzumab (SYD977, similar to Herceptin®) covalently bound to a 
linker-drug (SYD980). The linker-drug contains a cleavable linker and the prodrug seco-
DUocarmycin-hydroxyBenzamide-Azaindole (seco-DUBA, SYD978).  
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-citruline (vc) motif by proteases. 
Upon cleavage, two self-elimination reactions occur to generate the prodrug (seco-DUBA, SYD978), 
which then spontaneously rearranges to form the active toxin (DUBA, SYD986). The active toxin 
alkylates DNA resulting in DNA damage in both dividing and non-dividing cells, and ultimately cell 
death. SYD985 most likely also induces a bystander effect through extra-cellular cleavage of the 
linker-drug within the tumour by extracellular proteases. This bystander effect may not only kill the 
HER2-positive cell but potentially also (HER2-negative) neighbouring cells. 
The intent of this Phase III study is to investigate the efficacy and safety of SYD985 for the treatment 
of patients with unresectable locally advanced or metastatic HER2-positive breast cancer who have 
had progression either during or after at least two HER2-targeting treatment regimens in the locally 
advanced or metastatic setting or after (ado-)trastuzumab emtansine treatment. 


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5.2 
Patient population rationale 
Results of the first-in-human Phase I study (SYD985.001) suggest that SYD985 is efficacious and 
has an acceptable safety profile in heavily pre-treated patients with HER2-positive locally advanced 
or metastatic breast cancer.  
 
Part I of this Phase I study was a dose escalation study with patients with solid tumors of any origin. 
In this part 39 patients were enrolled and treated. For breast cancer patients only (n=25), the objective 
response rate (ORR) was 36.0% (95% CI 18.0; 57.5), with partial responses in 5 HER2-positive and 
4 HER2-negative breast cancer patients. The Kaplan Meier estimate of the median (95% CI) duration 
of progression free survival (PFS) was 24.3 weeks (12.0, 36.4) for the breast cancer patients. All but 
one HER2-positive breast cancer patients were pretreated with trastuzumab and (ado-)trastuzumab 
emtansine (see Investigator’s Brochure for details). Therefore, SYD985 represents a reasonable 
treatment option for the intended patient population in this study. 
 
Part II of the Phase I study is ongoing; expanded patient cohorts with specific cancer types, including 
50 heavily pre-treated patients with late-line HER2-positive locally advanced or metastatic breast 
cancer, are being evaluated for safety and efficacy. 
 
5.3 
Dosage rationale 
SYD985 will be administered in a dose of 1.2 mg/kg once every three weeks. After evaluation of all 
available data of the dose-escalation part of the Phase I study, it was concluded that doses above 1.2 
mg/kg did not seem to improve the benefit-risk as compared to the 1.2 mg/kg dose. Therefore, it was 
decided to select 1.2 mg/kg as the recommended Phase II dose (see Investigator’s Brochure for 
details). 
 
The 3-weekly interval was investigated in the dose-escalation part of the Phase I study and in addition, 
this interval is most convenient if SYD985 may be combined, in future studies, with other therapies 
which have predominantly 3-weekly intervals as well. Dosing delays and reductions are allowed to 
reduce toxicity in an individual patient (Section 9.5).  
 
5.4 
Primary endpoint rationale 
The primary endpoint of this study is to demonstrate that SYD985 is superior to physician’s choice 
in prolonging PFS on the basis of the blinded independent central review of tumour assessment.  
 
In a recent study with HER2-positive locally advanced or metastatic breast cancer patients, the 
TH3RESA study, the median (95% CI) PFS in the physician’s choice group was 3.3 (2.89 - 4.14) 
months. Since this study was conducted new treatments have been approved and are being prescribed 
to these patients in first and second line treatment. Therefore, it can be expected that patients included 
in the current study will have a prognosis that is at best comparable, but likely worse, than the 
prognosis for patients in the physician’s choice group in the TH3RESA study. The aim of this study 
is to show an improvement of at least 35% in PFS by SYD985, as compared to physician’s choice, in 
addition this is expected to be associated with a gain of at least 1.5 months in PFS. The European 
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this represents a direct clinical benefit to the patient if using standard treatment the median PFS is ≤ 
6 months.  
 
5.5 
Safety considerations 
5.5.1 
SYD985 treatment 
This section is primarily based on the data from the ongoing Phase I study. Additionally, non-clinical 
studies and data from trastuzumab and (ado-)trastuzumab emtansine have been taken into account. 
Please refer to the SYD985 Investigator’s Brochure for further information. It should be taken into 
account that clinical safety data and treatment duration with SYD985 is limited and that toxicity other 
than described in the Investigator’s Brochure may evolve. For the most up to date information one 
should always refer to the current version of the Investigator’s Brochure.  
 
The most common drug-related AEs reported in the ongoing Phase I study are: 
• Conjunctivitis, lacrimation increased, dry eye, keratitis, and blepharitis; 
• Fatigue and pyrexia; 
• Nausea, stomatitis, vomiting, constipation; 
• Dry skin, alopecia, skin hyperpigmentation; 
• Neutropenia, anemia, thrombocytopenia; 
• Dysgeusia, headache; 
• Decreased appetite; 
• Infusion related reactions.     
Adverse event with important safety consideration are described in more detail below. 
 
Interstitial Lung Disease ILD/Pneumonitis 
ILD/Pneumonitis was reported in the Phase I study. ILD/Pneumonitis and lung consolidations are 
also reported for other anticancer drugs, including anti-PD1 antibodies8;9, everolimus (mTOR 
inhibitor), and the anti-HER2 agents lapatinib and (ado-)trastuzumab emtansine10. 
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. Biomarkers 
for IDL/pneumonitis are exploratory and they should not be used for diagnosis or monitoring of drug-
induced ILD/pneumonitis. ILD/pneumonitis evaluation (regardless of stage) should always include a 
pulmonary consult, a high resolution CT, pulmonary function testing (PFTs), pulse oximetry and 
arterial blood gases (ABGs). 
To detect pulmonary toxicity in an early stage, the tumour evaluation CT scans, which are initially 
done every 6 weeks, should be carefully evaluated for lung changes e.g. by means of high resolution 
CT. Patients should be advised to promptly report any new or worsening respiratory symptoms.  
 
Eye toxicity 
Eye toxicity was commonly reported in the Phase I study, in more than 50% of the patients. Drug-
related eye disorders included e.g. lacrimation increased (watery eyes), dry eyes, conjunctivitis, 
keratitis, periorbital oedema, and blepharitis. The most common severe eye toxicity (grade 3) was 
keratitis. 


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Ophthalmological examination is required every other cycle to closely monitor eye toxicity. It is 
recommended to treat any eye disorder in an early stage, if possible. Prophylactic lubricating eye 
drops will be prescribed for all patients in the SYD985 group, to be used 3 times a day or as needed. 
Patients are advised not to wear contact lenses or rub their eyes during SYD985 treatment. Further 
evaluation of prophylactic measures is ongoing in the Phase I study and will be implemented per 
protocol amendment if shown to be effective. 
 
Cardiac toxicity 
Cardiac safety should be monitored in oncology patients commonly pre-treated with anthracycline 
therapy and/or treated with HER2-targeting agents. Transient, LVEF decreases have been observed 
in the Phase I study. LVEF decreases have also been observed in patients treated with trastuzumab 
and (ado-)trastuzumab emtansine and these often occur in the early treatment cycles11-13. Patients 
treated with these drugs are at increased risk of developing congestive heart failure or dysfunction, 
particularly following anthracycline therapy. 
Cardiotoxicity is closely monitored in the study by performing LVEF and ECGs, and by measuring 
cardiac troponin regularly during SYD985 treatment. Patients with an increased risk of developing 
cardiac dysfunction, as defined in this protocol, are not eligible to participate in the study. Any 
clinically relevant electrolyte disturbance (e.g. hypomagnesaemia and hypokalemia) should be 
corrected as appropriate.    
 
Infusion related reactions 
Infusion related reactions have occurred in the Phase I study.  Infusion related reactions are known to 
occur with the administration of monoclonal antibodies. These reactions consist of a symptom 
complex commonly characterized by fever and chills, but may also include other symptoms like 
nausea, vomiting, headache, and hypotension. Severe reactions may include among others 
bronchospasm, anaphylaxis, angioedema, and hypoxia. Infusion related reactions mostly occur during 
or immediately following the (initial) infusion. 
 
Injection site reactions 
A serious injection site reaction occurred in the Phase I study. For anthracycline treatments, which 
are also DNA-alkylating agents like SYD985, it is known that extravasation during the infusion may 
cause severe tissue lesions and necrosis. Although extravasation was not reported for the SYD985 
case, it is recommended to avoid the use of veins over joints or in extremities with compromised 
venous or lymphatic drainage, like for anthracycline administration.  
 
Immunogenicity 
All biotherapeutics, including ADCs, have the potential to elicit a host immune response that can 
impact pharmacokinetics, efficacy and safety profiles. After administration of (ado-)trastuzumab 
emtansine, approximately 5% of the patients tested positive for anti-drug-antibodies (ADAs) but the 
clinical relevance of these antibodies is unknown. So far, none of the blood samples of the patients 
in the Phase I study was found positive for SYD985 ADAs at any time point and no clinical symptoms 
or pharmacokinetic profiles suggestive of the development of SYD985 ADAs have been observed.  
In the study, blood samples will be drawn before every infusion to measure SYD985 ADAs. 
 
 


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Haematological toxicity 
Transient, mostly mild or moderate, neutropenia, thrombocytopenia, and anemia have been noted in 
some patients in the Phase I study. Routine haematology (and biochemistry) assessments are 
frequently performed in the study and should be used to monitor haematological toxicities. 
 
Skin toxicity 
In the Phase I study, drug-related dry skin and skin hyperpigmentation have been reported. Patients 
are advised to limit sun exposure by using protective clothing and/or sun screen. In vitro studies 
showed that UV radiation did not markedly enhance the cytotoxic potential of the toxin SYD986.  
 
Embryo-fetal toxicity 
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 the clinical study. Participating patients must use 
two methods of effective contraception. This is not required in case the patient or sole partner is 
surgically sterilized or in case the patient truly abstains from sexual activity. In case a patient becomes 
pregnant during SYD985 treatment, she must be discontinued from the study. 
 
5.5.2 
Physician’s choice treatment 
For safety considerations on the physician’s choice treatments the information as described in the 
local Summary of Product Characteristics/Prescribing Information (SmPC/PI) of the specific 
treatments should be consulted. SYD985.002 is a global study and details may differ per country, 
therefore the investigator should consult the SmPC/PI as approved by their local country medicines 
agency (e.g. FDA, EMA, MHRA etc.). The local SmPC/PI will be provided and is to be filed in the 
ISF. 
 
When evaluating a patient for participation into the study the investigator should first consider which 
combination treatment would be prescribed if the patient would be randomized to the physician’s 
choice group. During this evaluation, all routine clinical considerations, including treatment specific 
restrictions/contraindications as per SmPC/PI for the physician’s choice treatment options, should be 
taken into account. If, for example, based on information in the medical history or the laboratory 
values of the patient one of the treatment options in the physician’s choice group is contraindicated, 
that particular patient would have only three options of physician’s choice treatment. Only after it is 
concluded that at least one of the four treatment options in the physician’s choice group would be an 
appropriate way to treat the patient, the patient can be considered for the study as per 
inclusion/exclusion criteria. 
 
During physician’s choice treatment guidance from the SmPC/PI of the specific treatments should be 
followed. In particular with regards to:  
• Contraindications, Warnings and precautions, Adverse events;  
• Posology and method of administration, Dosage and administration; 
• Interactions; 
• Fertility, Special populations. 


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This protocol cannot address every safety consideration for all of the ‘physician’s choice’ options. 
The investigator is referred to respective local summaries of product characteristics or prescribing 
information for specific guidance. In particular it is noted that there is variation among the options 
with regard to:  
• duration of contraception after the last of study therapy administration; 
• duration to avoid live vaccines before, during, and after study therapy administration; 
• drug-drug interactions, in particular with regard to cytochrome P450 system. 
 
5.6 
Benefit – Risk assessment 
Based on the Phase I experience it can be concluded that there is a positive benefit/risk for patients 
with late-line HER2-positive locally advanced or metastatic breast cancer who have had progression 
either during or after at least two HER2-targeting treatment regimens in the locally advanced or 
metastatic setting or after (ado-)trastuzumab emtansine treatment in the locally advanced or 
metastatic setting. Therefore, SYD985 represents a reasonable treatment option for the intended 
patient population in this study. 
 
 
6 
Objective(s) 
6.1 
Efficacy objectives 
6.1.1 
Primary objective 
The primary objective of this study is to demonstrate that SYD985 is superior to physician’s choice 
in prolonging PFS on the basis of the blinded independent central review of tumour assessments.  
 
6.1.2 
Secondary objectives 
The secondary objectives of this study are to compare the two treatment groups with respect to: 
• Overall survival (OS); 
• Objective response rate (ORR) on the basis of the blinded independent central review; 
• Investigator assessed PFS; 
• Patient reported outcomes for health related quality of life; 
• Safety and tolerability. 
 
6.1.3 
Other objectives 
The other objectives of this study are as follows: 
• To describe time to response in each treatment group; 
• To describe duration of response in each treatment group; 
• To describe the clinical benefit rate (CBR) in each treatment group;  
• To evaluate the pharmacokinetics of SYD985; 
• To evaluate the formation of SYD985 anti-drug antibodies (ADAs); 
• To explore exposure/response and exposure/safety relationships. 
 
 


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7 
Study design 
This study is designed as a randomized, active-controlled, superiority study in patients with 
unresectable locally advanced or metastatic HER2-positive breast cancer. The patients should have 
had either progression during or after at least two HER2-targeting treatment regimens for locally 
advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine treatment. 
 
Eligible patients will be randomly assigned in a 2:1 ratio to receive SYD985 1.2 mg/kg infusions 
every three weeks or a combination treatment of physician’s choice in a 21-day regimen. Patients will 
remain on study treatment until investigator-assessed disease progression, unacceptable toxicity or 
study termination by the Sponsor. After discontinuation of study treatment patients will be followed 
for survival until death, lost to follow-up, withdrawal of consent, or study termination by the Sponsor. 
 
The study will end when: 
• All patients have completed the treatment discontinuation visit, or 
• Sufficient survival follow-up information is obtained to enable analysis, or 
• The trial is terminated by the Sponsor. 
 
When the study is ended before all patients have discontinued study treatment, individual patients 
who benefit from SYD985 treatment will be enabled to receive further SYD985 treatment.  
 
8 
Study Population 
The study population will consist of patients with HER2-positive unresectable locally advanced or 
metastatic breast cancer. 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. Waivers to include patients that 
do not fully comply with the inclusion and exclusion criteria will not be granted. 
 
Patients will be recruited from the investigator’s general practice or via referral networks.  
 
8.1 
Eligibility Criteria 
When evaluating a patient for participation into the study the investigator should first consider which 
combination treatment would be prescribed if the patient would be randomized to the physician’s 
choice group. During this evaluation all routine clinical considerations, including treatment specific 
restrictions/contraindications as per SmPC/PI for the physician’s choice treatment options, should be 
taken into account. Only after it is concluded that at least one of the four treatment options in the 
physician’s choice group would be an appropriate way to treat the patient, the patient can be 
considered for the study as per inclusion/exclusion criteria. 
 
8.1.1 
Inclusion Criteria  
Any patient must meet the following inclusion criteria: 
1. Female patients, age ≥ 18 years old at the time of signing informed consent; 
2. Patients with histologically-confirmed, unresectable locally advanced or metastatic breast 
cancer; 


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3. Patients should have had either progression during or after at least two HER2-targeting 
treatment regimens for locally advanced or metastatic disease or progression during or after 
(ado-)trastuzumab emtansine treatment for locally advanced or metastatic disease; 
4. HER2-positive tumour status according to the ASCO-CAP guidelines (defined as a 3+ score 
on immunohistochemistry (IHC) and/or positive by in situ hybridization (ISH)) confirmed by 
the central laboratory;  
5. Patients must have measurable or non-measurable disease that is evaluable per Response 
Evaluation Criteria for Solid Tumours (RECIST version 1.1). Patients with bone-only 
sclerotic disease without a lytic component, or patients who have bone-only metastases 
requiring endocrine therapy or patients with non-visceral metastases requiring endocrine 
therapy, are not eligible; 
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 
7. Estimated life expectancy > 12 weeks at randomization; 
8. 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;  
– 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;  
9. For women of childbearing potential two methods of effective contraception must be used 
during the study and up to 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. SYD985 at any time;  
b. Anthracycline treatment within 12 weeks prior to randomization;      
c. Other anticancer therapy including chemotherapy, immunotherapy, or investigational agents 
within 4 weeks prior to randomization; 
d. Radiotherapy within 2 weeks prior to randomization; 
e. Hormone therapy within 1 week prior to randomization;      
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, (ado-)trastuzumab 
emtansine or excipients of the study drug which led to permanent discontinuation of the treatment;  
3. History of keratitis; 
 


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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 or (ado-)trastuzumab emtansine leading to 
permanent discontinuation of treatment; 
6. Cardiac troponin value above the ULN (local laboratory) at screening;  
7. History (within 6 months prior to randomization) of clinically significant cardiovascular disease 
such as unstable angina, congestive heart failure (CHF), myocardial infarction, uncontrolled 
hypertension, or cardiac arrhythmia requiring medication;  
8. Untreated brain metastases, symptomatic brain metastases, brain metastases requiring steroids to 
manage symptoms, treatment for brain metastases within 8 weeks prior to randomization. Patients 
with prior treatment of brain metastasis must have evidence of disease stability on 
baseline brain imaging as compared to historical brain imaging; 
9. 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; 
10. Known active Hepatitis B or C infection; 
11. Major surgery within 4 weeks prior to randomization; 
12. Pregnancy or lactation; 
13. 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 “HER2 testing” and/or “Study”-ICF but subsequently failed to meet the 
inclusion and/or exclusion criteria are defined as 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. If a patient has clinically significant deviations in laboratory 
values as mentioned in inclusion criterion 8 and/or exclusion criterion 6 and/or clinically significant 
deviations in LVEF as detailed in exclusion criterion 5, it is not allowed to repeat the laboratory 
assessment and the patient cannot be randomized. 
 
The only two exceptions are: 
- 
If the result was HER2-negative based on archived material the site could consider sending 
fresh material to reassess the HER2 status.   
- 
Patients for whom during screening on the brain CT/MRI a previously unknown 
asymptomatic metastasis is observed. These patients can be candidates for re-screening when 
the following conditions apply: (1) The treatment for brain metastases should be finalized 
more than 8 weeks prior to start re-screening; (2) There should be evidence of disease stability; 
(3) Enrolment for the SYD985.002 study should still be open. Please contact the medical 
monitor for approval. Note that for these patients all screening procedures should be repeated, 
excluding the central HER2-testing and the whole body bone scan if the previous scan showed 
no bone metastasis and there is no clinical suspicion of newly developed metastatic bone 
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9 
Treatments 
9.1 
Treatment assignment, randomisation and stratification 
After signing the “HER2 testing” or “Study”-ICF, the investigator (or authorized delegate) will enter 
the electronic Case Report Form (eCRF) to obtain a patient number. The eCRF will be provided by 
an external vendor and detailed instructions will be made available through training sessions and/or 
in a separate manual, which is to be filed in the TMF and ISF. 
 
When all screening data are available, including confirmation by the central laboratory on the HER2 
status assessment, the patient can be randomized if the patient complies with all inclusion criteria and 
none of the exclusion criteria. 
 
A patient should be randomized within 28 days of signing the “Study”-ICF. To be able to randomize 
a patient, the investigator (or authorized delegate) should complete the required screening information 
in the eCRF. The randomization will be performed in the eCRF (Rave Balance module), detailed 
instructions will be made available through training sessions and/or in a separate manual, which is to 
be filed in the TMF and ISF. Randomization should be done on the day of first treatment or the day 
before if this turns out to improve logistics. 
 
Using a computer-generated randomization list, eligible patients will be randomly assigned in a 2:1 
ratio to receive SYD985 or Physician’s choice therapy. The allocation will be stratified for 
geographical region (Europe and Singapore, North America), the number of prior treatment lines for 
advanced breast cancer (excluding hormone therapy) (1 or 2, more than 2), and prior treatment with 
pertuzumab (yes, no). 
 
9.2 
Description of Study Drug 
Investigational medicinal product 
Test Product:  
SYD985: trastuzumab vc-seco-DUBA 
Formulation: 
Drug product vials contain 80 mg lyophilized SYD985 drug product 
which should be reconstituted prior to use with 8.0 of sterile water for 
injection to yield a solution of 10 mg/mL. 
Manufacturer: 
Byondis BV, The Netherlands 
 
 
 
 
 
 
 
 


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Reference therapy 
Reference Product:  
Physician’s choice therapy: 
• Option 1: Lapatinib + Capecitabine 
• Option 2: Trastuzumab + Capecitabine 
• Option 3: Trastuzumab + Vinorelbine  
• Option 4: Trastuzumab + Eribulin 
The choice of reference therapy will be at the investigator’s discretion 
and should be in accordance with local clinical practice. 
 
9.3 
Labeling, packaging and storage 
9.3.1 
SYD985 treatment 
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, 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. 
 
9.3.2 
Physician’s choice treatment 
Commercial available reference therapy medication will be obtained directly by the site/affiliated 
pharmacy or provided by a local distributor for use during this study.  
 
Once these drugs are allocated to the patient for use in this study it will be considered study drug. If 
required by local regulations labelling of the physician’s choice treatment will be performed 
according to the Pharmacy Manual. 
 
For details regarding packaging, handling, and storage the Summary of Product Characteristics and 
local Prescribing Information of these drugs should be followed. 
 
9.4 
Treatment regimen and individual administration procedure 
9.4.1 
SYD985 treatment 
SYD985 1.2 mg/kg will be administered every three weeks (± 3 day) by intravenous infusion.  
 
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 


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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 
be used immediately or can be temporarily stored (see below). 
 
The volume of the SYD985 solution needed for a particular patient should be calculated based on the 
weight of the patient. Weight measured on Cycle 1 Day 1 (or max 7 days earlier) should be used for 
the preparation of the infusion bag throughout the study. However, 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 an 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. 
 
For the infusions an infusion set with a filter as specified in the pharmacy manual should be used. 
 
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 indicated in 
the pharmacy manual, at the discretion of the investigator.  
 
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 interruption of infusion will be 
discontinued from study treatment. 
 
 
 


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9.4.2 
Physician’s choice treatment 
Physician’s choice therapy options: 
• Option 1: Lapatinib + Capecitabine 
• Option 2: Trastuzumab + Capecitabine 
• Option 3: Trastuzumab + Vinorelbine 
• Option 4: Trastuzumab + Eribulin 
 
The choice of reference therapy will be at the investigator’s discretion and should be in accordance 
with local clinical practice. During this evaluation all routine clinical considerations, including 
treatment specific restrictions/contraindications as per SmPC/PI for the physician’s choice treatment 
options, should be taken into account. During physician’s choice treatment guidance from the 
SmPC/PI of the specific treatments should be followed. In particular with regards to:  
• Contraindications, Warnings and precautions, Adverse events;  
• Posology and method of administration, Dosage and administration; 
• Interactions; 
• Fertility, Special populations. 
   
9.5 
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.  
 
9.5.1 
SYD985 treatment 
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 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. 


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• If toxicity does not resolve sufficiently within 42 days from the last dose received, the patient 
will be discontinued from study treatment and will be followed for survival follow-up as 
described in Section 11.22. 
 
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. 
 
As indicated in Section 9.4.1 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 interruption of 
infusion will be discontinued from study treatment. 
 
Protocol requirements for specific toxicities are outlined below. 
 
9.5.1.1 
SYD985 - 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 dose modification based on LVEF measurements 
 
SYD985 administration may be delayed to maximally 42 days after the last dose. Cardiac troponin 
values I or T (cTnI or cTnT) should also be taken into account for the final decision if a patient can 
continue or not. 
 
9.5.1.2 
SYD985 Dose modifications for eye toxicity 
Patients who experience Grade 3 (or higher) keratitis will be discontinued from treatment. For patients 
who experience Grade 3 conjunctivitis, dosing must be delayed for up to 42 days from the last 
received dose. When the conjunctivitis 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. 


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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. 
 
9.5.1.3 
SYD985 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.  
  
9.5.1.4 
SYD985 - Dose modifications for ILD/pneumonitis 
Patients who experience Grade 2, 3 or 4 ILD/pneumonitis 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. Biomarkers 
for IDL/pneumonitis are exploratory and they should not be used for diagnosis or monitoring of drug-
induced ILD/pneumonitis. ILD/pneumonitis evaluation (regardless of stage) should always include a 
pulmonary consult, a high resolution CT, PFTs, pulse oximetry and ABGs. 
To detect ILD/pneumonitis or other pulmonary toxicity in an early stage, the tumour evaluation CT 
scans should be carefully evaluated for lung changes e.g. by means of high resolution CT. Infectious 
and metastatic disease-related aetiologies should be ruled out. Patients should be advised to promptly 
report any new or worsening respiratory symptoms. 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. 
 
9.5.2 
Physician’s choice treatment  
During physician’s choice treatment guidance from the SmPC/PI of the specific treatments should be 
followed. In particular with regards to:  
• Contraindications, Warnings and precautions, Adverse events;  
• Posology and method of administration, Dosage and administration; 
• Interactions; 
• Fertility, Special populations. 
 
Dosing of physician’s choice treatments can be modified (reduced, delayed) according to local 
clinical practice. 
 
If one of the two agents of the combination regimen is discontinued the therapy can be continued with 
a single agent. However, if both agents of the regimen are discontinued for more than 42 days from 
the last dose the patient will be considered to have discontinued treatment. 


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9.6 
Treatment Compliance and accountability 
All study drugs (SYD985 and physician’s choice treatment) 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 according to the instructions provided in the 
Pharmacy Manual. 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 
CRA. 
 
9.6.1 
SYD985 treatment 
SYD985 will be administered to the patient by trained staff of the study site. Details of preparation 
and administration will be documented in the eCRF. 
 
At the end of the study all unused SYD985 vials must be returned for destruction according to 
instructions specified in the Pharmacy Manual. 
 
9.6.2 
Physician’s choice treatment 
Depending on the physician’s choice treatment regimen the study drug will be administered to the 
patient and/or dispensed to the patient by trained staff of the study site.  
 
Details of preparation, administration and/or dispensing will be documented in the eCRF. 
 
In the site drug accountability forms the following details on the physician’s choice treatment will be 
documented: 
• Brand name and international non-proprietary name (INN); 
• Batch number; 
• Dose and administration route; 
• Each dose administered (for drugs administered on site); 
• Number of doses administered (for drugs self-administered by the patient). 
 
At the end of the study all unused physician’s choice treatment dispensed to patients should be 
returned for accountability and destroyed according local hospital procedures. 
 
9.7 
Subject Emergency Card 
At start of treatment patients will be handed out a Subject Emergency Card (See Appendix 1). 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 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 end of the study, i.e. 
upon completion or premature discontinuation, the patient is to return the Subject Emergency Card.  
 


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10 
Pretreatment and concomitant medication and non-drug therapies 
Information on all prior received anticancer therapies must be recorded in the eCRF. Washout criteria 
apply for prior anticancer therapy as described in exclusion criterion 1. Other pre-treatment 
medication and concomitant medication used between 14 days prior to signing “Study”-ICF till the 
treatment discontinuation visit should be recorded in the eCRF. 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.  
 
Patients are allowed to receive supportive care therapies concomitantly during the study. Patients who 
receive anthracycline treatment within 12 weeks prior to randomization are not allowed to participate 
in the study. No other chemotherapy, immunotherapy, or experimental medications are permitted 
from 4 weeks prior to randomization, radiation therapy from 2 weeks prior to randomization, and 1 
week for hormone therapy, during study treatment and (if possible) up to 30 days after the last study 
treatment dose. 
 
During physician’s choice treatment guidance from the SmPC/PI of the specific treatments should be 
followed with regards to co-medications that are contraindicated or are to be used with precaution. 
 
During study treatment and up to 30 days after the last treatment dose palliative radiotherapy is 
allowed only for the symptomatic treatment of painful bone lesions identified at baseline. Please 
contact the Medical Monitor for approval.  
 
Patients who have disease control outside the brain, defined as having received clinical benefit (i.e. 
partial response (PR) or complete response (CR) of any duration, or stable disease (SD) for ≥ 4 
months) but who have brain metastases that will benefit from treatment with radiation in the opinion 
of the investigator will be allowed to continue to receive study therapy until they either experience 
systemic progression of their disease and/or further progression in the brain (based on investigator 
assessment). Please contact the Medical Monitor for approval. Patients must not miss more than one 
21-day cycle for the treatment of their brain disease to continue on therapy. 
 
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 will be prescribed to patients in the SYD985 group, 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.  


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Patients of childbearing potential must use 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.18 
Acceptable forms of contraception include two of the following: 
• Established use of oral, injected, implanted or other form of hormonal method of 
contraception; 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
• Condom with spermicidal foam/gel/film/cream/suppository; 
• Diaphragm or cervical/vault caps with spermicidal foam/gel/film/cream/suppository. 
 
The above contraception is not a requirement in the case of any of the following: 
• Patient or sole partner of patient is surgically sterilized; 
• True sexual abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). 
 
Periodic abstinence (e.g. calendar, ovulation, symptom-thermal, post-ovulation methods), 
progesterone-only oral hormonal contraception where inhibition of ovulation is not the primary mode 
of action, and withdrawal are not acceptable forms of contraception. 
 
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). 
 
Visits are based on a 21-day (3-week) cycle (±3 days), with Cycle 1 beginning at Day 1. Assessments 
scheduled on the day of study drug administration should be performed prior to study drug 
administration unless otherwise noted.  
 
In order to minimize variability of evaluations, it is preferred that the same individuals perform the 
same types of evaluations for all patients at each study site.  
 
11.1 
Obtain Informed Consent 
At the screening visit, 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 ICF will be signed in duplicate and the patient and/or the authorised 
representative obtain one original of the signed ICF. The second original is filed with the study 
documents at the investigational site.  
 
For potential eligible patients with archived tumour material available a “HER2 testing”-ICF may be 
used to allow the central assessment of HER2 tumour status. In case the patient’s tumour HER2 status 
complies with inclusion criterion 4 the patient should sign the “Study”-ICF before full screening is 
started. The maximum time between signing the “HER2 testing”-ICF and “Study”-ICF is 28 days. In 


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case the patient’s tumour HER2 status does not comply with inclusion criterion 4 there are two 
options. The first option is that the patient will not enter full screening. The second option is that the 
patient agrees to have a new biopsy taken for central HER2 status assessment. If a biopsy has to be 
performed to obtain tumour material for the central assessment of HER2 tumour status a patient will 
have to sign the “Study”-ICF. A patient may sign the “Study”-ICF without first signing the “HER2 
testing”-ICF, in this situation assessment of HER2 tumour status will be part of the screening.  
 
The patient should be randomized within 28 days of signing the “Study”-ICF. 
 
11.2 
Demographic 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), details on the hormone receptor (ER and/or PgR) status of the 
primary tumour and/or metastasis (if available), and classification of renal function and Child Pugh 
status. 
 
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 at screening and treatment discontinuation, which will 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. 
 
At all other visits, a targeted physical examination will be performed when indicated by the review 
of symptoms and AEs. Any AE should be reported in the eCRF. 
 
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 should be measured at screening and at the time points as indicated in 
the flowchart (see Section 1.1). On Day1 of each cycle vital signs should be recorded before study 
drug administration.  
 
Weight should be measured at screening and at the time points as indicated in the flowchart (see 
Section 1.1).  
Height will be recorded only at the screening visit. 
 


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11.6 
Eastern cooperative oncology group (ECOG) performance status 
The ECOG performance status quantifies the functional status of the patient (see Table 1). It should 
be recorded at screening and at the time points as indicated in the flowchart (see Section 1.1). The 
ECOG performance status should be recorded before study drug administration on the Day1 visits. 
 
Table 1: ECOG performance status14 
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 
Tumour material and central HER2 status assessment 
Archival tumour material should be submitted to the central pathology laboratory during screening. 
If no archived tumour material is available a biopsy should be performed to obtain tumour material. 
If a biopsy needs to be performed this should be done before the screening scan for tumour evaluation 
according to RECIST is performed. 
 
Tumour tissue samples should be submitted in the form of paraffin blocks. From submitted tumour 
blocks, a maximum of 10 slides will be cut at the central laboratory. The remaining part of the tumour 
block will be returned to the institution.  
 
If due to local procedures it is not possible to submit a tumour block, 15 unstained freshly cut slides 
of 4 μm should be submitted. Preparation of tissue should be performed as detailed in the Central 
Laboratory Manual. The slides must be sent to the central laboratory within 2 days of being cut.  
 
The HER2 tumour status (IHC and ISH) will be assessed by the central laboratory. A patient’s HER2 
status will be considered positive if the central laboratory reports grade 3+ staining intensity (on a 
scale of 0 to 3+) by means of IHC analysis and/or gene amplification by dual-signal ISH according 
to the ASCO-CAP criteria15. 
 
11.8 
Haematology, blood chemistry, cardiac troponin, and urinalysis 
Blood and urine samples will be taken at screening and at the time points as indicated in the flowchart 
(see Section 1.1). The samples will be analyzed by the local laboratory and central laboratory for 
haematology, blood chemistry, and cardiac troponin. The urinalysis will be performed locally.  
 
The results of the local laboratory will be used for clinical decision making by the investigator in the 
daily practice. The results of the central laboratory will be used for the safety evaluation of lab 
parameters in the clinical study report (CSR). 
 
 


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The following parameters will be included: 
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, reticulocytes. 
Serum biochemistry: Albumin, alkaline phosphatase, ALT, AST, total bilirubin, blood urea nitrogen 
(BUN), calcium, chloride, creatinine, creatine kinase (CK), GGT, glucose, 
inorganic phosphorus, LDH, magnesium, potassium, sodium, total protein, 
uric acid. 
Cardiac biomarkers:  cTnI or cTnT.   
Urinalysis:  
Dipstick for bilirubin, glucose, haemoglobin, ketones, and protein (microscopy 
if more than one parameter is positive). 
 
Sampling should be done at screening and during treatment 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 8 or exclusion criterion 6 are not eligible to enter the study 
(see Section 8.1). For dose modifications or treatment discontinuations based on abnormal laboratory 
values, see Section 9.5. 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. Any changes regarding the 
normal ranges and units for laboratory values assessed during the study must be reported via an 
updated tabulation indicating the new effective date. Additionally, if at any time a patient has 
laboratory parameters obtained from a different (outside) laboratory, the Sponsor must be provided 
with a copy of the certification and a tabulation of the applicable normal ranges and units for this 
laboratory as well. The investigator is responsible for reviewing all laboratory reports for patients in 
the study and evaluating any abnormalities for clinical significance. 
 
At the end of the study, local laboratory results and central laboratory results will not be reconciled. 
 
11.9 
Pregnancy test 
To exclude pregnancy in women of childbearing potential, a serum pregnancy test at screening 
(between day -10 and day -1) and serum or urine pregnancy tests during treatment on Day 1 of each 
cycle (may be done up to 3 days before) and at the treatment discontinuation visit will be performed 
at the local laboratory.  
 
Women of childbearing potential participating in this clinical study should be instructed to use 
adequate contraceptive barriers to prevent them from getting pregnant while using study drug (see 
also Section 10).  
 
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. 
 


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11.10 
Pharmacokinetics (PK) 
Blood samples for PK will be taken in the SYD985 group only. Blood sampling should be done 
according to the instructions in the Central Laboratory Manual and following the PK sampling 
schedule (see Section 1.1). Samples will be analyzed by a central laboratory using validated assays.  
 
Multiple analytes will be measured to characterize the PK of SYD985: 
• Total SYD985, which includes SYD985 with a drug-to-antibody ratio (DAR) of ≥ 0; 
• Conjugated SYD985, which includes SYD985 with a DAR of ≥ 1; 
• Free toxin (DUBA, SYD986). 
 
One or two spare aliquots will be stored per time point for re-analysis purpose, a DAR average assay 
(if considered relevant and feasible), and/or other exploratory PK, biotransformation / metabolite 
identification or mode of action related assays which may turn out to be useful for further 
development of duocarmycin-based ADCs. 
 
In case PK, immunogenicity, efficacy and/or safety data indicate a possible development of SYD985 
ADAs, the Sponsor may discuss an intensified PK and/or immunogenicity sampling scheme with the 
sites on a case-by-case basis. 
 
11.11 
Immunogenicity 
Blood samples to asses SYD985 ADAs will be taken in the SYD985 group only. Blood sampling 
should be done according to the instructions in the central laboratory manual and following the 
immunogenicity sampling schedule (see Section 1.1). Blood samples should be taken prior to 
SYD985 infusion, to avoid high concentrations of SYD985 which can influence the immunogenicity 
assessments. Samples will be analyzed by a central laboratory using validated assays.  
 
Samples will first be screened for immune responses and in case of a positive response, further testing 
will be done in a confirmatory assay. If confirmed positive, the titer will be determined and the 
neutralizing ability of the SYD985 ADAs will be determined. The measurement of the neutralizing 
ability may be performed after the study has been completed. 
 
In addition to the above described tests exploratory measurements for epitope mapping may be 
performed in the samples which are confirmed positive. These measurements may be performed after 
the study has been completed and possibly only in a selection of patients based on clinical data.  
 
One or two spare aliquots will be stored per time point for re-analysis purposes, and/or other 
exploratory assays which may turn out to be useful for further development of duocarmycin-based 
ADCs. 
 
In case PK, immunogenicity, efficacy and/or safety data indicate a possible development of anti-
SYD985 antibodies, the Sponsor may discuss an intensified PK and/or immunogenicity sampling 
scheme with the sites on a case-by-case basis. 
 
11.12 
Serum HER2 ECD levels 
Blood sampling to assess serum HER2 ECD levels should be done according to the instructions in 
the central laboratory manuals and following the sampling schedule (see Section 1.1). Blood samples 


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should be taken prior to study drug administration. Samples for serum HER2 ECD levels will be 
stored at a central laboratory. If indicated by the clinical safety or efficacy data and/or new scientific 
data the samples will be analyzed by a central laboratory. These measurements may be performed 
after the study has been completed and possibly only in a selection of patients based on clinical data.  
 
11.13 
Circulating tumour DNA 
Blood sampling for exploratory measurements of circulating tumour DNA (ctDNA) should be done 
according to the instructions in the central laboratory manuals and following the sampling schedule 
(see Section 1.1). Blood samples should be taken prior to study drug administration. Samples for 
ctDNA will be stored at a central laboratory. If indicated by the clinical safety or efficacy data and/or 
new scientific data the samples will be analyzed by a central laboratory. To interpret data, it may be 
needed to also analyse the germline DNA. These measurements may be performed after the study has 
been completed and possibly only in a selection of patients based on clinical data.  
 
11.14 
Ophthalmological examination 
At screening and the time points indicated in the flow chart (Section 1.1) an ophthalmologist (or 
qualified delegate) of the investigational site should perform an eye examination, which will include 
a slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry. 
Results of the examinations should be documented in the patient’s medical chart and the eCRF.  
 
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. 
 
11.15 
LVEF assessment 
At screening and the time points indicated in the flow chart (Section 1.1) LVEF will be measured. If 
LVEF is below 50% the next assessment should be performed the next cycle as indicated in the dose 
modification Section 9.5.1.1. 
 
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.  
 
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. 
 
11.16 
ECG assessment 
At screening and the time points indicated in the flow chart (Section 1.1) standard digital 12-lead 
ECG will be recorded in supine position after the patients being 5 minutes at rest. ECGs should be 
recorded with the ECG machine provided for the study.  
 
ECGs should be recorded in triplicate for at least 3 seconds at each of the time points indicated in 
Table 2 with approximately a 3-5 minutes gap between each of the triplicate readings. 


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ECGs will be evaluated locally and centrally. The ECGS should be submitted to the Central ECG 
Centre according to the instructions in the Cardiology Manual. 
 
The investigator or qualified delegate will evaluate the ECG at site and determine whether there are 
any abnormalities, and whether those abnormalities are clinically significant and need to be reported 
as (S)AEs and/or would lead to interruption/discontinuation of the treatment.  
 
The Central ECG Centre will evaluate the ECGs and send the results to the site. The key parameters, 
including the QT/QTc interval, will be recorded in the eCRF. If new safety information is provided 
this should be included in the eCRF. 
 
Table 2: ECG assessment schedule 
Cycle 
Time point 
Screening 
Screening 
1 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
2 
Day 1: Before study drug administration# 
3 
Day 1: Before study drug administration# 
4 
Day 1: Before study drug administration# 
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
Every subsequent 4th cycle 
Day 1: Before study drug administration# 
Treatment discontinuation 
Treatment discontinuation 
*not applicable for patients in physician’s choice group receiving the oral treatment combination Lapatinib + 
Capecitabine.  
#For patients in physician’s choice group receiving the oral treatment combination Lapatinib + Capecitabine 
the timing of the ECG on Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1 does not have to be correlated to 
the study drug administration. The ECG on Cycle 4 Day 2 should be 24 hours (± 2 hours) after the Cycle 4 
Day 1 ECG. 
 
11.17 
Tumour evaluation 
Measurable and non-measurable lesions must be documented at screening (within 28 days of 
randomization) and must be re-assessed at each subsequent tumour evaluation. Tumour response will 
be assessed locally and centrally according to RECIST version 1.1 until disease progression (for 
details see Appendix 2).  
 
The independent central review of tumour assessment scans will not determine eligibility or patient’s 
treatment. All treatment decisions will be made by the investigator using local assessments. 
 
Patients must have measurable or non-measurable disease that is evaluable per RECIST v1.1 (see 
Appendix 2) to be eligible for the study. 
 


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The tumour evaluation examinations at the visits indicated in the flowchart should include the scans 
as described below and as indicated in table 3: 
• CT (or MRI) scan of the chest, abdomen, and pelvis (including liver, spleen, and adrenals), 
should be performed at screening, in-treatment visits and at the treatment discontinuation visit. 
• CT (or MRI) scan of the brain at screening. It should be repeated in the event of clinical 
suspicion of progression of existing brain lesions and/or the appearance of new brain lesions. 
• A whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole 
body bone MRI, FDG-PET or sodium fluoride positron emission tomography (NaF PET)) at 
screening. Skeletal lesions identified on the whole body bone scan at screening, which are not 
visible on the chest, abdomen and pelvis CT (or MRI) scan should be imaged at screening and 
followed at scheduled visits using localized CT, MRI or X-ray. Whole body bone scan should 
be repeated in the event of clinical suspicion of the appearance of new bone lesions. 
• Colour photography, including a metric ruler to estimate the size of the lesions, must be 
acquired for all skin lesions present (if not evaluable by imaging) according to the instructions 
in the imaging manual at screening. These should be followed throughout the study according 
to the schedule outlined in Table 3. 
 
Table 3. Tumour imaging schedule 
Procedure 
Screening 
In treatment 
Treatment 
discontinuation* 
CT/MRI chest, 
abdomen, pelvis 
Mandated 
Every 6 weeks during 
the first 42 weeks and 
every 9 weeks 
thereafter 
Mandated 
CT/MRI of brain  
Mandated 
As clinically indicated As clinically indicated 
Whole body bone scan 
Mandated 
As clinical indicated 
As clinically indicated 
Localized bone X-ray/ 
CT/MRI 
Only if skeletal 
abnormalities 
identified by whole 
body bone scan at 
screening, which are 
not visible in the 
chest, abdomen, 
pelvis CT/MRI 
If bone lesion was 
present at screening, 
every 6 weeks during 
the first 42 weeks and 
every 9 weeks 
thereafter 
Mandated only if bone 
lesion at screening 
Skin colour 
photography 
Only if skin lesions 
present at screening 
(if not evaluable by 
CT/MRI) 
If skin lesion was 
present at screening 
every 6 weeks during 
the first 42 weeks and 
every 9 weeks 
thereafter or if 
clinically indicated 
Mandated only if skin 
lesion was present  at 
screening or if 
clinically indicated 
*Tumour evaluation at the treatment 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 visit. 
 
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 central imaging 


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centre within 7 days of the assessment. Preferably the same investigator/radiologist should assess all 
tumour responses for each patient. 
 
CT or MRI scans that were performed before a patient signed “Study”-ICF may be used to provide 
screening tumour status as long as they were performed within 28 days prior to randomization, 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. 
 
In-treatment tumour assessments will be performed every 6 weeks (± 3 days) after the date of 
randomization, for the first 42 weeks and every 9 weeks (± 3 days) thereafter. The timing of the 
tumour assessments is independent of changes to the study treatment schedule e.g., dosing delays. 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 randomization. 
 
In cases where there is a suspicion of progression before the next scheduled assessment an 
unscheduled assessment is to be performed. The reason for the unscheduled assessment should be 
reported on the eCRF. 
 
At the end of the study, local tumour evaluation results and independent central review tumour 
evaluation results will not be reconciled. 
 
11.18 
Quality of life questionnaire 
At the time points indicated in the flow chart (Section 1.1) all patient will complete the EORTC QLQ-
C30 questionnaire (version 3) and the EORTC QLQ-B23 breast cancer specific module. The general 
questionnaire contains 30 questions and the breast cancer specific module 23 questions. Both 
questionnaires are validated for use in cancer patients participating in clinical studies. 
 
11.19 
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 “Study”-ICF till the 
treatment discontinuation visit should be recorded in the eCRF. 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. 
 
11.20 
(Serious) adverse events 
For details of assessment and reporting of AEs, see Section 12. 
 
11.21 
Treatment discontinuation  
The treatment discontinuation visit should occur 4-6 weeks (28-42 days) after the last administration 
of study drug (SYD985, trastuzumab, vinorelbine, eribulin, lapatinib, or capecitabine, whichever is 
discontinued last) or before new anticancer treatment is initiated, whichever comes first.  
See the flowchart (Section 1.1) for the assessments to be performed at the treatment discontinuation 
visit. 
 


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11.22 
Survival follow-up 
Every three months after the treatment discontinuation visit a survival follow-up visit (or phone call) 
should be scheduled. During this visit data will be collected on disease progression, unresolved AEs, 
new anticancer therapies, and survival. These survival follow-up visits should continue until patient’s 
death, lost to follow-up, consent withdrawal or end of study data collection, whichever comes first. 
 
 
12 
Safety Monitoring  
12.1 
Definitions 
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. 
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. 
 


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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 
The following events are adverse events of special interest (AESIs) and will 
need to be reported to the CRO expeditiously, irrespective of regulatory 
seriousness criteria or causality: 
• ILD/Pneumonitis, 
• Severe eye toxicity grade ≥ 3, 
• Keratitis grade ≥ 2, 
• LVEF decrease to < 50%.  
 
12.2 
Adverse event monitoring  
During the study safety assessments will include physical examination, ECOG performance status, 
vital signs, weight assessment, ECG, LVEF measurements, laboratory measurements (haematology, 
chemistry, cardiac biomarkers, SYD985 ADA levels), urinalysis, ophthalmological examination, and 
AE reporting.  
 
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 “Study”-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 “Study”-ICF up to the treatment discontinuation visit. 
Events present before signing of the informed consent will be defined as medical history of the patient 


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participating in the study. 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 12.3.1 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 disease 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. 
 
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 will determine the severity of AEs according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) (version 4.03). AEs that are not listed in the CTCAE should 
be graded according to Table 4. 
 
Table 4: Adverse Event grading (for events not listed in the NCI CTCAE)  
Grade 
Equivalent to 
Definition 
Grade 1   Mild 
Discomfort noticed but no disruption of normal daily activity. 
Grade 2  
Moderate 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated, although this 
could improve the overall well-being or symptoms of the subject. 


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Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment or 
medical intervention is indicated in order to improve the overall 
well-being or symptoms; delaying the onset of treatment is not 
putting the survival of the subject at direct risk. 
Grade 4 
Life-threatening/ 
disabling 
An immediate threat to life or leading to a permanent mental or 
physical condition that prevents work or performing normal 
daily activities; treatment or medical intervention is required in 
order to maintain survival. 
Grade 5 
Death 
AE resulting in death. 
 
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 fulfil this definition. 
 
12.4 
Serious Adverse Events Documentation 
All SAEs and must be documented on an SAE Reporting Form. The following information must be 
provided:  
• Detailed patient data; 
• Exact documentation of the event; 
• Exact description of the temporal sequence to the therapy course; 
• Documentation of the results of diagnostic and therapeutic measurements; 
• Results of rechallenge (if applicable); 
• 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. 
 


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Hospitalizations due solely 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 SAEs from signing of the “Study”-ICF up to the treatment 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 by telephone, fax or email. The 
notification must include a completed SAE form. The contact details of the Syneos Health 
Pharmacovigilance Department are: 
 
Pharmacovigilance Department Syneos Health 
Address:  Farnborough Business Park, 1 Pinehurst Road,  
Farnborough, Hants GU14 7BF United Kingdom 
Fax:  
+1-877-464-7787 or to the dedicated fax number indicated on the SAE Reporting Form 
Email:  
INCdrugsafety@INCResearch.com 
 
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 in the form of a follow-up report 
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 CRF and to the Syneos Health Pharmacovigilance Department.  
 
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 section 6.8 of the Investigator’s 
Brochure contains the reference safety information and is to be used to assess the expectedness of an 
AE for SYD985. The reference Summary of product characteristics is to be used to assess 
expectedness for Physician’s choice treatments. 
Investigators must report all SAEs to their Independent Ethic Committee (IEC)/ Institutional Review 
Board (IRB) responsible for the study. In addition, in case of a SUSAR occurring in a patient treated 
with Physician’s Choice treatment the investigator is responsible for reporting the SUSAR to the 
respective manufacturer. 
 
 
 


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12.6 
Adverse Events of Special Interest 
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; 
• Severe eye toxicity grade ≥ 3; 
• Keratitis grade ≥ 2; 
• LVEF decrease to < 50%. 
 
All AESIs must be documented on an SAE Reporting Form and the same details need to be reported. 
 
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.  
 
The occurrence of any AESIs, from signing of the “Study”-ICF up to the treatment discontinuation 
visit (regardless of relationship to study drug) has to be notified (within 5 days of the investigator or 
designee becoming aware of the event) to the CRO by telephone, fax or email. The notification must 
include a completed SAE form. If a SAE occurs in conjunction with the AESI, then the reporting time 
frame for an SAE (24 hours) must be met.  
 
The contact details of the Syneos Health Pharmacovigilance Department are: 
Address:  Farnborough Business Park, 1 Pinehurst Road,  
Farnborough, Hants GU14 7BF United Kingdom 
Fax:  
+1-877-464-7787 or to the dedicated fax number indicated on the SAE Reporting Form 
Email:  
INCdrugsafety@INCResearch.com 
 
The investigator or designee must report (within 5 days of becoming aware of the event) clinically 
significant follow-up information pertaining to the AESI in the form of a follow-up report 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 AESI has to be reported in 
the CRF and to the Syneos Health Pharmacovigilance Department.  
 
12.7 
Reporting of Death 
Deaths that occur during the protocol-specified AE reporting period (from signing of the “Study”-
ICF up to the treatment discontinuation visit) that are, according to the investigator, due solely to the 
progression of underlying malignancy, should not be recorded as an AE. These deaths should be 
recorded only on the Study discontinuation eCRF or if the patient already discontinued treatment due 
to another reason on the Survival follow-up eCRF.  
 
All other deaths that occur during the protocol-specified AE reporting period should be recorded on 
an SAE eCRF and expeditiously reported. 
 
During post-study survival follow-up, deaths due to any cause should be recorded on the Survival 
follow-up eCRF. 
 


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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 case a UK site is 
participating in the study, the Medicines and Healthcare products Regulatory Agency (MHRA) in the 
UK should be notified according to their guidance. The CRO should notify the MHRA, on behalf of 
the Sponsor, within 7 days of becoming aware of the breach and investigate and take action 
simultaneously or after the notification. 
 
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 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. 
 
12.10 
Data Monitoring Committee 
Details on the responsibilities, activities and deliverables of the external Data Monitoring Committee 
(DMC) are detailed in a separate charter. As part of their evaluation the DMC assessed the validity 
of the initial assumptions underlying the sample size estimation with regards to drop-out rates.  Based 
on their pre-planned interim evaluation the independent DMC has recommended to adjust the sample 
size and enrol a total of 423 patients to ensure sufficient power for the primary endpoint analysis. 
 
13 
Criteria 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 


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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: 
• Progressive disease; 
• Unacceptable toxicity, including: 
o Clinically significant symptomatic cardiac disease (see Section 9.5.1.1); 
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 IDL/pneumonitis; 
• Pregnancy; 
• Substantial non-compliance with the requirements of the study; 
• Investigator decision based on the patient’s best interest. 
 
Patients who discontinue from study treatment for any of the above reasons should return to the clinic 
for a treatment discontinuation visit 4-6 weeks (28-42 days) after the last administration of study drug 
(SYD985, trastuzumab, vinorebine, eribulin, lapatinib or capecitabine, whichever is discontinued 
last). Subsequently, these patients will continue to be followed according to protocol for disease 
progression, unresolved AEs, new anticancer therapies, and survival status as detailed in Section 
11.22. 
 
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 Completion 
A patient is considered to have discontinued study treatment when study treatment is permanently 
discontinued due to any reason.  


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A patient is considered to have discontinued the study if the patient is lost to follow-up or withdrew 
consent or another reason exists that prevents additional data to be collected on the patient.  
 
A patient is considered to have completed the study when the patient has died while still in the study. 
 
13.3 
Patient replacement 
A patient that discontinues from treatment or study will not be replaced.  
 
13.4 
Study termination 
The clinical study may be stopped 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 addition, further recruitment may be stopped 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 medical, ethical, or business reason.  
In such case, all patients will be requested to return to the clinic for a final follow-up visit, during 
which all medication will need to be returned (if applicable) and 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. 
 
The Sponsor decides when to stop collection of survival follow-up data, which should be at least after 
all patients in the SYD985 group discontinued treatment and completed the treatment discontinuation 
visit (if possible) or were lost to follow-up, in order to finalize data analysis. This will be 
communicated to the participating clinical sites. 
 
 
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 at least before completion of study enrolment. 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 9.3 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 (%). 
 
All data from all clinical assessments will be presented in listings. 
 


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14.2 
Analysis Populations 
14.2.1 
Safety Set  
The Safety Set includes all patients who received at least one dose of study medication. Patients will 
be analyzed according to the study treatment they actually received. Treatment actually received is 
defined as the study treatment (SYD985 or Physician’s choice) the patient receives on Cycle 1 Day 
1. 
 
14.2.2 
Full analysis Set 
The Full Analysis Set (FAS) comprises all randomized patients. Following the intent to treat (ITT) 
principle, patients will be analyzed according to the treatment group and strata they have been 
assigned to during the randomization procedure. The FAS will be the primary population for all the 
efficacy analyses. 
 
14.2.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) will include the subset of the patients in the FAS who were administered 
at least one dose of study medication and who do not have any major protocol deviations or multiple 
minor deviations. All protocol deviations or conditions leading to exclusion from the PPS will be 
detailed in the SAP. Patients will be analyzed according to the treatment and strata they have been 
assigned to during the randomization procedure. Sensitivity analysis of the primary endpoint of PFS 
will be performed using PPS. 
 
14.3 
Study endpoints 
14.3.1 
Primary endpoint 
The primary efficacy endpoint is PFS based on blinded independent central review (ICR) of tumour 
assessment according to RECIST 1.1. PFS is defined as the time from the date of randomization to 
the date of first documented ICR-assessed disease progression according to RECIST 1.1 or death due 
to any cause (whichever occurs earlier). 
 
Data for patients without disease progression or death from any cause as of the data cut-off date will 
be censored at the time of the last tumour assessment with an outcome other than “unevaluable” or, 
if no tumour assessment was performed after the baseline visit, at the time of randomization plus 1 
day. Data for patients without disease progression or death from any cause as of the date when a new 
therapy for cancer is started will be censored at the time of the last tumour assessment with an 
outcome other than “unevaluable” or, if no tumour assessment was performed after the baseline visit, 
at the time of randomization plus 1 day. 
Data from patients who are lost to follow-up will be included in the analysis as censored observations 
on the last date of tumour assessment that the patient was known to be progression free. Data from 
patients whose disease progression or death occurs after two or more consecutive missed tumour 
assessment will not be counted. In these cases, the patient will be censored at the patient’s last tumour 
assessment prior to the missing assessment. If disease progression occurs after one missed tumour 
assessment, the event will be counted at the respective event date (details will be in the SAP). 
 


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14.3.2 
Secondary endpoints 
The secondary efficacy endpoints are: 
• Overall Survival; 
• Objective Response Rate on the basis of the blinded independent central review; 
• Investigator assessed PFS; 
• Patient reported outcomes for health related quality of life. 
 
Overall Survival (OS) is defined as the time from date of randomization 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 randomization plus 1 day.  
 
Objective Response Rate (ORR) is defined as the proportion of patients with ICR-assessed best 
overall response of complete response (CR) or partial response (PR) according to RECIST 1.1. Only 
patients with measurable disease at baseline will be included in the analysis of ORR. Patients without 
a post-baseline tumour assessment will be considered non-responders.  
 
Investigator assessed PFS is defined as the time from the date of randomization 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. 
 
Patient reported outcomes for health related quality of life are collected with the EORTC QLQ-C30 
questionnaire along with the disease-specific breast cancer module (EORTC QLQ-BR23). Scoring 
of raw QoL data and methods for handling missing items or missing assessments will be handled 
according to scoring manuals for each respective patient questionnaire.  
 
14.3.3 
Other endpoints 
• To describe time to response in each treatment group; 
• To describe duration of response in each treatment group; 
• To describe the CBR in each treatment group;  
• To evaluate the pharmacokinetics of SYD985; 
• To evaluate the formation of SYD985 ADAs; 
• To explore exposure/response and exposure/safety relationships. 
 
14.4 
Demographic and baseline characteristics 
Relevant demographic and baseline data will be summarized descriptively by treatment group using 
data from the FAS population and PPS population.  
 
14.5 
Efficacy analysis 
 
14.5.1 
Primary objective 
The primary objective of the study is to demonstrate that SYD985 is superior to physician’s choice, 
in prolonging PFS on the basis of blinded independent central review of tumour assessment. 


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14.5.1.1 
Timing of analysis 
The primary PFS analysis will be performed when at least 256 PFS events have occurred, as assessed 
by central review, or when at least 95% of patients have discontinued treatment, and only after all 
patients have been enrolled. 
 
14.5.1.2 
Analysis 
Progression will be assessed via blinded independent central review according to RECIST 1.1. 
Progression as assessed through local radiology assessment will be used for supportive evidence of 
the primary efficacy analysis. 
 
The primary efficacy endpoint PFS will be analyzed based on the data observed in the FAS 
population, according to the treatment group patients were randomized and the strata they were 
assigned at randomization. The stratification factors assigned at randomization are world region 
(Europe and Singapore/North-America), the number of prior treatment lines for locally advanced or 
metastatic breast cancer (excluding hormone therapy) (2/>2), and prior treatment with pertuzumab 
(yes/no). The survival distribution of PFS per treatment group will be estimated using the Kaplan-
Meier method. The median PFS along with 95% CIs will be presented by treatment group. 
 
The comparison of the survival distributions of PFS between the two treatment groups will be 
performed using a stratified log-rank test at the two-sided 5% level of significance, i.e., 
 
H01: S1T(t) = S1C(t) vs. Ha1: S1T(t) ≠ S1C(t), for all t ≥ 0 (t=timepoint) 
 
Where S1T(t) is the survival distribution function of PFS in the treatment group of SYD985 and S1C(t) 
is the survival distribution function of PFS in the reference treatment group (physician’s choice). 
 
or in words 
 
H01: there is no difference between the populations in the probability of an event (PFS) at any time 
point. 
versus 
Ha1: there is a difference between the populations in the probability of an event (PFS) at some time 
point. 
 
A stratified Cox regression analysis will be used to estimate the HR of PFS, along with 95% CIs 
(using the same strata information as above). 
 
14.5.1.3 
Supportive analyses 
Sensitivity analyses for the primary endpoint will be performed, particulars will be detailed in the 
SAP.  
 


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14.5.2 
Secondary objective 
The secondary objectives of this study are to compare the two treatment groups with respect to OS, 
ORR on the basis of the blinded independent central review and investigator assessed PFS. 
 
14.5.2.1 
Analysis  
14.5.2.1.1 Overall Survival 
 
The analysis for OS will be based on the FAS population. The following statistical hypothesis for OS 
will be tested: 
 
H02:  S2T(t) = S2R(t) vs. Ha2: S2R(t) ≠ S2C(t), for all t ≥ 0 (t=timepoint) 
 
Where S2T(t) is the survival distribution function of OS in the treatment group of SYD985 and S2R(t) 
is the survival distribution function of OS in the reference treatment group (physician’s choice). 
 
The distribution of OS will be compared between the two treatment groups using a stratified log-rank 
test at two-sided 5% level of significance. The strata information will be based on the data obtained 
from the system that was utilized for randomization. 
 
The first OS analysis will be performed at the time of the primary efficacy analysis of PFS.   
Subsequent analyses of the OS will be planned to support regulatory questions or scientific 
publications. 
 
The survival distribution function of OS will be estimated using the Kaplan-Meier method. The 
median OS along with 95% CIs will be presented by treatment group. The stratified Cox regression 
analysis will be used to estimate the HR of OS, along with 95% confidence interval. 
 
In addition, the 1-year survival rate and corresponding 95% CI will be estimated using the Kaplan-
Meier approach. 
 
14.5.2.1.2 Objective response rate 
ORR will be calculated based on the FAS population. Proportion of patients with ORR will be 
presented by treatment group along with 95% CIs. The Cochran-Mantel-Haenszel test (strata based 
on the baseline stratification factors) will be used to compare the two treatment groups with respect 
to the ORR at two-sided 5% level of significance.  
 
As a supportive analysis, patients ORR as assessed by local radiology assessment will be calculated 
by treatment group and presented along with the 95% CIs. 
 
14.5.2.1.3 Investigator assessed PFS 
Investigator assessed PFS will be calculated based on the FAS population. The survivor distribution 
of PFS will be estimated per treatment group using the Kaplan-Meier method. The median PFS along 
with 95% CI will be presented by treatment group. A stratified Cox regression analysis will be used 
to estimate the HR of PFS, along with the 95% CI. The treatment groups will be compared using the 
2-sided stratified log-rank test. 


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14.5.2.1.4 Patient reported outcomes 
The number of patients completing each patient questionnaire and the number of missing or 
incomplete assessments will be summarized by treatment group for each scheduled assessment time 
points for the EORTC QLQ-C30 and EORTC QLQ-B23 questionnaires. The FAS will be used for 
analyzing the data. 
 
Descriptive statistics will be used to summarize the scores scales for the EORTC questionnaires at 
each scheduled assessment time point. Additionally, change from baseline in the domain scores at the 
time of each assessment will be summarized. Patients with an evaluable baseline score and at least 
one evaluable post-baseline score during the treatment period will be included in the change from 
baseline analyses. 
 
The global health status/QoL scale score of the EORTC QLQ-C30 is identified as the primary patient-
reported outcome variable of interest. Physical functioning, emotional functioning and social 
functioning scale scores of the EORTC QLQ-C30, and the breast cancer symptoms scale score of the 
EORTC QLQ-BR23 are identified as secondary patient-reported outcome variables of interest. 
Analytic tests will be performed using parametric and non-parametric tests where necessary, further 
details will be provided in the SAP. 
 
14.5.3 
Other objectives 
14.5.3.1 
Time to response  
Time to response is the time between the date of randomization until first documented response (CR 
or PR) according to RECIST 1.1. All patients will be included in time to response calculations. 
Patients who did not achieve a CR or PR will be censored at the maximum follow-up time for patients 
who had a PFS event (i.e. either progressed of death due to any cause) or at the date of last adequate 
tumour assessment date otherwise.  
Time to response will be analyzed based on the data observed in the FAS population and will be 
determined primarily by independent central review of tumour assessment (an analysis based on 
investigator tumour assessment will also be performed). Time to response will be summarized for the 
two treatment groups using descriptive statistics.  
 
14.5.3.2 
Duration of response  
Duration of response only 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).  
Duration of response will be analyzed based on the data observed in the FAS population and will be 
determined primarily by independent central review of tumour assessment (an analysis based on 
investigator tumour assessment will also be performed). The censoring methods for this endpoint are 
similar to those described for PFS. The Kaplan-Meier approach will be used to estimate the median 
duration of response of each treatment group and the corresponding 95% CIs.  
 


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14.5.3.3 
Clinical benefit rate 
The CBR is defined as the proportion of patients with CR, PR, or SD (SD for 24 weeks (6 months) 
or longer). CR, PR and SD are defined according to RECIST 1.1. CBR will be analyzed based on the 
data observed in the FAS population and will be determined primarily by independent central review 
of tumour assessment (an analysis based on investigator tumour assessment will also be performed). 
CBR will be summarized for the two treatment groups using descriptive statistics.  
 
14.5.3.4 
Pharmacokinetic analysis 
Observed concentrations for total SYD985 (including SYD985 with a drug-to-antibody ratio (DAR) 
≥ 0), conjugated SYD985 with DAR ≥ 1, and for the free toxin (DUBA, SYD986) will be summarized 
for each specified PK sampling point. Non-compartmental, compartmental analysis and/or population 
PK approach will be used to analyze PK data if appropriate. The PK parameters for total SYD985, 
conjugated SYD985, and for SYD986 including, but not limited to, AUC, Cmax, Cmin, CL, V, T1/2 will 
be reported as data allow and the inter-patient variability will be assessed.  
The influence of patient covariates on PK will also be evaluated, further details will be given in the 
SAP. 
 
14.5.3.5 
SYD985 anti-drug antibody formation 
The formation of SYD985 ADAs will be assessed. A separate ADA assessment plan will be prepared. 
 
14.5.3.6 
Exposure response analysis 
If data allow, exploratory analysis or modeling techniques will be used to investigate the relationship 
between SYD985 exposure and safety/efficacy parameters (e.g. SYD985-related toxicity, PFS, and/or 
OS). 
 
14.6 
Safety data analysis  
Safety analysis will be based on the SAF 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 and including treatment discontinuation visit. Events starting before first dosing will be 
presented separately.  
 
14.6.1 
Extent of exposure 
The total cumulative dose, number of doses, dose intensity, and duration of exposure for the SYD985 
and Physician’s choice groups 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. 
 
14.6.2 
Treatments  
Concomitant medication and non-drug therapies will be listed by patient and summarized by ATC 
(Anatomical therapeutic chemical classification system) term for each treatment group. These 


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summaries will include medications starting on or after the start of study treatment and continuing 
after the start of study treatment. Any prior concomitant medications or significant non-drug therapies 
starting and ending prior to the start of study treatment will be listed. 
 
14.6.3 
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 4.03) 
 
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 by treatment group. 
 
Separate summaries presented by treatment group will be given for all and 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 presented by 
treatment group will be given for all AESI categories and drug-related AESIs. 
 
14.6.4 
Clinical Laboratory Evaluations 
Changes in laboratory data will be summarized by grade using the NCI CTCAE version 4.03 or higher 
for each treatment group. Changes from baseline will be presented in shift tables for the different lab 
assessments. 
 
14.6.5 
ECG analyses 
Standard ECGs parameters (e.g. heart rate, PR, QRS, and QT) will be summarized by treatment group 
and scheduled visits. The number of patients who discontinue drug due to cardiac function will be 
summarized. Further cut-points might be analyzed if appropriate. 
 
A separate ECG analysis plan will be prepared for a more detailed analysis of the ECGs including 
QTc interval analysis and exposure response analysis. 
 
14.6.6 
LVEF 
Absolute LVEF measurements, as well as changes from baseline as a function of time, will be 
summarized by treatment group and 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. Further cut-points might be analyzed if appropriate. 
 


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14.6.7 
Ophthalmological 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 treatment group and 
scheduled visits. 
 
The number of patients who develop Grade 3 (or higher) keratitis or Grade 3 conjunctivitis, or 
discontinue study drug due to eye toxicity will be summarized. More detailed analysis may be 
performed if appropriate. 
 
14.6.8 
Other Safety Measures 
ECOG performance status will be summarized by treatment group and scheduled visits, in addition, 
changes from baseline will be presented. The results of body weight and vital signs will be 
summarized by treatment group and scheduled visits.  
 
14.7 
Sample size 
The primary efficacy endpoint of this study is PFS based on independent central review of tumour 
assessment. The primary efficacy analysis will be event driven. 
 
In order to be able to detect a hazard ratio of 0.65 in PFS using the log-rank test, at 90% power, using 
a two-sided test at a significance level of p < 0.05, a total of 256 events are required. Assuming a 9 
month recruitment period and 10 month follow up period, a median time to progression of 4.1 months 
for the physician’s choice and assuming an average of 30% drop out in the physician’s choice group 
and 40% in the SYD985 group, a minimal number of 423 patients is required. Allocation is 2:1 
resulting in 282 to be allocated to the SYD985 group and 141 to the physician’s choice group. 
 
Randomization will be done by a permutated block design with a fixed block size, using world region 
(Europe and Singapore/North-America), the number of prior treatment lines for locally advanced or 
metastatic breast cancer (excluding hormone therapy) (2/>2), and prior treatment with pertuzumab 
(yes/no) as stratification factors. 
 
No formal interim analysis will be performed. As part of their evaluation the DMC assessed the 
validity of the initial assumptions underlying the sample size estimation with regards to drop-out rate. 
Such sample size re-estimation will not be considered a formal interim analysis as no between-group 
comparison of event-rates will be performed. Therefore, the primary analysis will be performed at 
the set 5% significance level. Details of methods used will be provided in a separate analysis plan. 
 
 
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 
The Sponsor/CRO will obtain regulatory approval from the competent authority prior to study start. 
The Sponsor/CRO will provide all necessary documents to obtain such approval.  
 
If any of the documents relevant to obtain approval is amended, the Sponsor/CRO will submit these 
documents for review and subsequent approval to the competent authority. 
 
An annual safety/progress report will be provided by Sponsor/CRO to the competent regulatory 
authority. 
 
15.1.2 
Review and Approval by Competent IRB or IEC 
The Sponsor or the Sponsor’s representatives will obtain ethical approval from the competent 
IEC(s)/IRB(s) prior to study start. The Sponsor or the Sponsor’s representatives will provide all 
necessary documents to obtain such approval. 
 
If any of the documents relevant to obtain approval is amended, the Sponsor or the Sponsor’s 
representatives will submit these documents for review and subsequent approval to the competent 
IEC(s)/IRB(s). 
 
An annual safety/progress report will be provided by Sponsor/CRO to the competent IEC(s)/IRB(s) 
as required. 
 
15.1.3 
Informed Consent 
Informed Consent will be obtained from the potential patient prior to any study-related activities and 
in accordance with local laws and all applicable regulatory requirements. For this study a specific 
“HER2 testing”-ICF may be used to allow the central assessment of HER2 status of available archived 
tumour tissue from patients who are interested to participate. This may avoid unnecessary study 
assessments and may speed up recruitment. The “Study”-ICF should be signed before full screening 
is started. 
 
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. The patient or the authorised representative must 
complete the printed name and personally enter the date of signature. If an authorised representative 
signs the ICF, all efforts should be made to obtain an additional personally-dated signature from the 
patient herself. 
 


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The ICF will be signed in duplicate and the patient and/or the authorised representative obtain one 
original of the signed ICF. The second original is filed with the study documents at in the 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. 
 
15.1.4 
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).  
  
15.1.5 
Amendments to Study Protocol 
Amendments to the study protocol are performed 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.  
 
15.1.6 
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. 
 
15.1.7 
Coordinating Investigator for Clinical Study Report 
An interim CSR will be prepared by the Sponsor/CRO to describe the results of the study following 
the primary analysis, a final CSR will be prepared at the end of the study. One (or several) of the 
investigator(s) will be selected by the Sponsor to review and approve the 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; 


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• 
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 and Sponsor’s/CRO’s procedures, 
monitors from Sponsor/CRO will perform the monitoring of this study. Investigational sites will be 
contacted and visited regularly by Sponsor/CRO staff. The investigational sites will be trained on all 
study procedures at an investigator meeting and during site initiation visit. 
 
During the study, the sites will be visited by Sponsor/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 Sponsor/CRO staff by evaluation of the data 
entered in the eCRF. 
 
At study end, the investigational sites will be closed at a final visit conducted by Sponsor/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 Sponsor/CRO, 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, laboratory 
reports and X-rays. The nature of source data and requirement for its maintenance will be described 
in a separate Source Data Agreement with the investigator. 
 
15.2.3 
Quality Assurance 
To ensure compliance with study protocol, ICH GCP, and applicable regulatory requirements, the 
Sponsor/CRO 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. 
 


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The Sponsor/CRO will evaluate processes and data that are critical to assure human subject 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.  On 
a regular basis medical safety monitoring meetings evaluating the accumulated safety data will be 
organized with the responsible persons from Sponsor/CRO. In addition, the accumulated protocol 
deviations will be evaluated and discussed on a regular basis by the responsible persons from 
Sponsor/CRO.  
 
15.3 
Data Handling and Records Retention 
15.3.1 
Collection of Data, 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. 
 
For patients who fail screening, data are to be collected from the time the informed consent is signed 
until it is determined that the patient has failed the screening. An eCRF with minimum information 
is to be completed, including demographics, reason for screen failure and (serious) AEs.  
 
The eCRFs must be kept in order and up-to-date so that they always reflect the latest observations on 
the patients enrolled in the study. 
 
The signed original ICF(s) should be attached to the patient’s medical chart. When the patient 
discontinued or completed the study, the signed ICF(s) should be kept with the printed copies of the 
eCRF, or a note made indicating where the consent form is located. All source data should be kept in 
conformance to applicable national laws and regulations. 
 
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. 
 
ECRFs must be completed for each patient enrolled in the study and signed-off by the investigator. 
This should be done as soon as possible after the patient discontinued or completed the study. A 
monitor will review the completed eCRF. 
 
Data management will be performed by the Sponsor/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 


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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 Sponsor/CRO will 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 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 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. 
 


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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. 


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16 
References 
 
 
(1)  Ferlay J, Steliarova FE, Lortet TJ et al. Cancer incidence and mortality patterns in Europe: 
estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-1403. 
 
(2)  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. 
 
(3)  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. 
 
(4)  Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive 
advanced breast cancer. N Engl J Med 2006;355:2733-2743. 
 
(5)  von MG, du BA, Schmidt M et al. Trastuzumab beyond progression in human epidermal 
growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast 
international group 03-05 study. J Clin Oncol 2009;27:1999-2006. 
 
(6)  Blackwell KL, Burstein HJ, Storniolo AM et al. Overall survival benefit with lapatinib in 
combination with trastuzumab for patients with human epidermal growth factor receptor 2-
positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 
2012;30:2585-2592. 
 
(7)  Mohd Sharial MS, Crown J, Hennessy BT. Overcoming resistance and restoring sensitivity 
to HER2-targeted therapies in breast cancer. Ann Oncol 2012;23:3007-3016. 
 
(8)  Cardoso F, Costa A, Norton L et al. ESO-ESMO 2nd international consensus guidelines for 
advanced breast cancer (ABC2). Breast 2014;23:489-502. 
 
(9)  Cherny NI, Sullivan R, Dafni U et al. A standardised, generic, validated approach to stratify 
the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the 
European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-
MCBS). Ann Oncol 2015;26:1547-1573. 
 (10)  Naidoo J, Page DB, Li BT et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune 
checkpoint antibodies. Ann Oncol 16 A.D.;26:2375-2391. 
 (11)  Nishino M, Sholl LM, Hodi FS, Hatabu H, Ramaiya NH. Anti-PD-1-Related Pneumonitis 
during Cancer Immunotherapy. N Engl J Med 16 A.D.;373:288-290. 
 (12)  Omarini C, Thanopoulou E, Johnston SR. Pneumonitis and pulmonary fibrosis associated 
with breast cancer treatments. Breast Cancer Res Treat 2014;146:245-258. 
 (13)  EMA. Summary of Product Characteristics of Herceptin (trastuzumab).  
 
 (14)  EMA. Summary of Product Characteristics of Kadcyla (trastuzumab emtansine).  
 
 (15)  Moslehi JJ. Cardiovascular Toxic Effects of Targeted Cancer Therapies. N Engl J Med 
2016;375:1457-1467. 


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 (16)  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. 
 (17)  Wolff AC, Hammond ME, Hicks DG et al. Recommendations for human epidermal growth 
factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of 
American Pathologists clinical practice guideline update. J Clin Oncol 2013;31:3997-4013. 
 
  (18)   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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17 
Appendices 
 
 


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Appendix 1 Sample Subject Emergency Card 
 
Front: 
 
 Mrs:__________________________Date of birth:_________________ 
(subject’s first and last name)                                    (ddMMMyyyy) 
 
is participating in a clinical study with protocol number SYD985.002 entitled: 
Multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the antibody-drug 
conjugate SYD985 to physician's choice in patients with HER2-positive unresectable locally advanced or 
metastatic breast cancer 
 
EudraCT number: 2017-001994-18 [where required in Europe] 
IND number:         131333 [where required in US] 
 
Subject number: _________________ [subject’s study identification number] 
 
In case of an emergency please contact the following doctor: 
 
_____________________________________________________________________ 
[Investigator’s name and contact information] 
 
[If applicable add other staff name and contact details, e.g. study coordinator] 
 
Emergency number of medical monitor to be used by medical staff only: 
______________________________________________ 
[Medical monitor name and telephone number]                                                                                                                        (See reverse side) 
 
Back: 
 
 
Study medication: SYD985 or physician’s choice 
SYD985 is a duocarmycin-based HER2-targeting antibody-drug conjugate. SYD985 is an investigational drug 
and is in development for the treatment of breast cancer. 
Physician’s choice is one of the following 4 options: 1) Lapatinib + Capecitabine, 2) Trastuzumab + 
Capecitabine, 3) Trastuzumab + Vinorelbine , 4) Trastuzumab + Eribulin. All these drugs are used to treat 
breast cancer. 
 
 
Please keep this card with you at all times and return it at your final visit to the clinic! 
 
[If applicable add additional country/site specific text here, e.g. as required per authority/IEC/IRB] 
 
Sponsor: 
Synthon Biopharmaceuticals BV 
Microweg 22  
6545 CM Nijmegen 
The Netherlands 
+31 24 372 7700 
 
 
 
 
[Study logo] 
 


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Appendix 2 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 caliper 
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. Leptomenngeal 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 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. 
 


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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. 
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 


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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 measuarable (± 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 = inevaluable 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the randomization 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 inevaluable.     
 
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 3 Protocol Amendment I 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
Protocol title: 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the 
antibody-drug conjugate SYD985 to physician’s choice in patients with HER2-positive unresectable 
locally advanced or metastatic breast cancer 
 
 
 
 
Abbreviated title: 
TULIP 
Protocol Number: 
SYD985.002 
Development phase: 
Phase III 
Drug product code: 
SYD985 
Drug substance: 
Trastuzumab vc-seco-DUBA  
EudraCT Number: 
2017-001994-18 
IND Number: 
131333 
Amendment: 
Protocol Amendment I 
(leading to Protocol Version 2.0) 
 
Amendment Date: 
25 August 2017 
Authors Byondis BV: 
 
Evelyn van den Tweel, Clinical Project Leader  
Mayke Oesterholt, Clinical Project Leader 
Ellen Mommers, Clinical Project Leader 
Roel Mulder, Biostatistician  
 
 
 
 
 
 
 
 
 
 
 
This document includes confidential and privileged information and data that contain trade secrets which are 
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 study at a clinical 
investigational site. 
 


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Justification for the amendment 
This substantial amendment has been prepared upon request of the regulatory authorities. The 
changes are summarized below:  
• Inclusion criterion 3 on previous HER2-targeting treatment has been specified in more detail. 
• Inclusion criterion 4 on HER2 status has been specified in more detail. 
• An exclusion criterion on prior pulmonary disease has been added as criterion 9. 
• Previous exclusion criterion 9 on HIV and hepatitis has been amended to allow the inclusion 
of HIV infected patients. 
• Two additional time points (Cycle 2 Day 1 and Cycle 4 Day 1) for assessments of the QoL 
questionnaires have been added to the flowchart. 
• The dose modification guidances for eye toxicity and pneumonitis have been adjusted. 
• The ECG assessments requirements for the physician’s choice group receiving Lapatinib + 
Capecitabine have been explained in more detail. 
• In addition to Europe and North-America also sites in Singapore are planned to participate, 
this has been added. 
• Details regarding the required infusion materials have been replaced by more general wording 
with reference to the pharmacy manual in which full details are described. 
 
Apart from editorial changes, version changes to the title page and table of contents, this has led to 
the following changes in the protocol text (all included in version 2 of the protocol). New text is 
underlined, deleted text is strikethrough: 
 
Protocol synopsis: Inclusion criteria (page 3) & Section 8.1.1 Inclusion criteria (page 24) 
3. Patients should have had either progression during or after at least two HER2-targeting treatment regimens 
for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine 
treatment; 
4. HER2-positive tumour status (defined as a 3+ score on immunohistochemistry (IHC) and/or positive by 
in situ hybridization (ISH)) confirmed by the central laboratory;  
 
Now reads as: 
3. Patients should have had either progression during or after at least two HER2-targeting treatment regimens 
for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine 
treatment for locally advanced or metastatic disease; 
4. HER2-positive tumour status according to the ASCO-CAP guidelines (defined as a 3+ score on 
immunohistochemistry (IHC) and/or positive by in situ hybridization (ISH)) confirmed by the central 
laboratory;  
 
Protocol synopsis: Exclusion criteria (page 4) & Section 8.1.2 Exclusion criteria (page 25) 
8. Untreated brain metastases, symptomatic brain metastases, brain metastases requiring steroids to manage 
symptoms, or treatment for brain metastases within 8 weeks prior to randomization. Patients with prior 
treatment of brain metastases must have evidence of disease stability on baseline brain imaging as 
compared to historical brain imaging; 
9. Known infection with HIV, or known active Hepatitis B or C infection; 
10. Major surgery within 4 weeks prior to randomization; 
11. Pregnancy or lactation; 
 


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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. 
 
Now reads as: 
8. Untreated brain metastases, symptomatic brain metastases, brain metastases requiring steroids to manage 
symptoms, or treatment for brain metastases within 8 weeks prior to randomization. Patients with prior 
treatment of brain metastases must have evidence of disease stability on baseline brain imaging as 
compared to historical brain imaging; 
9. 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; 
10. Known infection with HIV, or known active Hepatitis B or C infection; 
11. Major surgery within 4 weeks prior to randomization; 
12. Pregnancy or lactation; 
13. 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. 
 
Synopsis (page 4) 
The calculated amount of solution should be added to an infusion bag containing 100 mL of 0.9% 
sodium chloride without other additives. If reconstituted vials or the prepared infusion bag is not used 
immediately, it can be stored at 2 to 8 °C (36-46 °F) for a maximum of 24 hours up to start of infusion. 
 
Now reads as: 
The calculated amount of solution should be added to an infusion bag containing 100 mL of 0.9% 
sodium chloride without other additives. If reconstituted vials or the prepared infusion bag is not used 
immediately, it can be stored at 2 to 8 °C (36-46 °F) for a maximum of 24 hours up to start of infusion. 
 
Protocol synopsis: Study assessments and procedures (page 5) 
EORTC QLQ-C30 and breast module QLQ-BR23 questionnaires will be used every 2nd cycle to monitor 
changes in the patient's QoL. 
 
Now reads as: 
EORTC QLQ-C30 and breast module QLQ-BR23 questionnaires will be used on day 1 of the first 5 cycles 
and subsequently every 2nd cycle to monitor changes in the patient's QoL. 
 
Section 1.1 Study flowchart (page 9) 
10 Ophthalmological examination as well as LVEF assessment 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; 
 
Now reads as: 
10 Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as LVEF 
assessment 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; 
 
 
Section 9.4.1 SYD985 treatment (page 28) 


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The required volume needs to be withdrawn from the vial(s) and added to a polyethylene (PE)-lined 
polyolefin infusion bag (e.g. Baxter Viaflo bag) containing 100 mL of 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. 
 
For the infusions, a polyvinylchloride – trioctyl trimellitate (PVC-TOTM; e.g. From Codan) or 
polypropylene/polyurethane/silicone (PP/PUR/silicone; e.g. from Fresenius Kabi) infusion set with a 
0.2-micron in-line polyethersulfone (PES) filter should be used. 
 
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 up to 100 mL of sterile 0.9% sodium chloride solution for infusion, 
at the discretion of the investigator.  
 
Now reads as: 
The required volume needs to be withdrawn from the vial(s) and added to an a polyethylene (PE)-
lined polyolefin infusion bag as specified in the pharmacy manual (e.g. Baxter Viaflo bag) containing 
100 mL of 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. 
 
For the infusions an, a polyvinylchloride – trioctyl trimellitate (PVC-TOTM; e.g. From Codan) or 
polypropylene/polyurethane/silicone (PP/PUR/silicone; e.g. from Fresenius Kabi) infusion set with a 
0.2-micron in-line polyethersulfone (PES) filter as specified in the pharmacy manual should be used. 
 
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 


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infusion line must be flushed with up to 100 mL of sterile 0.9% sodium chloride solution for infusion 
as indicated in the pharmacy manual, at the discretion of the investigator.  
 
Section 9.5.1.2 SYD985 Dose modifications for eye toxicity (page 31) 
For patients who experience Grade 3 (or higher) keratitis or Grade 3 conjunctivitis, dosing must be 
delayed for up to 42 days from the last received dose. When the keratitis or conjunctivitis 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. 
 
Now reads as: 
Patients who experience Grade 3 (or higher) keratitis will be discontinued from treatment. For patients 
who experience Grade 3 (or higher) keratitis or Grade 3 conjunctivitis, dosing must be delayed for up 
to 42 days from the last received dose. When the keratitis or conjunctivitis 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. 
 
Section 9.5.1.4 SYD985 - Dose modifications for pneumonitis (page 31) 
For patients who experience Grade 2 (or higher) pneumonitis dosing must be delayed for up to 42 
days from the last received dose. When the pneumonitis resolves to Grade 1 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 pneumonitis persists. The pneumonitis should be monitored for recovery. 
 
Now reads as: 
Patients who experience Grade 3 or 4 pneumonitis will be discontinued from treatment. For patients 
who experience Grade 2 (or higher) pneumonitis dosing must be delayed for up to 42 days from the 
last received dose. When the pneumonitis resolves to Grade 1 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 
pneumonitis persists. The pneumonitis should be monitored for recovery. 
 
 
Section 11.16 ECG assessment (page 40) 
Table 5: ECG assessment schedule 
Cycle 
Time point 
Screening 
Screening 
1 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
2 
Day 1: Before study drug administration 
4 
Day 1: Before study drug administration 
Day 1: 30 minutes after end of infusion (±10 minutes)* 


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Day 2: 24 hours after study drug administration (±2 hours) 
Every subsequent 4th cycle 
Day 1: Before study drug administration# 
Treatment discontinuation 
Treatment discontinuation 
*not applicable for patients in physician’s choice group receiving Lapatinib + Capecitabine.  
 
Now reads as: 
Table 6: ECG assessment schedule 
Cycle 
Time point 
Screening 
Screening 
1 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
2 
Day 1: Before study drug administration# 
4 
Day 1: Before study drug administration# 
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)#  
Every subsequent 4th cycle 
Day 1: Before study drug administration# 
Treatment discontinuation 
Treatment discontinuation 
*not applicable for patients in physician’s choice group receiving Lapatinib + Capecitabine.  
#For patients in physician’s choice group receiving Lapatinib + Capecitabine the timing of the ECG on Cycle 
2 Day 1 and Cycle 4 Day 1 does not have to be correlated to the study drug administration. The ECG on Cycle 
4 Day 2 should be 24 hours (± 2hours) after the Cycle 4 Day 1 ECG. 
 
 
 


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Appendix 4 Protocol Amendment II 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
Protocol title: 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the 
antibody-drug conjugate SYD985 to physician’s choice in patients with HER2-positive unresectable 
locally advanced or metastatic breast cancer 
 
 
 
 
Abbreviated title: 
TULIP 
Protocol Number: 
SYD985.002 
Development phase: 
Phase III 
Drug product code: 
SYD985 
Drug substance: 
Trastuzumab vc-seco-DUBA  
EudraCT Number: 
2017-001994-18 
IND Number: 
131333 
Amendment: 
Protocol Amendment II 
(leading to Protocol Version 3.0) 
 
Amendment Date: 
09 November 2017 
Authors Byondis BV: 
 
Evelyn van den Tweel, Clinical Project Leader  
Mayke Oesterholt, Clinical Project Leader 
Ellen Mommers, Clinical Project Leader 
Roel Mulder, Biostatistician  
 
 
 
 
 
 
 
 
 
 
 
This document includes confidential and privileged information and data that contain trade secrets which are 
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 study at a clinical 
investigational site. 
 


Clinical Study Protocol 
SYD985.002 
TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 84 of 126 
 
 
Justification for the amendment 
This substantial amendment has been prepared upon request of the regulatory authorities. The 
changes are summarized below:  
• The flowchart has been updated to add pregnancy tests on Day 1 of every cycle and at the 
treatment discontinuation visit. 
• The flowchart has been updated to add an ECG assessment at Cycle 3 Day 1. 
• A total of 5 protocol sections have been updated to re-iterate and emphasize the importance 
to follow the SmPC guidance for patient selection and management in the physician’s choice 
group. 
• A section on the benefit/risk ratio has been added. 
• In relation to cardiotoxicity it has been added that clinically relevant electrolyte disturbances 
should be corrected. 
• The possibility to enable further SYD985 treatment when the study has ended is added. 
• The indicated contraception has been updated to be aligned with the CTFG recommendations. 
 
Apart from editorial changes, version changes to the title page and table of contents, this has led to 
the following changes in the protocol text (all included in version 3 of the protocol). New text is 
underlined, deleted text is strikethrough: 
 
 
Protocol synopsis: Study population (page 3)  
The study population will consist of patients with HER2-positive unresectable locally advanced or metastatic 
breast cancer complying with the following in- and exclusion criteria:  
Inclusion criteria 
1. Female patients, age ≥ 18 years old at the time of signing informed consent; 
2. Patients with histologically-confirmed, unresectable locally advanced or metastatic breast cancer; 
3. Patients should have had either progression during or after at least two HER2-targeting treatment regimens 
for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine 
treatment for locally advanced or metastatic disease; 
4. HER2-positive tumour status according to the ASCO-CAP guidelines (defined as a 3+ score on 
immunohistochemistry (IHC) and/or positive by in situ hybridization (ISH)) confirmed by the central 
laboratory;  
5. Patients must have measurable or non-measurable disease that is evaluable per Response Evaluation 
Criteria for Solid Tumours (RECIST version 1.1). Patients with bone-only sclerotic disease without a lytic 
componentare not eligible; 
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 
 
Now reads as: 
When evaluating a patient for participation into the study the investigator should first consider which 
combination treatment would be prescribed if the patient would be randomized to the physician’s choice group. 
During 
this 
evaluation 
all 
routine 
clinical 
considerations, 
including 
treatment 
specific 
restrictions/contraindications as per Summary of Product Characteristics/Prescribing Information for the 
physician’s choice treatment options, should be taken into account.  Only after it is concluded that at least 
one of the four treatment options in the physician’s choice group would be an appropriate way to treat 
the patient, the patient can be considered for the study as per inclusion/exclusion criteria. 


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The study population will consist of patients with HER2-positive unresectable locally advanced or metastatic 
breast cancer complying with the following in- and exclusion criteria: 
 
Inclusion criteria 
1. Female patients, age ≥ 18 years old at the time of signing informed consent; 
2. Patients with histologically-confirmed, unresectable locally advanced or metastatic breast cancer; 
3. Patients should have had either progression during or after at least two HER2-targeting treatment regimens 
for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine 
treatment for locally advanced or metastatic disease; 
4. HER2-positive tumour status according to the ASCO-CAP guidelines (defined as a 3+ score on 
immunohistochemistry (IHC) and/or positive by in situ hybridization (ISH)) confirmed by the central 
laboratory;  
5. Patients must have measurable or non-measurable disease that is evaluable per Response Evaluation 
Criteria for Solid Tumours (RECIST version 1.1). Patients with bone-only sclerotic disease without a lytic 
component, or patients who have bone-only metastases requiring endocrine therapy or patients with non-
visceral metastases requiring endocrine therapy, are not eligible; 
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 
  
Section 1.1 Study flowchart (page 8)  
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 “Study”-ICF an eligible patient should be randomized within 28 days. A “HER2 testing”-ICF may be used to assess the 
HER2 tumour status on archival tumour tissue to determine patient eligibility; 
2. 
Day 1 assessments are to be done prior to study drug administration; 
3. 
Weight should be measured before the start of a new cycle, this may be done up to 7 days before the Day 1 visit; 
4. 
Archived tumour material should be submitted for central analysis of HER2 status before randomization, this can be done after signing the “HER2 
testing”-ICF. If there is no archival tumour material available a biopsy should be performed to obtain tumour material, this can only be done after 
signing the “Study”-ICF. The HER2 tumour status will be assessed by a central laboratory using IHC and ISH; 
5. 
Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as closely as possible to the start of the new cycle, 
but may be done up to 3 days before. Analyses should be performed at a local laboratory. Results of the local laboratory should be available 
before the start of the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and 
cardiac troponin should also be performed at the central laboratory;   
6. 
Either cardiac troponin I or T (using a high sensitivity assay) can be measured as long as the same assay is used throughout the study for an 
individual patient;  
7. 
Pregnancy test in women of childbearing potential: serum test at screening, urinary tests during treatment in case of suspected pregnancy; 
8. 
PK samples will be taken in the SYD985 treatment group only. See for details the PK sampling scheme on page 10; 
9. 
Immunogenicity samples will be taken in the SYD985 group only; 
10. 
Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as 
LVEF assessment 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; 
11. 
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 
9.5.1.1 of the protocol; 
12. 
12-lead ECGs should be recorded in triplicate. ECGs should be obtained before study drug administration for all patients. In addition ECGs 
should be obtained 30 minutes after the end of infusion at the day of first study drug administration in cycle 1 and cycle 4 in all patients excluding 
the patients in the Physician’s choice group receivingLapatinib + Capacitabine. The ECGs should be submitted for central review; 
 
Now reads as: 
General note: in case assessments show abnormal results that warrant more extensive monitoring for safety, additional visits 
and assessments should be considered. For patients on physician’s choice treatment in addition to the assessments in the 
flowchart guidance from the Summary of Product Characteristics/Prescribing Information of the specific treatments should 
be followed with regards to patient monitoring. 
1. 
Following signing the “Study”-ICF an eligible patient should be randomized within 28 days. A “HER2 testing”-ICF may be used to assess the 
HER2 tumour status on archival tumour tissue to determine patient eligibility; 
2. 
Day 1 assessments are to be done prior to study drug administration; 


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3. 
Weight should be measured before the start of a new cycle, this may be done up to 7 days before the Day 1 visit; 
4. 
Archived tumour material should be submitted for central analysis of HER2 status before randomization, this can be done after signing the “HER2 
testing”-ICF. If there is no archival tumour material available a biopsy should be performed to obtain tumour material, this can only be done after 
signing the “Study”-ICF. The HER2 tumour status will be assessed by a central laboratory using IHC and ISH; 
5. 
Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as closely as possible to the start of the new cycle, 
but may be done up to 3 days before. Analyses should be performed at a local laboratory. Results of the local laboratory should be available 
before the start of the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and 
cardiac troponin should also be performed at the central laboratory;   
6. 
Either cardiac troponin I or T (using a high sensitivity assay) can be measured as long as the same assay is used throughout the study for an 
individual patient;  
7. 
Pregnancy test in women of childbearing potential: serum test at screening (between day -10 and day -1), urinary tests during treatment and at 
treatment discontinuation visit in case of suspected pregnancy; 
8. 
PK samples will be taken in the SYD985 treatment group only. See for details the PK sampling scheme on page 10; 
9. 
Immunogenicity samples will be taken in the SYD985 group only; 
10. 
Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as 
LVEF assessment 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; 
11. 
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 
9.5.1.1 of the protocol; 
12. 
12-lead ECGs should be recorded in triplicate. ECGs should be obtained before study drug administration for all patients. In addition ECGs 
should be obtained 30 minutes after the end of infusion at the day of first study drug administration in cycle 1 and cycle 4 in all patients excluding 
the patients in the Physician’s Choice group receiving the oral treatment combination lapatinib + capacitabine. The ECGs should be submitted 
for central review; 
 
Section 5.2 patient population rationale (page 20)  
Part II of the Phase I study is ongoing; expanded patient cohorts with specific cancer types, including 
late-line HER2-positive locally advanced or metastatic breast cancer, are being evaluated for safety 
and efficacy. 
 
Now reads as: 
Part II of the Phase I study is ongoing; expanded patient cohorts with specific cancer types, including 
50 heavily pre-treated patients with late-line HER2-positive locally advanced or metastatic breast 
cancer, are being evaluated for safety and efficacy. 
 
Section 5.5.1 SYD985 treatment (page 22)  
Cardiac toxicity 
Cardiac safety should be monitored in oncology patients commonly pre-treated with anthracycline 
therapy and/or treated with HER2-targeting agents. Transient, LVEF decreases have been observed 
in the Phase I study. LVEF decreases have also been observed in patients treated with trastuzumab 
and (ado-)trastuzumab emtansine and these often occur in the early treatment cycles11-13. Patients 
treated with these drugs are at increased risk of developing congestive heart failure or dysfunction, 
particularly following anthracycline therapy. 
Cardiotoxicity is closely monitored in the study by performing LVEF and ECGs, and by measuring 
cardiac troponin regularly during SYD985 treatment. Patients with an increased risk of developing 
cardiac dysfunction, as defined in this protocol, are not eligible to participate in the study.  
 
Now reads as: 
Cardiac toxicity 
Cardiac safety should be monitored in oncology patients commonly pre-treated with anthracycline 
therapy and/or treated with HER2-targeting agents. Transient, LVEF decreases have been observed 
in the Phase I study. LVEF decreases have also been observed in patients treated with trastuzumab 
and (ado-)trastuzumab emtansine and these often occur in the early treatment cycles11-13. Patients 


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treated with these drugs are at increased risk of developing congestive heart failure or dysfunction, 
particularly following anthracycline therapy. 
Cardiotoxicity is closely monitored in the study by performing LVEF and ECGs, and by measuring 
cardiac troponin regularly during SYD985 treatment. Patients with an increased risk of developing 
cardiac dysfunction, as defined in this protocol, are not eligible to participate in the study. Any 
clinically relevant electrolyte disturbance (e.g. hypomagnesaemia and hypokalemia) should be 
corrected as appropriate.    
 
Section 5.5.1 Physician’s choice treatment (page 23) has been added 
For safety considerations on the physician’s choice treatments the information as described in the 
local Summary of Product Characteristics/Prescribing Information (SmPC/PI) of the specific 
treatments should be consulted. SYD985.002 is a global study and details may differ per country, 
therefore the investigator should consult the SmPC/PI as approved by their local country medicines 
agency (e.g. FDA, EMA, MHRA etc.). The local SmPC/PI will be provided and is to be filed in the 
ISF. 
 
When evaluating a patient for participation into the study the investigator should first consider which 
combination treatment would be prescribed if the patient would be randomized to the physician’s 
choice group. During this evaluation, all routine clinical considerations, including treatment specific 
restrictions/contraindications as per SmPC/PI for the physician’s choice treatment options, should be 
taken into account. If, for example, based on information in the medical history or the laboratory 
values of the patient one of the treatment options in the physician’s choice group is contraindicated, 
that particular patient would have only three options of physician’s choice treatment. Only after it is 
concluded that at least one of the four treatment options in the physician’s choice group would be an 
appropriate way to treat the patient, the patient can be considered for the study as per 
inclusion/exclusion criteria. 
 
During physician’s choice treatment guidance from the SmPC/PI of the specific treatments should be 
followed. In particular with regards to:  
• Contraindications, Warnings and precautions, Adverse events;  
• Posology and method of administration, Dosage and administration; 
• Interactions; 
• Fertility, Special populations. 
 
This protocol cannot address every safety consideration for all of the ‘physician’s choice’ options. 
The investigator is referred to respective local summaries of product characteristics or prescribing 
information for specific guidance. In particular it is noted that there is variation among the options 
with regard to:  
• duration of contraception after the last of study therapy administration; 
• duration to avoid live vaccines before, during, and after study therapy administration; 
• drug-drug interactions, in particular with regard to cytochrome P450 system. 
 
Section 5.6 Benefit – Risk assessment (page 23) has been added 
Based on the Phase I experience it can be concluded that there is a positive benefit/risk for patients 
with late-line HER2-positive locally advanced or metastatic breast cancer who have had progression 


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either during or after at least two HER2-targeting treatment regimens in the locally advanced or 
metastatic setting or after (ado-)trastuzumab emtansine treatment in the locally advanced or 
metastatic setting. Therefore SYD985 represents a reasonable treatment option for the intended 
patient population in this study. 
 
 
Section 7 Study design (page 24)  
The study will end when: 
• All patients have completed the treatment discontinuation visit, or 
• Sufficient survival follow-up information is obtained to enable analysis, or 
• The trial is terminated by the Sponsor. 
 
Now reads as: 
The study will end when: 
• All patients have completed the treatment discontinuation visit, or 
• Sufficient survival follow-up information is obtained to enable analysis, or 
• The trial is terminated by the Sponsor. 
 
When the study is ended before all patients have discontinued study treatment, individual patients 
who benefit from SYD985 treatment will be enabled to receive further SYD985 treatment.  
 
Section 8.1 Eligibility Criteria (page 24) following details have been added 
When evaluating a patient for participation into the study the investigator should first consider which 
combination treatment would be prescribed if the patient would be randomized to the physician’s 
choice group. During this evaluation all routine clinical considerations, including treatment specific 
restrictions/contraindications as per SmPC/PI for the physician’s choice treatment options, should be 
taken into account. Only after it is concluded that at least one of the four treatment options in the 
physician’s choice group would be an appropriate way to treat the patient, the patient can be 
considered for the study as per inclusion/exclusion criteria. 
 
Section 8.1.1 Inclusion Criteria (page 24)  
5. Patients must have measurable or non-measurable disease that is evaluable per Response 
Evaluation Criteria for Solid Tumours (RECIST version 1.1). Patients with bone-only sclerotic 
disease without a lytic component are not eligible; 
 
Now reads as: 
5. Patients must have measurable or non-measurable disease that is evaluable per Response 
Evaluation Criteria for Solid Tumours (RECIST version 1.1). Patients with bone-only sclerotic 
disease without a lytic component, or patients who have bone-only metastases requiring endocrine 
therapy or patients with non-visceral metastases requiring endocrine therapy, are not eligible; 
 
Section 9.4.2 Physician’s choice treatment (page 29)  
Physician’s choice therapy options: 
• Option 1: Lapatinib + Capecitabine 
• Option 2: Trastuzumab + Capecitabine 


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• Option 3: Trastuzumab + Vinorelbine 
• Option 4: Trastuzumab + Eribulin 
 
The choice of reference therapy will be at the investigator’s discretion and should be in accordance 
with local clinical practice. 
 
For details on dosing and frequency the Summary of Product Characteristics of the prescribed drugs 
and local prescribing information should be used. 
 
Now reads as: 
Physician’s choice therapy options: 
• Option 1: Lapatinib + Capecitabine 
• Option 2: Trastuzumab + Capecitabine 
• Option 3: Trastuzumab + Vinorelbine 
• Option 4: Trastuzumab + Eribulin 
 
The choice of reference therapy will be at the investigator’s discretion and should be in accordance 
with local clinical practice. During this evaluation all routine clinical considerations, including 
treatment specific restrictions/contraindications as per SmPC/PI for the physician’s choice treatment 
options, should be taken into account. During physician’s choice treatment guidance from the 
SmPC/PI of the specific treatments should be followed. In particular with regards to:  
• Contraindications, Warnings and precautions, Adverse events;  
• Posology and method of administration, Dosage and administration; 
• Interactions; 
• Fertility, Special populations. 
 
For details on dosing and frequency the Summary of Product Characteristics of the prescribed drugs 
and local prescribing information should be used. 
 
Section 9.5.2 Physician’s choice treatment (page 31)  
Dosing of physician’s choice treatments can be modified (reduced, delayed) according to local 
clinical practice. 
 
If one of the two agents of the combination regimen is discontinued the therapy can be continued with 
a single agent. However, if both agents of the regimen are discontinued for more than 42 days from 
the last dose the patient will be considered to have discontinued treatment. 
 
Now reads as: 
During physician’s choice treatment guidance from the SmPC/PI of the specific treatments should be 
followed. In particular with regards to:  
• Contraindications, Warnings and precautions, Adverse events;  
• Posology and method of administration, Dosage and administration; 
• Interactions; 
• Fertility, Special populations. 
 


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Dosing of physician’s choice treatments can be modified (reduced, delayed) according to local 
clinical practice. 
 
If one of the two agents of the combination regimen is discontinued the therapy can be continued with 
a single agent. However, if both agents of the regimen are discontinued for more than 42 days from 
the last dose the patient will be considered to have discontinued treatment. 
 
Section 10 Pretreatment and concomitant medication and non-drug therapies (page 33)  
Information on all prior received anticancer therapies must be recorded in the eCRF. Washout criteria 
apply for prior anticancer therapy as described in exclusion criterion 1. Other pre-treatment 
medication and concomitant medication used between 14 days prior to signing “Study”-ICF till the 
treatment discontinuation visit should be recorded in the eCRF. 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.  
 
Patients are allowed to receive supportive care therapies concomitantly during the study. Patients who 
receive anthracycline treatment within 12 weeks prior to randomization are not allowed to participate 
in the study. No other chemotherapy, immunotherapy, or experimental medications are permitted 
from 4 weeks prior to randomization, radiation therapy from 2 weeks prior to randomization, and 1 
week for hormone therapy, during study treatment and (if possible) up to 30 days after the last study 
treatment dose. 
 
During study treatment and up to 30 days after the last treatment dose palliative radiotherapy is 
allowed only for the symptomatic treatment of painful bone lesions identified at baseline. Please 
contact the Medical Monitor for approval.  
 
Patients who have disease control outside the brain, defined as having received clinical benefit (i.e. 
partial response (PR) or complete response (CR) of any duration, or stable disease (SD) for ≥ 4 
months) but who have brain metastases that will benefit from treatment with radiation in the opinion 
of the investigator will be allowed to continue to receive study therapy until they either experience 
systemic progression of their disease and/or further progression in the brain (based on investigator 
assessment). Please contact the Medical Monitor for approval. Patients must not miss more than one 
21-day cycle for the treatment of their brain disease to continue on therapy. 
 
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. 
 


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Prophylactic lubricating eye drops will be prescribed to patients in the SYD985 group, 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.  
 
Patients of childbearing potential must use effective contraception during the study, and up to 6 
months after last study drug dose. Acceptable forms of contraception include two of the following: 
• Established use of oral, injected, implanted or other form of hormonal method of 
contraception; 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
• Condom with spermicidal foam/gel/film/cream/suppository; 
• Diaphragm or cervical/vault caps with spermicidal foam/gel/film/cream/suppository. 
 
The above contraception is not a requirement in the case of any of the following: 
• Patient or sole partner of patient is surgically sterilized; 
• True sexual abstinence. 
 
Periodic abstinence (e.g. calendar, ovulation, symptom-thermal, post-ovulation methods) and 
withdrawal are not acceptable forms of contraception. 
 
Now reads as: 
Information on all prior received anticancer therapies must be recorded in the eCRF. Washout criteria 
apply for prior anticancer therapy as described in exclusion criterion 1. Other pre-treatment 
medication and concomitant medication used between 14 days prior to signing “Study”-ICF till the 
treatment discontinuation visit should be recorded in the eCRF. 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.  
 
Patients are allowed to receive supportive care therapies concomitantly during the study. Patients who 
receive anthracycline treatment within 12 weeks prior to randomization are not allowed to participate 
in the study. No other chemotherapy, immunotherapy, or experimental medications are permitted 
from 4 weeks prior to randomization, radiation therapy from 2 weeks prior to randomization, and 1 
week for hormone therapy, during study treatment and (if possible) up to 30 days after the last study 
treatment dose. 
 
During physician’s choice treatment guidance from the SmPC/PI of the specific treatments should be 
followed with regards to co-medications that are contraindicated or are to be used with precaution. 
 
During study treatment and up to 30 days after the last treatment dose palliative radiotherapy is 
allowed only for the symptomatic treatment of painful bone lesions identified at baseline. Please 
contact the Medical Monitor for approval.  
 


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Patients who have disease control outside the brain, defined as having received clinical benefit (i.e. 
partial response (PR) or complete response (CR) of any duration, or stable disease (SD) for ≥ 4 
months) but who have brain metastases that will benefit from treatment with radiation in the opinion 
of the investigator will be allowed to continue to receive study therapy until they either experience 
systemic progression of their disease and/or further progression in the brain (based on investigator 
assessment). Please contact the Medical Monitor for approval. Patients must not miss more than one 
21-day cycle for the treatment of their brain disease to continue on therapy. 
 
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 will be prescribed to patients in the SYD985 group, 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.  
 
Patients of childbearing potential must use 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.18 
Acceptable forms of contraception include two of the following: 
• Established use of oral, injected, implanted or other form of hormonal method of 
contraception; 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
• Condom with spermicidal foam/gel/film/cream/suppository; 
• Diaphragm or cervical/vault caps with spermicidal foam/gel/film/cream/suppository. 
 
The above contraception is not a requirement in the case of any of the following: 
• Patient or sole partner of patient is surgically sterilized; 
• True sexual abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). 
 
Periodic abstinence (e.g. calendar, ovulation, symptom-thermal, post-ovulation methods), 
progesterone-only oral hormonal contraception where inhibition of ovulation is not the primary mode 
of action, and withdrawal are not acceptable forms of contraception. 
 
Section 11.9 Pregnancy test (page 37)  
To exclude pregnancy in women of childbearing potential, a serum pregnancy test at screening and 
urine pregnancy tests during treatment in case of suspected pregnancy will be performed at the local 
laboratory.  
 


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Now reads as: 
To exclude pregnancy in women of childbearing potential, a serum pregnancy test at screening 
(between day -10 and day -1) and urine pregnancy tests during treatment in case of suspected 
pregnancy on Day 1 of each cycle and at the treatment discontinuation visit will be performed at the 
local laboratory.  
 
Section 11.16 ECG assessment (page 40)  
Table 7: ECG assessment schedule 
Cycle 
Time point 
Screening 
Screening 
1 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
2 
Day 1: Before study drug administration# 
4 
Day 1: Before study drug administration# 
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)#  
Every subsequent 4th cycle 
Day 1: Before study drug administration# 
Treatment discontinuation 
Treatment discontinuation 
*not applicable for patients in physician’s choice group receiving Lapatinib + Capecitabine.  
#For patients in physician’s choice group receiving Lapatinib + Capecitabine the timing of the ECG on Cycle 
2 Day 1 and Cycle 4 Day 1 does not have to be correlated to the study drug administration. The ECG on Cycle 
4 Day 2 should be 24 hours (± 2hours) after the Cycle 4 Day 1 ECG. 
 
Now reads as: 
Table 8: ECG assessment schedule 
Cycle 
Time point 
Screening 
Screening 
1 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
2 
Day 1: Before study drug administration# 
3 
Day 1: Before study drug administration# 
4 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
Every subsequent 4th cycle 
Day 1: Before study drug administration# 
Treatment discontinuation 
Treatment discontinuation 
*not applicable for patients in physician’s choice group receiving the oral treatment combination Lapatinib + 
Capecitabine.  
#For patients in physician’s choice group receiving the oral treatment combination Lapatinib + Capecitabine 
the timing of the ECG on Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1 does not have to be correlated to 
the study drug administration. The ECG on Cycle 4 Day 2 should be 24 hours (± 2 hours) after the Cycle 4 
Day 1 ECG. 


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Section 16 References (page 67) a reference has been added 
(18)   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 5 Protocol Amendment III 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
Protocol title: 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the 
antibody-drug conjugate SYD985 to physician’s choice in patients with HER2-positive unresectable 
locally advanced or metastatic breast cancer 
 
 
 
 
Abbreviated title: 
TULIP 
Protocol Number: 
SYD985.002 
Development phase: 
Phase III 
Drug product code: 
SYD985 
Drug substance: 
Trastuzumab vc-seco-DUBA  
EudraCT Number: 
2017-001994-18 
IND Number: 
131333 
Amendment: 
Protocol Amendment III 
(leading to Protocol Version 4.0) 
 
Amendment Date: 
11 September 2018 
Authors Byondis BV: 
 
Evelyn van den Tweel, Clinical Project Leader  
Mayke Oesterholt, Clinical Project Leader 
Ellen Mommers, Clinical Project Leader 
Roel Mulder, Biostatistician  
 
 
 
 
 
 
 
 
 
 
 
This document includes confidential and privileged information and data that contain trade secrets which are 
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 study at a clinical 
investigational site. 
 


Clinical Study Protocol 
SYD985.002 
TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 96 of 126 
 
 
Justification for the amendment 
This substantial amendment has been prepared for the following reasons: 
• Section 9.5.1 has been updated to add the possibility to reduce dosing to 0.6 mg/kg which has 
been shown to be an effective and safe dose in the phase I study. 
• Section 11.9 and the flowchart have been updates to add the possibility for serum pregnancy 
test in addition to urine pregnancy test as routinely performed in several clinical sites. 
• Section 12.10, 14.7 and the synopsis have been updated to describe that the DMC will assess 
the assumptions underlying the sample size estimation. 
• Section 2 has been updated to reflect changes in the vendor responsibilities. 
 
Apart from editorial changes, version changes to the title page and table of contents, this has led to 
the following changes in the protocol text (all included in version 4 of the protocol). New text is 
underlined, deleted text is strikethrough: 
 
Protocol synopsis: Data Monitoring Committee (page 6) 
No interim analysis will be performed. Safety will be monitored on an ongoing basis during the entire study by 
an independent external Data Monitoring Committee (DMC), of which the composition, roles and responsibilities 
will be described in a separate charter. 
 
Now reads as: 
No interim analysis will be performed. Safety will be monitored on an ongoing basis during the entire study by 
an independent external Data Monitoring Committee (DMC), of which the composition, roles and responsibilities 
will be described in a separate charter.  As part of their evaluation the DMC will assess if the assumptions 
underlying the sample size estimation with regards to drop-out rates are met, and may advise to change the 
planned sample size in case of serious departures. 
 
Section 1.1 Study flowchart (page 9) 
2. 
Day 1 assessments are to be done prior to study drug administration; 
3. 
Weight should be measured before the start of a new cycle, this may be done up to 7 days before the Day 1 visit; 
4. 
Archived tumour material should be submitted for central analysis of HER2 status before randomization, this can be done after signing the “HER2 
testing”-ICF. If there is no archival tumour material available a biopsy should be performed to obtain tumour material, this can only be done after 
signing the “Study”-ICF. The HER2 tumour status will be assessed by a central laboratory using IHC and ISH; 
5. 
Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as closely as possible to the start of the new cycle, 
but may be done up to 3 days before. Analyses should be performed at a local laboratory. Results of the local laboratory should be available before 
the start of the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and cardiac 
troponin should also be performed at the central laboratory;   
6. 
Either cardiac troponin I or T (using a high sensitivity assay) can be measured as long as the same assay is used throughout the study for an 
individual patient;  
7. 
Pregnancy test in women of childbearing potential: serum test at screening (between day -10 and day -1), urinary tests during treatment and at 
treatment discontinuation visit; 
8. 
PK samples will be taken in the SYD985 treatment group only. See for details the PK sampling scheme on page 10; 
9. 
Immunogenicity samples will be taken in the SYD985 group only; 
10. Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as LVEF 
assessment 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; 
11. 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 
9.5.1.1 of the protocol; 
12. 12-lead ECGs should be recorded in triplicate. ECGs should be obtained before study drug administration for all patients. In addition ECGs should 
be obtained 30 minutes after the end of infusion at the day of first study drug administration in cycle 1 and cycle 4 in all patients excluding the 
patients in the Physician’s Choice group receiving the oral treatment combination lapatinib + capacitabine. The ECGs should be submitted for 
central review; 
13. ECG should be obtained 24 hours (± 2 hours) after study drug administration. The ECGs should be submitted for central review; 
14. For tumour measurements, a CT or MRI scan should be performed every 6 weeks (± 3 days) after the date of randomization for the first 42 weeks 
and every 9 weeks (± 3 days) thereafter, independent of dosing delays. The methodology and imaging levels should remain the same at baseline 
and subsequent evaluations for a given patient;  


Clinical Study Protocol 
SYD985.002 
TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 97 of 126 
 
 
15. The tumour measurements should be submitted for central review; 
16. Administration of SYD985 or administration of physician’s choice in a 21-days (3 weeks) regimen (± 3 days) until disease progression or 
unacceptable toxicity. For SYD985 no recalculation of the 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;  
17. Tumour evaluation at the treatment 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 visit; 
18. Patients should be followed up until death, lost to follow-up, consent withdrawal or end of study data collection, whichever comes first; 
19. During the survival follow-up only initiation of new anticancer medication should be documented. 
 
Now reads as: 
2 
Day 1 assessments are to be done prior to study drug administration; 
3 
Weight should be measured before the start of a new cycle, this may be done up to 7 days before the Day 1 visit; 
4 
Archived tumour material should be submitted for central analysis of HER2 status before randomization, this can be done after signing the “HER2 
testing”-ICF. If there is no archival tumour material available a biopsy should be performed to obtain tumour material, this can only be done after 
signing the “Study”-ICF. The HER2 tumour status will be assessed by a central laboratory using IHC and ISH; 
5 
Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as closely as possible to the start of the new cycle, but 
may be done up to 3 days before. Analyses should be performed at a local laboratory. Results of the local laboratory should be available before the 
start of the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and cardiac troponin 
should also be performed at the central laboratory;   
6 
Either cardiac troponin I or T (using a high sensitivity assay) can be measured as long as the same assay is used throughout the study for an 
individual patient;  
7 
Pregnancy test in women of childbearing potential: serum test at screening (between day -10 and day -1), serum or urinary tests during treatment 
and at treatment discontinuation visit; 
8 
PK samples will be taken in the SYD985 treatment group only. See for details the PK sampling scheme on page 10; 
9 
Immunogenicity samples will be taken in the SYD985 group only; 
10 Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as LVEF 
assessment 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; 
11 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 
9.5.1.1 of the protocol; 
12 12-lead ECGs should be recorded in triplicate. ECGs should be obtained before study drug administration for all patients. In addition ECGs should 
be obtained 30 minutes after the end of infusion at the day of first study drug administration in cycle 1 and cycle 4 in all patients excluding the 
patients in the Physician’s Choice group receiving the oral treatment combination lapatinib + capacitabine. The ECGs should be submitted for 
central review; 
13 ECG should be obtained 24 hours (± 2 hours) after study drug administration. The ECGs should be submitted for central review; 
14 For tumour measurements, a CT or MRI scan should be performed every 6 weeks (± 3 days) after the date of randomization for the first 42 weeks 
and every 9 weeks (± 3 days) thereafter, independent of dosing delays. The methodology and imaging levels should remain the same at baseline 
and subsequent evaluations for a given patient;  
15 The tumour measurements should be submitted for central review; 
16 Administration of SYD985 or administration of physician’s choice in a 21-days (3 weeks) regimen (± 3 days) until disease progression or 
unacceptable toxicity. For SYD985 no recalculation of the 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;  
17 Tumour evaluation at the treatment 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 visit; 
18 Patients should be followed up until death, lost to follow-up, consent withdrawal or end of study data collection, whichever comes first; 
19 During the survival follow-up only initiation of new anticancer medication should be documented. 
 
Section 2 (page 12) 
Central Image Analysis: 
(RECIST evaluation) 
Bioclinica 
Imaging Core Lab and Cardiac Safety Princeton Office 
100 Overlook Center 
Princeton, NJ 08540 
USA 
Central ECG Centre: 
(ECG evaluation) 
BMS 
Biomedical Systems 
77 Progress Parkway 
Maryland Heights, MO 63043 


Clinical Study Protocol 
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Version 8.0 
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Document number (version): CSP.NL03.57088 (8.0) 
Page 98 of 126 
 
 
USA 
Central Laboratory: 
(Safety laboratory & logistics) 
Eurofins 
Eurofins Central Laboratory, LCC 
22430 New Holland Pike, D100 
Lancaster, PA 17601 
USA 
Central Laboratory: 
(for PK total SYD985, SYD985 
DAR≥1 and immunogenicity) 
LGC Ltd 
Newmarket Road 
Fordham, Cambridgeshire 
CB7 5WW 
United Kingdom 
Central Laboratory: 
(for PK SYD986) 
Analytical Biochemical Laboratory (ABL) 
W.A. Scholtenstraat 7 
9403 AJ Assen 
The Netherlands 
Central Laboratory: 
(for HER2 Tumour expression) 
Targos Molecular Pathology 
Germaniastrasse 7 
D-34119 Kassel 
Germany 
 
Now reads as: 
Central Image Analysis: 
(RECIST evaluation) 
Bioclinica 
Imaging Core Lab and Cardiac Safety Princeton Office 
100 Overlook Center 
Princeton, NJ 08540 
USA 
Central ECG Centre: 
(ECG evaluation) 
ERT (formerly BMS) 
Biomedical systems 
77 Progress Parkway 
Maryland Heights, MO 63043 
USA 
Central Laboratory: 
(Safety laboratory & logistics) 
Eurofins 
Eurofins Central Laboratory, LCC 
22430 New Holland Pike, D100 
Lancaster, PA 17601 
USA 
Central Laboratory: 
(for PK total SYD985, SYD985 
DAR≥1 and immunogenicity) 
LGC Ltd 
Newmarket Road 
Fordham, Cambridgeshire 
CB7 5WW 
United Kingdom 
Central Laboratory: 
(for PK SYD986, total SYD985, 
SYD985 
DAR≥1 
and 
immunogenicity) 
Analytical Biochemical Laboratory (ABL) 
W.A. Scholtenstraat 7 
9403 AJ Assen 
The Netherlands 


Clinical Study Protocol 
SYD985.002 
TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 99 of 126 
 
 
Central Laboratory: 
(for HER2 Tumour expression) 
Targos Molecular Pathology 
Germaniastrasse 7 
D-34119 Kassel 
Germany 
Central Laboratory: 
(Neutralizing antibody assay) 
QPS Netherlands BV 
Petrus Campersingel 123 
9713 AG Groningen 
The Netherlands 
 
Section 9.4.1 (page 30) 
SYD985 1.2 mg/kg will be administered every three weeks (± 1 day) by intravenous infusion.  
 
Now reads as: 
SYD985 1.2 mg/kg will be administered every three weeks (± 13 day) by intravenous infusion.  
 
Section 9.5.1 (page 32) 
Dose delays for SYD985-related toxicities, other than the ones specified below, should be handeled 
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 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 
will be discontinued from study treatment and will be followed for survival follow-up as 
described in Section 11.22. 
 
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 
discontinued from treatment. Dose escalation is not allowed after a dose reduction. 
 
As indicated in Section 9.4.1 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 interruption of 
infusion will be discontinued from study treatment. 
 
Protocol requirements for specific toxicities are outlined below. 
 
Now reads as: 


Clinical Study Protocol 
SYD985.002 
TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 100 of 126 
 
 
Dose delays for SYD985-related toxicities, other than the ones specified below, should be handeled 
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 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 
will be discontinued from study treatment and will be followed for survival follow-up as 
described in Section 11.22. 
 
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. 
 
As indicated in Section 9.4.1 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 interruption of 
infusion will be discontinued from study treatment. 
 
Protocol requirements for specific toxicities are outlined below. 
 
Section 11.9 (page 40) 
To exclude pregnancy in women of childbearing potential, a serum pregnancy test at screening 
(between day -10 and day -1) and urine pregnancy tests during treatment on Day 1 of each cycle and 
at the treatment discontinuation visit will be performed at the local laboratory.  
 
Women of childbearing potential participating in this clinical study should be instructed to use 
adequate contraceptive barriers to prevent them from getting pregnant while using study drug (see 
also Section 10).  
 
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. 
 
Now reads as: 
To exclude pregnancy in women of childbearing potential, a serum pregnancy test at screening 
(between day -10 and day -1) and serum or urine pregnancy tests during treatment on Day 1 of each 
cycle and at the treatment discontinuation visit will be performed at the local laboratory.  
 


Clinical Study Protocol 
SYD985.002 
TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 101 of 126 
 
 
Women of childbearing potential participating in this clinical study should be instructed to use 
adequate contraceptive barriers to prevent them from getting pregnant while using study drug (see 
also Section 10).  
 
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. 
 
Section 11.16 (page 43) 
Table 9: ECG assessment schedule 
Cycle 
Time point 
Screening 
Screening 
1 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
2 
Day 1: Before study drug administration# 
3 
Day 1: Before study drug administration# 
4 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
Every subsequent 4th cycle 
Day 1: Before study drug administration# 
Treatment discontinuation 
Treatment discontinuation 
*not applicable for patients in physician’s choice group receiving the oral treatment combination Lapatinib + 
Capecitabine.  
#For patients in physician’s choice group receiving the oral treatment combination Lapatinib + Capecitabine 
the timing of the ECG on Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1 does not have to be correlated to 
the study drug administration. The ECG on Cycle 4 Day 2 should be 24 hours (± 2 hours) after the Cycle 4 
Day 1 ECG. 
 
Now reads as: 
Table 10: ECG assessment schedule 
Cycle 
Time point 
Screening 
Screening 
1 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
2 
Day 1: Before study drug administration# 
3 
Day 1: Before study drug administration# 
4 
Day 1: Before study drug administration# 
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
Every subsequent 4th cycle 
Day 1: Before study drug administration# 
Treatment discontinuation 
Treatment discontinuation 
*not applicable for patients in physician’s choice group receiving the oral treatment combination Lapatinib + 
Capecitabine.  


Clinical Study Protocol 
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Version 8.0 
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#For patients in physician’s choice group receiving the oral treatment combination Lapatinib + Capecitabine 
the timing of the ECG on Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1 does not have to be correlated to 
the study drug administration. The ECG on Cycle 4 Day 2 should be 24 hours (± 2 hours) after the Cycle 4 
Day 1 ECG. 
 
Section 12.10 (page 52) 
Details on the responsibilities, activities and deliverables of the external Data Monitoring Committee 
(DMC) are detailed in a separate charter. 
 
Now reads as: 
Details on the responsibilities, activities and deliverables of the external Data Monitoring Committee 
(DMC) are detailed in a separate charter. As part of their evaluation the DMC will assess if the 
assumptions underlying the sample size estimation with regards to drop-out rates are met, and may 
advise to change the planned sample size in case of serious departures. 
 
Section 14.5.3.1 (page 59) 
Time to response is the time between the date of randomization until first documented response (CR 
or PR) according to RECIST 1.1. All patients will be included in time to response calculations. 
Patients who did not achieve a confirmed CR or PR will be censored at the maximum follow-up time 
for patients who had a PFS event (i.e. either progressed of death due to any cause) or at the date of 
last adequate tumour assessment date otherwise.  
Time to response will be analyzed based on the data observed in the FAS population and will be 
determined primarily by independent central review of tumour assessment (an analysis based on 
investigator tumour assessment will also be performed). Time to response will be summarized for the 
two treatment groups using descriptive statistics.  
 
Now reads as: 
Time to response is the time between the date of randomization until first documented response (CR 
or PR) according to RECIST 1.1. All patients will be included in time to response calculations. 
Patients who did not achieve a confirmed CR or PR will be censored at the maximum follow-up time 
for patients who had a PFS event (i.e. either progressed of death due to any cause) or at the date of 
last adequate tumour assessment date otherwise.  
Time to response will be analyzed based on the data observed in the FAS population and will be 
determined primarily by independent central review of tumour assessment (an analysis based on 
investigator tumour assessment will also be performed). Time to response will be summarized for the 
two treatment groups using descriptive statistics.  
 
Section 14.7 (page 62) 
The primary efficacy endpoint of this study is PFS based on independent central review of tumour 
assessment. The primary efficacy analysis will be event driven. 
 
In order to be able to detect a hazard ratio of 0.65 in PFS using the log-rank test, at 90% power, using 
a two-sided test at a significance level of p < 0.05, a total of 256 events are required. Assuming a 9 
month recruitment period and 10 month follow up period, a median time to progression of 4.1 months 
for the physician’s choice and assuming an average of 20% drop out in the physician’s choice group 


Clinical Study Protocol 
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CONFIDENTIAL 
Version 8.0 
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Document number (version): CSP.NL03.57088 (8.0) 
Page 103 of 126 
 
 
and 30% in the SYD985 group, a minimal number of 309 patients is required. To adjust for departures 
from the assumptions (clinical and statistical) enrolment is targeted for at least 345 patients. 
Allocation is 2:1 resulting in 230 to be allocated to the SYD985 group and 115 to the physician’s 
choice group. 
 
Randomization will be done by a permutated block design with a fixed block size, using world region 
(Europe and Singapore/North-America), the number of prior treatment lines for locally advanced or 
metastatic breast cancer (excluding hormone therapy) (2/>2), and prior treatment with pertuzumab 
(yes/no) as stratification factors. 
 
Now reads as: 
The primary efficacy endpoint of this study is PFS based on independent central review of tumour 
assessment. The primary efficacy analysis will be event driven. 
 
In order to be able to detect a hazard ratio of 0.65 in PFS using the log-rank test, at 90% power, using 
a two-sided test at a significance level of p < 0.05, a total of 256 events are required. Assuming a 9 
month recruitment period and 10 month follow up period, a median time to progression of 4.1 months 
for the physician’s choice and assuming an average of 20% drop out in the physician’s choice group 
and 30% in the SYD985 group, a minimal number of 309 patients is required. To adjust for departures 
from the assumptions (clinical and statistical) enrolment is targeted for at least 345 patients. 
Allocation is 2:1 resulting in 230 to be allocated to the SYD985 group and 115 to the physician’s 
choice group. 
 
Randomization will be done by a permutated block design with a fixed block size, using world region 
(Europe and Singapore/North-America), the number of prior treatment lines for locally advanced or 
metastatic breast cancer (excluding hormone therapy) (2/>2), and prior treatment with pertuzumab 
(yes/no) as stratification factors. 
 
No formal interim analysis will be performed. As part of their evaluation the DMC will assess if the 
assumptions underlying the sample size estimation with regards to drop-out rate are met, and may 
advise to change the planned sample size in case of serious departures. Such sample size re-estimation 
will not be considered a formal interim analysis as no between-group comparison of event-rates will 
be performed. Therefore, the primary analysis will be performed at the set 5% significance level. 
 
Appendix 2 Tumour evaluation criteria (page 75) 
Target lesions should have their actual measurements recorded at each subsequent evaluation, even 
when very small (e.g. 2 mm). In cases where the radiologist are not comfortable assigning a 
measurement to a very small lesions, the lesions should either be recorded as likely disappears (I.e. 0 
mm) or 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). 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. 
 
Now reads as: 


Clinical Study Protocol 
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TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 104 of 126 
 
 
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 , even when very small (e.g. 2 mm). In cases where the radiologist are not comfortable 
assigning a measurement to a very small lesions, the lesions should either be recorded as likely 
disappears (I.e. 0 mm) 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. 
 
 


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Appendix 6 Protocol Amendment IV 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
Protocol title: 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the 
antibody-drug conjugate SYD985 to physician’s choice in patients with HER2-positive unresectable 
locally advanced or metastatic breast cancer 
 
 
 
 
Abbreviated title: 
TULIP 
Protocol Number: 
SYD985.002 
Development phase: 
Phase III 
Drug product code: 
SYD985 
Drug substance: 
Trastuzumab vc-seco-DUBA  
EudraCT Number: 
2017-001994-18 
IND Number: 
131333 
Amendment: 
Protocol Amendment IV 
(leading to Protocol Version 5.0) 
 
Amendment Date: 
12 April 2019 
Authors Byondis BV: 
 
Evelyn van den Tweel, Clinical Project Leader  
Mayke Oesterholt, Clinical Project Leader 
Ellen Mommers, Clinical Project Leader 
Roel Mulder, Biostatistician  
 
 
 
 
 
 
 
 
 
 
 
This document includes confidential and privileged information and data that contain trade secrets which are 
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 study at a clinical 
investigational site. 
 


Clinical Study Protocol 
SYD985.002 
TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 106 of 126 
 
 
Justification for the amendment 
This substantial amendment has been prepared for the following reasons: 
• Upon request of the DMC Keratitis grade ≥2 has been added as an adverse event of special 
interest 
• In consultation with the Steering committee and the DMC Section 8.2 has been updated to 
add the possibility to allow re-screening for patients for whom during screening on the brain 
CT/MRI a previously unknown asymptomatic metastasis is observed. 
• Section 11.9 and the flowchart have been updated to add the possibility to perform the 
pregnancy test up to 3 days before Day 1 of a new cycle for practical reasons. 
• Section 11.21 and the flowchart have been updated to add that the treatment discontinuation 
visit should be performed before new anti-cancer treatment is initiated. 
 
Apart from editorial changes, version changes to the title page and table of contents, this has led to 
the following changes in the protocol text (all included in version 5 of the protocol). New text is 
underlined, deleted text is strikethrough: 
 
Protocol synopsis: Sample size (page 6) 
Randomization will be done by a permutated block design with a fixed block size, using world region (Europe 
and Singapore/North-America), the number of prior treatment lines for locally advanced or metastatic breast 
cancer (excluding hormone therapy) (2/>2), and prior treatment with pertuzumab (yes/no) as stratification 
factors. 
 
Now reads as: 
Randomization will be done by a permutated block design with a fixed block size, using world region 
(Europe and Singapore/North-America), the number of prior treatment lines for locally advanced or 
metastatic breast cancer (excluding hormone therapy) (2/>2 1 or 2/more than 2), and prior treatment with 
pertuzumab (yes/no) as stratification factors. 
 
Study flowchart (page 9) 
2     Day 1 assessments are to be done prior to study drug administration; 
3 
Weight should be measured before the start of a new cycle, this may be done up to 7 days before the Day 1 visit; 
4 
Archived tumour material should be submitted for central analysis of HER2 status before randomization, this can be done after signing the “HER2 
testing”-ICF. If there is no archival tumour material available a biopsy should be performed to obtain tumour material, this can only be done after 
signing the “Study”-ICF. The HER2 tumour status will be assessed by a central laboratory using IHC and ISH; 
5 
Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as closely as possible to the start of the new cycle, but 
may be done up to 3 days before. Analyses should be performed at a local laboratory. Results of the local laboratory should be available before the 
start of the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and cardiac troponin 
should also be performed at the central laboratory;   
6 
Either cardiac troponin I or T (using a high sensitivity assay) can be measured as long as the same assay is used throughout the study for an 
individual patient;  
7 
Pregnancy test in women of childbearing potential: serum test at screening (between day -10 and day -1), serum or urinary tests during treatment 
and at treatment discontinuation visit; 
8 
PK samples will be taken in the SYD985 treatment group only. See for details the PK sampling scheme on page 10; 
9 
Immunogenicity samples will be taken in the SYD985 group only; 
10 Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as LVEF 
assessment 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; 
11 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 
9.5.1.1 of the protocol; 
12 12-lead ECGs should be recorded in triplicate. ECGs should be obtained before study drug administration for all patients. In addition ECGs should 
be obtained 30 minutes after the end of infusion at the day of first study drug administration in cycle 1 and cycle 4 in all patients excluding the 
patients in the Physician’s Choice group receiving the oral treatment combination lapatinib + capacitabine. The ECGs should be submitted for 
central review; 
13 ECG should be obtained 24 hours (± 2 hours) after study drug administration. The ECGs should be submitted for central review; 


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14 For tumour measurements, a CT or MRI scan should be performed every 6 weeks (± 3 days) after the date of randomization for the first 42 weeks 
and every 9 weeks (± 3 days) thereafter, independent of dosing delays. The methodology and imaging levels should remain the same at baseline 
and subsequent evaluations for a given patient;  
15 The tumour measurements should be submitted for central review; 
16 Administration of SYD985 or administration of physician’s choice in a 21-days (3 weeks) regimen (± 3 days) until disease progression or 
unacceptable toxicity. For SYD985 no recalculation of the 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;  
17 Tumour evaluation at the treatment 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 visit; 
18 Patients should be followed up until death, lost to follow-up, consent withdrawal or end of study data collection, whichever comes first; 
19 During the survival follow-up only initiation of new anticancer medication should be documented. 
 
Now reads as: 
2     Day 1 assessments are to be done prior to study drug administration; 
3 
Weight should be measured before the start of a new cycle, this may be done up to 7 days before the Day 1 visit; 
4 
Archived tumour material should be submitted for central analysis of HER2 status before randomization, this can be done after signing the “HER2 
testing”-ICF. If there is no archival tumour material available a biopsy should be performed to obtain tumour material, this can only be done after 
signing the “Study”-ICF. The HER2 tumour status will be assessed by a central laboratory using IHC and ISH; 
5 
Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as closely as possible to the start of the new cycle, but 
may be done up to 3 days before. Analyses should be performed at a local laboratory. Results of the local laboratory should be available before the 
start of the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and cardiac troponin 
should also be performed at the central laboratory;   
6 
Either cardiac troponin I or T (using a high sensitivity assay) can be measured as long as the same assay is used throughout the study for an 
individual patient;  
7 
Pregnancy test in women of childbearing potential: serum test at screening (between day -10 and day -1), serum or urinary tests during treatment 
(should be done on Day1 of the new cycle, but may be done up to 3 days before) and at treatment discontinuation visit; 
8 
PK samples will be taken in the SYD985 treatment group only. See for details the PK sampling scheme on page 10; 
9 
Immunogenicity samples will be taken in the SYD985 group only; 
10 Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as LVEF 
assessment 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; 
11 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 
9.5.1.1 of the protocol; 
12 12-lead ECGs should be recorded in triplicate. ECGs should be obtained before study drug administration for all patients. In addition ECGs should 
be obtained 30 minutes after the end of infusion at the day of first study drug administration in cycle 1 and cycle 4 in all patients excluding the 
patients in the Physician’s Choice group receiving the oral treatment combination lapatinib + capacitabine. The ECGs should be submitted for 
central review; 
13 ECG should be obtained 24 hours (± 2 hours) after study drug administration. The ECGs should be submitted for central review; 
14 For tumour measurements, a CT or MRI scan should be performed every 6 weeks (± 3 days) after the date of randomization for the first 42 weeks 
and every 9 weeks (± 3 days) thereafter, independent of dosing delays. The methodology and imaging levels should remain the same at baseline 
and subsequent evaluations for a given patient;  
15 The tumour measurements should be submitted for central review; 
16 Administration of SYD985 or administration of physician’s choice in a 21-days (3 weeks) regimen (± 3 days) until disease progression or 
unacceptable toxicity. For SYD985 no recalculation of the 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;  
17 Tumour evaluation at the treatment 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 visit; 
18 Patients should be followed up until death, lost to follow-up, consent withdrawal or end of study data collection, whichever comes first; 
19 During the survival follow-up only initiation of new anticancer medication should be documented. 
20 The end of treatment visit needs to be performed 28-42 days after the last dose of study drug or before new anticancer treatment is initiated, 
whichever comes first.  
 
Section 8.2 (page 28) 
Patients who signed the “HER2 testing” and/or “Study”-ICF but subsequently failed to meet the 
inclusion and/or exclusion criteria are defined as 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. If a patient has clinically significant deviations in laboratory 
values as mentioned in inclusion criterion 8 and/or exclusion criterion 6 and/or clinically significant 


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deviations in LVEF as detailed in exclusion criterion 5, it is not allowed to repeat the laboratory 
assessment and the patient cannot be randomized. 
 
The only exception is re-screening for HER2 status. If the result was HER2-negative based on 
archived material the site could consider sending fresh material to reassess the HER2 status.   
  
Now reads as: 
Patients who signed the “HER2 testing” and/or “Study”-ICF but subsequently failed to meet the 
inclusion and/or exclusion criteria are defined as 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. If a patient has clinically significant deviations in laboratory 
values as mentioned in inclusion criterion 8 and/or exclusion criterion 6 and/or clinically significant 
deviations in LVEF as detailed in exclusion criterion 5, it is not allowed to repeat the laboratory 
assessment and the patient cannot be randomized. 
 
The only two exceptions is re-screeing for HER2 status are: 
- 
If the result was HER2-negative based on archived material the site could consider sending 
fresh material to reassess the HER2 status.   
- 
Patients for whom during screening on the brain CT/MRI a previously unknown 
asymptomatic metastasis is observed. These patients can be candidates for re-screening when 
the following conditions apply: (1) The treatment for brain metastases should be finalized 
more than 8 weeks prior to start re-screening; (2) There should be evidence of disease stability; 
(3) Enrolment for the SYD985.002 study should still be open. Please contact the medical 
monitor for approval. Note that for these patients all screening procedures should be repeated, 
excluding the central HER2-testing and the whole body bone scan if the previous scan showed 
no bone metastasis and there is no clinical suspicion of newly developed metastatic bone 
lesion(s). 
 
Section 9.1 (page 29) 
Using a computer-generated randomization list, eligible patients will be randomly assigned in a 2:1 
ratio to receive SYD985 or Physician’s choice therapy. The allocation will be stratified for 
geographical region (Europe and Singapore, North America), the number of prior treatment lines for 
advanced breast cancer (excluding hormone therapy) (2, more than 2), and prior treatment with 
pertuzumab (yes, no). 
 
Now reads as: 
Using a computer-generated randomization list, eligible patients will be randomly assigned in a 2:1 
ratio to receive SYD985 or Physician’s choice therapy. The allocation will be stratified for 
geographical region (Europe and Singapore, North America), the number of prior treatment lines for 
advanced breast cancer (excluding hormone therapy) (1 or 2, more than 2), and prior treatment with 
pertuzumab (yes, no). 
 
Section 9.5.1.4 (page 33) 
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 


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scan. To detect pneumonitis or other pulmonary toxicity in an early stage, the 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. 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. 
 
Now reads as: 
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, the tumour evaluation CT 
scans should be carefully evaluated for lung changes e.g. by means of high resolution CT. Infectious 
and metastatic disease-related aetiologies should be ruled out. Patients should be advised to promptly 
report any new or worsening respiratory symptoms. 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. 
 
Section 11.9 (page 40) 
To exclude pregnancy in women of childbearing potential, a serum pregnancy test at screening 
(between day -10 and day -1) and serum or urine pregnancy tests during treatment on Day 1 of each 
cycle and at the treatment discontinuation visit will be performed at the local laboratory.  
 
Now reads as: 
To exclude pregnancy in women of childbearing potential, a serum pregnancy test at screening 
(between day -10 and day -1) and serum or urine pregnancy tests during treatment on Day 1 of each 
cycle (may be done up to 3 days before) and at the treatment discontinuation visit will be performed 
at the local laboratory.  
 
Section 11.21 (page 45) 
The treatment discontinuation visit should occur 4-6 weeks (28-42 days) after the last administration 
of study drug (SYD985, trastuzumab, vinorelbine, eribulin, lapatinib, or capecitabine, whichever is 
discontinued last).  
 
Now reads as: 
The treatment discontinuation visit should occur 4-6 weeks (28-42 days) after the last administration 
of study drug (SYD985, trastuzumab, vinorelbine, eribulin, lapatinib, or capecitabine, whichever is 
discontinued last) or before new anticancer treatment is initiated, whichever comes first.  
 
Section 12.1 (page 47) 
Protocol defined 
events of special 
interest 
The following events are adverse events of special interest (AESIs) and will 
need to be reported to the CRO expeditiously, irrespective of regulatory 
seriousness criteria or causality: 
• Pneumonitis, 
• Severe eye toxicity grade ≥ 3, 
• LVEF decrease to < 50%.  


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Now reads as: 
Protocol defined 
events of special 
interest 
The following events are adverse events of special interest (AESIs) and will 
need to be reported to the CRO expeditiously, irrespective of regulatory 
seriousness criteria or causality: 
• Pneumonitis, 
• Severe eye toxicity grade ≥ 3, 
• Keratitis grade ≥ 2, 
• LVEF decrease to < 50%.  
 
Section 12.3.1 (page 48) 
The investigator will determine the severity of AEs according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) (version 4.03 or higher). AEs that are not listed in the CTCAE 
should be graded according to Table 4. 
 
Now reads as: 
The investigator will determine the severity of AEs according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) (version 4.03 or higher). AEs that are not listed in the CTCAE 
should be graded according to Table 4. 
 
Section 12.5 (page 54) 
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 most recent version of Company 
Core Safety Information as appended to the the Investigator’s Brochure is to be used to assess the 
expectedness of an AE for SYD985. The reference Summary of product characteristics is to be used 
to assess expectedness for Physician’s choice treatments. 
Investigators must report all SAEs to their Independent Ethic Committee (IEC)/ Institutional Review 
Board (IRB) responsible for the study. In addition, in case of a SUSAR occurring in a patient treated 
with Physician’s Choice treatment the investigator is responsible for reporting the SUSAR to the 
respective manufacturer. 
 
Now reads as: 
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 most recent version of Company 
Core Safety Information as appended to the section 6.8 of the Investigator’s Brochure contains the 
reference safety information and is to be used to assess the expectedness of an AE for SYD985. The 
reference Summary of product characteristics is to be used to assess expectedness for Physician’s 
choice treatments. 
Investigators must report all SAEs to their Independent Ethic Committee (IEC)/ Institutional Review 
Board (IRB) responsible for the study. In addition, in case of a SUSAR occurring in a patient treated 
with Physician’s Choice treatment the investigator is responsible for reporting the SUSAR to the 
respective manufacturer. 
 


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Section 12.6 (page 54) 
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: 
• Pneumonitis; 
• Severe eye toxicity grade ≥ 3; 
• LVEF decrease to < 50%. 
 
Now reads as: 
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: 
• Pneumonitis; 
• Severe eye toxicity grade ≥ 3; 
• Keratitis grade ≥ 2; 
• LVEF decrease to < 50%. 
 
 
 
 


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Appendix 7 Protocol Amendment V 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
Protocol title: 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the 
antibody-drug conjugate SYD985 to physician’s choice in patients with HER2-positive unresectable 
locally advanced or metastatic breast cancer 
 
 
 
 
Abbreviated title: 
TULIP 
Protocol Number: 
SYD985.002 
Development phase: 
Phase III 
Drug product code: 
SYD985 
Drug substance: 
Trastuzumab vc-seco-DUBA  
EudraCT Number: 
2017-001994-18 
IND Number: 
131333 
Amendment: 
Protocol Amendment V 
(leading to Protocol Version 6.0) 
 
Amendment Date: 
24 May 2019 
Authors Byondis BV: 
 
Evelyn van den Tweel, Clinical Project Leader  
Mayke Oesterholt, Clinical Project Leader 
Ellen Mommers, Clinical Project Leader 
Roel Mulder, Biostatistician  
 
 
 
 
 
 
 
 
 
 
 
This document includes confidential and privileged information and data that contain trade secrets which are 
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 study at a clinical 
investigational site. 
 


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Justification for the amendment 
This substantial amendment has been prepared upon request of the regulatory authorities. The 
changes are summarized below:  
• Section 5.5.1 has been updated to include additional information on ILD/Pneumonitis. 
• Section 9.5.1.4 dose modifications for ILD/pneumonitis have been elaborated.  
• Section 11.5 oxygen saturation by pulse oximetry has been added to the vital signs 
assessments at all visits. 
 
Apart from editorial changes, version changes to the title page and table of contents, this has led to 
the following changes in the protocol text (all included in version 6 of the protocol). New text is 
underlined, deleted text is strikethrough: 
 
 
 
Protocol synopsis: Planned clinical study period (page 6) 
First patient first visit: Q3 2017 
Last patient first visit: Q2 2019 
Last patient last visit: H1 2019 
 
Now reads as: 
First patient first visit: Q3 2017 
Last patient first visit: Q2 2019 H2 2019 
Last patient last visit: H1 2019 H2 2020 
 
Study flowchart (page 9) 
2 
Day 1 assessments are to be done prior to study drug administration; 
3 
Weight should be measured before the start of a new cycle, this may be done up to 7 days before the Day 1 visit; 
4 
Archived tumour material should be submitted for central analysis of HER2 status before randomization, this can be done after signing the “HER2 
testing”-ICF. If there is no archival tumour material available a biopsy should be performed to obtain tumour material, this can only be done after 
signing the “Study”-ICF. The HER2 tumour status will be assessed by a central laboratory using IHC and ISH; 
5 
Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as closely as possible to the start of the new cycle, but 
may be done up to 3 days before. Analyses should be performed at a local laboratory. Results of the local laboratory should be available before the 
start of the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and cardiac troponin 
should also be performed at the central laboratory;   
6 
Either cardiac troponin I or T (using a high sensitivity assay) can be measured as long as the same assay is used throughout the study for an 
individual patient;  
7 
Pregnancy test in women of childbearing potential: serum test at screening (between day -10 and day -1), serum or urinary tests during treatment 
(should be done on Day1 of the new cycle, but may be done up to 3 days before) and at treatment discontinuation visit; 
8 
PK samples will be taken in the SYD985 treatment group only. See for details the PK sampling scheme on page 10; 
9 
Immunogenicity samples will be taken in the SYD985 group only; 
10 Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as LVEF 
assessment 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; 
11 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 
9.5.1.1 of the protocol; 
12 12-lead ECGs should be recorded in triplicate. ECGs should be obtained before study drug administration for all patients. In addition ECGs should 
be obtained 30 minutes after the end of infusion at the day of first study drug administration in cycle 1 and cycle 4 in all patients excluding the 
patients in the Physician’s Choice group receiving the oral treatment combination lapatinib + capacitabine. The ECGs should be submitted for 
central review; 
13 ECG should be obtained 24 hours (± 2 hours) after study drug administration. The ECGs should be submitted for central review; 
14 For tumour measurements, a CT or MRI scan should be performed every 6 weeks (± 3 days) after the date of randomization for the first 42 weeks 
and every 9 weeks (± 3 days) thereafter, independent of dosing delays. The methodology and imaging levels should remain the same at baseline 
and subsequent evaluations for a given patient;  
15 The tumour measurements should be submitted for central review; 


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16 Administration of SYD985 or administration of physician’s choice in a 21-days (3 weeks) regimen (± 3 days) until disease progression or 
unacceptable toxicity. For SYD985 no recalculation of the 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;  
17 Tumour evaluation at the treatment 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 visit; 
18 Patients should be followed up until death, lost to follow-up, consent withdrawal or end of study data collection, whichever comes first; 
19 During the survival follow-up only initiation of new anticancer medication should be documented. 
20 The end of treatment visit needs to be performed 28-42 days after the last dose of study drug or before new anticancer treatment is initiated, 
whichever comes first.  
 
Now reads as: 
2 
Day 1 assessments are to be done prior to study drug administration; 
3 
Weight should be measured before the start of a new cycle, this may be done up to 7 days before the Day 1 visit; 
4 
Archived tumour material should be submitted for central analysis of HER2 status before randomization, this can be done after signing the “HER2 
testing”-ICF. If there is no archival tumour material available a biopsy should be performed to obtain tumour material, this can only be done after 
signing the “Study”-ICF. The HER2 tumour status will be assessed by a central laboratory using IHC and ISH; 
5 
Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as closely as possible to the start of the new cycle, but 
may be done up to 3 days before. Analyses should be performed at a local laboratory. Results of the local laboratory should be available before the 
start of the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and cardiac troponin 
should also be performed at the central laboratory;   
6 
Either cardiac troponin I or T (using a high sensitivity assay) can be measured as long as the same assay is used throughout the study for an 
individual patient;  
7 
Pregnancy test in women of childbearing potential: serum test at screening (between day -10 and day -1), serum or urinary tests during treatment 
(should be done on Day1 of the new cycle, but may be done up to 3 days before) and at treatment discontinuation visit; 
8 
PK samples will be taken in the SYD985 treatment group only. See for details the PK sampling scheme on page 10; 
9 
Immunogenicity samples will be taken in the SYD985 group only; 
10 Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film break up time, and pachymetry) as well as LVEF 
assessment 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; 
11 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 
9.5.1.1 of the protocol; 
12 12-lead ECGs should be recorded in triplicate. ECGs should be obtained before study drug administration for all patients. In addition ECGs should 
be obtained 30 minutes after the end of infusion at the day of first study drug administration in cycle 1 and cycle 4 in all patients excluding the 
patients in the Physician’s Choice group receiving the oral treatment combination lapatinib + capacitabine. The ECGs should be submitted for 
central review; 
13 ECG should be obtained 24 hours (± 2 hours) after study drug administration. The ECGs should be submitted for central review; 
14 For tumour measurements, a CT or MRI scan should be performed every 6 weeks (± 3 days) after the date of randomization for the first 42 weeks 
and every 9 weeks (± 3 days) thereafter, independent of dosing delays. The methodology and imaging levels should remain the same at baseline 
and subsequent evaluations for a given patient;  
15 The tumour measurements should be submitted for central review; 
16 Administration of SYD985 or administration of physician’s choice in a 21-days (3 weeks) regimen (± 3 days) until disease progression or 
unacceptable toxicity. For SYD985 no recalculation of the 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;  
17 Tumour evaluation at the treatment 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 visit; 
18 Patients should be followed up until death, lost to follow-up, consent withdrawal or end of study data collection, whichever comes first; 
19 During the survival follow-up only initiation of new anticancer medication should be documented. 
20 The end of treatment visit needs to be performed 28-42 days after the last dose of study drug or before new anticancer treatment is initiated, 
whichever comes first.  
21 Vital signs include blood pressure, heart rate, body temperature, and oxygen saturation by pulse oximetry.  
 
Section 2 (page 11) 
CRO  
(clinical services) 
INC Research 
De Entrée 99-197, 14th floor 
1101 HE Amsterdam 
The Netherlands 


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Now reads as: 
CRO  
(clinical services) 
INC Research Syneos Health 
De Entrée 99-197, 14th floor 
1101 HE Amsterdam 
The Netherlands 
 
Section 5.5.1  (page 22) 
Pneumonitis 
Pneumonitis was reported in the Phase I study. Pneumonitis and lung consolidations are also reported 
for other anticancer drugs, including anti-PD1 antibodies8;9, everolimus (mTOR inhibitor), and the 
anti-HER2 agents lapatinib and (ado-)trastuzumab emtansine10. 
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 pulmonary toxicity in an early stage, the tumour evaluation CT scans, which are 
initially done every 6 weeks, should be carefully evaluated for lung changes e.g. by means of high 
resolution CT. Patients should be advised to promptly report any new or worsening respiratory 
symptoms.  
 
Now reads as: 
Interstitial Lung Disease ILD/Pneumonitis 
ILD/Pneumonitis was reported in the Phase I study. ILD/Pneumonitis and lung consolidations are 
also reported for other anticancer drugs, including anti-PD1 antibodies8;9, everolimus (mTOR 
inhibitor), and the anti-HER2 agents lapatinib and (ado-)trastuzumab emtansine10. 
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. Biomarkers 
for IDL/pneumonitis are exploratory and they should not be used for diagnosis or monitoring of drug-
induced ILD/pneumonitis. ILD/pneumonitis evaluation (regardless of stage) should always include a 
pulmonary consult, a high resolution CT, pulmonary function testing (PFTs), pulse oximetry and 
arterial blood gases (ABGs). 
To detect pulmonary toxicity in an early stage, the tumour evaluation CT scans, which are initially 
done every 6 weeks, should be carefully evaluated for lung changes e.g. by means of high resolution 
CT. Patients should be advised to promptly report any new or worsening respiratory symptoms. 
 
Section 9.5.1.4 (page 34) 
SYD985 - Dose modifications for pneumonitis 
Patients who experience Grade 3 or 4 pneumonitis will be discontinued from treatment. For patients 
who experience Grade 2 pneumonitis dosing must be delayed for up to 42 days from the last received 
dose. When the pneumonitis resolves to Grade 1 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 pneumonitis persists. The 
pneumonitis should be monitored for recovery. 
 


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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, the tumour evaluation CT 
scans should be carefully evaluated for lung changes e.g. by means of high resolution CT. Infectious 
and metastatic disease-related aetiologies should be ruled out. Patients should be advised to promptly 
report any new or worsening respiratory symptoms. 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. 
 
Now reads as: 
SYD985 - Dose modifications for ILD/pneumonitis 
Patients who experience Grade 2, 3 or 4 ILD/pneumonitis will be discontinued from treatment. For 
patients who experience Grade 2 1 ILD/pneumonitis dosing must be delayed for up to 42 days from 
the last received dose. When the ILD/pneumonitis resolves to Grade 1 or lower 0 patients may 
continue treatment and a dose reduction should be considered. 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 pneumonitis persists. Reversibility or stabilisation 
of The 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. Biomarkers 
for IDL/pneumonitis are exploratory and they should not be used for diagnosis or monitoring of drug-
induced ILD/pneumonitis. ILD/pneumonitis evaluation (regardless of stage) should always include a 
pulmonary consult, a high resolution CT, PFTs, pulse oximetry and ABGs. 
To detect ILD/pneumonitis or other pulmonary toxicity in an early stage, the tumour evaluation CT 
scans should be carefully evaluated for lung changes e.g. by means of high resolution CT. Infectious 
and metastatic disease-related aetiologies should be ruled out. Patients should be advised to promptly 
report any new or worsening respiratory symptoms. 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. 
 
Section 11.5 (page 38) 
Vital signs assessments include blood pressure, heart rate, and body temperature. Vital signs should 
be measured at screening and at the time points as indicated in the flowchart (see Section 1.1). On 
Day1 of each cycle vital signs should be recorded before study drug administration.  
 
Now reads as: 
Vital signs assessments include blood pressure, heart rate, and body temperature, and oxygen 
saturation by pulse oximetry. Vital signs should be measured at screening and at the time points as 
indicated in the flowchart (see Section 1.1). On Day1 of each cycle vital signs should be recorded 
before study drug administration.  
 


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Section 12.5 (page 50) 
The occurrence of any SAEs from signing of the “Study”-ICF up to the treatment 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 by telephone, fax or email. The 
notification must include a completed SAE form. The contact details of the INC Research 
Pharmacovigilance Department are: 
 
Pharmacovigilance Department INC Research 
Address:  The Meadows Business Park, Blackwater 
 
Camberley Surrey, GU17 9AB, United Kingdom 
Fax:  
+1-877-464-7787 or to the dedicated fax number indicated on the SAE Reporting Form 
Email:  
INCdrugsafety@INCResearch.com 
 
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 in the form of a follow-up report 
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 CRF and to the INC Research Pharmacovigilance Department.  
 
Now reads as: 
The occurrence of any SAEs from signing of the “Study”-ICF up to the treatment 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 by telephone, fax or email. The 
notification must include a completed SAE form. The contact details of the INC Research Syneos 
Health Pharmacovigilance Department are: 
 
Pharmacovigilance Department INC Research Syneos Health 
Address:  The Meadows Business Park, Blackwater 
 
Camberley Surrey, GU17 9AB, Farnborough Business Park, 1 Pinehurst Road,  
Farnborough, Hants GU14 7BF United Kingdom 
Fax:  
+1-877-464-7787 or to the dedicated fax number indicated on the SAE Reporting Form 
Email:  
INCdrugsafety@INCResearch.com 
 
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 in the form of a follow-up report 
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 CRF and to the INC Research Syneos Health Pharmacovigilance Department.  
 
 
Section 12.6 (page 50) 
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: 
• Pneumonitis; 
• Severe eye toxicity grade ≥ 3; 


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• Keratitis grade ≥ 2; 
• LVEF decrease to < 50%. 
 
All AESIs must be documented on an SAE Reporting Form and the same details need to be reported. 
 
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.  
 
The occurrence of any AESIs, from signing of the “Study”-ICF up to the treatment discontinuation 
visit (regardless of relationship to study drug) has to be notified (within 5 days of the investigator or 
designee becoming aware of the event) to the CRO by telephone, fax or email. The notification must 
include a completed SAE form. If a SAE occurs in conjunction with the AESI, then the reporting time 
frame for an SAE (24 hours) must be met.  
 
The contact details of the INC Research Syneos Health Pharmacovigilance Department are: 
Address:  The Meadows Business Park, Blackwater 
 Camberley Surrey, GU17 9AB, Farnborough Business Park, 1 Pinehurst Road,  
Farnborough, Hants GU14 7BF United Kingdom 
Fax:  
+1-877-464-7787 or to the dedicated fax number indicated on the SAE Reporting Form 
Email:  
INCdrugsafety@INCResearch.com 
 
The investigator or designee must report (within 5 days of becoming aware of the event) clinically 
significant follow-up information pertaining to the AESI in the form of a follow-up report 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 AESI has to be reported in 
the CRF and to the INC Research Syneos Health Pharmacovigilance Department.  
 
Now reads as: 
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; 
• Severe eye toxicity grade ≥ 3; 
• Keratitis grade ≥ 2; 
• LVEF decrease to < 50%. 
 
All AESIs must be documented on an SAE Reporting Form and the same details need to be reported. 
 
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.  
 
The occurrence of any AESIs, from signing of the “Study”-ICF up to the treatment discontinuation 
visit (regardless of relationship to study drug) has to be notified (within 5 days of the investigator or 
designee becoming aware of the event) to the CRO by telephone, fax or email. The notification must 


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include a completed SAE form. If a SAE occurs in conjunction with the AESI, then the reporting time 
frame for an SAE (24 hours) must be met.  
 
The contact details of the Syneos Health Pharmacovigilance Department are: 
Address:  Farnborough Business Park, 1 Pinehurst Road,  
Farnborough, Hants GU14 7BF United Kingdom 
Fax:  
+1-877-464-7787 or to the dedicated fax number indicated on the SAE Reporting Form 
Email:  
INCdrugsafety@INCResearch.com 
 
The investigator or designee must report (within 5 days of becoming aware of the event) clinically 
significant follow-up information pertaining to the AESI in the form of a follow-up report 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 AESI has to be reported in 
the CRF and to the Syneos Health Pharmacovigilance Department.  
 
Section 13.1 (page 53) 
The investigator should discontinue a patient from study treatment for reasons including but not 
limited to the following: 
• Progressive disease; 
• Unacceptable toxicity, including: 
o Clinically significant symptomatic cardiac disease (see Section 9.5.1.1); 
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 3 or 4 pneumonitis; 
• Pregnancy; 
• Substantial non-compliance with the requirements of the study; 
• Investigator decision based on the patient’s best interest. 
 
Now reads as: 
The investigator should discontinue a patient from study treatment for reasons including but not 
limited to the following: 
• Progressive disease; 
• Unacceptable toxicity, including: 
o Clinically significant symptomatic cardiac disease (see Section 9.5.1.1); 
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 IDL/pneumonitis; 
• Pregnancy; 


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• Substantial non-compliance with the requirements of the study; 
• Investigator decision based on the patient’s best interest. 
 
 
 
 


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Appendix 8 Protocol Amendment VI 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
Protocol title: 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the 
antibody-drug conjugate SYD985 to physician’s choice in patients with HER2-positive unresectable 
locally advanced or metastatic breast cancer 
 
 
 
 
Abbreviated title: 
TULIP 
Protocol Number: 
SYD985.002 
Development phase: 
Phase III 
Drug product code: 
SYD985 
Drug substance: 
Trastuzumab vc-seco-DUBA  
EudraCT Number: 
2017-001994-18 
IND Number: 
131333 
Amendment: 
Protocol Amendment VI 
(leading to Protocol Version 7.0) 
 
Amendment Date: 
22 October 2019 
Authors Byondis BV: 
 
Evelyn van den Tweel, Clinical Project Leader  
Mayke Oesterholt, Clinical Project Leader 
Ellen Mommers, Clinical Project Leader 
Roel Mulder, Biostatistician  
 
 
 
 
 
 
 
 
 
 
 
This document includes confidential and privileged information and data that contain trade secrets which are 
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 study at a clinical 
investigational site. 
 


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Justification for the amendment 
This substantial amendment has been prepared for the following reason:  
• As part of their evaluation the independent DMC assessed the validity of the initial assumptions 
underlying the sample size estimation with regards to drop-out rates. Based on their pre-planned 
interim evaluation the independent DMC has recommended to adjust the sample size and enrol 
a total of 423 patients to ensure sufficient power for the primary endpoint analysis. 
 
 
Apart from editorial changes, version changes to the title page and table of contents, this has led to 
the following changes in the protocol text (all included in version 7 of the protocol). New text is 
underlined, deleted text is strikethrough: 
 
Protocol synopsis: sample size (page 6) 
In order to be able to detect a hazard ratio of 0.65 in PFS using the log-rank test, at 90% power, using a two-
sided test at a significance level of p < 0.05, a total of 256 events are required. Assuming a 9 month recruitment 
period and 10 month follow up period, a median time to progression of 4.1 months for the physician’s choice 
and assuming an average of 20% drop out in the physician’s choice group and 30% in the SYD985 group, a 
minimal number of 309 patients is required. To adjust for departures from the assumptions (clinical and 
statistical) enrolment is targeted for at least 345 patients. Allocation is 2:1 resulting in 230 to be allocated to 
the SYD985 group and 115 to the physician’s choice group. 
 
Now reads as: 
In order to be able to detect a hazard ratio of 0.65 in PFS using the log-rank test, at 90% power, using a two-
sided test at a significance level of p < 0.05, a total of 256 events are required. Assuming a 9 month recruitment 
period and 10 month follow up period, a median time to progression of 4.1 months for the physician’s choice 
and assuming an average of 20 30% drop out in the physician’s choice group and 30 40% in the SYD985 
group, a minimal number of 309 423 patients is required. To adjust for departures from the assumptions 
(clinical and statistical) enrolment is targeted for at least 345 patients. Allocation is 2:1 resulting in 230 282 to 
be allocated to the SYD985 group and 115 141 to the physician’s choice group. 
 
Protocol synopsis: Data Monitoring Committee (page 6) 
Safety will be monitored on an ongoing basis during the entire study by an independent external Data Monitoring 
Committee (DMC), of which the composition, roles and responsibilities will be described in a separate charter.  
As part of their evaluation the DMC will assess if the assumptions underlying the sample size estimation with 
regards to drop-out rates are met, and may advise to change the planned sample size in case of serious departures. 
 
Now reads as: 
Safety will be monitored on an ongoing basis during the entire study by an independent external Data Monitoring 
Committee (DMC), of which the composition, roles and responsibilities will be described in a separate charter.  
As part of their evaluation the DMC will assess if the assessed the validity of the initial assumptions underlying 
the sample size estimation with regards to drop-out rates are met, and may advise to change the planned sample 
size in case of serious departures.. Based on their pre-planned interim evaluation the independent DMC has 
recommended to adjust the sample size and enrol a total of 423 patients to ensure sufficient power for the primary 
endpoint analysis. 
 
Section 12.10 (page 52) 
Details on the responsibilities, activities and deliverables of the external Data Monitoring Committee 
(DMC) are detailed in a separate charter. As part of their evaluation the DMC will assess if the 


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assumptions underlying the sample size estimation with regards to drop-out rates are met, and may 
advise to change the planned sample size in case of serious departures. 
 
Now reads as: 
Details on the responsibilities, activities and deliverables of the external Data Monitoring Committee 
(DMC) are detailed in a separate charter. As part of their evaluation the DMC will assess if the 
assessed the validity of the initial assumptions underlying the sample size estimation with regards to 
drop-out rates are met, and may advise to change the planned sample size in case of serious 
departures..  Based on their pre-planned interim evaluation the independent DMC has recommended to 
adjust the sample size and enrol a total of 423 patients to ensure sufficient power for the primary 
endpoint analysis. 
 
Section 14.7 (page 62) 
In order to be able to detect a hazard ratio of 0.65 in PFS using the log-rank test, at 90% power, using 
a two-sided test at a significance level of p < 0.05, a total of 256 events are required. Assuming a 9 
month recruitment period and 10 month follow up period, a median time to progression of 4.1 months 
for the physician’s choice and assuming an average of 20% drop out in the physician’s choice group 
and 30% in the SYD985 group, a minimal number of 309 patients is required. To adjust for departures 
from the assumptions (clinical and statistical) enrolment is targeted for at least 345 patients. 
Allocation is 2:1 resulting in 230 to be allocated to the SYD985 group and 115 to the physician’s 
choice group. 
 
Randomization will be done by a permutated block design with a fixed block size, using world region 
(Europe and Singapore/North-America), the number of prior treatment lines for locally advanced or 
metastatic breast cancer (excluding hormone therapy) (2/>2), and prior treatment with pertuzumab 
(yes/no) as stratification factors. 
 
No formal interim analysis will be performed. As part of their evaluation the DMC will assess if the 
assumptions underlying the sample size estimation with regards to drop-out rate are met, and may 
advise to change the planned sample size in case of serious departures. Such sample size re-estimation 
will not be considered a formal interim analysis as no between-group comparison of event-rates will 
be performed. Therefore, the primary analysis will be performed at the set 5% significance level. 
Details of methods used will be provided in a separate analysis plan. 
 
Now reads as: 
In order to be able to detect a hazard ratio of 0.65 in PFS using the log-rank test, at 90% power, using 
a two-sided test at a significance level of p < 0.05, a total of 256 events are required. Assuming a 9 
month recruitment period and 10 month follow up period, a median time to progression of 4.1 months 
for the physician’s choice and assuming an average of 20 30% drop out in the physician’s choice 
group and 30 40% in the SYD985 group, a minimal number of 309 423 patients is required. To adjust 
for departures from the assumptions (clinical and statistical) enrolment is targeted for at least 345 
patients.  Allocation is 2:1 resulting in 230 282 to be allocated to the SYD985 group and 115 141 to 
the physician’s choice group. 
 
Randomization will be done by a permutated block design with a fixed block size, using world region 
(Europe and Singapore/North-America), the number of prior treatment lines for locally advanced or 


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Version 8.0 
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metastatic breast cancer (excluding hormone therapy) (2/>2), and prior treatment with pertuzumab 
(yes/no) as stratification factors. 
 
No formal interim analysis will be performed. As part of their evaluation the DMC will assess if the 
assessed the validity of the initial assumptions underlying the sample size estimation with regards to 
drop-out rate are met, and may advise to change the planned sample size in case of serious departures. 
Such sample size re-estimation will not be considered a formal interim analysis as no between-group 
comparison of event-rates will be performed. Therefore, the primary analysis will be performed at 
the set 5% significance level. Details of methods used will be provided in a separate analysis plan. 
 
 
 


Clinical Study Protocol 
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CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
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Appendix 9 Protocol Amendment VII 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
Protocol title: 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the 
antibody-drug conjugate SYD985 to physician’s choice in patients with HER2-positive unresectable 
locally advanced or metastatic breast cancer 
 
 
 
 
Abbreviated title: 
TULIP 
Protocol Number: 
SYD985.002 
Development phase: 
Phase III 
Drug product code: 
SYD985 
Drug substance: 
Trastuzumab vc-seco-DUBA  
EudraCT Number: 
2017-001994-18 
IND Number: 
131333 
Amendment: 
Protocol Amendment VII 
(leading to Protocol Version 8.0) 
 
Amendment Date: 
18 January 2021 
Authors Byondis BV: 
 
Evelyn van den Tweel, Clinical Project Leader  
Mayke Oesterholt, Clinical Project Leader 
Ellen Mommers, Clinical Project Leader 
Roel Mulder, Biostatistician  
 
 
 
 
 
 
 
 
 
 
 
This document includes confidential and privileged information and data that contain trade secrets which are 
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 study at a clinical 
investigational site. 
 


Clinical Study Protocol 
SYD985.002 
TULIP 
 
CONFIDENTIAL 
Version 8.0 
January 2021 
 
Document number (version): CSP.NL03.57088 (8.0) 
Page 126 of 126 
 
 
Justification for the amendment 
This substantial amendment has been prepared for the following reason:  
• To include the possibility to analyse the primary endpoint of the trial when at least 95% of the 
patients have discontinued treatment. 
• Section 2 has been updated to reflect changes in the vendor responsibilities. 
 
Apart from editorial changes, version changes to the title page and table of contents, this has led to 
the following changes in the protocol text (all included in version 8 of the protocol). New text is 
underlined, deleted text is strikethrough: 
 
Protocol synopsis (efficacy analysis (page 5): 
The primary PFS analysis will be performed when at least 256 PFS events have occurred and only 
after all patients have been enrolled.  
 
Now reads as: 
The primary PFS analysis will be performed when at least 256 PFS events have occurred, or when at 
least 95% of patients have discontinued treatment, and only after all patients have been enrolled.  
 
 
Section 14.5.1.1 (page 57): 
The primary PFS analysis will be performed when at least 256 PFS events have occurred, as assessed 
by central review, or when at least 95% of patients have discontinued treatment, and only after all 
patients have been enrolled. 
 
Now reads as: 
The primary PFS analysis will be performed when at least 256 PFS events have occurred, as assessed 
by central review, or when at least 95% of patients have discontinued treatment, and only after all 
patients have been enrolled. 
 
 
Section 2 (page 12): 
 
 
Central Laboratory: 
(Neutralizing antibody assay) 
QPS Netherlands BV 
Petrus Campersingel 123 
9713 AG Groningen 
The Netherlands 
 
Now reads as: 
Central Laboratory: 
(Neutralizing antibody assay) 
QPS Netherlands BV 
Petrus Campersingel 123 
9713 AG Groningen 
The Netherlands 
 

SAP_001.pdf: 
 
 
A multi-centre, open-label, randomized clinical trial comparing the efficacy and 
safety of the antibody-drug conjugate SYD985 to physician’s choice in patients 
with HER2-positive unrespectable locally advanced or metastatic breast cancer. 
 
 
NCT03262935 
 
 
Version 3.0, dated 29 April 2021 


 
 
 
 
 
This document is confidential. 
SAP text and shells 3.0 29-Apr-2021 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 1 of 76 
Statistical Analysis Plan for Interventional Studies 
Text and TFL Shells 
SAP Text Version Number: 3.0 
SAP Text Date: 29-Apr-2021 
 
Sponsor Name: Byondis BV 
 
Protocol Number: SYD985-002 
Protocol Title: A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of 
the antibody-drug conjugate SYD985 to physician’s choice in patients with HER2-positive unrespectable 
locally advanced or metastatic breast cancer.   
 
Protocol Version and Date:  
Protocol 1 May-2017 
Protocol 2 25-Aug-2017 
Protocol 3 09-Nov-2017 
Protocol 4 11-Sep-2018 
Protocol 5 12-Apr-2019 
Protocol 6 25-May-2019 
Protocol 7 22-Oct-2019 
Protocol 8 18-Jan-2021 
 
 
Syneos Health Project Code: 1008451  
 
Authors: Carmen Raikes, Senior Biostatistician and Stephanie Gagnon, Senior Pharmacokineticist 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Byondis BV. Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or 
disclosed without prior written authorization from an official of Byondis BV. However, this document may 
be disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, Syneos Health should be 
notified promptly. 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Byondis BV; Protocol No.: SYD985.002 
 
This document is confidential. 
SAP text and shell 3.0 29-Apr-2021 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 2 of 76 
Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.0 
12-Apr-2018 
Carmen Raikes 
Initial Release Version  
2.0 
20-Jan-2021 
Carmen Raikes 
Include protocol amendments, COVID-19, top three eye 
disorders and BioClinica lung review 
3.0 
30-Apr-2021 
Carmen Raikes 
Clarify that visit windowing is used for the safety repeated 
measures, delete demographics table pre vs. during 
COVID for the FAS, indicate combining strata will be 
considered, clarify inferential analysis model for 
proportional hazards. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Byondis BV; Protocol No.: SYD985.002 
 
This document is confidential. 
SAP text and shell 3.0 29-Apr-2021 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 3 of 76 
I confirm that I have reviewed this document and agree with the content. 
 
Approvals 
Syneos Health Approval 
 
 
 
 
 
Carmen Raikes, Senior Biostatistician 
Lead Biostatistician  
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
 
John Williams, Senior Director, Biostatistics 
Senior Reviewing Biostatistician 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
 
 
Stephanie Gagnon, Senior Pharmacokineticist 
PK Scientist 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
Byondis BV Approval 
 
 
 
 
 
Evelyn van den Tweel 
Project Leader, Clinical Development 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
 
 
Sponsor Contact  
Roel Mulder 
Biostatistician, Clinical Development 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Byondis BV; Protocol No.: SYD985.002 
 
This document is confidential. 
SAP text and shell 3.0 29-Apr-2021 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 4 of 76 
Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 3 
1. 
Glossary of Abbreviations ................................................................................................... 8 
2. 
Purpose ............................................................................................................................ 12 
2.1. 
Responsibilities .....................................................................................................12 
2.2. 
Timings of Analyses ..............................................................................................12 
3. 
Study Objectives .............................................................................................................. 13 
3.1. 
Primary Objective .................................................................................................13 
3.2. 
Secondary Objective(s) .........................................................................................13 
3.2.1. 
Secondary Objectives ....................................................................................... 13 
3.2.2. 
Other Objectives ................................................................................................ 13 
4. 
Study Details/Design ........................................................................................................ 14 
4.1. 
Brief Description ...................................................................................................14 
4.2. 
Patient Selection ...................................................................................................14 
4.2.1. 
Inclusion Criteria .................................................................................................. 14 
4.2.2. 
Exclusion Criteria ................................................................................................. 14 
4.3. 
Determination of Sample Size ...............................................................................14 
4.4. 
Treatment Assignment and Blinding .....................................................................15 
4.5. 
Administration of Study Medication .......................................................................15 
4.5.1. 
SYD985 Treatment ............................................................................................. 15 
4.5.2. 
Physician’s Choice Treatment .......................................................................... 15 
4.6. 
Study Procedures and Flowchart ..........................................................................16 
5. 
Endpoints ......................................................................................................................... 19 
5.1. 
Primary Efficacy Endpoint .....................................................................................19 
5.2. 
Secondary Efficacy Endpoints ..............................................................................19 
5.2.1. 
Other Efficacy Endpoints .................................................................................. 19 
5.3. 
Exploratory Endpoints ...........................................................................................19 
5.4. 
Pharmacokinetic Endpoints...................................................................................19 
5.5. 
Safety Endpoints ...................................................................................................19 
6. 
Analysis Sets .................................................................................................................... 20 
6.1. 
Screened Set ........................................................................................................20 


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6.2. 
Full Analysis Set ...................................................................................................20 
6.3. 
Safety Analysis Set ...............................................................................................20 
6.4. 
Per-Protocol Set ...................................................................................................20 
6.5. 
Pharmacokinetic Set .............................................................................................20 
6.6. 
Protocol Deviations ...............................................................................................20 
7. 
General Aspects for Statistical Analysis ........................................................................... 22 
7.1. 
General Methods ..................................................................................................22 
7.2. 
Key Definitions ......................................................................................................22 
7.3. 
Missing Data .........................................................................................................23 
7.4. 
Visit Windows .......................................................................................................24 
7.5. 
Pooling of Centers ................................................................................................24 
7.6. 
Subgroups ............................................................................................................25 
8. 
Demographic, Other Baseline Characteristics and Medication ......................................... 26 
8.1. 
Patient Disposition, Withdrawals and Screen Failures ..........................................26 
8.2. 
Demographic and Baseline Characteristics ...........................................................26 
8.3. 
Medical History and Concomitant Diseases ..........................................................27 
8.4. 
Medication ............................................................................................................27 
8.4.1. 
Prior Systemic Therapy Related to Study Indication ..................................... 27 
8.4.2. 
Prior Medication (not Related to Study Indication) ........................................ 28 
8.4.3. 
Concomitant Medication ................................................................................... 28 
8.4.4. 
Other Therapies.................................................................................................. 28 
8.5. 
Extent of Exposure ...............................................................................................28 
8.5.1. 
SYD985 ................................................................................................................ 28 
8.5.2. 
Physician’s Choice ............................................................................................ 29 
8.6. 
Treatment Compliance ..........................................................................................29 
9. 
Efficacy ............................................................................................................................ 30 
9.1.1. 
Primary Analysis of the Primary Endpoint ...................................................... 30 
9.1.2. 
Secondary Analysis of the Primary Endpoint ................................................. 31 
9.1.3. 
Sensitivity Analyses of the Primary Endpoint ................................................ 31 
9.1.4. 
Additional Summary of the Primary Endpoint ................................................ 32 
9.2. 
Secondary Efficacy Endpoint(s) and Analyses ......................................................32 
9.2.1. 
Overall Survival .................................................................................................. 32 


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9.2.2. 
Objective Response Rate .................................................................................. 33 
9.2.3. 
Investigator Assessed PFS ............................................................................... 34 
9.2.4. 
Patient Reported Outcomes .............................................................................. 35 
9.3. 
Other Efficacy Endpoint(s) and Analyses ..............................................................37 
9.3.1. 
Time to Response (TTR) .................................................................................... 37 
9.3.2. 
Duration of Response (DOR) ............................................................................ 37 
9.3.3. 
Clinical Benefit Rate (CBR) based on Best Overall Response ...................... 38 
9.3.4. 
Percentage of Patients with Reduction in Target Lesions ............................ 38 
9.4. 
Subgroup Analysis of Efficacy Endpoints ..............................................................39 
10. 
Pharmacokinetics ............................................................................................................. 40 
10.1. 
PK Sampling Schedule .........................................................................................40 
10.2. 
Plasma PK Endpoint .............................................................................................41 
10.3. 
Presentation of Concentration Data ......................................................................41 
10.3.1. 
Handling of Missing Data .................................................................................. 41 
10.3.2. 
Listing and Presentation of Individual PK Data .............................................. 42 
10.3.3. 
Summary of PK Concentrations ....................................................................... 42 
10.3.4. 
PK Parameters Derivation ................................................................................. 43 
10.3.5. 
PK Parameters Summarization ......................................................................... 44 
10.3.6. 
Statistical Methods ............................................................................................ 44 
11. 
Pharmacodynamics .......................................................................................................... 45 
12. 
Safety ............................................................................................................................... 46 
12.1. 
Adverse Events / Adverse Drug Reactions ...........................................................46 
12.1.1. 
Adverse Events of Special Interest .................................................................. 47 
12.2. 
Laboratory Evaluations .........................................................................................49 
12.3. 
Vital Signs .............................................................................................................52 
12.3.1. 
Vital Sign Values of Potential Clinical Importance ......................................... 52 
12.4. 
Central 12-lead ECG.............................................................................................54 
12.5. 
Physical Examination ............................................................................................55 
12.6. 
Other Safety .........................................................................................................55 
12.6.1. 
LVEF .................................................................................................................... 55 
12.6.2. 
Ophthalmological Examination ........................................................................ 55 
12.6.3. 
ECOG ................................................................................................................... 56 


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12.6.4. 
Analysis of Immunogenicity ............................................................................. 56 
12.6.5. 
Lung Review ....................................................................................................... 56 
12.6.6. 
COVID-19 ............................................................................................................. 56 
13. 
Interim Analyses ............................................................................................................... 57 
14. 
Changes from Analysis Planned in Protocol ..................................................................... 58 
15. 
Reference List .................................................................................................................. 59 
16. 
Programming Considerations ........................................................................................... 60 
16.1. 
General Considerations ........................................................................................60 
16.2. 
Table, Listing, and Figure Format .........................................................................60 
16.2.1. 
General ................................................................................................................ 60 
16.2.2. 
Headers ............................................................................................................... 60 
16.2.3. 
Display Titles ...................................................................................................... 61 
16.2.4. 
Column Headers................................................................................................. 61 
16.2.5. 
Body of the Data Display ................................................................................... 61 
16.2.6. 
Footnotes ............................................................................................................ 63 
17. 
Quality Control ................................................................................................................. 64 
18. 
Index of Tables ................................................................................................................. 65 
19. 
Index of Figures................................................................................................................ 70 
20. 
Index of Listings ............................................................................................................... 73 
21. 
Shells ............................................................................................................................... 76 
 


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1. 
Glossary of Abbreviations 
Abbreviation 
Description 
ADA 
Anti-Drug Antibody 
ADaM 
Analysis Dataset Model 
ADaMIG 
Analysis Dataset Model Implementation Guidelines 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
ALanine aminoTransferase 
AP 
Alkaline phosphatase 
AST 
ASpartate aminoTransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Concentration-Time Curve 
BLQ 
Below Level of Quantification 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
C 
Cycle 
CDISC 
Clinical Data Interchange Standards Consortium 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CL 
Plasma Clearance 
Cmax 
Maximum Observed Plasma Concentration 
Cmin 
Minimum Concentration for the Dose Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
cTnI 
Cardiac Troponin I 
cTnT 
Cardiac Troponin T 
CV 
Coefficient of Variation 
D 
Day 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribose Nucleic Acid 
DOR 
Duration of Response 
DRM 
Data Review Meeting 


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Abbreviation 
Description 
ECD 
Extracellular Domain 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form  
EOI 
End of Infusion 
EORTC 
European Organisation for Research and Treatment of Cancer 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FU 
Follow Up 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transpeptidase 
HDL 
High Density Lipoprotein 
HER2 
Human Epidermal growth factor Receptor 2 
HR 
Hazard Ratio 
HRr 
Hormone Receptor 
IC 
Informed Consent 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonization 
ICR 
Independent Central Review 
IEC 
Independent Ethics Committee 
ITT 
Intent-to-Treat 
IV 
Intravenously 
λz 
Terminal Elimination Rate Constant 
LDL 
Low Density Lipoprotein 
LS 
Least squares 
LVEF 
Left Ventricular Ejection Fraction 
Max 
Maximum 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
MMRM 
Mixed Model Repeated Measurement 
MUGA 
Multigated Acquisition 
N/A 
Not Applicable 
NCI 
National Cancer Institute 
NE 
Not Evaluable 


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Abbreviation 
Description 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCI 
Potential Clinical Importance 
PD 
Pharmacodynamics 
PDS 
Pharmacodynamics Set 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetics Set 
PPS 
Per-Protocol Set 
PR 
Partial Response 
PT 
Preferred Term 
QC 
Quality Control 
QoL 
Quality of life 
RBC 
Red Blood cell Count 
RECIST 
Response Evaluation Criteria for Solid Tumours 
SACT 
Subsequent Anti-cancer Therapy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SD 
Stable Disease 
SE 
Standard Error 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Screened Set 
SYD985 
Trastuzumab vc-seco-DUBA 
SYD986 
DUocarmycin hydroxyBenzamide Azaindole (DUBA, active toxin) 
t1/2 
Terminal Elimination Half-life 
TEAE 
Treatment Emergent Adverse Event 
TFBUP 
Tear Film Break Up Time 
TLF 
Table, Listing and Figure 
Tmax 
Time to Cmax 
Tmin 
Time of Cmin 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
V 
Volume of Distribution 


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Abbreviation 
Description 
WBC 
White Blood cell 
WHO 
World Health Organization 
 


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2. 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies which will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
2.1. 
Responsibilities 
Syneos Health is responsible for the production and quality control of the baseline, efficacy, 
pharmacokinetic (PK), safety and quality of life (QoL) tables, listings and figures (TLFs) and will perform 
the statistical analyses for these.  
In addition to the current SAP, additional SAP(s) will be prepared to analyse immunogenicity, 
electrocardiogram (ECG) data and exploratory correlation analysis (e.g. exposure/response and 
exposure/safety). These analyses will not be performed by Syneos Health but be carried out by Byondis 
and/or other parties to which Byondis has delegated this responsibility. The results of these analyses will 
be reported separately. 
Listings will be provided by Syneos Health for ECG data and immunogenicity data as collected on the 
Case Report Form (CRF).  
For samples collected but not yet analysed (e.g. circulating tumour (ct) DNA and human epidermal growth 
factor receptor (HER) 2 – extracellular domain (ECD)) listings of sample dates and times will be provided.  
2.2. 
Timings of Analyses 
Analysis of the Primary Endpoint: Progression free survival (PFS) analysis will be performed when at 
least 256 PFS events have occurred, as assessed by central review, or at least 95% of patients have 
discontinued treatment and only after all patients have been enrolled. All TLFs and analysis will be 
completed at this time. An interim assessment of overall survival (OS) will be performed at this time with 
no implications in terms of future study conduct. 
Survival Follow Up: The final analysis is planned after the study is ended. The study will end when: 
• 
All patients have completed the treatment discontinuation visit, or 
• 
Sufficient survival follow-up information is obtained to enable analysis, or 
• 
The trial is terminated by the Sponsor. 
 
All TLFs and analysis, including PFS, will be completed at this time. Unless otherwise specified, the 
analysis includes all data collected in the database through to the time of the database lock.  
Data Monitoring Committee (DMC) Analysis: An independent DMC will review descriptive summaries of 
accumulating safety, subject disposition and limited efficacy data at 3 timepoints throughout the study. 
The summaries provided will be a subset of those described in this SAP. the composition, roles and 
responsibilities of the DMC are described in a separate charter.  As part of their evaluation the DMC 
assessed the validity of the initial assumptions underlying the sample size estimation with regards to drop-
out rates.  
Interim Analysis: No formal interim analysis will be performed. See section 13.0. 


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3. 
Study Objectives 
3.1. 
Primary Objective 
The primary objective of this study is to demonstrate that SYD985 is superior to physician’s choice in 
prolonging PFS on the basis of the blinded independent central review (ICR) of tumour assessments.  
3.2. 
Secondary Objective(s) 
3.2.1. 
Secondary Objectives 
The secondary objectives of this study are to compare the two treatment groups with respect to: 
 
• 
Overall survival (OS); 
• 
Objective response rate (ORR) on the basis of the blinded ICR; 
• 
Investigator assessed PFS (based on a local review); 
• 
Patient reported outcomes for health related quality of life; 
• 
Safety and tolerability. 
 
3.2.2. 
Other Objectives 
The other objectives of this study are as follows: 
• 
To describe time to response (TTR) in each treatment group; 
• 
To describe duration of response (DOR) in each treatment group; 
• 
To describe the clinical benefit rate (CBR) in each treatment group;  
• 
To evaluate the PK of SYD985; 
• 
To evaluate the formation of SYD985 anti-drug antibodies (ADAs); 
• 
To explore exposure/response and exposure/safety relationships. 


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4. 
Study Details/Design 
4.1. 
Brief Description 
This study is an open-label, phase III study. This study is designed as a randomized, active-controlled, 
superiority study in patients with unresectable locally advanced or metastatic HER2-positive breast 
cancer. The patients should have had either progression during or after at least two HER2-targeting 
treatment regimens for locally advanced or metastatic disease or progression during or after (ado-) 
trastuzumab emtansine treatment. 
Eligible patients will be randomly assigned in a 2:1 ratio to receive SYD985 1.2 mg/kg infusions every 
three weeks or a combination treatment of physician’s choice in a 21 day regimen. Patients will remain on 
study treatment until investigator-assessed disease progression, unacceptable toxicity or study 
termination by the Sponsor. After discontinuation of study treatment patients will be followed for survival 
until death, lost to follow-up, withdrawal of consent, or study termination by the Sponsor. 
The allocation will be stratified for geographical region (Europe and Singapore/North America), the 
number of prior treatment lines for advanced breast cancer (excluding hormone therapy) (1-2, more than 
2), and prior treatment with pertuzumab (yes, no). 
After a screening period of maximally 28 days, patients who are eligible will be randomized and treated 
until disease progression or unacceptable toxicity. Upon treatment discontinuation patients should return 
for a treatment discontinuation visit 4-6 weeks after the last administration of study drug. Thereafter 
patients will be contacted to follow up on clinical disease progression, unresolved adverse events (AEs), 
new anticancer therapies, and overall survival every 3 months after the treatment discontinuation visit up 
to death, lost to follow-up, consent withdrawal or end of study data collection, whichever comes first. 
The number of participating sites will be approximately 100 to ensure timely enrolment of the required 
number of patients. Sites will be located in Europe, Singapore and North America. Enrolment is targeted 
for at least 423 patients, resulting in 282 patients in the SYD985 group and 141 in the physician’s choice 
group. 
4.2. 
Patient Selection 
The study population will consist of female patients >= 18 years of age at informed consent with HER2-
positive unresectable locally advanced or metastatic breast cancer.  
4.2.1. 
Inclusion Criteria 
See protocol section 8.1.1. 
4.2.2. 
Exclusion Criteria 
See protocol section 8.1.2. 
4.3. 
Determination of Sample Size 
The primary efficacy endpoint of this study is PFS based on independent central review of tumour 
assessment. The primary efficacy analysis will be event driven. 
In order to be able to detect a hazard ratio of 0.65 in PFS using the log-rank test, at 90% power, using a 
two-sided test at a significance level of p < 0.05, a total of 256 events are required. Assuming a 9 month 


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recruitment period and 10 month follow up period, a median time to progression of 4.1 months for the 
physician’s choice and assuming an average of 30% drop out in the physician’s choice group and 40% in 
the SYD985 group, a minimal number of 423 patients is required. Allocation is 2:1 resulting in 282 to be 
allocated to the SYD985 group and 141 to the physician’s choice group. 
As part of their evaluation the DMC will assess if the assumptions underlying the sample size estimation 
with regards to drop-out rate are met, and may advise to change the planned sample size in case of 
serious departures. Such sample size re-estimation will not be considered a formal interim analysis as no 
between-group comparison of event-rates will be performed. Therefore, the primary analysis will be 
performed at the set 5% significance level. Details of methods used will be provided in a separate 
analysis plan. 
Based on their pre-planned interim evaluation the independent DMC has recommended to adjust the 
sample size and enrol a total of 423 patients to ensure sufficient power for the primary endpoint analysis. 
4.4. 
Treatment Assignment and Blinding 
After signing the “HER2 testing” or “Study” informed consent form (ICF), the investigator (or authorized 
delegate) will enter the electronic eCRF to obtain a patient number.  
When all screening data are available, including confirmation by the central laboratory on the HER2 
status assessment, the patient can be randomized if the patient complies with all inclusion criteria and 
none of the exclusion criteria. 
A patient should be randomized within 28 days of signing the “Study”-ICF. To be able to randomize a 
patient, the investigator (or authorized delegate) should complete the required screening information in 
the eCRF. The randomization will be performed in the eCRF (Rave Balance module). Randomization 
should be done on the day of first treatment or the day before if this turns out to improve logistics. 
Using a computer-generated randomization list, eligible patients will be randomly assigned in a 2:1 ratio 
to receive SYD985 or physician’s choice therapy via Balance/RAVE. The allocation will be stratified for 
geographical region (Europe and Singapore, North America), the number of prior treatment lines for 
advanced breast cancer (excluding hormone therapy) (1-2, more than 2), and prior treatment with 
pertuzumab (yes, no). 
Blinding of treatment assigned is not applicable as this is an open-label study. 
4.5. 
Administration of Study Medication 
4.5.1. 
SYD985 Treatment 
SYD985 1.2 mg/kg will be administered every three weeks (± 3 days) by intravenous infusion. Dose 
delays and dose reductions are allowed as described in the protocol section 9.5. 
4.5.2. 
Physician’s Choice Treatment 
Physician’s choice therapy options: 
1. Lapatinib + Capecitabine 
2. Trastuzumab + Capecitabine 
3. Trastuzumab + Vinorelbine 
4. Trastuzumab + Eribulin 


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The choice of reference therapy will be at the investigator’s discretion and should be in accordance with 
local clinical practice. 
 
4.6. 
Study Procedures and Flowchart 
See Protocol Section 1.1 for the study flowchart detailing assessments (including specific notes for 
assessments) and procedures by visit. 
The visit structure and allowable windows are as follows: 
 
Screen-
ing 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 
Cycle 5 
Onwards 
Treatment 
Disc. 
Survival 
Follow-up 
Visit Day D-28  
to -1 
D1 D2 D8 D15 D1 D8 D15 D1 
D1 D2 D15 D1 
28-42 days 
after last 
dose of study 
treatment or 
before the 
start of 
anticancer 
treatment, 
whichever 
comes first 
Every 3 
months 
after last 
contact 
Visit 
Window 
(Days) 
 
 
 
± 1 ± 1 
± 3 ± 1 ± 1 ± 3 
± 3  
± 3 ± 3 
 
± 14 
D = Day; Disc = discontinuation. 
In addition, there are notes to the study flowchart detailing variations to the above visit windows for 
certain assessments, these are specified below. 
Note 2: Day 1 assessments are to be done prior to study drug administration; 
Note 3: Weight should be measured before the start of a new cycle, this may be done up to 7 days before 
the Day 1 visit; 
Note 5: Blood sampling for haematology/chemistry, cardiac troponin, and urinalysis should be done as 
closely as possible to the start of the new cycle, but may be done up to 3 days before. Analyses should 
be performed at a local laboratory. Results of the local laboratory should be available before the start of 
the new cycle to determine whether the patient can continue. 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. Analyses for haematology/chemistry, and cardiac troponin should also be performed at 
the central laboratory; 
Note 7: Pregnancy test in women of childbearing potential: serum test at screening (between day -10 and 
day -1), serum or urinary tests during treatment and at treatment discontinuation visit; 
Note 10:  Ophthalmological examination (slit lamp exam, corneal sensitivity testing, fluorescence tear film 
break up time, and pachymetry) as well as left ventricular ejection fraction (LVEF) assessment 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; 


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Note 14: For tumour measurements, a CT or MRI scan should be performed every 6 weeks (± 3 days) 
after the date of randomization for the first 42 weeks and every 9 weeks (± 3 days) thereafter, 
independent of dosing delays. The methodology and imaging levels should remain the same at baseline 
and subsequent evaluations for a given patient;  
PK blood sampling scheme for the SYD985 treatment group: 
 
Cycle  
Day  
Sampling time*  
Cycle 1  
1  
Pre-dose  
End of infusion  
2 
24 hours (± 2h) after end of infusion 
8  
During the visit 
15  
During the visit 
Cycle 2  
1  
Pre-dose  
End of infusion  
8  
During the visit 
15  
During the visit 
Cycle 3  
1  
Pre-dose  
End of infusion  
Cycle 4  
1  
Pre-dose  
End of infusion  
2 
24 hours (± 2h) after end of infusion 
15  
During the visit 
Cycle 5 onwards  
1  
Pre-dose  
Treatment discontinuation  
 
During the visit 
* PK will be assessed for total SYD985 (includes SYD985 with a drug-to-antibody ratio (DAR) of ≥ 0), 
conjugated SYD985 (includes SYD985 with a DAR of ≥1), and for the free toxin (DUBA, SYD986) in cycle 
1 to 4. From cycle 5 onwards PK will be assessed for total SYD985 only.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ECG assessment schedule: 
Cycle 
Time point 
Screening 
Screening 
1 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
2 
Day 1: Before study drug administration# 
3 
Day 1: Before study drug administration# 
4 
Day 1: Before study drug administration  
Day 1: 30 minutes after end of infusion (±10 minutes)* 
Day 2: 24 hours after study drug administration (±2 hours)  
Every subsequent 4th cycle 
Day 1: Before study drug administration# 
Treatment discontinuation 
Treatment discontinuation 
*not applicable for patients in physician’s choice group receiving the oral treatment combination Lapatinib 
+ Capecitabine.  
 
#For patients in physician’s choice group receiving the oral treatment combination Lapatinib + 
Capecitabine the timing of the ECG on Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1 does not have to 
be correlated to the study drug administration. The ECG on Cycle 4 Day 2 should be 24 hours (± 2 hours) 
after the Cycle 4 Day 1 ECG. 
 


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5. 
Endpoints   
5.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS based on ICR of tumour assessment according to Response 
Evaluation Criteria for Solid Tumours (RECIST) 1.1 (Eisenhauer, 2009).  
5.2. 
Secondary Efficacy Endpoints 
• 
OS; 
• 
ORR on the basis of the blinded ICR; 
• 
Investigator assessed PFS (based on local review); 
• 
Patient reported outcomes for health related quality of life. 
 
5.2.1. 
Other Efficacy Endpoints 
• 
TTR; 
• 
DOR; 
• 
CBR. 
 
5.3. 
Exploratory Endpoints 
• 
Exposure/response and exposure/safety relationships (as described in section 2.1 not to be detailed 
in this SAP). 
5.4. 
Pharmacokinetic Endpoints 
To evaluate the pharmacokinetics of SYD985. 
5.5. 
Safety Endpoints 
• 
Incidence and severity of (serious) adverse events (AEs) and (serious) Adverse Events of Special 
Interest (AESIs). 
• 
Changes in LVEF and ECG and ophthalmological examinations. 
• 
Changes in vital signs and weight. 
• 
Changes in Eastern Cooperative Oncology Group (ECOG) performance status. 
• 
Changes in laboratory parameters, including cardiac biomarkers. 
• 
Formation of SYD985 ADAs. 
 
 


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6. 
Analysis Sets 
6.1. 
Screened Set 
The Screened Set (SS) will include all patients who have signed informed consent (HER2-ICF and/or 
Study-ICF). Unless specified otherwise, this set will be used for the summaries of patient disposition and 
to list disposition and randomization data and screen failure data at the end of the appropriate listing 
(informed consent, patient eligibility, demographics and (serious) adverse events).  
 
6.2. 
Full Analysis Set  
The Full Analysis Set (FAS) comprises all randomized patients. Following the intent to treat (ITT) 
principle, patients will be analyzed according to the treatment group and strata they have been assigned 
to during the randomization procedure. The FAS will be the primary population for all the efficacy 
analyses. The FAS will be used for all analyses of efficacy and for the protocol deviations, patient 
eligibility, baseline and efficacy listings. 
 
6.3. 
Safety Analysis Set  
The Safety Analysis Set (SAS) includes all patients who received at least one (partial) dose of study 
medication. Patients will be analyzed according to the study treatment they actually received. Treatment 
actually received is defined as the study treatment (SYD985 or Physician’s choice) the patient receives 
on Cycle 1 Day 1. The SAS will be used for all analyses of safety endpoints and the safety listings. 
 
6.4. 
Per-Protocol Set  
The Per-Protocol Set (PPS) will include the subset of the patients in the FAS who were administered at 
least one (partial) dose of study medication and who do not have any major protocol deviations or 
multiple minor deviations. Protocol deviations or conditions leading to exclusion from the PPS are 
specified in section 6.6. Patients will be analyzed according to the treatment and strata they have been 
assigned to during the randomization procedure. The PPS will be used for baseline summaries, a 
secondary analysis of the primary endpoint of PFS and a number of additional efficacy endpoints as 
described in SAP section 9.0. 
 
6.5. 
Pharmacokinetic Set   
The Pharmacokinetic Set (PKS) will include all patients who received at least one (partial) dose of the 
study drug SYD985 and for whom at least one PK parameter can be calculated. The PKS will be used for 
the analyses of all PK endpoints. The final PKS will be determined by the Syneos Health study PK 
Scientist. 
6.6. 
Protocol Deviations 
Protocol deviation management at Syneos Health is detailed in the Protocol Deviation and Non-
compliance Management Plan.  
Two protocol deviation summaries and corresponding listings will be provided: 1) all major deviations; 2) 
major protocol deviations leading to PPS exclusion.   


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The list of major protocol deviations leading to PPS exclusion includes at least the following deviations: 
• 
Patients younger than 18 years old. 
• 
Violation of inclusion criteria 2: Patients with histologically-confirmed, unresectable locally 
advanced or metastatic breast cancer. 
• 
Violation of inclusion criteria 3: Patients should have had either progression during or after at 
least two HER2-targeting treatment regimens for locally advanced or metastatic disease or 
progression during or after (ado-)trastuzumab emtansine treatment for locally advanced or 
metastatic disease. 
• 
Violation of inclusion criteria 8: adequate organ function. 
• 
Violation of exclusion criteria 3: history of keratitis. 
• 
Failure to obtain ICF. 
• 
Treatment allocation error (patient is randomized to SYD985 but receives the Physician’s Choice 
or vice versa), or treatment error (switch of treatments SYD985 to Physician’s Choice or vice 
versa, during the study). 
The final list of patients that are to be included in the PPS will be determined at the Data Review Meeting 
(DRM). The DRM will occur when all or nearly all queries have been resolved and the database is near to 
final. For the DRM meeting, a DRM Preparation Plan will be prepared. This plan will detail further the 
types of protocol deviation criteria and will include, as a minimum: 1) the exact criteria which will be used 
to determine if a patient will be excluded from the PPS; 2) the listings which will be prepared for sponsor 
review in order to determine which patients to exclude from the PPS. Details of patient specific exclusions 
from the PPS will be detailed in the DRM Highlights document. 
Note: a separate summary and listing of COVID-19 related protocol deviations will be provided using the 
FAS. COVID-19 related protocol deviations are reviewed and confirmed during the scheduled protocol 
deviation review meetings as described in the Protocol Deviation and Non-compliance Management Plan. 
 
 


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7. 
General Aspects for Statistical Analysis 
7.1. 
General Methods 
• 
SAS version 9.3 or higher will be used. 
• 
Phoenix WinNonLin version 6.4 or higher will be used for PK parameter derivation. 
• 
Analysis datasets used for statistical analyses will be developed according to CDISC (Clinical Data 
Interchange Standards Consortium) Analysis Data Model (ADaM) Version 2.1 corresponding to 
Version 1.0 of the Analysis Data Model Implementation Guide (ADaMIG). Documentation 
(DEFINE.xml) will be provided. 
• 
Unless otherwise specified, summaries will be presented for each treatment group, ‘SYD985’ then 
‘Physician’s Choice’. A ‘Total’ column will be added to the baseline tables. 
• 
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using number 
of observations (n), frequency and percentages of patients. 
• 
Unless stated otherwise, the calculation of percentages will be based on the total number of patients 
in the population of interest. Thus counts of missing observations will be included in the denominator 
and presented as a separate category.  
• 
Multiple assessments on the same day (planned, repeat) will not be included in summary tables 
unless specified otherwise, but will be included in the listings. If there are multiple valid results at a 
given visit (i.e. the same day), e.g. a repeated lab test within a visit, the earliest value will be used.  
• 
In general, unscheduled visit data will be listed but not included in the summary tables by 
visit/timepoint. Unscheduled data will be included to identify the worst case post-first dose for safety 
shift tables.  
• 
Time to event data (e.g. PFS, OS) will be analyzed using Kaplan-Meier survival estimates. Summary 
statistics will include median, 25th, and 75th percentile survival times and corresponding 95% 
confidence intervals (CIs).  
• 
Unless otherwise specified, listings will be sorted by treatment group ‘SYD985’, physician’s choice – 
in the order: ‘Lapatinib + Capecitabine’, ‘Trastuzumab + Capecitabine’, ‘Trastuzumab + Vinorelbine’, 
‘Trastuzumab + Eribulin’, patient number and assessment date and time. 
• 
All relevant patient data will be included in listings. All patients entered into the database will be 
included in patient data listings. Screen failure data will be included at the end of the appropriate 
listings and labelled ‘Screen Failures’. 
• 
Missing records will be omitted from the listings, and missing data within a record will be left blank. 
7.2. 
Key Definitions 
Study day is the day relative to the date of first dose of study medication where Day 1 is the day of study 
medication. 
 


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The first dose date is defined as the first non-missing date where a non-zero dose of study medication 
was recorded.  
 
The last dose date is defined as the last non-missing date where a non-zero dose of study medication was 
recorded.  
 
Unless otherwise specified, baseline is the last non-missing observation before or on the start of study 
medication, which is expected to be Day 1 of Cycle 1 (pre-dose), or screening if the Day 1 data are not 
available. 
7.3. 
Missing Data 
Missing data will be treated as missing except for adverse events where toxicity grade and relationship to 
study drug are missing (see SAP section 12.1). 
 
Incomplete start dates of adverse events or prior medication or concomitant medication will be imputed 
according to the following conventions: 
 
Missing item 
Condition 
Imputed date 
Day 
MMMYYYY = Date of first dose 
Date of first dose 
MMMYYYY < Date of first dose 
Date of IC or 01MMMYYY, whichever is 
the later 
MMMYYYY > Date of first dose 
01MMMYYYY 
Day and month 
YYYY = Date of first dose 
Date of first dose 
YYYY < Date of first dose 
Date of IC or 01JANYYYY, whichever is 
the later 
YYYY > Date of first dose 
01JANYYYY 
Year 
DDMMM 
Date of first dose 
Day, month, year 
None 
Date of first dose 
IC = Informed Consent 
 
For incomplete diagnosis dates, a missing day will be imputed as 01 and a missing month as JUL. If the 
date is missing entirely, there will be no imputation. No imputation of incomplete or missing dates for any 
other historical data will be done. 
Note: a listing of missing assessments and a listing of missing visits due to COVID-19 will be provided. 
The FAS will be used. 
 
 
 
 
 
 
 


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7.4. 
Visit Windows 
In general, if multiple (planned) assessments fall within the same window, the assessment closest to the 
scheduled/planned day will be used in summaries and analysis. 
 
Visit windows for unscheduled visits are defined as follows: 
 
Planned Visit/Assessment Day 
Window (Days) for the Planned Visit/Assessment 
(related to cycle) 
Cycle 
Day 
1 
1 
1 
2 
2 - 4 
                          
8 
5 - 11                                  
15 
12 - start next cycle*           
2 
1 
1 - 4 
                       
8 
5 - 11                                  
15 
12 - start next cycle*          
3 
1 
1- start next cycle*            
4 
1 
1   
2 
2 - 4                                     
15 
5 - start next cycle*              
5 (and onwards) 
1 
1-start next cycle*              
Treatment disc. 
Visit – 30 days after visit     
*Or treatment discontinuation visit, if this was the last cycle; the next cycle is defined as Day 1 of the next 
cycle. If an assessment is in the middle of a window, the earliest assessment will be selected e.g. Cycle 
1 Day 8, the visit window is 5 -11 days. There is an assessment on Day 7 and another assessment on 
Day 9 so both are +/- 1 day from day 8, the Day 7 assessment will be used. FU = follow up. 
 
For certain assessments there are the following specific windows: 
• 
Weight on Cycle x Day 1: day -7 to day 1 
• 
Haematology/chemistry/cardiac troponin and urinalysis (central and local) on Cycle 1 Day 1: day -5 to 
day 1 
• 
Haematology/chemistry/cardiac troponin and urinalysis (central and local) on Cycle 2 (and onwards) 
Day 1: day -3 to day 1 
• 
Ophthalmological examinations (slit lamp exam, corneal sensitivity testing, fluorescence tear film 
break up time, and pachymetry) on Cycle x Day 1: day -7 to day 1 
• 
LVEF on Cycle x Day 1: day -7 to day 1 
 
Tumour measurement analysis is being performed on the basis of actual assessment time points, 
windows are not applicable. 
 
PK sampling analysis is being performed on the basis of actual sampling time points, windows are not 
applicable. 
 
As previously described, in addition to the current SAP, additional SAP(s) will be prepared to analyse 
immunogenicity, ECG data therefore possible visit windows for these parameters will not be specified in 
this SAP. 
7.5. 
Pooling of Centers 
As it is anticipated that accrual will be spread thinly across centres and summaries of data by centre 
would be unlikely to be informative, data from all participating centres will be pooled prior to analysis. 


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7.6. 
Subgroups 
Both PFS by ICR and OS based on the FAS will be sub-analyzed for the following categories:  age, world 
region (randomization stratum), race, ECOG, hormone receptor status, disease involvement, number of 
previous regimens for advanced and/or metastatic disease, brain lesions at screening, T-DM1 pre-
treatment, pertuzumab pre-treatment, pertuzumab and T-DM1 pre-treatment. See SAP section 9.4 for 
further details of categorization and statistical methods. 


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8. 
Demographic, Other Baseline Characteristics and Medication 
8.1. 
Patient Disposition, Withdrawals and Screen Failures 
The study disposition summary table will include the number and percentage of patients in each of the 
analysis sets for the screened set. This summary will also include the number of patients screened, 
randomized and screen failures (including reason for screen failure, ie failed criteria). The table will be 
presented by treatment group (the 4 subgroups for Physician’s Choice will be summarized separately) 
overall and by country. 
 
In addition, a separate disposition summary for the FAS will include the number and percentage of 
patients who discontinued treatment (including the reason for treatment discontinuation) and who 
discontinued from the study (including the reason for study discontinuation) by treatment group. The 
disposition table will also include randomization strata, country, how many patients received which 
Physician’s Choice treatment regimen and the number of patients attending each cycle to determine the 
number of cycles received. This will be determined by the study drug administration data – a non-missing 
dose greater than zero for any day within a cycle will be counted. Cycles received will be presented as a 
categorical and continuous variable. The table will be presented overall and by country. 
 
Disposition (including reasons for exclusion from analyses sets), randomization (planned from 
Balance/RAVE and actual as captured on the eCRF; any differences will be flagged) and eligibility criteria 
(including failed criteria for screen failures), signing of Study-ICF date, signing of HER2–testing-ICF date 
and protocol version will be listed. Screen failure data will be listed in the appropriate listing and will 
appear at the end of the listing. 
 
Patients impacted by COVID-19 related treatment/study discontinuations will be listed separately using 
the FAS. The ‘End of Treatment’ and ‘Discontinuation from Study’ eCRF data will be used. E.g. if End of 
Treatment reason is ‘Adverse Event’, the AE coding is checked for ‘COVID’. Similarly, the ‘other, specify’ 
comments are checked for ‘COVID’ for other treatment/study discontinuation reasons (e.g. ‘Withdrawn 
Consent’, ‘Lost to Follow Up’, ‘Other’).  
 
Major protocol deviations will be summarized by treatment group using the FAS. All protocol deviations 
will be listed by treatment group, patient number, deviation type (major or minor) and date. 
8.2. 
Demographic and Baseline Characteristics 
Age (years) at signing ICF (as collected on the eCRF), weight (kg) and height (cm) will be summarized by 
treatment group using summary statistics for continuous variables; demography (child bearing status, 
race, ethnicity) will be summarized as categorical variables. Demography data will be summarized for the 
FAS, PPS and SAS. 
 
The following conversions will be used: 
 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
Body Mass Index (BMI) (kg/m2) = Weight(kg)/[Height(m)2] 
 
Demographics will be summarized as described above using the SAS comparing patients who started 
treatment before vs. during the COVID-19 pandemic. For Italy and Singapore, a cut-off date of 01-Jan-
2020 will be used. That is if the first dose date is before 01-Jan-2020, then a patient will have started 


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treatment before the pandemic vs. a first dose date of the 01-Jan-2020 or later a patient will be 
considered as having started treatment during the pandemic. For all other countries, a cut-off date of 01-
Mar-2020 will be used and applied based on first dose date as described above. 
 
Assessment of disease at baseline will be summarized by treatment group including cancer type, 
histological classification, time from diagnosis to study entry in months ([derived as study IC date – 
diagnosis date + 1]/30.5), time from diagnosis of locally advanced or metastatic disease to study entry in 
months ([derived as study IC date – diagnosis date of locally advanced or metastatic disease + 1]/30.5) 
(see SAP section 7.3 which details how partial or missing diagnosis dates will be imputed), stage, disease 
type (locally advanced or metastatic), metastatic sites, visceral/non-visceral disease, brain metastases 
and hormone receptor (HRr) status for ER and PR, if available. Overall HRr status will be derived:  if ER 
or PR is positive then HRr status is positive; if ER and PR is negative then HRr status is negative. Central 
HER2 status assessment will also be summarized. The FAS, PPS and SAS will be used. All other 
baseline characteristic data (e.g. previous treatment of brain metastases etc) will be listed for the FAS.  
 
Tables will be presented by treatment group (the 4 subgroups for Physician’s Choice will be summarized 
separately) overall and by country. 
 
Brain scan and whole body bone scan data will be listed and sorted by patient number, treatment group 
and examination date.  
8.3. 
Medical History and Concomitant Diseases 
Medical history consists of any significant events (conditions or diseases) that were present before 
signing IC. Medical history/concurrent illness will be coded by using the Medical Dictionary for Regulatory 
Activities (MedDRA) latest version. Medical history frequencies will be summarized by treatment group 
and will be ordered by descending frequency within the SYD985 treatment group by system organ class 
(SOC) then, within a SOC, by overall descending frequency of preferred term (PT). If incidence for more 
than 1 term is identical, they will be sorted alphabetically. The Child-Pugh classification for hepatic 
impairment will be summarized with the medical histories. The FAS and SAS will be used. Medical history 
conditions, as recorded on the eCRF at screening, will be listed for the FAS. The medical history listing 
will be sorted by treatment group, patient number and onset date.  
8.4. 
Medication 
8.4.1. 
Prior Systemic Therapy Related to Study Indication 
 
Prior systemic therapies related to study indication (as recorded on the eCRF page ‘PRIOR SYSTEMIC 
THERAPY (RELATED TO STUDY INDICATION)’) in the locally advanced/metastatic setting will be 
presented in tabular form using Anatomical Therapeutic Chemical (ATC) classification system level 2 
(therapeutic subgroup) and preferred name via the World Health Organization Drug classification 
Dictionary (WHO DRUG) latest version. All medications will be sorted by descending frequency within the 
SYD985 treatment group at ATC level 2 and then, within ATC level 2, by descending frequency of 
preferred name. If incidence for more than 1 term is identical, they will be sorted alphabetically. The 
number and percentage of patients who took at least one drug within each specific preferred name will be 
presented. Patients will only be counted once if they are taking more than one medication or take the 
same medication more than once.  
 
In addition, for the prior systemic therapy related to the study indication, the number of prior treatment 
regimens (categorized as 1–2, 3-4, 5-8, >=9 and also summarized as a continuous variable), the number 


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of prior regimens in metastatic setting (categorized as 1–2, 3, >=4 and also summarized as a continuous 
variable ), the number of HER2 targeting regimens in the metastatic setting (categorized as 1–2, >=3) and 
prior treatment regimens in the metastatic setting (Trastuzumab + Pertuzumab + Taxane (taxane can 
include docetaxel and paclitaxel), Trastuzumab + Pertuzumab, Trastuzumab + Capecitabine, 
Trastuzumab + Lapatinib, Trastuzumab + Vinorelbin, Trastuzumab + Eribulin, (Ado)trastuzumab-
Emtansine, Lapatinib + Capecitabine) will be summarized by treatment group. Tables will be presented by 
treatment group (the 4 subgroups for Physician’s Choice will be summarized separately) overall and by 
country. 
 
Medication will be listed for the FAS and will be sorted by treatment group, patient number and start date. 
The FAS and SAS will be used for medication summaries.  
 
8.4.2. 
Prior Medication (not Related to Study Indication) 
 
Prior medications (medications where the stop date is prior to the date of first dose of study medication) 
not related to study indication will be listed.  
 
All prior medications will be listed including the derived study day relative to first dose (for both start and 
stop dates) and a flag for prior medications. 
 
8.4.3. 
Concomitant Medication 
 
Concomitant medications (medications starting on or after the start of study treatment and continuing 
after the start of study treatment) will be presented in tabular form using ATC classification system level 2 
(therapeutic subgroup) and ATC level 4 (chemical subgroup). All medications will be sorted by 
descending frequency within the SYD985 treatment group at ATC level 2 and then, within ATC level 2, by 
descending frequency of ATC level 4. If incidence for more than 1 term is identical, they will be sorted 
alphabetically. The number and percentage of patients who took at least one drug within each specific 
ATC level 4 will be presented. Patients will only be counted once if they are taking more than one 
medication or take the same medication more than once. SAP section 7.3 describes how to deal with 
partial medication start and stop dates. Section 10 of the protocol details the excluded prior and 
concomitant medications.   
 
Medication will be listed for the FAS and will be sorted by treatment group, patient number and start date. 
The FAS and SAS will be used for medication summaries.  
 
8.4.4. 
Other Therapies  
 
Prior radiotherapy and surgery (related to study indication) will be listed and sorted by treatment group, 
patient number and date (first dose date for prior radiotherapy and date of surgery).  
 
8.5. 
Extent of Exposure 
8.5.1. 
SYD985 
SYD985 1.2 mg/kg will be administered every three weeks (± 3 day) by intravenous infusion.  
The extent of exposure will be examined by summarizing the variables below: 
 


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• 
Total dose (mg) of SYD985 administered overall. 
• 
Number of cycles started (where a non-null value for ‘Total Calculated Dose (mg)’ is captured on 
Day 1. Presented as a categorical (1-4 cycles, > 4 cycle; the final categories will be determined 
based on the final distribution of the data) and a continuous variable. 
• 
Duration of exposure (expressed in months and weeks) for SYD985. This is calculated as follows:  
 
[(last dose date – first dose date) + 22] / 30.5 (for months) or 7 (for weeks) 
 
Note, as the last dose may continue to cause an effect for at least 3 weeks (dosing schedule is 
every 3 weeks), 21 days will be added to the interval between first dose and last dose (in addition 
to 1 day for cases where the first and last dose may have been the same date). Death date will 
be used if death occurs earlier. 
• 
Dose intensity (mg/weeks) overall. Computed as the ratio of the total actual dose received and 
duration of exposure. 
• 
Patient years for exposure. 
• 
SYD985 infusion rate reductions, interruptions, dose reductions and dose delays overall. A 
patient is only counted once. If there are any rate reductions, interruptions, delays or dose 
reductions a patient will be counted as ‘Yes’. The number of rate reductions, interruptions, dose 
reductions and dose delays per patient will also be summarized. The categories for rate 
reductions, interruptions and dose reductions are ‘0’, ‘1’, ‘2’, ‘>2’. The categories for dose delays 
are ‘0’, ‘1-3’, ‘4-6’ and ‘>6’. Dose modifications (dose delay and/or reduction) will be also 
summarized as described above using the categories for dose delays. 
 
All SYD985 administration data will be listed and will include whether a patient is continuing to the next 
cycle. 
 
A swimmer plot will be provided for duration of treatment in weeks.  
 
8.5.2. 
Physician’s Choice 
The extent of exposure will be assessed by summarizing for, capecitabine, vinorelbine (oral and 
intravenously (IV)), eribulin and trastuzumab as described above for SYD985: total dose administered, 
total number of cycles started, duration of exposure and patient years. For the oral administration of 
vinorelbine, total dose administered will be determined based on dose, regimen and the number of days 
missed. For lapatinib (administered daily orally), total dose administered will be based on dose and 
number of days missed.  
All lapatinib, capecitabine, vinorelbine (oral and IV), eribulin and trastuzumab data will be listed and will 
include whether a patient is continuing to the next cycle. 
 
Swimmer plots will be provided for duration of each physician’s choice treatment in weeks.  
8.6. 
Treatment Compliance  
Not applicable. 
 


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9. 
Efficacy 
The efficacy analysis will be performed using the FAS. The PPS will be used for a secondary analysis of 
the primary endpoint.  
 
9.1.1. 
Primary Analysis of the Primary Endpoint 
The primary efficacy endpoint is PFS based on blinded independent central review (ICR) of tumour 
assessment according to RECIST 1.1. PFS is defined as the time (in months) from the date of 
randomization to the date of first documented ICR-assessed disease progression according to RECIST 
1.1 or death due to any cause (whichever occurs earlier). 
 
PFS (months) = [(Date of progression/death – date of randomization) + 1] / 30.5 
 
Data for patients without disease progression or death from any cause as of the data cut-off date will be 
censored at the time of the last tumour assessment with an outcome other than “unevaluable” or, if no 
tumour assessment was performed after the baseline visit, at the time of randomization plus 1 day. Data 
for patients without disease progression or death from any cause as of the date when a new therapy for 
cancer is started will be censored at the time of the last tumour assessment with an outcome other than 
“unevaluable” prior to the date when a new therapy for cancer is started, or, if no tumour assessment was 
performed after the baseline visit, at the time of randomization plus 1 day. Data from patients who are lost 
to follow-up will be included in the analysis as censored observations on the last date of tumour 
assessment that the patient was known to be progression free. Data from patients whose disease 
progression or death occurs after two or more consecutive missed tumour assessment will not be 
counted. In these cases, the patient will be censored at the patient’s last tumour assessment prior to the 
first missing assessment. If disease progression occurs after one missed tumour assessment, the event 
will be counted at the respective event date. These rules are summarized in the table below: 
 
Situation  
Date of Progression or 
Censoring  
Outcome  
No baseline tumour assessments  
Randomization  
Censored  
Progression documented between 
scheduled visits  
Date of radiological assessment 
of measured lesions 
Progressed  
No progression  
Date of last radiological 
assessment of measured 
lesions 
Censored  
Treatment discontinuation for 
undocumented progression  
Date of last radiological 
assessment of measured 
lesions 
Censored  
Treatment discontinuation for 
toxicity or other reason  
Date of last radiological 
assessment of measured 
lesions 
Censored  
New anticancer treatment started  
Date of last radiological 
assessment of measured 
lesions prior to start new 
treatment 
Censored  
Death before first PD assessment  
Date of death  
Progressed  
Death between adequate 
assessment visits  
Date of death  
Progressed  


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Death or progression after more 
than one missed tumor 
assessment 
Date of last radiological 
assessment of measured 
lesions prior to first missing 
assessment 
Censored  
 
The primary efficacy endpoint PFS will be analyzed based on the data observed in the FAS population. 
The stratification factors assigned at randomization are world region (Europe and Singapore, North-
America), the number of prior treatment lines for locally advanced or metastatic breast cancer (excluding 
hormone therapy) (1-2, more than 2), and prior treatment with pertuzumab (yes, no). Pooling of strata will 
be considered depending on the counts of patients in the randomization strata and specifically if there are 
any low counts in any stratum. The survival distribution of PFS per treatment group will be estimated 
using the Kaplan-Meier method. The median PFS along with 95% CIs will be presented in tabular form by 
treatment group. The table will be presented overall and by country. Kaplan Meier plots will be provided; 
treatment group will be differentiated with a different line style.  
 
The comparison of the survival distributions of PFS between the two treatment groups will be performed 
using a stratified log-rank test at the two-sided 5% level of significance, i.e., 
 
H01: S1T(t) = S1R(t) vs. Ha1: S1T(t) ≠ S1R(t), for all t ≥ 0 (t=timepoint) 
 
Where S1T(t) is the survival distribution function of PFS in the treatment group of SYD985 and S1R(t) is the 
survival distribution function of PFS in the reference treatment group (physician’s choice). 
or in words 
 
H01: there is no difference between the populations in the probability of an event (progression or death) at 
any timepoint. 
 
versus 
 
Ha1: there is a difference between the populations in the probability of an event (progression or death) at 
some timepoint. 
 
A stratified Cox regression analysis will be used to estimate the hazard ratio (HR) of PFS, along with 95% 
CIs (using the same strata information as above). The stratification variables will be included as 
covariates in the model statement and ties=exact (or ties=efron) will be included.  
 
9.1.2. 
Secondary Analysis of the Primary Endpoint 
The analysis as described in section 9.1.1 as for the primary analysis will be repeated using the PPS and 
presented overall only, not by country. 
 
9.1.3. 
Sensitivity Analyses of the Primary Endpoint 
The analysis as described in section 9.1.1 will be repeated as follows (overall only, not by country, the 
FAS will be used): 
 
1. If there are any treatment allocation errors or mis-stratification errors at randomization, analyze 
according to actual treatment and strata. 


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2. Analyze without the stratification factors to derive the p-value and hazard ratio. 
3. Analyze using the date of progression calculated as the earlier of the IRC or investigator 
assessments. 
4. Analyze with the date of progression shifted to the day after the last preceding tumour evaluation 
where progression was known not to have occurred, ie the worst case. 
 
9.1.4. 
Additional Summary of the Primary Endpoint 
PFS by ICR will be summarized for SYD985 and the 4 Physician’s Choice subgroups separately using 
the FAS. No inferential analyses will be completed. 
 
9.2. 
Secondary Efficacy Endpoint(s) and Analyses 
 
The secondary efficacy endpoints of this study are overall survival, ORR based on blinded ICR, 
investigator assessed PFS according to the RECIST data captured on the eCRF (local review) and 
patient reported outcomes for health related QoL. 
  
9.2.1. 
Overall Survival 
 
Overall survival is defined as the time (in months and years) from date of randomization to date of death 
due to any cause.  
 
OS (Months) = [(Date of death – date of randomization) + 1] / 30.5 
OS (Years) = [(Date of death – date of randomization) + 1] / 365.25 
 
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 randomization plus 1 day.  
 
The analysis for OS will be based on the FAS population. The following statistical hypothesis for OS will 
be tested: 
 
H02:  S2T(t) = S2R(t) vs. Ha2: S2T(t) ≠ S2R(t), for all t ≥ 0 (t=timepoint) 
 
Where S2T(t) is the survival distribution function of OS in the treatment group of SYD985 and S2R(t) is the 
survival distribution function of OS in the reference treatment group (physician’s choice). 
 
or in words 
 
H02: there is no difference between the populations in the probability of an event (death) at any timepoint. 
 
versus 
 
Ha2: there is a difference between the populations in the probability of an event (death) at some timepoint. 
 
The distribution of OS will be compared between the two treatment groups using a stratified log-rank test 
at two-sided 5% level of significance. The strata information will be based on the data obtained from the 
system that was utilized for randomization. 


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The survival distribution function of OS will be estimated using the Kaplan-Meier method. The median OS 
along with 95% CIs will be presented in tabular form by treatment group. The stratified Cox regression 
analysis will be used to estimate the HR of OS, along with 95% CI. In addition, the 1-year survival rate 
and corresponding 95% CI will be estimated using the Kaplan-Meier approach. The table will be 
presented overall and by country. Kaplan Meier plots will be provided; treatment group will be 
differentiated with a different line style.  
 
The OS data will be listed by treatment group and patient number.  
 
A sensitivity analysis of OS as described above will be repeated using the PPS (overall only, not by 
country).  
 
A further summary will compare SYD985 to each of the 4 Physician’s Choice subgroups separately using 
the FAS. No inferential analyses will be completed. 
 
9.2.1.1. 
Survival Follow Up 
Survival follow-up data including progression, progression date and subsequent anti-cancer therapy 
(SACT) will be collected at treatment discontinuation and then every 3 months after last contact. Time 
since discontinuation of study treatment (last dose date) to progression date, first SACT date and second 
progression will be derived and summarized for the FAS as follows: 
1. Time to progression (days) = progression date - last dose date + 1 (for patients who discontinued 
treatment for a non-progressive disease reason from the ‘End of Treatment’ eCRF page).   
2. Time to start first SACT (days) = first SACT date - last dose date + 1 (for all patients) 
3. Time to 2nd progression (days) = progression date - last dose date + 1 (for patients who 
discontinued treatment due to disease progression from the ‘End of Treatment’ eCRF page).   
The survival follow-up data, including reason for death, will be listed for the FAS. 
9.2.2. 
Objective Response Rate 
 
Objective response rate is defined as the percentage of patients with ICR-assessed best overall response 
of complete response (CR) or partial response (PR) according to RECIST 1.1 (i.e. ‘Responders’). Only 
patients with measurable disease at baseline will be included in the analysis of ORR. Patients without a 
post-baseline tumour assessment will be considered non-responders. 
 
If a best overall tumour response of CR or PR is obtained at any post-first dose timepoint, then a patient 
is considered a ‘Responder’; if best overall response is ‘Stable Disease’, ‘Progressive Disease’, ‘Non-
CR/Non-PD’ or ‘Not evaluable’, then a patient is considered a ‘Non-responder’.  
 
ORR will be calculated based on the FAS population. The percentage of patients with a response will be 
summarized by treatment group along with 95% CIs. The Cochran-Mantel-Haenszel test (strata based on 
the baseline stratification factors) will be used to compare the two treatment groups with respect to the 
ORR at two-sided 5% level of significance. The table will be presented overall and by country. The 
analysis described above will be repeated using the PPS (overall only, not by country). This will be 
considered a sensitivity analysis. 
 
The following sensitivity analysis will also be calculated using the FAS (overall only, not by country): 


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• 
Confirmed ORR by ICR. A response will be considered confirmed by a second assessment at 
least 4 weeks after first assessment. 
• 
ORR as assessed by local review. 
• 
Confirmed ORR by local review. 
 
For the local review, (as captured on the eCRF page ‘RECIST 1.1 OVERALL TUMOUR RESPONSE 
(LOCAL REVIEW), ‘Overall Tumour Response’ variable) the same rules apply as for ICR-assessed best 
response. A response will be considered confirmed by a second assessment at least 4 weeks after first 
assessment.  
 
Further summaries of ORR and confirmed ORR will compare SYD985 to each of the 4 Physician’s Choice 
subgroups separately using the FAS. No inferential analyses will be completed. 
 
The RECIST 1.1 target and non-target lesion measurements and new lesion as collected on the eCRF 
(local review) and the ICR data will be listed separately by treatment group, patient number and 
evaluation date. Study day will be included on the listings.  
Overall tumour response (local review and as reported by ICR) will be listed in a similar manner. Further, 
any differences in overall tumour response between central and local review of RECIST 1.1 assessments 
will be listed separately by treatment group, evaluation date and review type (‘ICR’ then ‘Local’). Note – 
all records per patient will be listed if there are any differences in overall tumour response between the 
ICR and local review. 
 
9.2.3. 
Investigator Assessed PFS 
 
Investigator assessed PFS, based on local review data captured in the eCRF, is defined as the time (in 
months) from the date of randomization to the date of first documented investigator-assessed disease 
progression according to RECIST 1.1 (as captured on the eCRF page ‘RECIST 1.1 OVERALL TUMOUR 
RESPONSE (LOCAL REVIEW), ‘Overall Tumour Response’ variable) or death due to any cause 
(whichever occurs earlier). Handling of missing values will be as described for the primary endpoint (see 
SAP section 9.1.1). 
 
Investigator assessed PFS will be calculated based on the FAS population. The survivor distribution of 
PFS will be estimated per treatment group using the Kaplan-Meier method. The median PFS along with 
95% CI will be presented by treatment group. A stratified Cox regression analysis will be used to estimate 
the HR of PFS, along with the 95% CI. The treatment groups will be compared using the 2-sided stratified 
log-rank test. The table will be presented overall and by country. Kaplan Meier plots will be provided; 
treatment group will be differentiated with a different line style. The PFS analysis described above will be 
repeated using the PPS (overall only, not by country).  
 
A summary will compare SYD985 to each of the 4 Physician’s Choice subgroups separately using the 
FAS.  
 
Investigator assessed PFS will be determined using the progression date from the Survival Follow Up 
eCRF page for patients who discontinued treatment for a non-progressive disease reason. Patients with 
no progression in follow up will be censored at the last follow up date. If a patient discontinues treatment 
due to PD, but the last local RECIST evaluation was not PD (i.e. clinical PD). PFS will be censored at the 


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date of treatment discontinuation from the ‘End of Treatment’ eCRF. The PFS analysis will be completed 
as described above for investigator assessed PFS using the FAS.  
 
Any differences in ICR and investigator assessed PFS will be flagged in the listing investigator assessed 
PFS listing. 
 
9.2.4. 
Patient Reported Outcomes 
 
Patient reported outcomes for health related quality of life are collected with the EORTC (European 
Organisation for Research and Treatment of Cancer) QLQ-C30 questionnaire (version 3.0) (Aaronson et 
al, 1993) along with the disease-specific breast cancer module (EORTC QLQ-BR23) (Sprangers et al, 
1996) on Day 1 of Cycles 1 – 5 then every 2nd cycle and at treatment discontinuation. Scoring of raw QoL 
data and methods for handling missing items or missing assessments will be handled according to 
scoring manuals for each respective patient questionnaire (Fayers et al, 2001). 
 
The QLQ-C30 (version 3.0) is composed of multi-item scales and single-item measures. These include 1 
global health status/QoL scale, 5 functional scales, 9 symptom scales/items as follows: 
 
Global Health Status/QoL Scale 
• 
Global Health Status/QoL 
 
Functional Scales 
• 
Physical Functioning 
• 
Role Functioning 
• 
Emotional Functioning 
• 
Cognitive Functioning 
• 
Social Functioning 
 
Symptom Scales/Items: 
• 
Fatigue 
• 
Nausea and Vomiting 
• 
Pain 
• 
Dyspnoea 
• 
Insomnia 
• 
Appetite Loss 
• 
Constipation 
• 
Diarrhoea 
• 
Financial Difficulties 
 
The breast cancer specific module QLQ-B23 has 4 functional scales, 4 symptom scales/items as follows: 
   
Functional Scales 
• 
Body Image 
• 
Sexual Functioning 
• 
Sexual Enjoyment 
• 
Future Perspective 
 
Symptom Scales/Items: 
• 
Systemic Therapy Side Effects 


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• 
Breast Symptoms 
• 
Arm Symptoms 
• 
Upset by Hair Loss 
 
The number of patients completing each patient questionnaire in full and the number of missing or 
incomplete items will be summarized by treatment group for each scheduled assessment timepoints for 
the EORTC QLQ-C30 and EORTC QLQ-B23 questionnaires. The table will include the number of 
completed and missing questionnaires and items. The denominator for the percentage of 
completed/missing questionnaires will be the number of patients expected per visit (from eCRF page ‘Visit 
Date’ and the response is ‘Yes’ for ‘Was this visit performed?’) 
 
Descriptive statistics will be used to summarize the scale scores/items for the EORTC questionnaires at 
each scheduled assessment timepoint. Additionally, change from baseline in the scale scores/items at the 
time of each assessment will be summarized. Patients with an evaluable baseline scale scores/items and 
at least one evaluable post-baseline scale score/item during the treatment period will be included in the 
change from baseline analyses. Both transformed and raw scores will be presented. 
 
The global health status/QoL scale score of the EORTC QLQ-C30 is identified as the primary patient-
reported outcome variable of interest. The change from baseline in the global health status/QoL scale 
transformed score will be analyzed using a mixed model repeated measurement (MMRM) approach. The 
model will use the change from baseline in the reported QoL scale score as the dependent variable and 
will include a fixed effect of treatment group, randomization strata, cycle, baseline QoL scale score, and a 
treatment-by-time interaction. The baseline QoL scale score will be included in the model as a covariate. 
The Kenward-Roger approximation will be used to adjust the denominator degrees of freedom.  Patient is 
a random effect. An unstructured (general) covariance structure will be assumed initially to model the 
within-patient errors; however, other covariance structures will be tested and may be used in the final 
model if a better fit is evident. The least squares (LS) means, differences between LS means, 95% CIs for 
each difference and the p values from model effects will be reported to evaluate the treatment effect. LS 
means ± 95% CI will be presented by visit graphically; treatment group will be differentiated with a 
different line style. The inferential analysis will be presented overall and by country using the FAS.  
 
The inferential analysis described above will be repeated using the PPS (overall only, not by country). 
This will be considered a sensitivity analysis. 
 
In addition, a further sensitivity analysis will be conducted - the distribution of time to definitive 10% 
deterioration in the global health status/QoL transformed scale score in months will be assessed in the 
treatment groups. The time to definitive 10% deterioration is defined as the time from the date of 
randomization to the date of event, which is defined as at least 10% worsening of the corresponding scale 
score relative to baseline (without further improvement above the threshold) or death due to any cause 
(whichever occurs earlier).  
 
Time to 10% deterioration in global health status/QoL score (Months) = [(Date of 10% deterioration/date 
of death – date of randomization) + 1] / 30.5 
 
If a patient has not had an event, time to deterioration will be censored at the date of the last non-missing 
global health status/QoL score. If a patient did not have any baseline QoL assessment, time to 
deterioration will be censored at the date of randomization plus 1 day. Summary statistics from Kaplan-
Meier distributions will be determined, including the median time to definitive 10% deterioration along with 


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two-sided 95% CI. Additionally, time to definitive deterioration with different cut off definitions (e.g. 5%, 
15%) may be analyzed. A stratified Cox regression will be used to estimate the hazard ratio, along with 
two-sided 95% CI. Kaplan Meier plots will be provided; treatment group will be differentiated with a 
different line style.    
 
Physical functioning, emotional functioning and social functioning scale scores of the EORTC QLQ-C30, 
and the breast cancer symptoms scale score of the EORTC QLQ-BR23 are identified as secondary 
patient-reported outcome variables of interest and will be analyzed descriptively as detailed above.  
 
A summary will compare global health status/QoL score between SYD985 to each of the 4 Physician’s 
Choice subgroups separately using the FAS.  
 
9.3. 
Other Efficacy Endpoint(s) and Analyses 
 
Other efficacy endpoints are: 
 
• 
To describe Time to Response (TTR) in each treatment group; 
• 
To describe Duration of Response (DOR) in each treatment group; 
• 
To describe Clinical Benefit Rate (CBR) in each treatment group. 
 
 
9.3.1. 
Time to Response (TTR) 
TTR is the time between the dates of randomization until first documented response (CR or PR) 
according to RECIST 1.1. All patients in the FAS will be included in time to response calculations. 
Patients who did not achieve a CR or PR will be censored at the maximum follow-up time for patients who 
had a PFS event (i.e. either progressed or death due to any cause) or at the date of last adequate tumour 
assessment date otherwise.  
 
TTR (months) = [(Date of PR/CR – date of randomization) + 1] / 30.5 
 
TTR will be analyzed based on the data observed in the FAS population and will be determined primarily 
by ICR of tumour assessment (an analysis based on investigator tumour assessment will also be 
performed). The survivor distribution of TTR will be estimated per treatment group using the Kaplan-Meier 
method. The median TTR along with 95% CI will be presented by treatment group in tabular form. TTR 
will also be evaluated using all responses (confirmed and unconfirmed) for both the ICR and local review. 
 
Any differences in ICR and investigator assessed TTR will be flagged in the listing. 
  
9.3.2. 
Duration of Response (DOR) 
DOR only 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).  
DOR (months) = [(Date of progression/death – date of first PR/CR) + 1] / 30.5 
DOR will be analyzed based on the data observed in the FAS population and will be determined primarily 
by ICR of tumour assessment (an analysis based on local review will also be performed). The censoring 


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methods for this endpoint are similar to those described for PFS. The Kaplan-Meier approach will be used 
to estimate the median duration of response of each treatment group and the corresponding 95% CIs.  
 
Any differences in ICR and investigator assessed DOR will be flagged in the listing. 
9.3.3. 
Clinical Benefit Rate (CBR) based on Best Overall Response 
The CBR is defined as the percentage of patients with:  
 
• 
measurable disease with: 
o 
CR  
o 
PR  
o 
SD (SD for 6 months or longer)  
 
• 
non-measurable disease with: 
o 
CR  
o 
non-CR/non-PD (non-CR/non-PD for 6 months or longer).  
 
according to RECIST 1.1. 
 
Duration of clinical benefit for patients with SD or non-CR/non-PD (to be at least 6 months defined as 183 
days) will be determined by the randomization date until a response of PD is first recorded. Note if a later 
SD or non-CR/non-PD follows NE it is assumed that SD continued.  
 
Duration of CB (days) = (Date of first PD – randomization date) + 1 
 
CBR will be analyzed based on the data observed in the FAS population and will be determined primarily 
by ICR of tumour assessment (an analysis based on local review will also be performed).  
 
Patients with missing overall responses (but who do have a post-first dose record for overall tumour 
response) will be treated as CBR = ‘No’, i.e. they will be included in the denominator when calculating the 
percentage.  
 
CBR will be summarized for the two treatment groups using descriptive statistics.  
 
9.3.4. 
Percentage of Patients with Reduction in Target Lesions 
The analysis described in section 9.3.3 will be repeated using the percentage of patients with reduction of 
target lesions (sum of diameters). This analysis will only apply to patients who had measureable disease 
at baseline. The denominator will be all patients in the FAS with measurable disease at baseline. 
Additionally, a waterfall plot for best percentage change from baseline in the sum of target lesion longest 
diameters will be provided by treatment group. The Y axis will be percent change from baseline and 
patient number on the X axis. A positive result indicates an increase in tumor size; a negative result 
indicates a decrease (shrinkage). Response (confirmed responder, unconfirmed responder, SD, and PD) 
as assessed by ICR will be differentiated by different bar styles. The FAS will be used. 
 
 
 
 
 


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9.4. 
Subgroup Analysis of Efficacy Endpoints 
Subgroup analyses will be performed to evaluate the associations between baseline covariates and the 
primary efficacy endpoint PFS and OS (months) for the FAS population using forest plots. The following 
subgroups will be investigated: 
• 
Age (Less than 65 yrs, >= 65 yrs) 
• 
World region (Europe and Singapore, North America) 
• 
Race (White vs. Non-white and not-disclosed)  
• 
ECOG (0-1, >=2)  
• 
Hormone receptor status (Positive vs. Negative)  
• 
Disease involvement (Visceral vs. Non-visceral)  
• 
Number of previous regimens for advanced and/or metastatic disease (1-2 vs. >2)  
• 
Brain lesions at screening (Yes vs. No) 
• 
T-DM1 pre-treatment (Yes vs. No)  
• 
Pertuzumab pre-treatment (Yes vs. No)  
• 
Pertuzumab and T-DM1 pre-treatment (Yes vs. No) 
 
The forest plots will show 95% CIs for the HR for PFS. CIs will be presented for each subgroup.  A 2-
sided p-value for the null hypothesis of a HR of 1 will also be presented for each subgroup.  
All subgroup analyses will be regarded as exploratory.  


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10. 
Pharmacokinetics 
The PK set will be used for the pharmacokinetic analysis. 
 
PK parameters will be derived using Phoenix WinNonLin version 6.4 or higher. The TLFs will be done in 
SAS 9.3. The PK concentrations (all sampling timepoints) and parameters (at Cycles 1, 2 and 4) will be 
available for total SYD985 (includes SYD985 with a DAR of ≥ 0), conjugated SYD985 (includes SYD985 
with a DAR of ≥ 1) and free toxin (SYD986) from the SYD985 treatment group and will be evaluated for 
PK analysis.  
 
10.1. 
PK Sampling Schedule  
During the study, venous blood samples will be collected at the following timepoints: 
 
Cycle  
Day  
Sampling time 
Cycle 1  
1  
Pre-dose  
End of infusion  
2 
24 hours (± 2h) after end of infusion 
8  
During the visit 
15  
During the visit 
Cycle 2  
1  
Pre-dose (Can be used as Cycle 1 
Day 21) 
End of infusion  
8  
During the visit 
15  
During the visit 
Cycle 3  
1  
Pre-dose (Can be used as Cycle 2 
Day 21) 
 
End of infusion  
Cycle 4  
1  
Pre-dose  
End of infusion  
2 
24 hours (± 2h) after end of infusion 
15  
During the visit 
Cycle 5 onwards  
1  
Pre-dose (Can be used as Cycle 4 
Day 21) (total SYD985 only) 
Treatment discontinuation  
During the visit 
 
Additional unscheduled PK sampling may be performed. The handling of these data is described in the 
SAP section 7.1. 
 
 
 
 
 
 


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10.2. 
Plasma PK Endpoint 
The following PK parameters will be derived for all 3 analytes for Cycle 1, Cycle 2 and Cycle 4 where 
possible: 
 
• 
Cmax - the maximum plasma concentration, (μg/mL for total and conjugated SYD985; pg/mL for 
SYD986). 
• 
Cmax_D – dose normalized maximum plasma concentration, ((μg/mL)/(mg/kg) for total and 
conjugated SYD985; (pg/mL)/(mg/kg) for SYD986). 
• 
Tmax – time to Cmax, (h). 
• 
Cmin - the minimum plasma concentration, (μg/mL for total and conjugated SYD985; pg/mL for 
SYD986). 
• 
Tlast – time of last quantifiable concentration for dose interval, (h).  
• 
Clast - last quantifiable concentration for dose interval, (μg/mL for total and conjugated SYD985; 
pg/mL for SYD986). 
• 
AUClast - area under the plasma concentration time curve from zero to the time of the last 
measurable concentration (μg/mL*h for total and conjugated SYD985; pg/mL*h for SYD986).   
• 
AUCtau - area under the plasma concentration time curve from zero to the end of dosing interval, 
may need extrapolation (μg/mL*h for total and conjugated SYD985; pg/mL*h for SYD986).   
• 
AUCinf - area under the plasma concentration time curve from zero to infinity, (μg/mL*h for total 
and conjugated SYD985; pg/mL*h for SYD986).  
• 
AUCinf_D – dose normalized area under the plasma concentration time curve from zero to infinity, 
((μg/mL*h)/(mg/kg) for total and conjugated SYD985; (pg/mL*h)/(mg/kg) for SYD986).  
• 
CL – plasma clearance (total and conjugated SYD985 only) (L/h). 
• 
CLss – plasma clearance at steady state (total and conjugated SYD985 at Cycle 4 only) (L/h).  
• 
Vz – volume of distribution (total and conjugated SYD985 only) (L). 
• 
Vss – steady state volume of distribution (total and conjugated SYD985 at Cycle 4 only) (L). 
• 
λz - terminal rate constant (1/h).  
• 
points λz – number of data points in the regression line for calculating λz. 
• 
λz-Lower – lower data point in the regression line for calculating λz (h). 
• 
λz-Upper – upper data point in the regression line for calculating λz (h). 
• 
t½ - terminal elimination half-life (h). 
• 
RCmax, RAUCtau and RAUClast – accumulation ratio assessed as the ratios of Cmax, AUCtau 
or AUClast for Cycle 2 vs. Cycle 1 and Cycle 4 vs. Cycle 1.  
 
 
10.3. 
Presentation of Concentration Data 
10.3.1. 
Handling of Missing Data  
Missing concentration data for all patients who are administered SYD985 will be considered as non-
informative missing and will not be imputed. No concentration estimates will be provided for missing 
sample values. 
 
For the derivation of AUC and for the individual plasma concentration versus time curves, the following 
rules will apply: 
 
Concentration values below the assay’s lower limit of quantification (BLQ) in pre-dose samples and in 
samples taken before the time of the first quantifiable concentration will be treated as zero; 
 
The sampling time of pre-dose samples relative to dosing will also be treated as zero; 


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Post-dose BLQ values after the first quantifiable timepoint will be set to missing. 
 
If the actual time of sampling is missing, the planned time may be used. 
 
Samples taken outside the sampling windows may be excluded from by-timepoint summary statistics; this 
will be determined prior to database lock. 
 
For plasma concentration summary the following rules will apply: 
 
Plasma concentrations BLQ in pre-dose samples and in samples taken before the time of the first 
quantifiable value will be set to zero; 
 
The plasma concentrations BLQ after quantifiable concentration will be set to zero. 
 
No further imputation will be applied to any missing values. 
 
10.3.2. 
Listing and Presentation of Individual PK Data 
The actual sampling time of PK blood sample collection will be listed for each patient. 
All concentrations will be presented in μg/mL units for total and conjugated SYD985, and pg/mL units for 
SYD986 free toxin. 
 
Individual patient plasma concentration data for total SYD985 (μg/mL), conjugated SYD985 (μg/mL) and 
SYD986 free toxin (pg/mL) will be listed by patient and timepoint and will be summarized at each 
timepoint.  
 
Individual patient PK parameters will be listed for the PK set by patient and will be summarized by cycle. 
Unreliable PK parameters will be listed but flagged and excluded from summary. 
 
Individual patient linear and semi-logarithmic concentration-time plots by analyte (total SYD985 from 
Cycle 1 to 5 and onwards, conjugated SYD985 and SYD986 free toxin from Cycle 1 to 4 only) will be 
produced. 
 
10.3.3. 
Summary of PK Concentrations  
PK concentration data for each analyte will be summarized using the following descriptive statistics: n, 
number and % BLQ, arithmetic mean, standard deviation, coefficient of variation (CV)%, minimum, 
median and maximum, geometric mean, CV% for geometric mean.  
 
Mean concentrations of each analyte will not be presented if 50% or more of the actual values at any one 
timepoint in the terminal phase are BLQ or missing. 
 
Samples taken outside the allowed time windows may be excluded from summarization.  
This will be determined prior to database lock. The exclusions will be defined based on the review of 
protocol deviation log and communicated to the sponsor prior to implementation. 
 


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Mean ± standard deviation concentration-time profiles will be presented on linear and log-linear scales vs. 
nominal time separately for each analyte. 
 
10.3.4. 
PK Parameters Derivation 
The PK parameters for total SYD985, conjugated SYD985, and SYD986 free toxin will be estimated using 
concentrations in μg/mL (total and conjugated SYD985) and pg/mL (SYD986) units as follows: 
 
PK Parameters 
Parameter Derivation 
Cmax and Tmax 
Cmax and the corresponding Tmax will be read directly from individual 
concentration-time plot for Cycles 1, 2, and 4  
Cmin and Tmin 
Cmin and the corresponding Tmin will be determined directly for Cycles 1, 2, and 
4  
AUClast 
AUClast will be calculated using the log-linear trapezoidal interpolation rule for 
intravenous model for Cycle 1, 2, and 4 
AUCtau  
AUCtau will be calculated using the log-linear trapezoidal interpolation rule for 
intravenous model with the possible extrapolation to the end of dosing interval 
if needed for Cycles 1, 2, and 4, where tau is the 21-day dosing interval 
AUCinf 
AUCinf will be calculated using the log-linear trapezoidal interpolation rule for 
intravenous model as AUC∞ = AUClast + AUCextrap. AUCextrap is calculated by the 
program as: Clast/λz, where Clast is the observed concentration at time tlast and λz 
is the elimination rate constant during the apparent terminal elimination phase; 
AUC∞ will only be presented for patients with a reliable λz for Cycle 1, 2, and 4 
t1/2 and λz  
t1/2 is calculated by the program as ln2/λz for Cycles 1, 2, and 4;  the terminal 
elimination rate constant (λz) will be determined by log linear regression 
obtained on at least the 3 last quantifiable concentrations and will not include 
Cmax. 
CL and CLss  
CL will be calculated by program as (dose/AUC∞) for Cycle 1 and 2 (total and 
conjugated SYD985 only); For Cycle 4 CLss – Clearance at steady state will be 
calculated by program as (dose/AUCtau); 
Vz and Vss 
Vz will be calculated by the program as (dose/AUC∞)/λz (total and conjugated 
SYD985 only) for Cycle 1 and 2;  Vss for Cycle 4 will be calculated by program 
as (MRTinf/CLss) where MRTinf is mean residence time 
RCmax, RAUCtau 
and RAUClast 
RCmax, RAUCtau and RAUClast will be calculated as ratios of the parameters for 
Cycle 2 vs. Cycle 1 and Cycle 4 vs. Cycle 1. 
 
The following PK acceptance criteria will be applied to assess the reliability of elimination parameters: 
 
• Number of points to calculate λz is greater than or equal to 3 excluding Cmax point; 
• Interval for calculation of λz is longer than half-life; 
• The adjusted square of the correlation coefficient (Rsquare adjusted) for the goodness    
   of fit of the regression line through the data points must be ≥0.85;  
• AUCextrap% ≤30%.  
 


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10.3.5. 
PK Parameters Summarization 
PK Summary Statistics 
 
Variable 
Summarized with: 
AUClast, AUCtau, AUCinf, 
AUCinf/D, Cmax, Cmax/D, Cmin, 
Clast, CL, CLss, Vz, Vss, t1/2, and 
λZ 
n, arithmetic mean, SD, CV%, minimum, median, maximum, 
geometric mean and geometric CV%  
RCmax, RAUCtau and RAUClast 
n, arithmetic mean, SD, CV%, minimum, median, and 
maximum 
Tmax, Tmin and Tlast 
n, minimum, median, and maximum 
 
The following conventions will be used for the presentation of the descriptive statistics of PK parameters 
and of plasma concentrations: 
 
PK Reporting Precision 
 
Statistics 
Degree of Precision 
Minimum, Maximum 
3 significant digits or as needed based on actual 
measured values (for example PK 
concentrations) 
Mean (arithmetic and geometric), Median 
4 significant digits 
Standard deviation 
5 significant digits 
CV and Geometric CV 
1 decimal point 
 
10.3.6. 
Statistical Methods 
The relationship between randomization strata and demographic covariates (e.g. age, weight and 
randomization strata) and PK parameter for CL and CLss for total SYD985 only will be explored 
graphically using regression scatter plots. 
 


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11. 
Pharmacodynamics 
The Pharmacodynamic (PD) analysis is to be completed by Byondis. A listing of ctDNA and HER2 ECD 
sampling will be presented by treatment group, patient number and collection date and time. 


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12. 
Safety 
The population used for safety analyses will be the Safety Analysis Set (SAS).  Safety will be assessed 
on the basis of AE reports, clinical laboratory data, vital signs, ECG parameters, LVEF data, 
ophthalmological examination, ECOG performance scores, physical examinations and immunogenicity. 
12.1. 
Adverse Events / Adverse Drug Reactions 
AEs will be summarized by the SOC and PT based on the latest MedDRA dictionary.  
 
The Common Terminology Criteria for Adverse Events (CTCAE) grades will be summarized by SOC and 
PT, using the National Cancer Institute (NCI) CTCAE version 4.03. 
 
Only treatment-emergent adverse events (TEAE) will be summarized. TEAEs are AEs reported to start 
within the in-treatment period. The in-treatment period is defined as the period starting from the first 
dosing of study drug up to and including the treatment discontinuation visit. Events starting before first 
dosing will be listed.  
SAP section 7.3 describes how to deal with partial or missing AE dates. If the relationship to SYD985 or 
any of the physician’s choice treatments is missing then the relationship will be counted as related for the 
summary tables.  Note related is defined as ‘possibly’ or ‘probably’. Similarly, missing severity will be 
counted as Grade 3.  
 
The summary tables will include the number of patients and the number of events.  Percentages will be 
based on the number of patients. For summaries by SOC and PT, a patient will be counted once at the 
SOC level and once at each PT within the SOC level.  For summaries by SOC, PT, and maximum 
intensity, a patient will be counted once at the highest intensity level for which the event occurred at the 
SOC level and the highest intensity level for each unique PT within that SOC level. Therefore, patients 
may only contribute once to each PT and once to each SOC level. The number of events will not be 
included in the maximum intensity summaries.    
 
The summaries presenting frequency of AEs by SOC and PT will be ordered by descending frequency of 
SOC and then, within a SOC, by descending frequency of PT within the SYD985 treatment group. 
 
Note for tables and listings: ‘Conjunctivitis’ will be recoded under the SOC ‘Eye Disorder’. The original 
SOC of ‘Infections and Infestations’ will be kept in the ADaM. 
 
The following AE tables will be provided: 
 
• 
An overall summary of the number and percentage of patients reporting TEAEs, serious TEAEs, 
any treatment-related TEAEs (i.e. relationship to either SYD985, and/or lapatinib, and/or 
capecitabine, and/or trastuzumab, and/or vinorelbine and/or eribulin is ‘possibly’ or ‘probably’. For 
the Physician’s Choice group, if the drug relationship is related to one or to both of the drugs in 
the combination, the drug relationship is ‘related’. An AE will be counted as ‘Not related’ only if 
the AE is not related to both of the drugs in the combination), TEAEs leading to any drug 
withdrawal (i.e. action taken is ‘study drug permanently withdrawn’. For the Physician’s Choice 
treatment group, two summaries will be provided: 1) TEAEs leading to withdrawal of both drugs; 
2) TEAEs leading to withdrawal of one drug, TEAEs leading to death, AESIs, treatment-related 
serious TEAEs, treatment-related TEAEs leading to drug withdrawal (see above), treatment-


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related TEAEs leading to death and treatment-related AESIs by treatment group. The 4 
subgroups for Physician’s Choice will be summarized separately. The table will be presented 
overall and by country. 
• 
TEAEs overall and by SOC and PT by treatment group. 
• 
TEAEs overall and by SOC and PT and by maximum severity, including a summary of Grade ≥ 3 
by SOC and PT by treatment group.  
• 
Serious TEAEs, overall and by SOC and PT by treatment group. 
• 
TEAEs leading to discontinuation of study treatment, overall and by SOC and PT by treatment 
group. For the Physician’s Choice treatment group, two summaries will be provided: 1) TEAEs 
leading to withdrawal of both drugs; 2) TEAEs leading to withdrawal of one drug. 
• 
TEAEs leading to dose modification of study treatment (where action is ‘dose delayed’ or ‘dose 
reduced’), overall and by SOC and PT by treatment group. 
• 
Treatment-emergent AESIs, overall and by SOC and PT by treatment group. See section 12.1.1. 
• 
Treatment-emergent AESIs by SOC and PT and by maximum severity, including a summary of 
Grade ≥ 3 by SOC and PT by treatment group. See section 12.1.1. 
• 
Serious treatment-emergent AESIs, overall and by SOC and PT by treatment group. See section 
12.1.1. 
• 
TEAEs leading to death, overall and by SOC and PT by treatment group. 
• 
Related TEAEs overall and by SOC and PT by treatment group. 
• 
Related TEAEs overall and by SOC and PT and by maximum severity, including a summary of 
Grade ≥ 3 by SOC and PT by treatment group.  
• 
Related serious TEAEs, overall and by SOC and PT by treatment group. 
• 
Related TEAEs leading to discontinuation of study treatment, overall and by SOC and PT by 
treatment group. For the Physician’s Choice treatment group, two summaries will be provided: 1) 
TEAEs leading to withdrawal of both drugs; 2) TEAEs leading to drug withdrawal of one drug. 
• 
Related TEAEs leading to dose modification of study treatment (where action is ‘dose delayed’ or 
‘dose reduced’), overall and by SOC and PT by treatment group. 
• 
Related treatment-emergent AESIs, overall and by SOC and PT by treatment group. 
• 
Related treatment-emergent AESIs by SOC and PT and by maximum severity, including a 
summary of Grade ≥ 3 by SOC and PT by treatment group. 
• 
Related serious treatment-emergent AESIs, overall and by SOC and PT by treatment group. 
• 
Related TEAEs leading to death, overall and by SOC and PT by treatment group. 
 
Only the TEAEs will be included in the summary tables, however all AEs will be included in the listings. 
Non-TEAEs will be flagged in the listings. Additional listings will be provided for deaths, SAEs, AEs 
leading to discontinuation of study treatment and AESIs. 
 
12.1.1. 
Adverse Events of Special Interest 
The AESIs are defined in the protocol as: 
 
• 
Interstitial Lung Disease/Pneumonitis 
• 
Severe eye toxicity grade >=3 
• 
Keratitis grade >=2 
• 
LVEF decrease to <50% 
 
Any AESI is flagged on the AE eCRF. These records will be selected and summarized as described 
above. 
 


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For ocular toxicity, in addition to summaries by SOC/PT, a Kaplan Meier table and figure with time (in 
weeks) to first episode of ocular toxicity (any grade) will be provided. Time is defined as the time from the 
start of the treatment to the first episode of ocular toxicity (any grade). If the patient does not have any 
ocular toxicity, censoring at the date of the patient was last assessed for adverse events. 
 
Time to first ocular toxicity episode (weeks) = ([Date of first ocular toxicity episode – date of first dose] + 
1) / 7 
 
Time will be analyzed using Kaplan Meier quartile and 60 %, 70 %, 80 % and 90 % percentiles estimates 
along with 2-sided 95% CIs. Kaplan Meier plots will be provided and each treatment will be differentiated 
with a different line style. 
 
The above analysis will be repeated for time (in weeks) to first episode of ocular toxicity grade >=2 and 
time (in weeks) to first episode of ocular toxicity grade >=3. 
 
Additional Kaplan Meier tables and figures, as described above for ocular toxicity, will also be produced 
for time (in weeks) to the first episode of keratitis, time (in weeks) to the first episode of keratitis grade 
>=2 and time (in weeks) to first episode of keratitis grade >=3. The analysis will be repeated for 
conjunctivitis and dry eye. 
 
The top three reported eye events (conjunctivitis, dry eye and keratitis) will be evaluated further. A 
summary table for each event will be provided detailing the number of events and the number of patients 
with an event overall and by grade 1, grade 2 and grade >=3. The number of patients with a fluctuation 
will be summarized. A fluctuation is a decrease in severity followed by an increase in severity. The 
duration of each event will be summarized overall (total) and by grade.  
 
Event duration is derived as: 
 
Event duration = ((AE end date - AE start date) + 1) / 7.  
If event is ongoing the last of the 3 dates: 1) last visit date up to the EOT visit; 2) last AE start date (any 
AE); 3) last AE end date (any AE) will be selected. 
 
The duration of no event will be determined by subtracting the total event duration from the patients AE 
assessment time: 
 
No event duration = AE assessment time ((end of AE follow up – first dose date) + 1) – total event 
duration + 1 
 
An event will be defined as recovered where an AE end date is not missing. Duration of recovery for each 
patient will be summarized and is the start date of the highest grade to the end date of the last AE (if the 
AE is ongoing, an end date is imputed as described above for event duration): 
 
Recovery duration = sum of each event duration from the event with the highest grade to the last event. 
 
Duration of an AE following a dose modification (delay or reduction) will also be determined per patient 
follows: 
 


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Duration following dose modification = sum of each event duration from the event after dose modification 
to the last event. 
The total duration per patient with a dose modification vs. without a dose modification will be summarized 
overall and by grade. 
 
The number of patients with a grade decrease, no grade change or grade increase will be summarized. 
The time (weeks) to an increase or decrease in grade following dose modification will be summarized by 
patient and is derived as follows: 
 
Time = (AE start date – dose reduction/delay date) + 1 / 7. 
A swimmers plot (SYD985 only) detailing event duration by grade for each patient will be produced for 
each of the three events. The x axis is time (weeks) and the y axis will be patient number. One lane will 
be produced for each patient and time starts at the first dose date and finishes at the end of AE follow up. 
Each event start and stop date will be plotted using study day. Each lane will be divided into the period of 
time with no event, grade 1, grade 2, grade 3 and grade 4. 
 
A listing (SYD985 only) will be produced, with a sub-heading for each of the three events, detailing event 
start and stop times (and study day from first dose), SYD985 dose (mg/kg) at AE start and end, action 
taken, grade, seriousness, relatedness, medication given and  outcome. Event duration, duration by 
grade, total duration, total duration by grade and event recovery will be listed separately. A similar listing 
of event duration and recovery will be produced following dose reduction/delay. 
 
12.2. 
Laboratory Evaluations 
Blood and urine samples will be taken at screening and at the timepoints as indicated in the flowchart 
(see protocol Section 1.1). The samples will be analyzed by the local laboratory and central laboratory for 
haematology, blood chemistry and cardiac troponin. The urinalysis will only be performed locally. The 
central data will be used for haematology, blood chemistry and cardiac troponin summaries and CTCAE 
grading. Both central and local lab data will be listed. The following parameters will be included: 
Heamatology: 
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, reticulocytes. 
Serum biochemistry: 
Albumin, alkaline phosphatase, ALT (alanine aminotransferase), AST (aspartate 
aminotransferase), total bilirubin, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, creatine kinase (CK), GGT (gamma glutamyl transpeptidase), 
glucose, inorganic phosphorus, LDH, magnesium, potassium, sodium, total 
protein, uric acid. 
Cardiac biomarkers:  
Cardiac troponin I (cTnI) or cardiac troponin T (cTnT).   
Urinalysis:  
Dipstick for bilirubin, glucose, haemoglobin, ketones, and protein (microscopy if 
more than one parameter is positive). 
All summaries will be based on results in SI units and will be output in the order listed above. High/low 
classifications will be derived relative to the result and normal range in SI units where normal ranges 


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exist. The eCRF states that differential counts can be entered as ‘Absolute’ values OR ‘Percentage’ 
values. Percentage white blood cell (WBC) differential counts will be converted to absolute values. As 
each differential always adds up to 100%, the total WBC can be used to derive absolute values. For 
example, if a relative neutrophil value = 70% and the total WBC = 6.20 109/L, then the absolute neutrophil 
value = 4.34 109/L (0.7 x 6.20).  
Toxicity grading following the NCI CTCAE grades version 4.03 will also be derived for laboratory variables 
where applicable (see tables below). Note, where gradings require investigator/clinical input, this will not 
be considered and only the numeric criteria will be used for the assignments. If this results in the criteria 
for more than one grade being met, the highest (worst) CTCAE grade will be assigned.  For creatinine 
only, the criteria based on the upper limit of normal (ULN) will be used (changes compared to the 
baseline value will not be used), e.g. CTCAE defines Grade 1 as >ULN - 1.5 x ULN or >1 - 1.5 x baseline. 
Only the ULN – 1.5 x ULN criterion will be used (and not the baseline criterion). 
The following parameters are gradable: 
Parameter 
NCI-CTCAE Term 
Haemoglobin 
Anemia 
Haemoglobin 
Haemoglobin increased 
Lymphocytes 
Lymphocyte count decreased 
Neutrophils 
Neutrophil count decreased 
Platelets 
Platelet count decreased 
WBC 
Leukocytosis 
WBC 
White blood cell decreased 
Albumin 
Albuminuria 
ALP 
Alkaline phosphatase increased 
ALT 
Alanine aminotransferase increased 
AST 
Aspartate aminotransferase increased 
Total bilirubin (note that direct bilirubin appear 
on the eCRF but it is only the Total bilirubin 
that is gradable) 
Blood bilirubin increased 
Calcium (corrected for albumin) 
Hypercalcemia 
Calcium (corrected for albumin) 
Hypocalcemia 
Creatinine 
Creatinine increased 
GGT 
GGT increased 
Glucose 
Hyperglycemia 
Glucose 
Hypoglycemia 
Magnesium 
Hypermagnesemia 
Magnesium 
Hypomagnesemia 
Potassium 
Hyperkalemia 
Potassium 
Hypokalemia 
Sodium 
Hypernatremia 
Sodium 
Hyponatremia 
 
 
 
 
 


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The following parameters will not be graded as there is no corresponding term in the NCI-CTCAE 
document:  
 
Erythrocyte count 
Haematocrit 
MCV 
Basophils 
Eosinophils 
Monocytes 
Reticulocytes 
MCHC 
BUN 
Chloride 
Creatinine kinase 
Inorganic phosphorous 
LDH 
Total protein 
Uric acid 
cTnI 
cTnT 
 
For haematology, blood chemistry and cardiac biomarker summary tables by visit and change from 
baseline to visit for each laboratory parameter will be provided. Baseline is defined as the last non-
missing assessment before the first dose of study drug. The baseline value is expected to be Day 1 pre-
dose. Summaries will include data from scheduled assessments only. If there are multiple results at a 
given visit, the earliest value will be used in the tables (see SAP section 7.1). SAP section 7.4 describes 
visit windows. 
Urinalysis parameters will be summarized by treatment group and listed in CRF order. 
Shift tables for haematology and blood chemistry from baseline CTCAE toxicity for each visit and to the 
maximum grade on treatment for each parameter will be provided. Patients with both a non-missing 
baseline and at least one non-missing post-baseline grade will be included in the shift tables. 
Unscheduled data will be included in the worst case across all scheduled and unscheduled visits after the 
first dose of study treatment. This means that if there are CTCAE grades derived from both unscheduled 
and scheduled visits data per test per patient then the highest grade will be summarized.  
For non-CTCAE gradable tests, a shift table will be provided showing shifts relative to the normal ranges 
(supplied by the central laboratory). This summary of normal range category changes illustrates the 
number and percentage of patients who fall into specified categories (Decrease to Low, Change to 
Normal or No Change, Increase to High) by comparing the baseline normal range category to the planned 
time normal range category and the worst-case on-therapy normal range category. The worst-case post-
baseline row will be used to summarize the patients’ overall worst-case normal range category change 
during the on-therapy period. The determination of the worst-case during the on-therapy period takes into 
account both planned and unscheduled assessments. Only laboratory tests which cannot be graded per 
CTCAE v4.03 specified criteria will be included. Patients with missing baseline value are to be assumed 
to have normal baseline value. Worst-case can be either High or Low. If a patient has a Decrease to Low 
and an Increase to High during the same time interval, then the patient is counted in both the ‘Decrease 
to Low’ and ‘Increase to High’ categories. If a patient was high at baseline and decreases to Low during 


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the time interval, then the patient is counted in the ‘Decrease to Low’ category. Likewise, if a patient was 
Low at baseline and increases to High during the time interval, then the patient is counted in the ‘Increase 
to High’ category. Patients are only counted in the ‘Change to Normal or No Change’ category if they are: 
• 
Normal at baseline and have no normal range High and no normal range Low values during the 
time interval 
• 
High at baseline and do not change to Low during the time interval 
• 
Low at baseline and do not change to High during the time interval   
 
All laboratory results in original and SI units will be included in data listings. Listings will be sorted by 
treatment group, patient number, assessment date and parameter (in the order listed above). 
Pregnancy test data will be listed by treatment group, patient number and date. 
 
12.3. 
Vital Signs  
Systolic and diastolic blood pressure, heart rate, oral temperature and oxygen saturation will be 
measured at Screening, Day 1 of all cycles, Day 8 and 15 of Cycle 1 and 2 and the Treatment 
Discontinuation visit. Weight is to be measured at Screening, Day 1 of all cycles and the Treatment 
Discontinuation visit. 
 
12.3.1. 
Vital Sign Values of Potential Clinical Importance  
 
The Potential Clinical Importance (PCI) Ranges are given in the table below for blood pressure and heart 
rate results. The values outside these ranges will be flagged on the listings as either ‘Low’ or ‘High’ 
relative to the PCI ranges.  
 
Vital Signs Parameter 
PCI Range 
Unit 
Systolic Blood Pressure 
< 85 (L) and >= 160 (H) 
mmHg 
Diastolic Blood Pressure 
< 45 (L) and >= 100 (H) 
mmHg 
Heart Rate 
< 40 (L) and > 110 (H) 
bpm 
 
The change from baseline values will be compared to the ranges in the tables below and be flagged on 
the listings if outside of these PCI ranges. 
Vital Signs Parameter 
PCI Range 
Unit 
Systolic Blood Pressure (Change from Baseline) 
Increase ≥ 20 and ≥ 40 
mmHg 
Decrease ≥ 20 and ≥ 40 
Diastolic Blood Pressure  (Change from Baseline) 
Increase  ≥ 10 and ≥ 20 
mmHg 
Decrease ≥ 10 and ≥ 20 
Heart Rate (Change from Baseline) 
Increase ≥ 15 and ≥ 30 
bpm 
 
 
 
 
 


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12.3.2. Summary of Changes in Heart Rate from Baseline 
 
A summary of changes in heart rate comparing the baseline value to the worst-case post baseline value 
will be provided.   
For heart rate, both an increase and decrease in value are of clinical concern.  The worst-case post 
baseline summary is used to summarize the patients’ overall worst-case shifts post baseline.  The 
determination of the worst-case post baseline will take into account both planned and unscheduled 
assessments.      
Patients with missing baseline value are to be assumed to have a normal baseline value.  The 
percentages are based on the number of patients with heart rate data at the specified planned time.   
The oncology standard categories of clinical concern are: 
 
• 
Heart Rate (bpm): ‘Decrease to <60’, ‘Increase to >100’   
 
Worst-case can be either High (ie >100) or Low (ie <60).  If a patient has a Decrease to Low and an 
Increase to High during the same time interval, then the patient is counted in both the “Decrease to <60” 
category and the “Increase to >100” category.  If a patient was High at baseline and decreases to Low 
during the time interval, then the patient is counted in the ‘Decrease to <60’ category.  Likewise, if a 
patient was Low at baseline and increases to High during the time interval, then the patient is counted in 
the ‘Increase to >100’ category.   
Patients are only counted in the ‘Change to Normal or No Change’ category if they are: 
 
• 
Normal at baseline and have no normal range High and no normal range Low values during 
the time interval 
• 
High at baseline and do not change to Low during the time interval 
• 
Low at baseline and do not change to High during the time interval    
 
 
12.3.3. 
Summary of Increases in Blood Pressure from Baseline 
 
A summary of increases in blood pressure parameters comparing the baseline value to each planned 
time and to the worst-case post baseline value will be provided.  The worst-case post baseline will be 
summarized separately from the by-visit summaries. These summaries apply to blood pressure 
parameters where increases in value are of clinical concern.  The worst-case post baseline summary is 
used to summarize the patients’ overall worst-case shifts post baseline.  The determination of the worst-
case post baseline takes into account both planned and unscheduled assessments.   
Patients with missing baseline values are assumed to have baseline value below the lowest threshold.  
The percentages are based on the number of patients in the treatment group with data for the vital sign 
parameter at the specified planned time.   
The oncology standard categories for Systolic Blood Pressure in mmHg are: 
• 
‘Any Grade Increase’ 
• 
‘Increase to Grade 2 (140-159)’  


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• 
‘Increase to Grade 3 (≥160)’ 
 
Note: ‘Any Grade Increase’ will be footnoted as Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159), 
or Grade 3 (≥160). 
The oncology standard categories for Diastolic Blood Pressure in mmHg are: 
 
• 
‘Any Grade Increase’ 
• 
‘Increase to Grade 2 (90-99)’  
• 
‘Increase to Grade 3 (≥100)’ 
 
Note: ‘Any Grade Increase’ will be footnoted as Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), or 
Grade 3 (≥100). 
Note:  Whole numbers are expected for systolic and diastolic blood pressure in mmHg.  For values with 
decimal places in the data the following cut-offs will be used for programming of the oncology standard 
categories.  For systolic blood pressure:  Any Increase to ≥120, Increase to ≥140-<160, and Increase to 
≥160.  For diastolic blood pressure:  Any Increase to ≥80, Increase to ≥90-<100, and Increase to ≥100. 
An increase is defined as an increase in grade (eg, for diastolic blood pressure, if a patient had Grade 1 
hypertension [84 mmHg] at baseline and at week 4 had an increase to 85 mmHg [still Grade 1], this is 
NOT counted as an increase).  However, if the patient had an increase to 101 mmHg (Grade 3) this is 
counted as an increase and the patient will be counted in the ‘Any Grade Increase’ and the ‘Increase to 
Grade 3 (≥100)’ categories). 
Summary statistics for vital signs and weight at each scheduled timepoint and changes from baseline will 
be presented. Baseline is defined as the last non-missing assessment before the first dose of study drug. 
The baseline value is expected to be Day 1 pre-dose. Summaries will include data from scheduled 
assessments only. If there are multiple results at a given visit, the earliest value will be used in the tables 
(see SAP section 7.1). SAP section 7.4 describes visit windows. 
Note temperature will be reported in centigrade. Any conversions required will be as follows: 
Temperature (in °C) = 5/9 (Temperature [in °F]-32). 
Note weight will be reported in kg. Any conversions required will be as follows: 
Weight (in kg) = weight (in lbs) * 0.4536 
All vital signs and body weight will be provided in data listings. Listings will be sorted by treatment group, 
patient number, assessment date and parameter (in the order systolic blood pressure, diastolic blood 
pressure, heart rate, oral temperature and weight). 
12.4. 
Central 12-lead ECG  
Detailed ECG assessment will be described in a separate SAP. The SAP and any subsequent analysis 
will be completed by Byondis. 
All ECG data collected in the eCRF will be provided in data listings. Listings will be sorted by treatment 
group, patient number, assessment date and timepoint for the SAS. 
Any clinically significant findings will be reported on the medical history or AE page as applicable.  


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12.5. 
Physical Examination 
Clinically significant findings from the physical examinations will be reported as either medical history or 
AEs as applicable.  
Physical examination data will be listed by treatment group, patient number and date of examination.  
12.6. 
Other Safety 
12.6.1. 
LVEF 
LVEF assessments will be conducted at Screening, Cycle 2 Day 1, Cycle 4 Day 1 then every 4th cycle 
and at the Treatment Discontinuation Visit. Any clinically significant findings will be reported on the 
medical history or AE page as applicable.  
A summary table of % LVEF by visit and change from baseline to visit will be provided. Baseline is 
defined as the last non-missing assessment before the first dose of study drug. The baseline value is 
expected to be Screening. Summaries will include data from scheduled assessments only. If there are 
multiple results at a given visit, the earliest value will be used in the tables (see SAP section 7.1). SAP 
section 7.4 describes visit windows. 
An additional table will be provided summarizing the dose modification categories for cardiotoxicity as 
described in protocol section 9.5.1.1. This table will also include a worst case post-baseline summary. 
The worst-case post baseline row is used to summarize the patients’ overall worst-case shifts post 
baseline. The determination of the worst-case post baseline takes into account both planned and 
unscheduled assessments. Lower values represent the worst case, i.e. ‘<40’ is the worst value; if a 
patient is within ‘40-<50’ then ‘>=10’ absolute decrease from baseline is worse. 
LVEF data will be listed by treatment group, patient number and assessment date. 
12.6.2. 
Ophthalmological Examination 
Ophthalmological examinations will be conducted at Screening, Cycle 2 Day 1, then on Day 1 of every 2nd 
cycle and at the Treatment Discontinuation Visit.  
Ophthalmological examination results will be summarized for any clinically significant (CS) findings (i.e. if 
‘Yes’ is selected for slit lamp exam and/or corneal sensitivity testing and/or pachymetry) overall and by 
visit. Time to first CS finding in months (date of first CS finding – date of first dose + 1 / 30.5) will be 
summarized overall and by visit. Slit lamp exam, corneal sensitivity testing and pachymetry tests will be 
summarized separately as described above for any CS findings.  
Values by visit and change from baseline will be summarized for tear film break up time (TFBUT) and 
corneal thickness. Summaries will be presented for the mean of both eyes and each eye separately. 
Baseline is defined as the last non-missing assessment before the first dose of study drug. The baseline 
value is expected to be Screening. Summaries will include data from scheduled assessments only. If 
there are multiple results at a given visit, the earliest value will be used in the tables (see SAP section 
7.1). SAP section 7.4 describes visit windows. TFBUT time will also be summarized using the following 
categories: >10 sec, >5-10 sec, <5 sec for the mean of both eyes and each eye separately. 
Any clinically significant findings will be reported on the medical history or AE page as applicable.  


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Ophthalmological examination data will be listed by treatment group, patient number and assessment 
date. 
12.6.3. 
ECOG 
 
ECOG performance status assessments will be conducted at Screening, pre-dose on Day 1 of each cycle 
and the Treatment Discontinuation visit. A summary table will be provided with the number and 
percentage of patients with change from baseline, ‘Improved’, ‘No Change’ and ‘Deteriorated’, by visit by 
treatment group. Baseline is defined as the last non-missing assessment before the first dose of study 
drug. The baseline value is expected to be Day 1 pre-dose. Summaries will include data from scheduled 
assessments only. If there are multiple results at a given visit, the earliest value will be used in the tables 
(see SAP section 7.1). SAP section 7.4 describes visit windows. A summary table will also be provided 
where ECOG is presented as a continuous variable. Values by visit and change from baseline will be 
included. 
ECOG data will be listed by treatment group, patient number and assessment date. 
12.6.4. 
Analysis of Immunogenicity 
Detailed ADA assessment will be described in a separate SAP. The SAP and any subsequent analysis 
will be completed by Byondis. 
Blood samples for SYD985 antibodies are collected at pre-dose on Day 1 of each cycle and the 
Treatment Discontinuation visit for the SYD985 treatment group only. This data will be listed by patient 
number, visit and collection date and time for the SAS. 
12.6.5. 
Lung Review 
An external vendor will complete a lung review (pneumonitis) by timepoint. This data will be listed by 
patient number and collection date for the SAS. Other variables may be listed depending on the data 
imported. 
12.6.6. 
COVID-19 
The following analysis will be completed: 
 
1. COVID-19 related protocol deviations, summary and listing. See section 6.6 
2. Missing assessments and missing visits due to COVID-19. See section 7.3 
3. Subjects impacted by COVID-19 related study/treatment discontinuations. See section 8.1 
4. Baseline demographics for patients starting treatment before vs. during the COVID-19 pandemic. 
See section 8.2. 
 
 
 
 


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13. 
Interim Analyses 
There are no formal interim analyses planned for this study. An interim assessment of OS will occur with 
no implications in terms of future study conduct when the primary PFS analysis will be performed (i.e. at 
least 256 PFS events have occurred, as assessed by central review, or at least 95% of patients have 
discontinued treatment and only after all patients have been enrolled).    
 
 


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14. 
Changes from Analysis Planned in Protocol 
There are no changes from the planned analyses as described in the protocol. 


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15. 
Reference List 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, 
Flechtner H, Fleishman SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, 
Rofe PB, Schraub S, Sneeuw KCA, Sullivan M, Takeda F. The European Organisation for Research and 
Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in 
oncology. Journal of the National Cancer Institute 1993; 85: 365-376. 
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther 
S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J.  New response 
evaluation criteria in solid tumours:  Revised RECIST guidelines (version 1.1).  European Journal of 
Cancer. 2009; 45: 228-247. 
 
The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European Organisation for Research 
and Treatment of Cancer, Brussels 2001. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, 
Bottomley A, on behalf of the EORTC Quality of Life Group. 
 
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. U.S. 
Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and 
Research. Center for Biologics Evaluation and Research. FDA May 2007 
 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles for Clinical 
Trials (E9), 5 February 1998. 
 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and Content of Clinical 
Study Reports (E3), 30 November 1995. 
 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Integrated Addendum to ICH 
E6(R1): Guidance for Good Clinical Practice E6 (R2), November 2016.  
 
SAS® Version 9.3.  SAS Institute Inc., Cary, NC 
 
 
Sprangers MAG, Groenvold M, Arraras JI, et al. The European Organisation for 
Research and Treatment of Cancer: Breast Cancer Specific Quality of Life 
Questionnaire Module: First results from a three-country field study. J. Clin. Oncol 
14:2756-2768, 1996. 
 


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16. 
Programming Considerations 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using SAS® for 
Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure 
output will adhere to the following specifications.   
Phoenix WinNonLin version 6.4 or higher (Pharsight Corporation, Mountain View, California, USA) will be 
being used to generate PK parameters. 
16.1. 
General Considerations 
• 
One SAS program can create several outputs or a separate SAS program can be created for each 
output at statistical programmer’s discretion.    
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in Word (rtf) format. 
• 
Numbering of TLFs will follow ICH E3 guidance. 
 
16.2. 
Table, Listing, and Figure Format 
16.2.1. 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 8 (or 9. To be determined prior to 
programming)  
• 
The data displays for all TLFs will have a 1.5-inch blank binding margin on top of a landscape 
oriented page and a minimum 1-inch blank margin on the other 3 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8 (or 9. To be determined prior to 
programming). 
• 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• 
TLFs will be in black and white (no colour), unless otherwise specified 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and subscripted 
text, will not be used in the TLFs, unless otherwise specified. On some occasions, superscripts 1, 2, 
or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help display 
math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be employed on a 
case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
16.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 
Byondis BV SYD985.002          
 
• 
All output should have Page n of N at the top or bottom right corner of each page. TLFs should be 
internally paginated in relation to the total length (i.e., the page number should appear sequentially as 
page n of N, where N is the total number of pages in the corresponding TLF output). 


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• 
The date output was generated should appear along with the program name as a footer on each 
page. 
 
16.2.3. 
Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 
numbering will be used. A decimal system (x.y and x.y.z) will be used to identify TLFs with related 
contents. The title is centred. The analysis set will be identified on the line immediately following the 
title. The title and table designation are single spaced. A solid line spanning the margins will separate 
the display titles from the 
• 
 Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Full Analysis Set 
 
16.2.4. 
Column Headers 
• 
Column headings will be displayed immediately below the solid line described above in initial upper-
case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed by 
the treatment group columns and total column. P-values will be presented under the total column or in 
separate p-value column (if applicable). Within-treatment comparisons may have p-values presented 
in a row beneath the summary statistics for that treatment. 
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or in 
the row headings if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of patients in the analysis set. 
• 
The order of treatments in the tables and listings will be SYD985 first, and then physician’s choice. A 
total column will be included for the disposition and demographic summary tables. 
 
16.2.5. 
Body of the Data Display 
16.2.5.1. 
General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
 
16.2.5.2. 
Table Conventions 
• 
Units will be included where available 
• 
If the categories of a parameter are ordered, then all categories between the maximum and minimum 
category should be presented in the table, even if n=0 for all treatment groups in a given category 
that is between the minimum and maximum level for that parameter. For example, the frequency 
distribution for symptom severity would appear as: 


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Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be presented and so any 
counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the Study, 
etc.), then only those categories for which there is at least 1 patient represented in 1 or more groups 
should be included. 
• 
An Unknown or Missing category should be added to any parameter for which information is not 
available for 1 or more patients.  
• 
Unless otherwise specified, the estimated mean and median for a set of values should be printed out 
to 1 more significant digit than the original values, and standard deviations should be printed out to 2 
more significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
 
N 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Any p-value less than 0.001 will be presented as <0.001. If the p-value should be less than 0.0001 
then present as <0.0001. If the p-value is returned as >0.999 then present as >0.999 
• 
Percentage values should be printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down to 
0.0.  A common convention is to display as '<0.1', or as appropriate with additional decimal places. 
Unless otherwise noted, for all percentages, the number of patients in the analysis set for the 
treatment group who have an observation will be the denominator. Percentages after zero counts 
should not be displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places.  
• 
Tabular display of data for medical history, prior / concomitant medications, and all tabular displays of 
adverse event data should be presented by the body system, treatment class, or SOC with the 
highest occurrence in the active treatment group in decreasing order, assuming all terms are coded. 
Within the body system, drug class and SOC, medical history (by preferred term), drugs (by ATC1 
code), and adverse events (by preferred term) should be displayed in decreasing order. If incidence 
for more than 1 term is identical, they should then be sorted alphabetically. Missing descriptive 
statistics or p-values which cannot be estimated should be reported as “-”. 
• 
The percentage of patients is normally calculated as a proportion of the number of patients assessed 
in the relevant treatment group (or overall) for the analysis set presented. However, careful 
consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of patients exposed. Details of this will be in footnotes 
or programming notes. 
• 
For categorical summaries (number and percentage of patients) where a patient can be included in 
more than one category, describe in a footnote or programming note if the patient should be included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting the 
criteria. 


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• 
Where a category with a subheading (such as system organ class) has to be split over more than one 
page, output the subheading followed by “(cont)” at the top of each subsequent page.  The overall 
summary statistics for the subheading should only be output on the first relevant page. 
 
16.2.5.3. 
Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, patient number, 
visit/collection day, and visit/collection time. 
• 
Missing data should be represented on patient listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of 
dates should be represented on patient listings as dashes (--JUL2000). Dates that are missing 
because they are not applicable for the patient are output as “N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or HH:MM:SS format (e.g., 
11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
• 
Units will be included where available 
 
16.2.5.4. 
Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
 
16.2.6. 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the solid line underneath 
the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote should start on a new line where possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data listing. If more than 
six lines of footnotes are planned, then a cover page may be used to display footnotes, and only 
those essential to comprehension of the data will be repeated on each page.  
• 
The last line of the footnote section will be a standard source line that indicates the date the program 
was run and the listing source (i.e., ‘Table Generation: ddmmmyyyy hh:mm Listing source: 16.x.y.z’). 


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17. 
Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health Developing Statistical Programs SOP (3907). 
Syneos Health Developing Statistical Programs SOP (3907), Conducting the Transfer of Biostatistical 
Deliverables SOP (3908) and the SAS Programming and Validation Plan describes the quality control 
procedures that are performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs produce the output by 
checking for their logic, efficiency and commenting and by review of the produced output.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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18. 
Index of Tables 
 
Table Number 
Name 
Population 
14.1.1.1 
Patient Disposition – Study Populations 
SS 
14.1.1.2 
Patient Disposition 
FAS 
14.1.2.1 
Major Protocol Deviations 
FAS 
14.1.2.2 
COVID-19 Related Protocol Deviations 
FAS 
14.1.2.3 
Major Protocol Deviations Leading to Exclusion from the PPS 
FAS 
14.1.3.1.1 
Patient Demographic and Baseline Characteristics 
FAS 
14.1.3.1.2 
Patient Demographic and Baseline Characteristics 
PPS 
14.1.3.1.3 
Patient Demographic and Baseline Characteristics 
SAS 
14.1.3.1.4 
Patient Demographic and Baseline Characteristics Before vs. 
During the COVID-19 Pandemic 
SAS 
14.1.3.2.1.1 
Baseline Disease Characteristics 
FAS 
14.1.3.2.1.2 
Baseline Disease Characteristics 
PPS 
14.1.3.2.1.3 
Baseline Disease Characteristics 
SAS 
14.1.3.2.2.1 
Central HER2 Assessment 
FAS 
14.1.3.2.2.2 
Central HER2 Assessment 
PPS 
14.1.3.2.2.3 
Central HER2 Assessment 
SAS 
14.1.3.3.1 
Medical History 
FAS 
14.1.3.3.2 
Medical History 
SAS 
14.1.4.1.1 
Prior Systemic Therapy (Related to Study Medication) 
FAS 
14.1.4.1.2 
Prior Systemic Therapy (Related to Study Medication) 
SAS 
14.1.4.2.1 
Concomitant Medications 
FAS 
14.1.4.2.2 
Concomitant Medications 
SAS 
14.2.1.1.1 
Progression Free Survival (PFS) – Independent Central Review. 
Primary Analysis 
FAS 
14.2.1.2.1 
Progression Free Survival (PFS) – Independent Central Review. 
Secondary Analysis 
PPS 
14.2.1.3.1 
Progression Free Survival (PFS) – Independent Central Review. 
Sensitivity Analysis. Actual Treatment and Strata 
FAS  
14.2.1.4.1 
Progression Free Survival (PFS) – Independent Central Review. 
Sensitivity Analysis. Without any Stratification Factors. 
FAS 
14.2.1.5.1 
Progression Free Survival (PFS). Sensitivity Analysis. Earliest 
Calculated Progression Date from ICR or Local Review 
FAS 
14.2.1.6.1 
Progression Free Survival (PFS) – Independent Central Review. 
Sensitivity Analysis. Worst Case (Progression Date One Day after 
the Last Tumour Evaluation where Progression was known not to 
have Occurred) 
FAS 
14.2.1.7.1 
Progression Free Survival (PFS) – Independent Central Review.  
SYD985 versus Physician’s Choice Four Subgroups 
FAS 
14.2.2.1.1.1 
Overall Survival (OS). 
FAS 
14.2.2.1.2.1 
Overall Survival (OS). Sensitivity Analysis 
PPS 


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Table Number 
Name 
Population 
14.2.2.1.3.1 
Overall Survival (OS). SYD985 versus Physician’s Choice Four 
Subgroups 
FAS 
14.2.2.1.4 
Survival Follow Up 
FAS 
14.2.2.2.1 
Objective Response Rate (ORR) – Independent Central Review.  
FAS 
14.2.2.2.2 
Objective Response Rate (ORR) – Independent Central Review. 
Sensitivity Analysis 
PPS 
14.2.2.2.3 
Objective Response Rate (ORR) – Independent Central Review. 
Sensitivity Analysis. Confirmed Responses 
FAS 
14.2.2.2.4 
Objective Response Rate (ORR) – Local Review. Sensitivity 
Analysis 
FAS 
14.2.2.2.5 
Objective Response Rate (ORR) – Local Review. Sensitivity 
Analysis. Confirmed Responses 
 
14.2.2.2.6 
Objective Response Rate (ORR) – Independent Central Review. 
SYD985 versus Physician’s Choice Four Subgroups 
FAS 
14.2.2.2.7 
Objective Response Rate (ORR) – Independent Central Review. 
SYD985 versus Physician’s Choice Four Subgroups. Confirmed 
Responses 
FAS 
14.2.2.3.1.1 
Progression Free Survival (PFS) – Local Review.  
FAS 
14.2.2.3.1.2 
Progression Free Survival (PFS) – Local Review. Sensitivity 
Analysis 
PPS 
14. 2.2.3.1.3 
Progression Free Survival (PFS) – Local Review. Sensitivity 
Analysis. Progression date from the Survival Follow Up for 
Patients who Discontinued Treatment for a Non-Progressive 
Disease Reason 
FAS 
14.2.2.3.1.4 
Progression Free Survival (PFS) – Local Review. SYD985 versus 
Physician’s Choice Four Subgroups 
FAS 
14.2.2.4.1 
Quality of Life. Summary of Missing Data by Visit 
FAS 
14.2.2.4.2 
EORTC QLQ-C30 Quality of Life Responses. Summary by Visit 
FAS 
14.2.2.4.3 
EORTC QLQ-BR23 Quality of Life Responses. Summary by Visit 
FAS 
14.2.2.4.4 
EORTC QLQ-C30 Quality of Life Raw Scores. Summary by Visit 
and Change from Baseline  
FAS 
14.2.2.4.5 
EORTC QLQ-C30 Quality of Life Transformed Scores. Summary 
by Visit and Change from Baseline 
FAS 
14.2.2.4.6 
EORTC QLQ-BR23 Quality of Life Raw Scores. Summary by Visit 
and Change from Baseline 
FAS 
14.2.2.4.7 
EORTC QLQ-BR23 Quality of Life Transformed Scores. 
Summary by Visit and Change from Baseline 
FAS 
14.2.2.4.8.1.1 
Mixed Model Repeated Measures Analysis of Global Health 
Status/QoL Transformed Score 
FAS 
14.2.2.4.8.2.1 
Mixed Model Repeated Measures Analysis of Global Health 
Status/QoL Transformed Score. Sensitivity Analysis 
PPS 
14.2.2.4.9.1.1 
Time to 10 % Deterioration in the Transformed Global Health 
Status/QoL Score. Sensitivity Analysis 
FAS 
14.2.2.4.9.2.1 
Time to 10 % Deterioration in the Transformed Global Health 
Status/QoL Score. Sensitivity Analysis 
PPS 


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Table Number 
Name 
Population 
14.2.2.4.10 
EORTC QLQ-C30 Global Health Status/QoL Transformed Score. 
Summary by Visit and Change from Baseline. SYD985 versus 
Physician’s Choice Four Subgroups 
FAS 
14.2.2.5 
Time to Response (TTR) - Independent Central and Local Review 
FAS 
14.2.2.6 
Duration of Response (DOR) - Independent Central and Local 
Review 
FAS 
14.2.2.7 
Clinical Benefit Rate (CBR) – based on Best Overall Response. 
Independent Central and Local Review 
FAS 
14.2.2.8 
Reduction in Target Lesion Measurement - Independent Central 
and Local Review 
FAS 
14.2.2.9.1 
Summary of PK Concentrations 
PKS 
14.2.2.9.2 
Summary of PK Parameters 
PKS 
14.3.1.1 
Treatment Emergent Adverse Events – Overall Summary 
SAS 
14.3.1.2 
Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term 
SAS 
14.3.1.3 
Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term and Maximum Severity 
SAS 
14.3.1.4 
Serious Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term 
SAS 
14.3.1.5.1 
Treatment Emergent Adverse Events Leading to Permanent 
Discontinuation of Study Drug (Both Drugs for Physician’s Choice 
Group) by System Organ Class and Preferred Term 
SAS 
14.3.1.5.2 
Treatment Emergent Adverse Events Leading to Permanent 
Discontinuation of Study Drug (One Drug for Physician’s Choice 
Group) by System Organ Class and Preferred Term 
SAS 
14.3.1.6 
Treatment Emergent Adverse Events Leading to Dose 
Modification of Study Drug by System Organ Class and Preferred 
Term 
SAS 
14.3.1.7.1 
Treatment Emergent Adverse Events of Special Interest by 
System Organ Class and Preferred Term 
SAS 
14.3.1.7.2 
Treatment Emergent Adverse Events of Special Interest by 
System Organ Class, Preferred Term and Maximum Severity 
SAS 
14.3.1.7.3 
Serious Treatment Emergent Adverse Events of Special Interest 
by System Organ Class and Preferred Term 
SAS 
14.3.1.8 
Treatment Emergent Adverse Events with an Outcome of Death 
by System Organ Class and Preferred Term 
SAS 
14.3.1.9 
Related Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term 
SAS 
14.3.1.10 
Related Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and Maximum Severity 
SAS 
14.3.1.11 
Related Serious Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
SAS 
14.3.1.12.1 
Related Treatment Emergent Adverse Events Leading to 
Permanent Discontinuation of Study Drug (Both Drugs for 
Physician’s Choice Group) by System Organ Class and Preferred 
Term 
SAS 


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Table Number 
Name 
Population 
14.3.1.12.2 
Related Treatment Emergent Adverse Events Leading to 
Permanent Discontinuation of Study Drug (One Drug for 
Physician’s Choice Group) by System Organ Class and Preferred 
Term 
SAS 
14.3.1.13 
Related Treatment Emergent Adverse Events Leading to Dose 
Modification of Study Drug by System Organ Class and Preferred 
Term 
SAS 
14.3.1.14.1 
Related Treatment Emergent Adverse Events of Special Interest 
by System Organ Class and Preferred Term 
SAS 
14.3.1.14.2 
Related Treatment Emergent Adverse Events of Special Interest 
by System Organ Class, Preferred Term and Maximum Severity 
SAS 
14.3.1.14.3 
Related Serious Treatment Emergent Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
SAS 
14.3.1.15 
Related Treatment Emergent Adverse Events with an Outcome of 
Death by System Organ Class and Preferred Term 
SAS 
14.3.2.1 
Adverse Events with an Outcome of Death, Listing 
SAS 
14.3.2.2 
Serious Treatment Emergent Adverse Events, Listing 
SAS 
14.3.2.3.1 
Treatment Emergent Adverse Events Leading to Permanent 
Discontinuation of Study Drug (Both Drugs for Physician’s 
Choice), Listing 
SAS 
14.3.2.3.2 
Treatment Emergent Adverse Events Leading to Permanent 
Discontinuation of Study Drug (One Drug for Physician’s Choice), 
Listing 
SAS 
14.3.2.4 
Treatment Emergent Adverse Events of Special Interest, Listing 
SAS 
14.3.3.1.1.1 
Time to First Episode of Ocular Toxicity (Weeks) 
SAS 
14.3.3.1.2.1 
Time to First Episode of Ocular Toxicity Grade >=2 (Weeks) 
SAS 
14.3.3.1.3.1 
Time to First Episode of Ocular Toxicity Grade >=3 (Weeks) 
SAS 
14.3.3.2.1.1 
Time to First Episode of Conjunctivitis (Weeks) 
SAS 
14.3.3.2.2.1 
Time to First Episode of Conjunctivitis Grade >=2 (Weeks) 
SAS 
14.3.3.2.3.1 
Time to First Episode of Conjunctivitis Grade >=3 (Weeks) 
SAS 
14.3.3.3.1.1 
Time to First Episode of Dry Eye (Weeks) 
SAS 
14.3.3.3.2.1 
Time to First Episode of Dry Eye Grade >=2 (Weeks) 
SAS 
14.3.3.3.3.1 
Time to First Episode of Dry Eye Grade >=3 (Weeks) 
SAS 
14.3.3.4.1.1 
Time to First Episode of Keratitis (Weeks) 
SAS 
14.3.3.4.2.1 
Time to First Episode of Keratitis Grade >=2 (Weeks) 
SAS 
14.3.3.4.3.1 
Time to First Episode of Keratitis Grade >=3 (Weeks) 
SAS 
14.3.3.5.1.1 
Incidence, Duration and Severity of Conjunctivitis  
SAS 
14.3.3.5.2.1 
Incidence, Duration and Severity of Dry Eye 
SAS 
14.3.3.5.3.1 
Incidence, Duration and Severity of Keratitis 
SAS 
14.3.4.1.1.1 
Haematology: Summary by Visit and Change from Baseline 
SAS 
14.3.4.1.1.2 
Haematology: Shifts in CTCAE Grades  
SAS 
14.3.4.1.1.3 
Haematology: Shifts in Non-CTCAE Gradable Parameters 
Relative to the Normal Range 
SAS 
14.3.4.1.2.1 
Blood Chemistry: Summary by Visit and Change from Baseline 
SAS 
14.3.4.1.2.2 
Blood Chemistry: Shifts in CTCAE Grades  
SAS 


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Table Number 
Name 
Population 
14.3.4.1.2.3 
Blood Chemistry: Shifts in Non-CTCAE Gradable Parameters 
Relative to the Normal Range 
SAS 
14.3.4.1.3 
Cardiac Biomarkers: Summary  by Visit and Change from 
Baseline 
SAS 
14.3.4.1.4 
Urinalysis: Summary  by Visit and Change from Baseline 
SAS 
14.3.4.2.1 
Summary of Changes in Heart Rate from Baseline 
SAS 
14.3.4.2.2 
Summary of Increased Systolic Blood Pressure from Baseline 
SAS 
14.3.4.2.3 
Summary of Increased Diastolic Blood Pressure from Baseline 
SAS 
14.3.4.2.4 
Vital Signs: Summary by Visit and Change from Baseline 
SAS 
14.3.4.2.4 
Weight (kg): Summary by Visit and Change from Baseline 
SAS 
14.3.4.3.1 
Left Ventricular Ejection Fraction (LVEF): Summary by Visit and 
Change from Baseline 
SAS 
14.3.4.3.2 
Left Ventricular Ejection Fraction (LVEF): Change from Baseline 
Categories by Visit 
SAS 
14.3.4.4.1 
Ophthalmological Examination: Overall Summary of Clinically 
Significant Findings 
SAS 
14.3.4.4.2 
Ophthalmological Examination: Summary by Visit of Clinically 
Significant Findings 
SAS 
14.3.4.4.3 
Ophthalmological Examination: Summary by Visit of Tear Film 
Break Up Time (TFBUT) and Corneal Thickness 
SAS 
14.3.4.5.1 
Eastern Cooperative Oncology Group (ECOG) Performance: 
Summary by Visit 
SAS 
14.3.4.5.2 
Eastern Cooperative Oncology Group (ECOG) Performance: 
Summary by Visit and Change from Baseline 
SAS 
14.3.4.6.1 
Extent of Exposure – SYD985 
SAS 
14.3.4.6.2.1 
Extent of Exposure – Physician’s Choice. Lapatinib + 
Capecitabine 
SAS 
14.3.4.6.2.2 
Extent of Exposure – Physician’s Choice. Trastuzumab + 
Capecitabine 
SAS 
14.3.4.6.2.3 
Extent of Exposure – Physician’s Choice. Trastuzumab + 
Vinorelbine 
SAS 
14.3.4.6.2.4 
Extent of Exposure – Physician’s Choice. Trastuzumab + Eribulin 
SAS 


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19. 
Index of Figures 
Figure Number 
Name 
Population 
14.2.1.1.2 
Kaplan Meier Plot of Progression Free Survival (PFS) – 
Independent Central Review. Primary Analysis 
FAS 
14.2.1.2.2 
Kaplan Meier Plot of Progression Free Survival (PFS) – 
Independent Central Review. Secondary Analysis 
PPS 
14.2.1.3.2 
Kaplan Meier Plot of Progression Free Survival (PFS) – 
Independent Central Review. Sensitivity Analysis. Actual 
Treatment and Strata 
FAS  
14.2.1.4.2 
Kaplan Meier Plot of Progression Free Survival (PFS) – 
Independent Central Review. Sensitivity Analysis. Without any 
Stratification Factors. 
FAS 
14.2.1.5.2 
Kaplan Meier Plot of Progression Free Survival (PFS). Sensitivity 
Analysis. Earliest Calculated Progression Date from ICR or Local 
Review 
FAS 
14.2.1.6.2 
Kaplan Meier Plot of Progression Free Survival (PFS) – 
Independent Central Review. Sensitivity Analysis. Worst Case 
(Progression Date One Day after the Last Tumour Evaluation 
where Progression was known not to have Occurred) 
FAS 
14.2.1.7.2 
Kaplan Meier Plot of Progression Free Survival (PFS) – 
Independent Central Review. Sensitivity Analysis. SYD985 
versus Physician’s Choice Four Subgroups 
FAS 
14.2.1.8 
Forest Plot of Progression Free Survival (PFS) – Independent 
Central Review. Sensitivity Analysis.  
FAS 
14.2.2.1.1.2 
Kaplan Meier Plot of Overall Survival (OS) in Months. Primary 
Analysis 
FAS 
14.2.2.1.1.3 
Kaplan Meier Plot of Overall Survival (OS) in Years.  
FAS 
14.2.2.1.2.2 
Kaplan Meier Plot of Overall Survival (OS) in Months. Sensitivity 
Analysis 
PPS 
14.2.2.1.2.3 
Kaplan Meier Plot of Overall Survival (OS) in Years. Sensitivity 
Analysis 
PPS 
14.2.2.1.3.2 
Kaplan Meier Plot of Overall Survival (OS) in Months. SYD985 
versus Physician’s Choice Four Subgroups 
FAS 
14.2.2.1.3.3 
Kaplan Meier Plot of Overall Survival (OS) in Years. SYD985 
versus Physician’s Choice Four Subgroups 
FAS 
14.2.2.1.5 
Forest Plot of Overall Survival (OS). Sensitivity Analysis.  
FAS 
14.2.2.3.2.1 
Kaplan Meier Plot of Progression Free Survival – Local Review.  
FAS 
14.2.2.3.2.2 
Kaplan Meier Plot of Progression Free Survival – Local Review. 
Sensitivity Analysis. 
PPS 
14.2.2.3.2.3 
Kaplan Meier Plot of Progression Free Survival (PFS) – Local 
Review. Sensitivity Analysis. Progression Date from the Survival 
Follow Up for Patients who discontinued Treatment for a Non-
Progressive Disease Reason 
FAS 
14.2.2.3.2.4 
Kaplan Meier Plot of Progression Free Survival (PFS) – Local 
Review. SYD985 versus Physician’s Choice Four Subgroups 
FAS 


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Figure Number 
Name 
Population 
14.2.2.7.3 
Waterfall Plot of Best Percentage Change in Sum of Longest 
Diameters by Response (Independent Central Review) 
FAS 
14.2.2.4.8.1.2 
Linear Plot of Least Squared Means of Change from Baseline of 
Global Health Status/QoL Transformed Score.  
FAS 
14.2.2.4.8.2.2 
Linear Plot of Least Squared Means of Change from Baseline of 
Global Health Status/QoL Transformed Score. Sensitivity 
Analysis 
PAS 
14.2.2.4.9.1.2 
Kaplan Meier Plot of Time to 10 % Deterioration in the 
Transformed Global Health Status/QoL Score. Sensitivity 
Analysis 
FAS 
14.2.2.4.9.2.2 
Kaplan Meier Plot of Time to 10 % Deterioration in the 
Transformed Global Health Status/QoL Score. Sensitivity 
Analysis. 
PAS 
14.2.2.9.3.1 
Mean +/- SD Plasma Concentration-Time Profiles All Cycles 
PKS 
14.2.2.9.3.2 
Mean +/- SD Plasma Concentration-Time Profiles Cycle 1 
PKS 
14.2.2.9.3.3.1 
Mean +/- SD Plasma Concentration-Time Profiles for All Analytes 
Combined – All Cycles. Separate Y axis for SYD986 Free Toxin 
(pg/mL) 
PKS 
14.2.2.9.3.3.2 
Mean +/- SD Plasma Concentration-Time Profiles for All Analytes 
Combined (ng/mL) – All Cycles 
PKS 
14.2.2.9.3.4 
Mean +/- SD Plasma Concentration-Time Profiles for All Analytes 
Combined – Cycle 1 
PKS 
14.2.2.9.3.5 
Mean +/- SD Plasma Concentration-Time Profiles for All Analytes 
Combined – Cycle 4 
PKS 
14.2.2.9.4 
Individual Plasma Concentration-Time Profiles 
PKS 
14.2.2.9.5 
Regression/Scatter Plots to Investigate the Relationship between 
PK Parameters for Total SYD985 and Demographic Covariates - 
Linear Scale 
PKS 
14.3.3.1.1.2 
Kaplan Meier Plot of Time to First Episode of Ocular Toxicity 
(Weeks) 
SAS 
14.3.3.1.2.2 
Kaplan Meier Plot of Time to First Episode of Ocular Toxicity 
Grade >=2 (Weeks) 
SAS 
14.3.3.1.3.2 
Kaplan Meier Plot of Time to First Episode of Ocular Toxicity 
Grade >=3 (Weeks) 
SAS 
14.3.3.2.1.2 
Kaplan Meier Plot of Time to First Episode of Conjunctivitis 
(Weeks) 
SAS 
14.3.3.2.2.2 
Kaplan Meier Plot of Time to First Episode of Conjunctivitis 
Grade >=2 (Weeks) 
SAS 
14.3.3.2.3.2 
Kaplan Meier Plot of Time to First Episode of Conjunctivitis 
Grade >=3 (Weeks) 
SAS 
14.3.3.3.1.2 
Kaplan Meier Plot of Time to First Episode of Dry Eye (Weeks) 
SAS 
14.3.3.3.2.2 
Kaplan Meier Plot of Time to First Episode of Dry Eye Grade >=2 
(Weeks) 
SAS 


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Figure Number 
Name 
Population 
14.3.3.3.3.2 
Kaplan Meier Plot of Time to First Episode of Dry Eye Grade >=3 
(Weeks) 
SAS 
14.3.3.4.1.2 
Kaplan Meier Plot of Time to First Episode of Keratitis (Weeks) 
SAS 
14.3.3.4.2.2 
Kaplan Meier Plot of Time to First Episode of Keratitis Grade >=2 
(Weeks) 
SAS 
14.3.3.4.3.2 
Kaplan Meier Plot of Time to First Episode of Keratitis Grade >=3 
(Weeks) 
SAS 
14.3.3.5.1.2 
Swimmer Plot of Duration (Weeks) by Grade of Conjunctivitis 
(SYD985 Only) 
SAS 
14.3.3.5.2.2 
Swimmer Plot of Duration (Weeks) by Grade of Dry Eye (SYD985 
Only) 
SAS 
14.3.3.5.3.2 
Swimmer Plot of Duration (Weeks) by Grade of Keratitis 
(SYD985 Only) 
SAS 
14.3.4.6.2.5 
Swimmer Plot of Duration of Treatment 
SAS 


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20. 
Index of Listings 
Listing Number 
Name 
Population 
16.2.1.1 
Patient Disposition including Randomization 
SS 
16.2.1.2 
Subjects Impacted by COVID-19 Related Study Discontinuations 
FAS 
16.2.1.3 
Missing Assessments due to COVID-19 
FAS 
16.2.1.4 
Missing Visits due to COVID-19 
FAS 
16.2.2.1 
Major Protocol Deviations  
SS 
16.2.2.2 
COVID-19 Related Protocol Deviations  
FAS 
16.2.3.1 
Analysis Populations and Reasons for Exclusion 
SS 
16.2.3.2 
Informed Consent and Patient Eligibility 
SS 
16.2.4.1 
Demographics 
SS 
16.2.4.2 
Medical History 
FAS 
16.2.4.3.1.1 
Disease Assessment 
FAS 
16.2.4.3.1.2 
Disease Assessment – Hormone Receptor Status 
FAS 
16.2.4.3.2 
Central HER2 Status Assessment 
FAS 
16.2.4.3.3 
Brain and Whole Body Bone Scan 
FAS 
16.2.4.4 
Prior and Concomitant Medications 
FAS 
16.2.4.5.1 
Prior Systemic Therapy (Related to Study Indication) 
FAS 
16.2.4.5.2 
Prior Radiotherapy (Related to Study Indication) 
FAS 
16.2.4.5.3 
Prior Surgery (Related to Study Indication) 
FAS 
16.2.5.1.1 
Study Drug Administration – SYD985 
SAS 
16.2.5.1.2 
Study Drug Administration – Physician’s Choice, Lapatinib 
SAS 
16.2.5.1.3 
Study Drug Administration – Physician’s Choice, Capecitabine 
SAS 
16.2.5.1.4 
Study Drug Administration – Physician’s Choice, Vinorelbine 
(Oral) 
SAS 
16.2.5.1.5 
Study Drug Administration – Physician’s Choice, Vinorelbine (IV) 
SAS 
16.2.5.1.6 
Study Drug Administration – Physician’s Choice, Vinorelbine 
(Oral and IV) 
SAS 
16.2.5.1.7 
Study Drug Administration – Physician’s Choice, Eribulin 
SAS 
16.2.5.1.8 
Study Drug Administration – Physician’s Choice, Trastuzumab 
SAS 
16.2.5.2 
Pharmacokinetic Plasma Concentrations 
PKS 
16.2.5.3 
Pharmacokinetic Parameters for Cycle 1 
PKS 
16.2.5.4 
Serum HER2 ECD Sampling 
FAS 
16.2.5.5 
Serum ctDNA Sampling 
FAS 
16.2.6.1 
Progression Free Survival (PFS) – Independent Central Review 
FAS 
16.2.6.2 
Overall Survival (OS) 
FAS 
16.2.6.3.1 
Overall Tumour Response (RECIST v1.1), Objective Tumour 
Response, Clinical Benefit and Best Overall Response. 
Independent Central Review 
FAS 
16.2.6.3.2 
Overall Tumour Response (RECIST v1.1), Objective Tumour 
Response, Clinical Benefit and Best Overall Response. Local 
Review 
FAS 
16.2.6.3.3 
RECIST 1.1. Central Independent vs. Local Review 
FAS 
16.2.6.4 
Progression Free Survival (PFS) – Investigator Assessed 
FAS 
16.2.6.5.1 
Quality of Life EORTC QLQ-C30 – Response to Questions  
FAS 


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Listing Number 
Name 
Population 
16.2.6.5.2 
Quality of Life EORTC QLQ-C30 – Functional/Symptom Scales 
and Items 
FAS 
16.2.6.5.3 
Quality of Life EORTC QLQ-BR23 – Response to Questions  
FAS 
16.2.6.5.4 
Quality of Life EORTC QLQ-BR23 – Functional/Symptom Scales 
and Items 
FAS 
16.2.6.5.5 
Time to 10 % Deterioration in the Transformed Global Health 
Status/QoL Score 
FAS 
16.2.6.6 
Time to Response 
FAS 
16.2.6.7 
Duration of Response 
FAS 
16.2.6.8.1 
Target Lesions (RECIST v1.1) – Independent Central Review  
FAS 
16.2.6.8.2 
Target Lesions (RECIST v1.1) – Local Review  
FAS 
16.2.6.9.1 
Non-target Lesions (RECIST v1.1) – Independent Central Review  FAS 
16.2.6.9.2 
Non-target Lesions (RECIST v1.1) – Local Review  
FAS 
16.2.6.10.1 
New Lesions (RECIST v1.1) – Independent Central Review  
FAS 
16.2.6.10.2 
New Lesions (RECIST v1.1) – Local Review  
FAS 
16.2.6.11 
Survival Follow Up 
FAS 
16.2.7 
All Adverse Events 
SS 
16.2.7.1.1 
Time to Ocular Toxicity any Grade 
SAS 
16.2.7.1.2 
Time to Ocular Toxicity Grade >=2 
SAS 
16.2.7.1.3 
Time to Ocular Toxicity Grade >=3 
SAS 
16.2.7.2.1 
Time to Conjunctivitis any Grade 
SAS 
16.2.7.2.2 
Time to Conjunctivitis Grade >=2 
SAS 
16.2.7.2.3 
Time to Conjunctivitis Grade >=3 
SAS 
16.2.7.3.1 
Time to Dry Eye any Grade 
SAS 
16.2.7.3.2 
Time to Dry Eye Grade >=2 
SAS 
16.2.7.3.3 
Time to Dry Grade >=3 
SAS 
16.2.7.4.1 
Time to Keratitis any Grade 
SAS 
16.2.7.4.2 
Time to Keratitis Grade >=2 
SAS 
16.2.7.4.3 
Time to Keratitis Grade >=3 
SAS 
16.2.7.5.1 
Top Three Treatment Emergent Eye Disorder Adverse Events 
(SYD985 Only) 
SAS 
16.2.7.5.2 
Duration (Weeks) and Recovery (Weeks) of the Top Three 
Treatment Emergent Eye Disorder Adverse Events (SYD985 
Only) 
SAS 
16.2.7.5.3 
Duration (Weeks) and Severity of the Top Three Treatment 
Emergent Eye Disorder Adverse Events after Dose Modification 
(SYD985 Only) 
SAS 
16.2.8.1.1.1 
Haematology – Central Laboratory 
SAS 
16.2.8.1.1.2 
Haematology – Local Laboratory 
SAS 
16.2.8.1.2.1 
Blood Chemistry – Central Laboratory  
SAS 
16.2.8.1.2.2 
Blood Chemistry - Local Laboratory 
SAS 
16.2.8.1.3.1 
Cardiac Biomarkers – Central Laboratory  
SAS 
16.2.8.1.3.2 
Cardiac Biomarkers - Local Laboratory 
SAS 
16.2.8.1.4 
Urinalysis 
SAS 
16.2.8.1.5 
Pregnancy Test 
SAS 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Byondis BV; Protocol No.: SYD985.002 
 
This document is confidential. 
SAP text and shell 3.0 29-Apr-2021 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 75 of 76 
Listing Number 
Name 
Population 
16.2.8.2.1 
Vital Signs 
SAS 
16.2.8.2.2 
Electrocardiogram (ECG) 
SAS 
16.2.8.2.3 
Physical Examination 
SAS 
16.2.8.2.4 
Left Ventricular Ejection Fraction (LVEF) 
SAS 
16.2.8.2.5 
Ophthalmological Examination  
SAS 
16.2.8.2.6 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status 
SAS 
16.2.8.2.7 
Immunogenicity Sampling 
SAS 
16.2.8.2.8 
Lung Review 
SAS 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Byondis BV; Protocol No.: SYD985.002 
 
This document is confidential. 
SAP text and shell 3.0 29-Apr-2021 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 76 of 76 
21. 
Shells 
The TFL shells will be provided as a separate document.