A Phase I/II Open-Label, Three-Part, Dose-Finding and Separate Cohort Expansion Trial to Assess the Safety, Tolerability and Preliminary Efficacy of Repeated Doses of CLEVER-1 Antibody FP-1305, in Subjects With Advanced Solid Tumours
Phase: PHASE1
Conditions: Cancer
Sponsor: Faron Pharmaceuticals Ltd

 
 
 
 
 
 
 
A Phase I/II Open-Label, Three-Part, Dose-Finding and Separate 
Cohort Expansion Trial to Assess the Safety, Tolerability and 
Preliminary Efficacy of Repeated Doses of CLEVER-1 Antibody 
FP-1305, in Subjects with Advanced Solid Tumours  
 
MATINS Study Protocol 
 
Macrophage Antibody To INhibit Immune Suppression 
 
 
Sponsor Study Number: 
FP2CLI001 
EudraCT Number: 
2018-002732-24 
IND Number: 
144585  
Protocol Version: 
11 
Protocol Date: 
22Dec2021 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and the property of Faron 
Pharmaceuticals Ltd. No unpublished information contained herein may be disclosed  
without prior written approval of Faron Pharmaceuticals Ltd. 
 
 
 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 2 (109) 
 
 
CONFIDENTIAL 
 
 
TRIAL CONTACTS 
 
Sponsor  
 
 
Faron Pharmaceuticals Ltd 
 
 
 
Joukahaisenkatu 6 
 
 
 
20520 Turku 
 
 
 
Finland 
Sponsor Contact Person 
 
 
, MD, PhD, Interim CMO 
 
 
 
Tel. 
 
Global Co-ordinating Investigator 
 
, MD, PhD  
 
 
Terveystalo Finland and University of Helsinki 
 
 
Jaakonkatu 3 
 
 
00100 Helsinki 
 
 
Finland 
Contract Research Organisation 
 
Orion Clinical Services Ltd 
 
 
Simbec House, Merthyr Tydfil Industrial Estate 
 
 
Pentrebach, Merthyr Tydfil 
 
 
Wales, CF48 4DR  
 
 
United Kingdom 
Lead Statistical Methodologist 
 
 
(for Part I TITE-CRM) 
 
ICR Clinical Trials & Statistics Unit (ICR-CTSU) 
 
 
The Institute of Cancer Research 
Lead Statistical Methodologist  
 
 
(for current protocol version) 
 
Faron Pharmaceuticals Ltd 
 
 
 
 
 
 
Consultant, Data management and Statistics 
Central Laboratory  
 
 
Labcorp Central Laboratory Services LP 
 
 
 
 
 
 
7 rue Moïse-Marcinhes 
 
 
 
 
 
 
Meyrin, Geneva, 1217 
 
 
 
 
 
 
Switzerland 
Serious Adverse Event (SAE) /Adverse Event of Special Interest (AESI)/Dose Limiting 
Toxicity (DLT) & Delayed Toxicity Reporting 
PREFERRED:  
Reporting in Electronic Case Report Form (eCRF) Adverse Events page [preferred] 
BACK-UP: 
Paper SAE/AESI Form [back-up method for SAE/AESI] 
Email to Medical Monitor [back-up method for DLT/delayed Toxicity] 
Paper SAE Form (back-up method for SAE/AESI) 
E-mail: pharmacovigilance@simbecorion.com  
Fax: +44 (0) 1753 695 101 (Europe) / +00 1 609 514 1000 (USA) 
Back-up fax +44 (0) 1753 695 124 (Europe) / +00 1609 452 7888, +00 1 800 429 2217 (USA) 
Simbec-Orion Pharmacovigilance  
Tel:  +44 (0) 1753 578080  
 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 3 (109) 
 
 
CONFIDENTIAL 
 
 
SIGNATURE PAGE 
 
A Phase I/II Open-Label, Three-Part, Dose-Finding and Separate Cohort Expansion Trial to Assess 
the Safety, Tolerability and Preliminary Efficacy of Repeated Doses of CLEVER-1 Antibody 
FP-1305, in Subjects with Advanced Solid Tumours  
 
Protocol Version: 11, 22Dec2021 
 
 
This protocol has been approved by: 
 
Name: 
Dr. 
, MD, PhD 
Trial Role:  Interim Chief Medical Officer 
Signature 
and Date:  
_____________________________ 
 
Address: 
Faron Pharmaceuticals Ltd  
Joukahaisenkatu 6 
20520 Turku  
Finland 
Phone: 
+35824695151 
 
 
 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 4 (109) 
 
 
CONFIDENTIAL 
 
 
SIGNATURE PAGE 
 
A Phase I/II Open-Label, Three-Part, Dose-Finding and Separate Cohort Expansion Trial to Assess 
the Safety, Tolerability and Preliminary Efficacy of Repeated Doses of CLEVER-1 Antibody 
FP-1305, in Subjects with Advanced Solid Tumours 
 
Protocol Version: 11, 22Dec2021 
 
Name: 
Dr. 
, MD, PhD 
Trial Role: Global Co-ordinating Investigator 
Signature 
and Date: 
_____________________________ 
Address: 
Terveystalo, Finland and University of Helsinki 
Jaakonkatu 3 
00100 Helsinki 
Finland 
 
 
 
This protocol describes the MATINS trial and provides information about procedures for trial 
subjects taking part in the trial. The protocol should not be used as a guide for treatment of patients 
not taking part in the MATINS trial. 
 
 
 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 5 (109) 
 
 
CONFIDENTIAL 
 
 
SIGNATURE PAGE 
 
A Phase I/II Open-Label, Three-Part, Dose-Finding and Separate Cohort Expansion Trial to Assess 
the Safety, Tolerability and Preliminary Efficacy of Repeated Doses of CLEVER-1 Antibody 
FP-1305, in Subjects with Advanced Solid Tumours  
 
Protocol Version: 11, 22Dec2021 
 
Name: 
                                               
Trial Role: Principal Investigator 
Signature: 
_____________________________ 
Date: 
__________________________ 
Site address: ___________________________________________________________________ 
___________________________________________________________________ 
Phone: 
____________________________ 
 
 
This protocol describes the MATINS trial and provides information about procedures for trial 
subjects taking part in the trial. The protocol should not be used as a guide for treatment of patients 
not taking part in the MATINS trial. 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 6 (109) 
 
 
CONFIDENTIAL 
 
 
AMENDMENTS 
The following amendments and/or administrative changes have been made to this protocol since the 
implementation of the first approved version: 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment 
Summary of amendment 
01 
24Apr2019 
04 
Substantial Revision of the eligibility criteria, treatment beyond 
progression (defined by RECIST 1.1 criteria) and 
possibility to continue on study treatment beyond 
one year. Several clarifications in e.g. dose 
escalation rules, schedule of assessments and AE 
reporting.  
Administrative 
change (FI) 
17Jun2019 
04.1 
Non-
substantial 
A typo was corrected on page 54 according to 
Fimea´s request dated 13Jun2019. 
Substantial 
change (UK) 
01Jul2019 
04.2 
Substantial Safety monitoring during the second year of 
treatment and exclusion criterion 6 were defined 
according to MHRA´s request dated 25Jun2019. 
02 
20Aug2019 
05 
Substantial PK-sampling time-points adjusted. New laboratory 
tests (endocrine panel) added. New cohorts added 
for Part II. Trial subject numbers increased for Parts 
I, II and III. Number of sites amended. Possibility to 
include sites in the United States added. Possibility 
to collect and analyse diagnostic sample added. A 
brain CT-scan procedure added in screening and 
subjects with brain metastases excluded. A 
possibility to adjust a dose for first subject with a 
liver specific cancer for safety reasons. IMP dose 
adjustment according to the subject’s weight 
clarified. Corticosteroid usage instructed in more 
detail. Text regarding immune-mediated hepatitis 
clarified. Possibility for treatment hold for subjects 
with complete response and rechallenge added. 
Safety reporting after 28-day follow-up period 
clarified. Text clarifications and address changes. 
Substantial 
change (US) 
20Nov2019 
05.1 
Substantial Sections 3.1 (Dose Limiting Toxicity) and 7.9 
(Management 
of 
Toxicities) 
were 
modified 
according to FDA´s request dated 19Nov2019. 
Substantial 
change (US) 
25Nov2019 
05.2 
Substantial Section 14.7 (Power Calculations) was modified 
according to FDA´s request dated 22Nov2019. 
03 
28Nov2019 
06 
Substantial Possibility to add more subjects in Part I of the study 
by DMC to ensure sufficient data for optimal dose 
selection for Part II. Adjustment of time-points for 
research blood samples. PK sample adjustments in 
Parts I and II. Post treatment tumor biopsy advanced 
from Cycle 4 to Cycle 2. Mandatory biopsy changed 
to optional in Part III. Biomarkers for Part II and III 
were modified/updated. P-PTH measurement added. 
Definition of time period for collecting concomitant 
medication. Clarification for assessments and dosing 
if the treatment for subject with CR is re-initiated. 
Text clarifications and correction of typos. 
Restructuring the synopsis format. 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 7 (109) 
 
 
CONFIDENTIAL 
 
 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment 
Summary of amendment 
03 
28Nov2019, 
revision 
25Feb2020 
06 
Non-
substantial 
Wording describing genetic analyses was revised. 
Research blood sample lines  “Monocytes” and 
“Blood sample  for  PBMCs  isolation”  were 
merged. A typo regarding the PK sampling (Section 
8.4.5) and some other typos were corrected.  
04 
 
24Jul2020 
07 
 
Substantial 
 
Not implemented. 
05 
15Sep2020 
08 
Substantial 
 
Anaplastic thyroid cancer cohort added and the 
estimated 
number 
of 
the 
subjects 
revised 
accordingly based on 10/cohort (at each selected 
dose level) in Part II and possibility for a cohort to 
continue to Part III. The first subject with HCC and 
underlying liver cirrhosis in Part II may be 
administered one level lower than the recommended 
dose level for the first dose. Revision of the Data 
Monitoring Committee responsibilities. ctDNA 
blood samples added in Parts II and III (applicable 
only when genetic consent obtained). Laboratory 
tests for parameters that may be analysed on plasma 
or serum can be performed according to local 
practice. Inclusion criterion #3 regarding the tumour 
sample clarified and tumour sample in Part III 
changed to optional at the discretion of the Sponsor. 
Added possibility to utilise tumour samples 
collected due other reasons (e.g. unscheduled biopsy 
or another informative sample for clinical reasons) 
for scientific purpose when available. Tumour 
imaging at the follow-up visit removed to avoid 
unnecessary imaging. Objectives and outcome 
measures clarified. Timeframe set for follow-up 
period of any reported pregnancy. 
 
Separate country specific protocol addendum 
introduced investigating Q2W and Q1W dosing 
schemes in selected countries. 
06 
(Submitted to 
FI only) 
23Apr2021 
09 
Substantial New investigated dose levels of 30 mg/kg and 100 
mg/kg added. Any dose level below 100 mg/kg may 
also be tested before escalating the dose to 100 
mg/kg. Testing of higher doses (30 and 100 mg/kg) 
will proceed in parallel with the treatment of other 
Part II cohorts. HCC subjects may be enrolled to 
these higher doses only after the safety data of the 
first 10 subjects on any dose level have been 
assessed. Exclusion criteria have been revised (3, 4 
and 9) and a new exclusion criterion (19) ‘Subjects 
with known hypersensitivity to the IMP or any of the 
pharmaceutical ingredients’ has been added. DW-
MRI is no longer done in Part II. New laboratory 
tests added: troponin for Parts II and III and RO 
samples (selected sites and cohorts only) in Part II. 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 8 (109) 
 
 
CONFIDENTIAL 
 
 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment 
Summary of amendment 
Timepoints for PBMC samples revised. Safety of 
Covid-19 vaccines addressed in the protocol. Safety 
reporting related instructions and wording revised 
and consistency improved. Infusion rates changed; 
detailed guidance for the infusions on different dose 
levels provided in Pharmacy Manual.   
07 
09Jun2021 
10 
Substantial Study drug induced liver injury and any new or 
worsening of existing autoimmunity after the 
administration of the study drug added as adverse 
events of special interest. 
 
Protocol Addendum investigating Q2W and Q1W 
dosing will be submitted to all participating 
countries along with this protocol version. 
08 
22Dec2021 
11 
Substantial The patient cohorts for which DLT and delayed 
toxicity follow-up applies are clarified. Delayed 
toxicity follow-up criteria and practices are 
specified. Assessment of DLTs in Part II dose-
escalation subjects is added as primary endpoint to 
evaluate tolerability of new doses in Part II.  
 
New intermediate dose level of 45mg/kg is added to 
protocol for the Q3W dose escalation (section 4.3) in 
Part II, as well as de -escalation level of 20 mg/kg.  
 
The dose-escalation practices with clear stopping 
rules are clarified in the protocol for the applicable 
part II cohorts testing new dosing schemas. 
 
For Parts II and III: the frequency of endocrine panel 
follow-up is increased. Additional time-points for 
comprehensive metabolic panel are included. For the 
females with child-bearing potential, monthly 
pregnancy test (urine/serum) is added (in Q3W every 
cycle). Additional sCLEVER samples are included. 
Possibility to obtain biopsy from new lesions is 
introduced as optional assessment.  
 
Time window for Follow-Up visit has been revised 
for Parts II and III. 
 
For clarity the entire Hy’s criteria has been written 
to AESI, and not just referring to Hy’s Law 
 
Description of the re-screen process has been added 
in the protocol.  
 
Composition of the Data Monitoring Committee has 
been revised.  

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 9 (109) 
 
 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
 
1 
PROTOCOL SUMMARY ...................................................................................................................... 15 
1.1 Synopsis ............................................................................................................................................ 15 
1.2 Schema .............................................................................................................................................. 18 
1.3 Schedule of Activities ....................................................................................................................... 20 
1.3.1 
Schedule of Assessment tables for Q3W dosing schema in Parts I-III are shown below 
(Tables 1-3). Schedule of Assessment tables for Q2W and Q1W schemas in Part II are 
presented in Protocol Addendum (Tables 1A and 1B). ....................................................... 20 
2 
BACKGROUND AND RATIONALE ................................................................................................... 33 
2.1 Immunotherapy for Cancer ............................................................................................................... 33 
2.2 CLEVER-1 and FP-1305 .................................................................................................................. 34 
2.2.1 
Background to CLEVER-1 .................................................................................................. 34 
2.2.2 
CLEVER-1 Antibody FP-1305 ........................................................................................... 35 
2.2.3 
Nonclinical Data of CLEVER-1 Inhibition and FP-1305 ................................................... 35 
2.3 Rationale for Targeting CLEVER-1 in the Tumour Microenvironment .......................................... 36 
2.3.1 
Safety in Non-Human Primates ........................................................................................... 37 
2.3.2 
Pharmacokinetics in Non-Human Primates ......................................................................... 37 
2.3.3 
Summary of Pre-Clinical Observations ............................................................................... 38 
2.4 Clinical Experience of FP-1305........................................................................................................ 38 
2.4.1 
Clinical Experience of Macrophage Targeting Agents ....................................................... 38 
2.5 Rationale for Tumour Types ............................................................................................................. 38 
2.5.1 
Hepatobiliary Cancers ......................................................................................................... 39 
2.5.2 
Pancreatic Cancer ................................................................................................................ 39 
2.5.3 
Colorectal Adenocarcinoma ................................................................................................ 40 
2.5.4 
Ovarian Cancer .................................................................................................................... 40 
2.5.5 
Cutaneous Melanoma .......................................................................................................... 41 
2.5.6 
Uveal Melanoma.................................................................................................................. 41 
2.5.7 
Gastric adenocarcinoma ...................................................................................................... 42 
2.5.8 
Estrogen receptor (ER)+ breast cancer ................................................................................ 42 
2.5.9 
Anaplastic thyroid cancer .................................................................................................... 42 
2.6 Trial Rationale .................................................................................................................................. 43 
2.6.1 
Justification for Trial Subject Populations .......................................................................... 43 
2.6.2 
Justification for Design ........................................................................................................ 43 
2.6.3 
Justification for Initial Dose, Dosing Interval and Dose Escalation.................................... 44 
3 
OBJECTIVES .......................................................................................................................................... 44 
3.1 Primary Objective for Part I ............................................................................................................. 44 
3.2 Secondary Objectives for Part I ........................................................................................................ 44 
3.3 Exploratory Objectives for Part I ...................................................................................................... 45 
3.4 Primary Objective for Part II ............................................................................................................ 45 
3.5 Secondary Objectives for Part II....................................................................................................... 45 
3.6 Exploratory Objectives for Part II .................................................................................................... 45 
3.7 Primary Objective for Part III ........................................................................................................... 46 
3.8 Secondary Objectives for Part III ..................................................................................................... 46 
3.9 Exploratory Objectives for Part III ................................................................................................... 46 
3.10 Outcome Measures ........................................................................................................................... 46 
4 
TRIAL DESIGN ...................................................................................................................................... 50 
4.1 Dose Limiting Toxicity .................................................................................................................... 53 
4.2 Stopping and Dose Escalation Rule(s) ............................................................................................. 54 
4.2.1 
DLT at the Initial Dose after the First Infusion (Part I)....................................................... 54 
4.2.2 
DLTs during the DLT Assessment Period at the First Dose Level (Part I) ........................ 54 

Faron Pharmaceuticals Ltd. 
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CONFIDENTIAL 
 
 
4.2.3 
Predefined Dose Escalation Rules for TITE-CRM (Part I) ................................................. 54 
4.2.4 
DLTs during the DLT Assessment Period after the Dose has been Escalated (Part I) ....... 55 
4.2.5 
Delayed Toxicities That Occur after the Full DLT Assessment Period (For Part I subjects 
and Part II subjects that are in cohorts investigating new exposure levels) ........................ 55 
4.3 Dose Escalation to 30, 45 and 100 mg/kg Doses (Q3W, Part II) ..................................................... 55 
4.3.1 
Enrolment of Subjects (30 - 100 mg/kg Q3W) and Dose Escalation (Part II) .................... 56 
4.3.2 
Dosing Rules (30 - 100 mg/kg) (Q3W, Part II) ................................................................... 56 
5 
ELIGIBILITY .......................................................................................................................................... 56 
5.1 Inclusion and Exclusion Criteria ...................................................................................................... 57 
5.1.1 
Inclusion Criteria ................................................................................................................. 57 
5.1.2 
Exclusion Criteria ................................................................................................................ 58 
5.1.3 
Specific Additional Exclusion Criteria for HCC ................................................................. 58 
6 
SCREENING AND CONSENT .............................................................................................................. 59 
6.1 Informed Consent ............................................................................................................................. 59 
6.2 Screening .......................................................................................................................................... 59 
7 
TRIAL ENTRY ........................................................................................................................................ 60 
8 
TREATMENT DETAILS ....................................................................................................................... 61 
8.1 Investigational Medicinal Product .................................................................................................... 61 
8.1.1 
Dosage Form and Composition ........................................................................................... 61 
8.1.2 
Instructions for Storage ....................................................................................................... 61 
8.1.3 
Instructions for Handling the Investigational Medicinal Product ....................................... 61 
8.2 Trial Treatment ................................................................................................................................. 61 
8.2.1 
First Infusion........................................................................................................................ 61 
8.2.2 
Subsequent Infusions ........................................................................................................... 62 
8.3 Treatment Schedule .......................................................................................................................... 62 
8.4 Assessments during Treatment Period.............................................................................................. 63 
8.4.1 
Parameters Collected during Pre-Dose Evaluation in Part I................................................ 63 
8.4.2 
Parameters Collected during Pre-Dose Evaluation in Part II .............................................. 64 
8.4.3 
Parameters Collected during Pre-Dose Evaluation in Part III ............................................. 65 
8.4.4 
Samples Collected and Parameters Analysed during and after IMP Administration in Part I
 ............................................................................................................................................. 66 
8.4.5 
Samples Collected and Parameters Analysed during and after IMP Administration in Part 
II........................................................................................................................................... 67 
8.4.6 
Samples Collected and Parameters Analysed during and after IMP Administration in Part 
III ......................................................................................................................................... 68 
8.4.7 
Tumour Assessment ............................................................................................................ 68 
8.5 Assessments during the Post-Treatment Period ............................................................................... 68 
8.6 Sample Collection ............................................................................................................................. 69 
8.6.1 
Tumour Paraffin Blocks ...................................................................................................... 69 
8.6.2 
Blood Samples ..................................................................................................................... 69 
8.7 Dose Modifications, Infusion Delays, Missed Doses and Special Cases ......................................... 70 
8.7.1 
Treatment beyond One Year................................................................................................ 70 
8.7.2 
Treatment Hold in Complete Response ............................................................................... 71 
8.8 Possible Toxicities ............................................................................................................................ 71 
8.9 Management of Toxicities ................................................................................................................ 73 
8.9.1 
Infusion Reactions ............................................................................................................... 73 
8.9.2 
Immune Related Adverse Events ........................................................................................ 74 
8.9.3 
Tumour Lysis Syndrome ..................................................................................................... 76 
8.9.4 
Increased Fibrosis in Response to Liver Injury ................................................................... 77 
8.10 Treatment beyond RECIST defined disease progression ................................................................. 77 
8.11 Treatment Compliance...................................................................................................................... 77 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 11 (109) 
 
 
CONFIDENTIAL 
 
 
9 
SUPPORTIVE TREATMENT ............................................................................................................... 78 
10 CONCOMITANT INTERVENTIONS / MEDICATIONS ................................................................. 78 
10.1 Allowed Interventions ...................................................................................................................... 78 
10.2 Prohibited Interventions.................................................................................................................... 78 
10.3 Contraception and Pregnancy ........................................................................................................... 78 
10.4 Trial Subject Withdrawal/Discontinuation ....................................................................................... 79 
10.5 COVID-19 Vaccination .................................................................................................................... 79 
11 ADVERSE EVENT REPORTING ........................................................................................................ 79 
11.1 Reporting Requirements ................................................................................................................... 79 
11.2 Definition of Adverse Event ............................................................................................................. 80 
11.3 Adverse Events ................................................................................................................................. 80 
11.3.1 Grading of Adverse Event Severity ..................................................................................... 81 
11.3.2 Relationship of Adverse Event to Study Medication .......................................................... 81 
11.4 Serious Adverse Events .................................................................................................................... 81 
11.4.1 Monitoring Pregnancies for Potential Serious Adverse Events........................................... 82 
11.5 Adverse Events of Special Interest ................................................................................................... 82 
11.6 AE/SAE Recording and Reporting Period ....................................................................................... 83 
11.7 Reporting to Competent Authorities and Independent Ethics Committees ...................................... 83 
11.8 Safety Reporting to Investigators ..................................................................................................... 84 
12 DATA HANDLING AND RECORD KEEPING .................................................................................. 84 
12.1 Data Collection ................................................................................................................................. 84 
12.2 Archiving .......................................................................................................................................... 84 
13 QUALITY MANAGEMENT.................................................................................................................. 84 
13.1 Site Set-up and Initiation .................................................................................................................. 84 
13.2 On-Site Monitoring ........................................................................................................................... 85 
13.3 Audit and Inspection ......................................................................................................................... 85 
13.4 Notification of Serious Breaches ...................................................................................................... 85 
14 END OF TRIAL DEFINITION.............................................................................................................. 85 
15 STATISTICAL CONSIDERATIONS ................................................................................................... 86 
15.1 Trial Population ................................................................................................................................ 86 
15.2 Objectives and Outcome Measures .................................................................................................. 86 
15.3 Analyses of Outcome Measures ....................................................................................................... 87 
15.3.1 Primary Outcome (Part I) .................................................................................................... 87 
15.3.2 Primary Outcome (Part II) ................................................................................................... 87 
15.3.3 Primary Outcome (Part III).................................................................................................. 87 
15.3.4 Secondary and Exploratory Outcomes ................................................................................ 87 
15.4 Analysis of Efficacy Parameters ....................................................................................................... 88 
15.5 Planned Interim Analysis .................................................................................................................. 89 
15.6 Planned Main Analyses .................................................................................................................... 89 
15.7 Power Calculations ........................................................................................................................... 89 
16 ACCESS TO SOURCE DATA AND RELATED DOCUMENTS ...................................................... 90 
17 TRIAL ORGANISATIONAL STRUCTURE ....................................................................................... 90 
17.1 Sponsor ............................................................................................................................................. 90 
17.2 Data Monitoring Committee ............................................................................................................. 90 
17.3 Finance .............................................................................................................................................. 91 
18 ETHICAL CONSIDERATIONS............................................................................................................ 91 
19 CONFIDENTIALITY AND DATA PROTECTION ........................................................................... 91 
20 PUBLICATION POLICY ....................................................................................................................... 92 

Faron Pharmaceuticals Ltd. 
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page 12 (109) 
 
 
CONFIDENTIAL 
 
 
21 REFERENCE LIST ................................................................................................................................. 93 
22 APPENDIX 1 - RECIST CRITERIA..................................................................................................... 97 
23 APPENDIX 2 - IMMUNE-RELATED RESPONSE CRITERIA ..................................................... 100 
24 APPENDIX 3 - WMA DECLARATION OF HELSINKI ................................................................. 102 
25 APPENDIX 4 - DEFINITION OF ADVERSE EVENTS ................................................................... 106 
26 APPENDIX 5 - COMMON TOXICITY CRITERIA GRADINGS .................................................. 107 
27 APPENDIX 6 - ECOG PERFORMANCE STATUS.......................................................................... 108 
28 APPENDIX 7 - NYHA CLASSIFICATION ....................................................................................... 109 
 
 
TABLE OF FIGURES 
 
FIGURE 1: 
TRIAL OVERALL SCHEMA ............................................................................................... 19 
FIGURE 2: 
CLEVER-1 EXPRESSION IN LIVER CANCER. ............................................................... 37 
 
 
TABLE OF TABLES 
 
TABLE 1: 
SCHEDULE OF ASSESSMENTS FOR PART I .................................................................. 20 
TABLE 2: 
SCHEDULE OF ASSESSMENTS FOR PART II ................................................................ 24 
TABLE 3: 
SCHEDULE OF ASSESSMENTS FOR PART III ............................................................... 29 
TABLE 4: 
DOSE LEVELS IN PART I OF THE TRIAL ....................................................................... 51 
TABLE 5: 
GRADING OF ADVERSE EVENT SEVERITY ................................................................. 81 
 
 
 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 13 (109) 
 
 
CONFIDENTIAL 
 
 
ABBREVIATIONS 
5-FU 
5-fluorouracil  
ADA 
Anti-drug antibody 
AE 
AESI 
Adverse event  
Adverse Event of Special Interest 
AFP 
Alpha fetoprotein 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase  
ATC 
AUC 
Anaplastic thyroid cancer 
Area under the curve 
BCLC 
Barcelona Clinic Liver Cancer 
BRCA  
Breast cancer gene 
CA 
Cancer antigen  
CBC 
Complete blood count 
CBR 
Clinical benefit rate (CR, PR or SD by RECIST 1.1) 
CD 
Cluster of differentiation 
CEA 
Carcinoembryonic antigen 
CK 
Creatine kinase 
CLEVER-1 
Common lymphatic endothelial and vascular endothelial receptor-1 
Cmax 
Maximum serum concentration of a drug  
Cmin 
Minimum serum concentration of a drug  
CMP 
Comprehensive metabolic panel 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response  
CRC 
Colorectal adenocarcinoma 
CRP 
C-reactive protein 
CSF1R 
Colony Stimulating Factor 1 Receptor  
CT 
ctDNA 
Computerized tomography 
Circulating tumour deoxyribonucleic acid 
CTLA-4 
Cytotoxic T-lymphocyte antigen-4 
D 
Day  
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form  
ER 
Estrogen receptor 
GCP 
Good clinical practice  
GE 
Gastro-esophageal 
h 
Hour  

Faron Pharmaceuticals Ltd. 
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FP-1305 25 mg/mL concentrate for solution for infusion 
page 14 (109) 
 
 
CONFIDENTIAL 
 
 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use  
IEC 
Independent Ethics Committee  
IFN 
Interferon 
IL 
Interleukin 
IMP 
Investigational medicinal product 
irORR 
Immune-related objective response rate 
IRB 
ISF 
Institutional Review Board  
Investigator Site File 
IUD 
Intra-uterine device 
I.V. 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein  
M1 
Pro-inflammatory macrophage  
M2 
Immunosuppressive macrophage 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
Mean fluorescence intensity 
MoA 
Mode of action 
mmol 
Millimole 
MRC 
Mannose receptor 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events  
OxLDL 
Oxidized LDL 
OC 
Ovarian cancer  
ORR 
Objective response rate (CR or PR by RECIST 1.1) 
PD  
Pharmacodynamic  
PD-1 
Programmed cell death protein-1 
PDAC 
Pancreatic ductal adenocarcinoma 
PK 
Pharmacokinetic 
PARP  
Poly (ADP-ribose) polymerase 
PR 
Partial response 
PTH 
Parathyroid hormone  
Q3W 
Every three weeks 
Q2W 
Every two weeks 
Q1W 
Every one week 
RECIST 
Response Evaluation Criteria In Solid Tumors  
RNA 
SAE 
sCLEVER-1 
Ribonucleic acid 
Serious adverse event 
Soluble CLEVER-1 
SD 
Stable disease  
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
TAM 
Tumour associated macrophage 

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TITE-CRM 
Time-to-event continual reassessment method 
TME 
Tumour microenvironment 
ULN 
Upper Limit of Normal 
 
1 
PROTOCOL SUMMARY 
1.1 Synopsis 
Title: 
A Phase I/II Open-Label, Three-Part, Dose-Finding and Separate Cohort Expansion 
Trial to Assess the Safety, Tolerability and Preliminary Efficacy of Repeated Doses of 
CLEVER-1 Antibody FP-1305, in Subjects with Advanced Solid Tumours 
Study 
description: 
It is hypothesised that by blocking common lymphatic endothelial and vascular 
endothelial receptor-1 (CLEVER-1) protein with FP-1305 the immune system is 
reactivated to eradicate tumour cells. This is a first in human study to test the safety, 
tolerability and preliminary efficacy of FP-1305 in advanced solid tumours. The study 
is run in three parts. 
Part I will escalate the dose at pre-determined dose levels to determine the maximum 
tolerated dose (MTD).  
Part II will test the selected dose(s) from Part I and may explore new doses in distinct 
cohorts of predefined tumour types. 
Part III will expand the Part II cohorts demonstrating efficacy signal.   
Objectives: 
 
Primary objectives: 
Part I 
• To determine the safety, tolerability and recommended dose of FP-1305 for Part II 
and III in subjects with advanced (inoperable or metastatic) hepatobiliary, pancreatic, 
colorectal or ovarian cancer or melanoma subjects without standard treatment 
options 
Part II 
• To determine the safety, tolerability and preliminary efficacy of FP-1305 
monotherapy with the objective response rate (ORR), clinical benefit rate (CBR) and 
immune-related ORR (irORR) in distinct expansion groups of subjects with 
advanced (inoperable or metastatic) solid tumours of the selected tumour types 
Part III  
• To assess the ORR, CBR and irORR in distinct expansion groups of subjects with 
advanced solid tumours in CLEVER-1 positive subjects from selected tumour types 
at a selected dose 
 
Secondary objectives: 
Part I 
• To characterize the pharmacokinetic (PK) profile of a single dose of FP-1305 after 
the first dosing 
• To characterize the PK profile of FP-1305 during repeated dosing 
• To assess the host immune response to FP-1305 (immunogenicity) 
• To assess the preliminary efficacy of FP-1305 monotherapy with the ORR and 
irORR in each cohort of different tumour type 
Part II 
• To determine CLEVER-1 positivity in each tumour type 
• To characterize the PK profile of a single dose of FP-1305 after the first dosing for 
each cohort of different tumour type 

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• To characterize the PK profile of FP-1305 during repeated dosing in each cohort of 
different tumour type 
• To assess the host immune response to FP-1305 (immunogenicity) in each tumour 
type 
• To explore potential predictive markers associated with FP-1305 clinical activity as 
determined by ORR, CBR and irORR 
• To investigate the duration of response in the subject group that has a complete or 
partial response, or stable disease (SD) 
Part III 
• To characterize population PK of FP-1305 in each selected tumour type during 
repeated dosing 
• To assess the host immune response to FP-1305 (immunogenicity) 
• To assess the duration of response in distinct expansion groups of subjects with 
advanced solid tumours in CLEVER-1 positive subjects from selected tumour types 
at a selected dose 
• To assess progression free survival in subjects who receive at least 1 dose of FP-1305 
• To assess the overall survival in subjects who receive at least 1 dose of FP-1305 
• To determine the safety and tolerability of FP-1305 during repeated dosing in each 
tumour type at a selected dose 
Endpoints: 
Primary outcome measures: 
Part I 
• Tolerable dose(s) will be determined by the TITE-CRM based on the 
occurrence/non-occurrence of dose limiting toxicities (DLT) in the trial subjects 
according to definitions in Section 4.1. 
Part II 
• Safety and tolerability will be defined by physical examination, adverse events and 
by safety laboratory tests. Adverse events are collected, graded and reported 
according to the NCI-CTCAE version 5.0. Medical Dictionary for Regulatory 
Activities (MedDRA) terminology will be used to classify, record, manage, and 
analyse the data. Tolerability of  new dose(s) will be determined based on the 
occurrence/non-occurrence of DLT during 28 days following the first dose of FP-
1305 in subjects evaluable for DLT assessment in Part II . 
• The response (ORR, CBR, and irORR separately) to the treatment will be determined 
by tumour imaging according to Response Evaluation Criteria In Solid Tumors 
(RECIST) 1.1 based on images obtained by Cycle 7. Results from each tumour type, 
dose level and dosing frequency will be reported separately. 
Part III 
 
• The response (ORR, CBR and irORR separately) to the treatment will be determined 
by tumour imaging according to RECIST 1.1 based on images obtained by Cycle 7. 
Results from each tumour type will be reported separately. 
 
Secondary outcome measures: 
Part I 
• The PK profile of a single dose (during Cycle 1) and repeated doses (during Cycles 
1-5) of FP-1305 will be determined by repeated measurements of the drug 
concentration in the circulation. Peak concentration (Cmax), trough concentration 
(Cmin), area under the serum concentration versus time curve (AUC), clearance, 
volume of distribution, and terminal half-life (t1/2) for each dose level will be 
determined. 
• Immunogenicity will be evaluated by assessing anti-drug antibodies in the circulation 
periodically during treatment and follow-up. 

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• The ORR to the treatment will be determined by tumour imaging according to 
RECIST 1.1. The CBR is the proportion of subjects that have a complete response, 
partial response, or stable disease. The irORR will also be calculated. 
Part II 
• The PK profile of a single dose (during Cycle 1) and repeated doses (during Cycles 
2-5) of FP-1305 will be determined by repeated measurements of the drug 
concentration in the circulation. Peak concentration (Cmax), trough concentration 
(Cmin), AUC, clearance, volume of distribution, and terminal half-life (t1/2) for each 
dose level will be determined. Results from each tumour type will be reported 
separately. 
• Immunogenicity will be evaluated by assessing anti-drug antibodies in the circulation 
periodically during treatment and follow-up. Results from each tumour type will be 
reported separately. 
• Potential genetic, cellular and other predictive markers will be associated with 
FP-1305 clinical activity as determined by ORR, CBR and irORR. This includes but 
is not limited to the correlation of response and immune cell profile, 
cytokine/chemokine profile and the proportion of CLEVER-1-positive monocytes, 
Cluster of differentiation (CD)4, CD8, their ratio and regulatory T-cells in the 
circulation and in tumour specimens prior to treatment and in circulation during the 
first cycle of treatment. 
• The duration of response is measured from the time of initial response until 
documented tumour progression, death, or dropout. 
• Safety and tolerability will be defined by physical examination, adverse events and 
by safety laboratory tests. Adverse events are graded and reported according to the 
NCI-CTCAE version 5.0. MedDRA terminology will be used to classify, record, 
manage, and analyse the data. 
Part III 
• The population PK of FP-1305 will be determined by measurements of the drug 
concentration in the circulation between Cycles 1 and 5. Results from each tumour 
type will be reported separately. 
• Immunogenicity will be evaluated by assessing anti-drug antibodies in the circulation 
periodically during treatment and follow-up. Results from each tumour type will be 
reported separately. 
• The duration of response is measured from the time of initial response until 
documented tumour progression, death, or dropout. 
• Progression free survival as the time from subject allocation into the trial until 
documented disease progression according to RECIST 1.1 or death will be measured 
in the population that has been dosed at least once. 
• Overall survival is defined as the time from subject allocation into the trial until death 
from any cause and will be measured in the population that has been dosed at least 
once. Data will be censored on the last documented data that the subject has been 
alive.  
• Safety and tolerability will be defined by physical examination, adverse events and 
by safety laboratory tests. Adverse events are graded and reported according to the 
NCI-CTCAE version 5.0. MedDRA terminology will be used to classify, record, 
manage, and analyse the data. 
Study 
population: 
Subjects with advanced hepatobiliary tumours (including hepatocellular carcinoma 
(HCC), gallbladder cancer, intra- and extrahepatic cholangiocarcinoma), pancreatic 
ductal adenocarcinoma, colorectal adenocarcinoma, serous poorly differentiated 
(Grade 3) ovarian adenocarcinoma or undifferentiated ovarian cancer, and cutaneous 
melanoma can participate in Part I of the trial. In addition, subjects with uveal 
melanoma, gastric adenocarcinoma (including gastro-eosophageal (GE) junction), ER+ 

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breast cancer and anaplastic thyroid cancer may participate in Parts II and III of the 
trial. 
Phase: 
I/II 
Description of 
sites enrolling 
study subjects: 
Approximately 20-30 investigational sites in 5-8 countries located in Europe and in the 
United States will participate in the trial.  
Description 
of study 
intervention: 
In Part I, the pre-determined dose levels of FP-1305 are 0.3 mg/kg, 1.0 mg/kg, 
3.0 mg/kg and 10.0 mg/kg, and the pre-specified reserve de-escalation or escalation 
dose levels are 0.05 mg/kg and 0.1 mg/kg or 20 mg/kg, respectively. FP-1305 is 
administered intravenously every three weeks. In Parts II and III, the dose(s) is based 
on the results of Part I. Additional doses 30-100 mg/kg are included to be investigated 
in Part II. However, the maximum amount of FP-1305 in one investigational medicinal 
product (IMP) infusion is 10 g and cannot be exceeded irrespective of the calculated 
weight based dose. More frequent dosings (Q1-2W) investigated in Part II are described 
in Protocol Addendum.    
Study duration: 
November 2018 – December 2024  
Participant 
duration: 
For each subject, the trial will consist of a screening period (maximum 28 days), 
treatment phase with FP-1305 (one year with potential to continue longer), and a post-
treatment period for safety assessment (maximum 4 weeks). Survival data will be 
collected beyond the subject’s active participation in the trial. The collection of the 
survival data of a subject is limited to 2 years from the first IMP dose or 1 year from 
the last IMP dose if duration of dosing is more than one year. In case that, as judged by 
the investigator, it would be beneficial to continue the treatment beyond one year, the 
protocol allows the treatment according to normal clinical practice, in order to allow 
the treatment continuation of the study subjects, provided that the clinical development 
and manufacturing of FP-1305 continues and it is not available via other routes.  
1.2 Schema 
This is an open label, three-part (Figure 1), Phase I/II, dose-finding and separate cohorts expansion 
trial to determine the safety, tolerability and preliminary efficacy of repeated doses of CLEVER-1 
antibody FP-1305 administered in three-week intervals (Q3W). This interval is called a cycle. In 
addition to the Q3W dosing , Protocol Addendum introduces once in two weeks (Q2W) and once in 
week (Q1W) dosing schemes to be investigated. In Part I 30 subjects were enrolled, in Part II up to 
10 subjects in each selected Part II cohort (cancer type, dose level and dosing scheme) will be 
enrolled; in addition, testing of higher doses (30-100 mg/kg) in cohorts with multiple cancer types 
will proceed in parallel with the treatment of other Part II cohorts. In Part III additional subjects will 
be enrolled based on the continuation rules set in this protocol. Subjects are enrolled into a specific 
part of the study and continue in that part until they discontinue (i.e. subjects do not progress from 
one part to the next). It is estimated that the total number of subjects in the whole trial is up to 700. 
 

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second additional measurement), and in Cycle 1 at 5 h (+/- 2 h) after IMP infusion completion. After Cycle 3 vital signs to be taken before and after IMP administration only 
and if clinically indicated  
4 Predose assessment at screening, Cycles 1, 2, 4, 6, and every second cycle thereafter; and Follow-up; postdose assessment at Cycles 1 and 4; ECG must be performed also 
always if clinically indicated 
5 Pregnancy test (serum) for women of child-bearing potential only 
6 Cycles 1, 2, 3, 4 and 5 only; Post IMP administration timepoints in Cycles 1, 2 and 4: 0 h after infusion and flushing the line, 1 h (+/- 5 mins), 5 h (+/- 30 mins), D2 (+/- 4 h), 
D3 (+/- 4 h), D4 (+/- 4 h), D5 (+/- 8 h), and D8 (+/- 24 h) 
7 Cycles 1, 2, 4, 6, and every second cycle thereafter, or if clinically indicated, and Follow-up 
8 Predose assessments, local and research laboratory blood samples are permitted to be taken up to three days before the Day 1 of each cycle. The only exception is vital signs 
which should be taken on the day of IMP administration 
9 Complete blood cell counts: white blood cells, neutrophils, lymphocytes, platelets, haemoglobin  
10 Comprehensive metabolic panel: glucose, calcium, sodium, potassium, chloride, creatinine, ALT, ALP, AST, CK, total bilirubin, albumin 
11 Endocrine panel 1: Cortisol, lipase and amylase (pancreas specific) on cycles 1, 4 and 8 and when clinically indicated  
12 Endocrine panel 2: thyroid stimulating hormone, PTH, free thyroxine (T4), free triiodothyronine (T3) on each cycle 
13 Screening test may be immunochemical. If positive, nucleic acid test should be performed on Cycles 1, 2, 4 and 6. If negative at screening no additional tests should be 
performed 
14 Predose assessment in Cycles 1, 2, 3 and 4. Post IMP administration timepoints in Cycles 1 and 2: D2 (+/- 4 h), D8 (+/- 24 h), and D15 (+/- 24 h) 
15 Predose assessment in Cycles 1, 2, 3 and 4. Post IMP administration timepoints in Cycles 1 and 2 D2 (+/- 4 h), D8 (+/- 24h) and D15 (+/- 24 h) 
16 Predose assessment in Cycles 1, 2, 3 and 4. Post IMP administration timepoints in Cycles 1 and 2 D8 (+/-24 h) and D15 (+/- 24 h) 
17 Predose assessment in Cycles 1 and 4. Post IMP administration timepoints in Cycle 1 D5 (+/- 4 h) 
18 First tumour biopsy must be less than 6 months old from the date of consent or taken during the screening period. In addition, an archival block may be used if needed; the 
biopsy in Cycle 2 within 10 days after the IMP administration.  
19 The same imaging method (CT, MRI) per subject must be used throughout the trial. First scan (C1) must be less than 6 weeks prior the first dose (routine diagnostic image 
can be used); the scans in other cycles within +/- 10 days from the IMP administration 
20 Cycles 4, 7, 10, and every third cycle thereafter, up to one year. If the treatment extends beyond one year, 18- (± 1 month) and 24- (± 1 month) month images are mandatory 
to take if not routinely taken at these timepoints. In addition to the imaging time-points specified here, also any other imaging performed by the site will also be collected. 
21 Brain imaging (CT) for exclusion of CNS metastasis. Routine diagnostic image (CT/MRI) can be used if available within two weeks prior to the date of consent or done 
during the screening period.  
22 All subjects in the dose-escalation cohorts should be closely monitored for safety for the first 24 h after the first IMP infusion and for a minimum of 6 h after the second IMP 
infusion at the trial site hospital. Subjects in the dose-expansion cohorts should be monitored for a minimum of 6 h after the first and the second IMP infusions at the trial site 
hospital. After Cycle 2 all subjects should be observed for a minimum of 2 h after the IMP infusions. Post-dose observation will be longer if deemed appropriate. AE assessment 
done if visit indicated. 
23 Follow-up visit will be performed for 3 weeks (+/- 1 week) after the decision to discontinue the IMP. In addition, survival data will be collected for up to 2 years post the 
first IMP dose (at 1 year and 2 years after the first IMP dose), or 1 year from the last IMP dose if duration of dosing is more than one year.  

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See the Laboratory Manual for sample collection and handling procedures in detail.  
1 Main ICF must be signed by the subject before any trial related procedures can be initiated. Genetic ICF is voluntary. 
2 Vital signs: blood pressure, heart rate, temperature, respiratory rate 
3 Cycles 1-3 vital signs to be taken at the following 4 time-points: prior to the start of the infusion, 20 minutes after the start of the infusion, 40 minutes after the start of the 
infusion and at 1 h after the start of the infusion or at the end of the infusion (immediately after flushing the line), whichever occurs later, and in Cycle 1 at 5 h (+/- 2 h) after 
IMP infusion completion. After Cycle 3 vital signs to be taken before and after IMP administration only and at additional time-points if clinically indicated 
4 Predose assessment at screening, Cycles 1, 2, 4, 6, and every second cycle thereafter; and Follow-up; postdose assessment at Cycles 1 and 4; ECG must be performed also 
always if clinically indicated 
5 Pregnancy test for women of child-bearing potential only. Screening and Follow-up visit: test in serum, Predose assessments: test in serum or urine. 
6 Cycles 1, 2, 3 and 4 only; Post IMP administration timepoints in Cycles 1 and 2: 0 h after infusion and flushing the line, 1 h (+/- 5 mins), 5 h (+/- 30 mins), D2 (+/- 4 h), D3 
(+/- 4 h), D4 (+/- 4 h), D5 (+/- 8 h), and D8 (+/- 24 h) 
7 Cycles 1, 2, 4, 6, and every second cycle thereafter, or if clinically indicated, and Follow-up 
8 Predose assessments, local and research laboratory blood samples are permitted to be taken up to three days before the Day 1 of each cycle. The only exception is vital signs 
which should be taken on the day of IMP administration 
9 Complete blood cell counts: white blood cells, neutrophils, lymphocytes, platelets, haemoglobin  
10 Comprehensive metabolic panel: glucose, calcium, sodium, potassium, chloride, creatinine, ALT, ALP, AST, CK, total bilirubin, albumin.  
11 Screening, predose at every cycle; postdose at Cycle 1 D5 (+/- 8 h), Cycles 2 and 3 D8 (+/- 24 h), and Follow-up 
12 Endocrine panel: cortisol, lipase and pancreas-specific amylase, thyroid stimulating hormone, PTH, free thyroxine (T4), free triiodothyronine (T3), troponin on all cycles 
13 Screening test may be immunochemical. If positive, nucleic acid test should be performed on Cycles 1, 2, 4 and 6. If negative at screening no additional tests should be 
performed 
14 At selected sites and cohorts only. Predose assessment in Cycles 1 and 2. Post IMP administration timepoints in Cycle 1: D2 (+/- 4 h), D8 (+/- 24 h), and D15 (+/- 24 h) 
15 Collected at sites that do not collect ‘Blood sample for RO and PBMC’ (see footnote 14 above). Predose assessment in Cycles 1 and 2. Post IMP administration timepoints 
in Cycle 1: D2 (+/- 4 h), D8 (+/- 24 h), and D15 (+/- 24 h) 
16Analysed from the plasma fraction of the blood sample collected for PBMC isolation or blood sample for RO and PBMC during Cycle 1 predose, D2 (+/- 4 h), D8 (+/- 24 h) 
and D15 (+/- 24 h) and Cycle 2 predose. Collected as an independent sample in Cycle 2 D2 (+/- 4 h), D8 (+/- 24 h), D15 (+/- 24 h), and Cycle 3 predose. See Central Laboratory 
Services manual for further details. 
17 Predose assessment in Cycles 1, 2, 3 and 4. Post IMP administration timepoints in Cycles 1 and 2 D2 (+/- 4 h), D8 (+/- 24h) and D15 (+/- 24 h) 
18 Predose assessment in Cycles 1, 2, 3 and 4. Post IMP administration timepoints in Cycles 1 and 2 D8 (+/-24 h) and D15 (+/- 24 h) 
19 First tumour biopsy must be less than 6 months old from the date of consent or taken during the screening period. In addition, an archival block may be used if needed; the 
biopsy in Cycle 2 within 10 days after the IMP administration. Biopsy from new lesions is recommended if assessed feasible by the investigator considering the location of the 
lesions and condition of the subject. 
20The same imaging method (CT, MRI) per subject must be used throughout the trial. First scan (C1) must be less than 6 weeks prior the first dose (routine diagnostic image 
can be used); the scans in other cycles within +/- 10 days from the IMP administration 
21 Cycles 1, 4, 7, 10, and every third cycle thereafter, up to one year. If the treatment extends beyond one year, 18- (± 1 month) and 24- (± 1 month) month images are mandatory 
to take if not routinely taken at these timepoints. In addition to the imaging time-points specified here, also any other imaging performed by the site will also be collected. 
22Brain imaging (CT) for exclusion of CNS metastasis. Routine diagnostic image (CT/MRI) can be used if available. The brain scan within six weeks prior to the  1st dose is 
acceptable.  

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23 First three subjects testing new doses or dosing frequencies in Part II  should be closely monitored for safety for the first 24 h after the first IMP infusion and for a minimum 
of 6 h after the second IMP infusion at the trial site hospital. Other subjects in Part II  will be monitored for a minimum of 6 h after the first IMP infusion. After Cycle 1 all 
subjects should be observed for a minimum of 2 h after the IMP infusions. In any part of the trial, post-dose observation will be longer if deemed appropriate. AE assessment 
done if visit indicated. 
24 Once it has been decided that a patient will permanently stop treatment, a Follow-up Visit should be performed 4 weeks (+/- 1 week) after their last dose of IMP.  If the last 
IMP dose was >5 weeks at the time of the decision, the Follow-up Visit should be performed as soon as possible In addition, survival data will be collected for up to 2 years 
post the first IMP dose (at 1 year and 2 years after the first IMP dose), or 1 year from the last IMP dose if duration of dosing is more than one year.  
 
 
 

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13 Comprehensive metabolic panel: glucose, calcium, sodium, potassium, chloride, creatinine, ALT, ALP, AST, CK, total bilirubin, albumin 
14 Screening, predose at every cycle; postdose at Cycle 1 D5 (+/- 8 h), Cycles 2 and 3 D8 (+/- 24 h), and Follow-up 
15 Endocrine panel: cortisol, lipase and pancreas-specific amylase, thyroid stimulating hormone, PTH, free thyroxine (T4), free triiodothyronine (T3), troponin on all cycles 
16 Screening test may be immunochemical. If positive, nucleic acid test should be performed on Cycles 1, 2, 4 and 6. If negative at screening no additional tests should be 
performed 
17 Predose assessment in Cycles 1 and 4. Post IMP timepoint in Cycle 1 D8 (+/- 24 h).  
18 Predose assessment in Cycles 1 and 2. Post IMP administration timepoints in Cycle 1 D8 (+/- 24h) and D15 (+/- 24 h) 
19 Predose assessment in Cycles 1 and 2. Post IMP administration timepoints in Cycle 1 D8 (+/-24 h) and D15 (+/- 24 h) 
20 First tumour biopsy must be less than 6 months old from the date of consent or taken during the screening period. In addition, an archival block may be used if needed; the 
biopsy in Cycle 2 within 10 days after the IMP administration. Biopsy from new lesions is recommended if assessed feasible by the investigator considering the location of the 
lesions and condition of the subject.  
21 The same imaging method (CT, MRI) per subject must be used throughout the trial. First scan (C1) must be less than 6 weeks prior the first dose (routine diagnostic image 
can be used); the scans in other cycles within +/- 10 days from the IMP administration 
22 Cycles 1, 4, 7, 10, and every third cycle thereafter, up to one year. If the treatment extends beyond one year, 18- (± 1 month) and 24- (± 1 month) month images are mandatory 
to take if not routinely taken at these timepoints 
23 Brain imaging (CT) for exclusion of CNS metastasis. Routine diagnostic image (CT/MRI) can be used if available. The brain scan within six weeks prior to the  1st dose is 
acceptable 
24 All subjects will be monitored for minimum of 4 h after the first IMP infusion. After Cycle 1 subjects should be observed for a minimum of 2 h after the IMP infusions. Post-
dose observation will be longer if deemed appropriate. AE assessment done if visit indicated. 
25 Once it has been decided that a patient will permanently stop treatment, a Follow-up Visit should be performed 4 weeks (+/- 1 week) after their last dose of IMP.  If the last 
IMP dose was >5 weeks at the time of the decision, the Follow-up Visit should be performed as soon as possible. In addition, survival data will be collected for up to 2 years 
post the first IMP dose (at 1 year and 2 years after the first IMP dose), or 1 year from the last IMP dose if duration of dosing is more than one year.  

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2 
BACKGROUND AND RATIONALE 
2.1 Immunotherapy for Cancer 
In recent years, there have been major breakthroughs in harnessing the immune system to treat 
cancer.  Cancer research prior to this has successfully identified many of the pathways which drive 
malignant cell transformation and we now know the genetic aberrations which drive most cancers.  
Unfortunately, therapies for many cancers still remain ineffective or only demonstrate short term 
effectiveness. It is now increasingly understood that the tumour microenvironment (TME) is a vital 
player in the growth, progression and response to treatment of most cancers (Balkwill et al. 2012).  
It is clear that the TME helps malignant cells avoid immune destruction. The TME broadly comprises 
angiogenic cells, stromal cells and infiltrating immune cells (Hanahan et al. 2012).  
Neovascularization of the tumour has long been known to be crucial for cancer progression (Folkman 
et al. 1989) and more recently it is clear that tumour endothelial cells can actively secrete growth 
promoting factors (Butler et al. 2010).  There is also evidence that stromal cells around tumours have 
a particular phenotype which also release pro-tumorigenic factors such as promoters of growth, 
migration and epithelial-mesenchymal transformation and are termed cancer-associated fibroblasts 
(Hanahan et al. 2011).  These factors lead to an immune environment that reflects wound healing and 
is characterised by populations of immune cells that suppress excessive immune activation including 
regulatory T cells, myeloid derived suppressor cells, alternatively activated macrophages  and 
immature dendritic cells which prevent cytotoxic T cells and Natural Killer /T cells from eradicating 
tumour cells (Ruffell et al. 2010). Several molecular receptors on immune cells play a role in 
balancing the effector (tumour killing) and suppressive (tumour-promoting) actions of T cells. Two 
examples on lymphocytes are the cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor and the 
programmed cell death receptor-1 (PD-1) (Pardoll 2012). They have been termed immune 
checkpoints and monoclonal antibodies have been developed to block their actions, this has led to 
several successful clinical studies in cancers, and European Medicines Agency/U.S. Food and Drug 
Administration approval for their use in malignant melanoma, lung cancer, and other malignancies 
(Garon et al. 2015; Hodi et al. 2010; Robert et al. 2015). 
 
There is also gathering evidence that other immune cells such as macrophages also play a critical 
role in promoting the growth and spread of cancers to distant sites (Qian et al. 2010). Nonclinical 
studies have now confirmed that macrophages in the TME, termed tumour associated macrophages 
(TAMs) have several properties which allow tumour escape from immune destruction (Curiel et al. 
2004; DeNardo et al. 2011). 
 
Cancer immunotherapy, particularly checkpoint inhibition, has evolved to a key part of the clinical 
management of cancer. PD-1 blockade is generally well tolerated and may induce durable tumour 
control. However, the majority of cancers does not respond to current immunotherapy or eventually 
develop treatment resistance. 
 
Macrophages are key cells in the control of the immune system activation. They play a dual role in 
the host defence. They form the first line of defence as a component of the innate immune response 
and act as important accessory cells in the adaptive immune response. During immune system 
activation, cells of the monocyte lineage define the direction and the magnitude of the immune 
reaction. Pro-inflammatory macrophages (M1) cells amplify the immune activation during 
inflammation, whereas alternatively activated immunosuppressive macrophages (M2) contribute 
during the healing phase. Most of the tumour associated macrophages that infiltrate the tumour have 
the M2 phenotype and promote tumour progression (Mantovani et al. 2002). 

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Tumours that are resistant to PD-1-related therapy often induce the downregulation of the expression 
of important molecules in the antigen presentation pathway, including the major histocompatibility 
complex class I and II, as well as β2-microglobulin, most likely due to the reduced production of 
interferon (IFN)-γ (Wang et al. 2016). Therapies that increase IFN-γ production and/or eliminate M2 
macrophages to boost the function of immune system may be used either alone or in combination 
with PD-1 blockage to achieve cancer elimination. The elimination of M2 macrophages by different 
colony stimulating factor 1 receptors (CSF1R) targeting antibodies and small molecular inhibitors 
are currently investigated in several clinical trials. However, the elimination of highly 
immunosuppressive tumour associated macrophages appears to be extremely difficult with this 
strategy (Pradel et al. 2016). Thus, alternative strategies to target tumour associated M2 macrophages 
are needed. 
2.2 CLEVER-1 and FP-1305 
2.2.1 Background to CLEVER-1  
CLEVER-1, also known as Stabilin-1, STAB1, FEEL-1, or KIAA0246, is a 280 kilodalton 
multifunctional type-1 transmembrane protein with a large extracellular part containing clusters of 
epidermal growth factor-like domains, seven fasciclin domains, and one X-link domain. CLEVER-1 
deficient mice do not display any obvious physical or behavioural abnormalities and breed 
comparably to wild type control animals on C57BL/6 as well as Balb/c genomic background 
(Schledzewski et al. 2011). CLEVER-1 deficient mice demonstrate mildly increased fibrogenesis 
within the liver parenchyma, which is otherwise normal (Schledzewski et al. 2011; Rantakari et al. 
2016). 
 
CLEVER-1 is expressed in the following human structures or cells: specialised vascular beds of the 
liver, lymph, adrenal cortex and spleen (sinusoidal endothelium), and sub-populations of tissue 
resident macrophages. Stabilin-2 is highly expressed in non-continuous sinusoidal endothelium of 
liver, lymph node, spleen and bone marrow. 
 
In human monocyte-derived macrophages, CLEVER-1 protein can be detected after the cells have 
been stimulated with interleukin (IL)-4 in combination with dexamethasone or with dexamethasone 
alone, whereas IFN-γ has a negative effect on CLEVER-1 expression. CLEVER-1 is expressed on 
M2 tissue macrophages and sinusoidal endothelial cells in the human spleen, liver, adrenal cortex, 
lymph nodes, and bone marrow as well as on the lymphatic endothelium. In kinetic analyses of 
tumours on days 3, 6, and 10, the first macrophage mannose receptor (MRC)-positive M2 
macrophages were seen in day 6 samples, whereas CLEVER-1 was first detected on macrophages in 
day 10 samples. CLEVER-1–positive monocytes can also be detected in the circulation of tumour-
bearing mice. All tumour associated CLEVER-1-positive macrophages are MRC-positive, but only 
about 50% of these macrophages express CLEVER-1. Low pH induces CLEVER-1 expression (Park 
et al. 2012). Thus, CLEVER-1 is also expressed on blood vessels in various angiogenic conditions, 
including during wound healing, tumour vascularization, and chronic inflammation of the skin, such 
as psoriasis. 
  
CLEVER-1 supports transendothelial migration of CD4 FoxP3+ regulatory T cells across hepatic 
sinusoidal endothelial cells (Shetty et al. 2011). It is also highly expressed in a subset of tumour 
associated macrophages (David et al. 2012). High expression of CLEVER-1 on the surface of 
macrophages suppresses the activation of Th1 lymphocytes. Blocking of CLEVER-1 on 
macrophages leads to increased IFN-γ and decreased IL-4 production in a T-cell co-culture (Palani 
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In different tumour models, CLEVER-1 controls cancer growth and metastasis. In these models, the 
density of F4/80 and MRC-positive macrophages and FoxP3-positive T cells in the primary tumours 
as well as in metastases is diminished in the absence of CLEVER-1. Importantly, the numbers of 
intratumoural CD3- and CD8-expressing T cells are not affected, indicating that the immune balance 
is changed (Karikoski et al. 2014). 
 
In sum, these findings lend support to a hypothesis that blocking of CLEVER-1 with an anti-
CLEVER-1 antibody, such as FP-1305, will lead to immune system activation, which, in turn, may 
lead to cancer elimination. 
2.2.2 CLEVER-1 Antibody FP-1305 
The IMP, FP-1305 is a humanized IgG4 antibody that binds to a discontinuous epitope in the 
FAS1/FAS2 domains of human CLEVER-1. The IMP is manufactured by Patheon (Patheon S.p.A. 
Italia, part of Thermo Fisher Scientific), II Trav. SX Via Morolense 5, 03013 Ferentino FR, Italy. 
The IMP is a sterile clear to opalescent solution. Each 10 mL glass vial contains 250 mg of FP-1305 
in histidine buffer containing stability increasing excipients. The concentration of FP-1305 in the 
formulation is 25 mg/mL. Further details are available in Investigator’s Brochure of FP-1305. 
 
The IMP will be administered intravenously over approximately 40-120 minutes infusion according 
to the dosing schedule (Q3W, Q2W or Q1W). 
 
The IMP will be delivered to the hospital pharmacy. In clinical trials, FP-1305 is stored at 2-8 °C. 
After preparing the infusion, the IMP must be administered during the same day. The shelf-life and 
detailed instructions for the handling of the IMP are given in the Pharmacy Manual.  
2.2.3 Nonclinical Data of CLEVER-1 Inhibition and FP-1305 
The role of CLEVER-1 has been evaluated in mice. Gene knockout studies have demonstrated that 
mice deficient of CLEVER-1 are phenotypically normal except for healing from experimental liver 
injury. Since CLEVER-1 deficient mice do not display any clear phenotype when grown in normal 
conditions, it is believed that CLEVER-1 blockage with FP-1305 will be safe. Redundant functions 
of CLEVER-1 and Stabilin-2 and their similar expression in the sinusoidal endothelium may well 
explain that no clear phenotype is observed in CLEVER-1 deficient mice (Schledzewski et al. 2011). 
CLEVER-1 deficiency, or inhibition of CLEVER-1 in mouse tumour models, leads to decreased 
tumour growth and metastasis potential, but does not affect bacterial clearance or immunisation of 
the animals (Karikoski et al. 2009; Karikoski et al. 2014). In addition, CLEVER-1 inhibition did not 
modify the disease course (neither severity nor incidence) of neutrophil- or lymphocyte-dominated 
models of arthritis, induced by anti-collagen II antibodies (leading to collagen antibody-induced 
arthritis) or collagen type I (leading to collage-induced arthritis), respectively. Similar results were 
also obtained in arthritis experiments performed with Ncf1-mutated mice, which normally display a 
severe form of collage-induced arthritis (Karikoski et al. 2014). 
  
In vitro, an α-CLEVER-1 antibody blocks the transendothelial migration of CD4 lymphocytes 
through hepatic sinusoidal endothelial cells, whereas CD8 T cell migration remains unchanged. 
Especially the migration of CD4+CD25+FoxP3+ Tregs is significantly blocked, whereas the 
migration of CD4+CD25+-cells is not (Shetty et al. 2011). The same antibody also blocks the 
adhesion of tumour cells to the lymphatic endothelium of lymph nodes or on the endothelium of the 
high endothelial venule-like vessels (Irjala, Alanen, et al. 2003). 
 

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Peripheral blood mononuclear cells (PBMCs) blocked with an anti-CLEVER-1 antibody in vitro at 
the concentration of 20 µg/mL produced high numbers of IFN-γ spot forming cells in comparison to 
PBMCs treated with control antibodies in tetanus toxoid re-stimulation experiments. It was 
concluded that the ligation of CLEVER-1 on monocytes with a function blocking antibody shifts the 
antigen specific recall response to a pro-inflammatory Th1 direction (Palani et al. 2016). 
 
In vivo, the FP-1305 antibody binds CLEVER-1 on lymphatic sinuses, and controls lymphocyte 
trafficking in lymph nodes (Irjala, Elima, et al. 2003). In addition, the antibody blocked the trafficking 
of EL-4 lymphoma cells from the footpad to the draining popliteal lymph nodes (Karikoski et al. 
2014). 
2.3 Rationale for Targeting CLEVER-1 in the Tumour Microenvironment 
CLEVER-1 is expressed on sinusoidal endothelium and subsets of macrophages (Kzhyshkowska 
2010). On the endothelium, it functions as an adhesion receptor and mediates the transmigration of 
lymphocytes, and on macrophages it functions as a scavenger receptor for several ligands including 
acetylated low density lipoproteins (LDLs), SPARC and placental lactogen (Kzhyshkowska 2010; 
Salmi et al. 2004). Several features of CLEVER-1 function demonstrate that it has pro-tumourigenic 
and pro-metastatic properties: 1) On the liver endothelium it has been shown to specifically support 
the recruitment of regulatory T cells (Shetty et al. 2011), 2) It has been shown to directly mediate the 
binding of cancer cells to lymphatic endothelium (Irjala, Alanen et al. 2003), 3) It is expressed on 
type 2 macrophages and found at sites of several human cancers  as well as on tumour associated 
vessels (Palani et al. 2011; Algars et al. 2012; Ammar et al. 2011). 
 
Subsequent functional interventions which inhibited CLEVER-1 in nonclinical studies confirmed 
that blocking CLEVER-1 is a potential therapeutic strategy for treating cancers and metastatic spread. 
These included studies with human monocytes which confirmed that CLEVER-1 on macrophages 
suppress Th1 activation of lymphocytes and could be reversed with antibody blockade (Palani et al. 
2016).   In vivo animal models of malignant melanoma and lymphoma were used to demonstrate that 
CLEVER-1 antibody blockade could successfully inhibit tumour progression (Karikoski et al. 2014).  
These studies support the role of CLEVER-1 as a tissue microenvironmental promoter of cancer and 
its blockade as a novel anti-cancer therapy. Our data from human tumours also supports the 
hypothesis that CLEVER-1 promotes an immunosuppressive environment around tumours. Using 
tissue samples from patients with a primary liver cancer, it was shown that CLEVER-1 is expressed 
on tumour associated vessels and macrophages. It was further identified, that tumours with high 
CLEVER-1 expression in the peri-tumoral region correlated with a high regulatory T cell/ CD8 
cytotoxic T cell ratio, which favours an immunosuppressive environment. Tumours with high 
CLEVER-1 expression in the peri-tumoral region also had poor prognostic markers, such as poor 
differentiation and microvascular invasion (Figure 2). 
 

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Figure 2: CLEVER-1 expression in liver cancer. 
(A) Immunohistochemical staining of serial sections from primary liver cancer samples for CLEVER-1, CD8 T cells and 
FoxP3 positive regulatory T cells.  (B)  Quantification of CD8/FoxP3 ratios from CLEVER-1 low and CLEVER-1 high 
tumours. (C) Correlation of tumour differentiation and microvascular invasion with CLEVER-1 expression in primary 
liver cancer.  
 
Preclinical studies have demonstrated that CLEVER-1 supports tumour growth and metastasis 
formation. Both in vitro and in vivo studies suggest that therapeutic inhibition of CLEVER-1 blocks 
the migration of immunosuppressive Tregs and converts immunosuppressive M2 macrophages to 
immunostimulatory M1 macrophages that support IFNγ production. In several preclinical tumour 
models, this results in tumour cell apoptosis, reduced tumour growth and suppressed metastasis 
formation. The aim of this trial is to investigate whether FP-1305 can safely be administered to cancer 
patients. 
2.3.1 Safety in Non-Human Primates 
The PK, pharmacodynamic (PD), and safety of FP-1305 has been studied only in non-human 
primates (cynomolgus monkeys) because FP-1305 binds to cynomolgus monkey CLEVER-1 but not 
to rodent CLEVER-1. The binding affinity is very similar compared to the human CLEVER-1. Thus, 
the cynomolgus monkey is a highly relevant species for toxicity analysis. The toxicity of FP-1305 
has been tested in two studies. In both studies, the test subjects have received a single intravenous 
(I.V.) bolus injection of FP-1305. The doses in the first (pilot) study were 3, 10 and 30 mg/kg. No 
relevant changes were observed at clinical observations, body weights, electrocardiography (ECG) 
examinations, haematology, serum chemistry and at necropsy. In the second study, the administered 
single doses were 3, 30 and 100 mg/kg. No relevant changes were observed at clinical observations, 
body weights, ECG examinations, haematology, serum chemistry and at necropsy. 
2.3.2 Pharmacokinetics in Non-Human Primates 
After I.V. administration of FP-1305, mean  SD C0 (5 minutes post-dosing) was 67.05 6.1, 
73172.6 and 2755 250.2 g/mL following 3, 30 and 100 mg/kg single dosing, respectively. The 
corresponding AUC were 677.2 95.8, 20683 3241.6 and 144000 20174.2 gh/mL, 
respectively. The terminal half-life of FP-1305 was 18.3 7.8, 13.7 7.75 and 23.9 5.9 hours at 3, 

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30 and 100 mg/kg, respectively. The compound was characterized by low serum clearance and 
limited volume of distribution. 
  
Before dosing of FP-1305, the percentage of FP-1305 positive CD14+ monocytes in cynomolgus 
circulation ranged from 50 to 80%. After dosing, the proportion of FP-1305 positive CD14+ 
monocytes was clearly reduced in all doses indicating that FP-1305 occupies CLEVER-1 in those 
cells. The number of CD14+ monocytes remained unchanged. 
2.3.3 Summary of Pre-Clinical Observations 
• CLEVER-1 is present in human and cancer associated lymphatics. 
• HEV-like vessels in inflammation and cancer express CLEVER-1. 
• CLEVER-1 mediates endothelial transcytosis of immune and tumour cells. 
• No clear autoimmune or other phenotype develops in anti-CLEVER-1 treated mice. 
• Blocking of CLEVER-1 induces IFN- production in antigen specific immune response. 
• Cancer progression and metastasis require host CLEVER-1 expression 
• Function-blocking antibody against mouse CLEVER-1 has anti-tumour activity 
• FP-1305 does not provoke significant adverse events in non-human primates after single-dose 
I.V. administration at the dose level 100 mg/kg 
2.4 Clinical Experience of FP-1305 
FP-1305 has not been studied previously in human. This is a first-in-human trial. 
2.4.1 Clinical Experience of Macrophage Targeting Agents 
Several molecules targeting macrophages (CSF1R or colony stimulating factor 1 antibodies, or small 
inhibitory molecules against CSF1R) are in development. The frequency of serious adverse events 
related to these compounds is low. Emactuzumab (RG7155) is a monoclonal antibody that inhibits 
CSF1R activation. Based on a safety evaluation of 80 patients treated with emactuzumab for solid 
tumours, one patient experienced a Grade 4 adverse event (a cerebrovascular accident), one patient 
had Grade 3 Klebsiella sepsis, and one Grade 3 dermatomyositis (Gomez-Roca et al. 2015). AMG 
820 is another CSF1R targeting antibody. Twenty-five patients received AMG 820 during a dose 
escalation study. No serious or fatal treatment-related adverse events were observed (Papadopoulos 
et al. 2017). Common treatment related adverse events were peripheral/facial/periorbital oedema, 
asthenia, pruritus, fatigue, decreased appetite, nausea, rash, pyrexia, and diarrhoea (Papadopoulos et 
al. 2017; Gomez-Roca et al. 2015). Grade 3 asthenia and fatigue were observed in 3 and 1 out of the 
80 evaluable patients, respectively, who were treated with emactuzumab (Gomez-Roca et al. 2015). 
Two patients developed cutaneous and mucosal lesions consistent with subacute lupus 
erythematosus, but no visceral involvement specific to systemic lupus disease. These patients were 
treated with hydroxychloroquine and low-dose steroids, which led to rapid clinical improvement. 
The clinical signs and symptoms resolved without late sequelae in both patients (Cassier et al. 2015). 
2.5 Rationale for Tumour Types 
The overall rationale for selecting study subjects with certain tumours is based on the non-clinical 
research. Based on immunohistochemistry analysis, the included tumour types contain macrophages 
that express CLEVER-1 on their surface. In addition, surrogate antibody targeting mouse CLEVER-1 
has demonstrated robust anti-tumour activity for example in a melanoma model. 

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2.5.1 Hepatobiliary Cancers 
Hepatobiliary tumours comprise several major global cancers including hepatocellular (HCC) and 
biliary tract cancers (Kabbach et al. 2015). Biliary tract cancers are sub-classified into intrahepatic 
cholangiocarcinoma, originating from the biliary tree within the liver, and extrahepatic 
cholangiocarcinoma, outside the liver parenchyma; the latter is further subdivided into perihilar 
cholangiocarcinoma and distal cholangiocarcinoma, with a frequency of 10%–20% intrahepatic, 50% 
perihilar and 30%–40% extrahepatic cholangiocarcinoma (Valle et al. 2016).  
 
Despite advances in surgical techniques and chemotherapeutic agents, the overall survival in these 
patients remains extremely poor. Statistics from Cancer Research UK demonstrate that since the 
1970s liver cancer rates have more than tripled (236% increase) in Great Britain and a study from 
two major UK centres demonstrate an overall 5-year survival of less than 20% for these patients 
(Than et al. 2017).  
 
The Barcelona Clinic Liver Cancer (BCLC) staging system is widely used and encompasses all HCC 
patients. The system identifies those patients with early HCC who may benefit from curative 
therapies (stage 0 and A), those at intermediate (stage B) or advanced stage (stage C) who may benefit 
from palliative treatments and those with a very poor life expectancy (stage D). Median survival 
without therapy is >36 months for stage 0 and A, 16 months for stage B, 4–8 months for stage C and 
<4 months for stage D. Over 50% of patients with moderately or poorly differentiated HCC are 
CLEVER-1 positive and this positivity correlates with low CD8/FoxP3 ratio (see Figure 2 in Section 
2.3)  
 
Sorafenib is the standard systemic therapy for patients with advanced HCC and well- preserved liver 
function (BCLC stage C) and those with intermediate-stage HCC who progress following 
transarterial chemoembolization. In case of disease progression or intolerance to sorafenib, best 
supportive care or inclusion into clinical trials for new therapeutic agents are the only options for 
patients. Systemic chemotherapy, tamoxifen, immunotherapy, anti-androgen or somatostatin 
analogues are not recommended for the clinical management of HCC patients (Verslype et al. 2012). 
Thus, there is a high unmet medical need for HCC patients. 
  
Biliary tract cancers comprise <1% of all human cancers and ∼10–15% of all primary liver cancers. 
The preferred treatment is surgery. Systemic chemotherapy, consisting of gemcitabine and cisplatin, 
is the standard of treatment for advanced biliary tract cancers. There is no established second-line 
systemic therapy following progression after first-line treatment and patients should be encouraged 
to participate in clinical trials (Valle et al. 2016).  
2.5.2 Pancreatic Cancer 
Patients with pancreatic cancer succumb to the disease. Metastases are frequent even when the 
primary tumour is small, hampering the efficacy of local treatments including surgery and 
chemoradiotherapy. The available systemic treatments also have limited efficacy. Gemcitabine 
combined with another agents, such as nab-paclitaxel or S1, or FOLFIRINOX, are often used as the 
first-line treatment for advanced disease (Cascinu et al. 2010), but the response rates are relatively 
low and the responses usually short. Moreover, conventional chemotherapy frequently has adverse 
effects, and not all patients are candidates for chemotherapy due to poor performance status or other 
reasons. Therefore, there is an unmet need for more effective and well tolerated systemic therapies 
for patients with pancreatic cancer. 
  

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Thus far, results with the current immunotherapies have mostly remained unimpressive in pancreatic 
cancer. Most pancreatic cancers often do not respond to PD-1 therapy even though cancer mutational 
rate is often high. This may not be surprising, since pancreatic cancer is characterized with a highly 
immunosuppressive microenvironment with a high macrophage content. Many patients with 
pancreatic cancer whose disease progresses on the first-line treatment are candidates for a clinical 
trial since the efficacy of the currently available second-line systemic treatments remains limited. 
 
The immune microenvironment in pancreatic cancer has also been shown to significantly correlate 
with tumour stage and prognosis.  Advanced and aggressive pancreatic cancers are associated with 
high levels of regulatory T cells and TAMs (Ikemoto et al. 2006; Ino et al. 2013) many of which are 
CLEVER-1 positive (Faron data on file). These cancers have been shown to be characterised by a 
disproportionally high level of Th2 cells (pro-tumour) in comparison to Th1 cells (anti-tumour) cells 
(Gabitass et al. 2011). Furthermore, preclinical studies have demonstrated a major role for tumour 
associated macrophages in the progression and metastases of pancreatic ductal adenocarcinomas 
(Nielsen et al. 2016). 
2.5.3 Colorectal Adenocarcinoma 
The majority of patients with colorectal cancer have metastatic disease that initially is not suitable 
for potentially curative resection. The backbone of first-line palliative chemotherapy consists of a 
fluoropyrimidine (I.V. 5-fluorouracil (5-FU) or the oral capecitabine) in various combinations and 
schedules. Combination chemotherapy with 
5-FU/Leucovorin/oxaliplatin (FOLFOX) or 
5-FU/Leucovorin/irinotecan (FOLFIRI) provides higher response rates, longer progression-free 
survival and better survival than 5-FU/Leucovorin alone. Biological agents against vascular 
endothelial growth factor and against the epidermal growth factor receptor in combination with 
chemotherapy further improve the outcome of metastatic colorectal cancer, but also increase the rate 
of adverse reactions. Epidermal growth factor receptor targeting agents may only be used when 
patients are tested to have normal (wildtype) RAS genes in expanded gene analysis. The treatment 
of metastatic colorectal cancer should be approached as a continuum of care in the strategic choice 
of a regimen or sequence in the different lines. Regorafenib is to be considered a standard option in 
pre-treated patients. PD-1 blockage in second- or third-line therapy could be considered as a 
treatment option but only in patients with metastatic deoxyribonucleic acid (DNA) mismatch repair 
(MMR-deficient) colorectal cancer. The survival of colorectal cancer patients is longer if patients 
can be exposed to all of the available cytotoxic agents. Therefore, different scenarios of colorectal 
cancer treatment include even four to five lines of therapy. The choice of the combinations in 
different lines will depend on the molecular characterisation of the tumour, the goal of treatment, the 
toxicity of the agents and the knowledge of mutation status of the tumour. Although the outcome of 
patients with metastatic colorectal cancer has clearly improved during recent years, the median 
survival is reaching only 30 months in clinical trials. Colorectal adenocarcinoma contains 
macrophages that are positive for CLEVER-1. In stage IV disease this positivity correlated with poor 
survival (Algars et al. 2012)   
2.5.4 Ovarian Cancer 
High grade (type II) ovarian carcinomas are biologically aggressive tumours that do not have a 
recognised precursor lesion and may arise de novo from the coelomic epithelium. The prototype of 
type II ovarian cancer is serous carcinoma. Included in this group are high-grade transitional 
carcinomas, malignant mixed mesodermal tumours, and undifferentiated carcinomas. Type II 
tumours show considerable genetic instability and TP53 mutations. Hereditary cancers with breast 
cancer gene (BRCA) 1 or 2 mutations belong to type II tumours (Vang et al. 2009). Practically all 
macrophages in type II ovarian cancer are CLEVER-1 positive (Faron data on file). There are limited 

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treatment options for patients with platinum/taxane-refractory disease, as salvage chemotherapy with 
either platinum-based treatments or other drugs (including topotecan, docetaxel, oral etoposide, 
liposome encapsulated doxorubicin, gemcitabine, ifosfamide and hexamethylmelamine) produce a 
modest response rate that is around 10%. Some targeted agents, including bevacizumab and poly 
(ADP-ribose) polymerase (PARP) inhibitors, such as 41laparib and rucaparib, have been approved 
for the treatment of advanced ovarian cancer, the PARP inhibitors showing efficacy mainly in 
patients with BRCA mutation. Yet, cure from advanced (stage IV) epithelial ovarian cancer that is 
refractory to platinum agents is rare. Patients with such a disease and a good performance status, and 
who are motivated to receive further treatment, may be considered for experimental trials with new 
drugs (Colombo et al. 2010). Many ovarian cancers are CLEVER-1 positive (Faron data on file). 
2.5.5 Cutaneous Melanoma 
Systemic treatment of advanced cutaneous melanoma has recently substantially improved after the 
introduction of BRAF inhibitors and immunotherapy with checkpoint inhibitors. Responses to these 
novel agents are frequent. A subset of patients with advanced cutaneous melanoma treated with 
checkpoint inhibitors survive for at least 5 years after starting the therapy, which is an important 
advance in the treatment of this disease that is notoriously resistant to most conventional 
chemotherapy agents. 
  
There are, however, few effective treatment options for patients with immunotherapy resistant 
cutaneous melanoma. The response rate for CTLA-4 blockage in treatment naïve patients is around 
10%, and the responses with this therapy after the failure of anti-PD-1 treatment are infrequent. 
Cytotoxic chemotherapy has only very modest efficacy with about 10% response rates in advanced 
cutaneous melanoma. BRAF-inhibitor therapy alone or in combination with mitogen-activated 
protein kinase inhibitor is an effective option for patients advanced cutaneous melanoma, if the 
patient has a cutaneous melanoma with BRAF V600 mutation, but drug resistance will usually 
emerge. Patients with cutaneous melanoma resistant to PD-1 targeting agents often have high serum 
lactate dehydrogenase (LDH) levels, which may indicate a low pH in the tumour tissue. 
  
Thus, most patients whose advanced cutaneous melanoma does not respond to immunotherapy, or 
whose disease progresses on immunotherapy, have few viable treatment options, and may have an 
immunosuppressive tumour environment with increased CLEVER-1 expression. In addition, mouse 
anti-CLEVER-1 antibody demonstrates robust anti-tumour activity in B16 melanoma model 
(Karikoski et al. 2014). 
2.5.6 Uveal Melanoma 
Uveal melanoma is the most common primary intraocular malignancy in adults, representing ∼85% 
of ocular melanomas. Cutaneous and uveal melanomas are biologically distinct. Uveal melanoma is 
composed of a number of chromosomal abnormalities and somatic gene alterations. Despite the 
development of effective local therapies, 5-year survival rates (∼80%) have not changed in the past 
three decades and up to 50% of patients develop metastases. There are no effective adjuvant systemic 
therapies nor systemic therapies against metastatic disease and the NCCN (National Comprehensive 
Cancer Network) guideline first recommendation for metastatic disease is a clinical trial. One-year 
survival of patients with metastatic disease is reported to be 15%, with reported median survival 
ranging from 4 to 15 months (Carvajal et al. 2017). The risk of death among uveal melanoma patients 
is significantly higher if CLEVER-1 expression is high in comparison to patients with low 
CLEVER-1 expression (Goldman et al. 2018).  

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2.5.7 Gastric adenocarcinoma 
Surgical resection of gastric cancer (including GE junction), specifically at early stages, is potentially 
curative. However, the majority of patients still relapse following perioperative chemotherapy and 
resection. Patients with inoperable locally advanced and/or metastatic (stage IV) disease should be 
considered for a systemic treatment (chemotherapy). Doublet combinations of platinum and 
fluoropyrimidines are generally used and triplet regimens containing anthracycline, platinum and 
fluoropyrimidine may improve efficacy. Second-line treatment is associated with proven 
improvements in overall survival and quality of life compared with best supportive care in patients 
with adequate performance status. In human epidermal growth factor receptor 2-positive gastric 
cancer trastuzumab in combination with capecitabine or fluorouracil and cisplatin is a standard first 
line treatment. However, the median overall survival of metastatic gastric adenocarcinoma is 
approximately 12 months (Smyth et al. 2016). 
 
Immune checkpoint inhibitors demonstrate some activity in unresectable advanced or recurrent 
gastric or esophago-gastric junction cancer patients refractory to or intolerant to two or more prior 
chemotherapy regimens. However, the response rates in later line settings are close to 10% and a 
median overall survival remains poor (approximately 5 months) even though the responders may 
have long term benefit from the therapy (Kang et al. 2017). Thus, prognosis remains poor in presence 
of metastatic disease and new treatment approaches are desirable. Based on gene expression analysis, 
high CLEVER-1 expression correlates with poor survival in gastric adenocarcinoma (Goldman et al. 
2018). 
2.5.8 Estrogen receptor (ER)+ breast cancer 
Advanced breast cancer comprises both locally advanced breast cancer and metastatic breast cancer. 
The preferred treatment for metastatic ER+ (luminal) breast cancer is endocrine therapy even in the 
presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance. 
Adequate ovarian function suppression or ablation is crucial in the treatment of pre-menopausal 
patients with ER+ advanced breast cancer. The addition of a cyclin dependent kinase 4/6 inhibitor to 
an aromatase inhibitor is recommended to aromatase inhibitor naïve patients or patients previously 
treated with endocrine therapy in adjuvant setting and not considered resistant to the treatment. 
Systemic chemotherapy with anthracycline- or taxane-based regimens is also reasonable option. 
These agents may be used in combinations or sequential single agents. Optimal sequence of all these 
treatments and best management for patients who progressed during or less than 1 year after adjuvant 
is still unknown. Despite all the treatment options, metastatic breast cancer remains virtually an 
incurable disease with a median overall survival of approximately 3 years. 5-year survival is only 
approximately 25%. The European School of Oncology–European Society of Medical Oncology 
International Consensus Guidelines recommends inclusion of patients in well-designed, prospective, 
independent trials. High CLEVER-1 expression is associated with poor survival in ER+ breast cancer 
(Goldman et al. 2018). 
2.5.9 Anaplastic thyroid cancer  
Anaplastic thyroid cancer (ATC) is an aggressive form of thyroid cancer with a mortality approaching 
100%. It is rare and accounts for about 2% of all thyroid cancers. Patients are diagnosed based on 
clinical symptoms. Patients with the disease present with extensive local invasion. Distant metastases 
are found at initial disease presentation in 15% to 50% of patients. No curative therapy exists for 
ATC. Surgery, external beam radiotherapy or chemoradiotherapy are options for local disease 
control. For metastatic disease, systemic therapies include combinations of paclitaxel and carboplatin 
or docetaxel and doxorubicin. Paclitaxel or doxorubicin may also be used alone. However, the 

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median survival from ATC diagnosis is about five months. The one-year survival rate is about 20% 
(Smallridge et al. 2012). 
2.6 Trial Rationale 
The trial will be conducted according to the trial protocol, International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) good clinical 
practice  (GCP) and applicable regulations. 
2.6.1 Justification for Trial Subject Populations  
Preclinical studies have demonstrated that CLEVER-1 supports tumour growth and metastasis 
formation. Both in vitro and in vivo studies suggest that therapeutic inhibition of CLEVER-1 blocks 
the migration of immunosuppressive Tregs and converts immunosuppressive M2 macrophages to 
immunostimulatory M1 macrophages that present antigens to T-cells and support IFN-γ production. 
In several preclinical tumour models, including melanoma, this results in tumour cell apoptosis, 
reduced tumour growth and suppressed metastasis formation. As stated earlier, the patients with 
advanced cutaneous melanoma, uveal melanoma, cholangiocarcinoma, gallbladder cancer, ER+ 
breast, gastric, ovarian, pancreatic, colorectal, liver or anaplastic thyroid cancer who have exhausted 
all licenced therapeutic options will die due to their disease. Based on our existing data CLEVER-1 
is expressed in these tumour types. Inhibition of CLEVER-1 with FP-1305 may have an anti-tumour 
effect in these patients.   
2.6.2 Justification for Design  
The proposed trial design enables a flexible approach to identify a safe and tolerable dose which has 
a biological effect and to expand the cohorts of different tumour types after the dose has been 
selected. Analysis of the primary efficacy in the expansion cohorts early enough with sufficient 
statistical power allows for a rapid adaptation of the protocol in order to focus on the tumour types 
in which the treatment demonstrates the most promising activity. Subject safety will be closely 
monitored after the first infusion and regularly throughout the trial (see Section 8.2). The highest 
dose that can be tolerated (maximum tolerated dose (MTD)) will be first determined using an 
efficient, adaptive dose-finding design, a modified time-to-event continual reassessment method 
(TITE-CRM), which allows for more accurate determination of the MTD and shorter trial duration 
than conventional dose-finding designs (Cheung and Chappell 2000). This initial design allows a 
simple and rapid escalation scheme (whilst still ensuring safety) in the absence of DLT.  
 
Due to its mechanism of action it is likely that a therapeutic response with FP-1305 will require 
repeated dosing. Therefore, the trial design is based on repeated infusions in three-week intervals. 
There is a minimum waiting period of three weeks prior to the recruitment of the next study subject 
at the same dose level. Both recruited subjects dosed at the first dose level will be observed for a 
minimum of three weeks for DLT before dose will be escalated into next level. 
 
More subjects may be allocated during Part I to MTD or any dose below it to obtain necessary 
information for proper dose selection for Part II. It is estimated that a total of 30 subjects will be 
accrued for the MTD determination during Part I. Detailed PK and PD data will be collected to further 
inform the optimal dose selection for the expansion cohorts.  
 
Early termination of an individual cohort in case there is no efficacy ensures that subjects are not 
enrolled into the trial if the treatment is not efficacious. The subject will continue the trial treatment 
until the participation in the trial is no longer considered to be in the best interest of the subject (as 

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judged by the investigator), or until any of the other discontinuation rules is met (see 10.4). If a 
subject is treated with a dose that does not show activity, the dose will be escalated when the dose 
level above it has been shown to be safe and PK data from Cycle 4 has been collected from the initial 
dose level.  
2.6.3 Justification for Initial Dose, Dosing Interval and Dose Escalation  
The selection of the initial dose was based on the nonclinical safety findings, receptor occupancy at 
the 3 mg/kg dose, the affinity of FP-1305 to CLEVER-1 and the binding of FP-1305 to CD14+ 
monocytes derived from healthy volunteers in vitro. No relevant toxicities in non-human primates 
were observed after 100 mg/kg dosing. Thus, there is over a 300-fold safety margin with the initial 
0.3 mg/kg dose in humans. However, CLEVER-1 on monocytes should already be occupied at the 
0.3 mg/kg dose level, based on the receptor occupancy and in vitro monocyte binding. 
Based on the FP-1305 pharmacokinetics in non-human primates, the 3-week dosing interval (Q3W) 
and the dose escalation scheme is considered appropriate.  
 
In addition to the Q3W dosing, Protocol Addendum introduces once in two weeks (Q2W) and once 
in week (Q1W) dosing schemes to be investigated in the Part II of the study. The scientific rationale 
for investigating more frequent dosing (Q2W and Q1W) is based on Part I PK and receptor occupancy 
of the CLEVER-1 (refer to Investigator’s Brochure). This Protocol Addendum may not be submitted 
to all countries participating in the study. The countries selected to participate to enrol patients under 
the Protocol Addendum will be formally notified, and the Protocol Addendum will be submitted with 
the main protocol for Competent Authority and Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) approval.  
 
During Part II, additional dose levels are tested to investigate tolerability and safety in a broader dose 
range, and to receive additional data about the PK, RO and preliminary efficacy. The selected doses 
are 30 mg/kg and 100 mg/kg;  an intermediate dose of 45 mg/kg may be included if deemed necessary 
based on accumulated data. The scientific rationale for investigating higher doses (30 mg/kg-100 
mg/kg) is based on the cumulative study data, e.g. PK (relatively fast T1/2) and RO (transient) of the 
CLEVER-1 at dose levels of 0.1 – 10 mg/kg (refer to Investigator’s Brochure), and accumulated 
safety data indicating good tolerability of the IMP and no DLT events registered.   
 
Inclusion of multiple distinct cancer types to the first cohort of ten subjects at a new dose level is 
possible, justified by allowing the investigation of the safety of the dose level in a wider population 
than just one particular cancer type in Part II. However, if deemed necessary, multiple cohorts with 
distinct cancer types may be selected to be explored at a dose level. This approach is justified by 
allowing the investigation of the safety and preliminary efficacy properly in Part II, as distinct cancer 
types may respond differently to the treatment. 
 
3 
OBJECTIVES  
3.1 Primary Objective for Part I 
• To determine the safety, tolerability and recommended dose of FP-1305 for Part II and III in 
subjects with advanced (inoperable or metastatic) hepatobiliary, pancreatic, colorectal or 
ovarian cancer or melanoma subjects without standard treatment options 
3.2 Secondary Objectives for Part I  
• To characterize the PK profile of a single dose of FP-1305 after the first dosing 

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• To characterize the PK profile of FP-1305 during repeated dosing 
• 
To assess the host immune response to FP-1305 (immunogenicity) 
• 
To assess the preliminary efficacy of FP-1305 monotherapy with the ORR and irORR in each 
cohort of different tumour type 
3.3 Exploratory Objectives for Part I 
• To determine CLEVER-1 positivity in each tumour type 
• To characterize the receptor occupancy of FP-1305 on circulating monocytes 
• To explore potential predictive markers associated with FP-1305 clinical activity  
• To explore potential markers associated with FP-1305 clinical activity during the treatment 
• To assess cytokine and chemokine concentrations (consisting of a panel of cytokines and 
chemokines) in the peripheral blood prior to FP-1305 treatment and during the FP-1305 
treatment up to Cycle 4 
• To measure the immune cell profile in circulation 
• To assess if treatment elicits a change in LDH, LDL and oxLDL, C-reactive protein (CRP), 
Cancer 
antigen 
(CA)-125 
(ovarian 
cancer 
(OC) 
subjects), 
CA19-9 
(PDAC, 
cholangiocarcinoma subjects), alpha fetoprotein (AFP) (HCC subjects), Carcinoembryonic 
antigen (CEA) (colorectal adenocarcinoma (CRC) subjects) levels or other relevant markers 
pre- and post-treatment  
• To investigate the duration of response in the subject group that has a complete or partial 
response 
• To assess progression free survival in subjects who receive at least 1 dose of FP-1305 
• To assess the overall survival in subjects who receive at least 1 dose of FP-1305 
3.4 Primary Objective for Part II 
• To determine the safety, tolerability and preliminary efficacy of FP-1305 monotherapy with 
the ORR, CBR and irORR in distinct expansion groups of subjects with advanced (inoperable 
or metastatic) solid tumours of the selected tumour types 
3.5 Secondary Objectives for Part II  
• To determine CLEVER-1 positivity in each tumour type 
• To characterize the PK profile of a single dose of FP-1305 after the first dosing for each 
cohort of different tumour type 
• To characterize the PK profile of FP-1305 during repeated dosing in each cohort of different 
tumour type 
• To assess the host immune response to FP-1305 (immunogenicity) in each tumour type 
• To explore potential predictive markers associated with FP-1305 clinical activity as 
determined by ORR, CBR and irORR 
• To investigate the duration of response in the subject group that has a complete or partial 
response, or SD 
3.6 Exploratory Objectives for Part II  
• To assess the amount of soluble CLEVER-1 (sCLEVER-1) in the patients prior to treatment 
• To characterize the receptor occupancy of FP-1305 on sCLEVER-1 and/or on circulating 
monocytes at different dose levels/dosing frequencies 
• To assess the CBR of trial subjects according to the number of CD8 positive cells within the 
tumour stroma 

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• To assess progression free survival in trial subjects who receive at least 1 dose of FP-1305 
• To assess the overall survival in trial subjects who receive at least 1 dose of FP-1305 
• To measure cytokine and chemokine concentration in peripheral blood 
• To measure the immune cell profile in circulation 
• To assess if treatment elicits a change in LDH, LDL and oxLDL, CRP, CA-125 (OC subjects), 
CA19-9 (PDAC, gallbladder cancer, cholangiocarcinoma, gastric adenocarcinoma subjects), 
AFP (HCC subjects), CEA (CRC, ER+ BC, gastric adenocarcinoma subjects), CA-15-3 (ER+ 
BC subjects) levels or other relevant markers pre- and post-treatment  
3.7 Primary Objective for Part III 
• To assess the ORR, CBR and irORR in distinct expansion groups of subjects with advanced 
solid tumours in CLEVER-1 positive subjects from selected tumour types at a selected dose 
3.8 Secondary Objectives for Part III 
• To characterize population PK of FP-1305 in each selected tumour type during repeated 
dosing 
• To assess the host immune response to FP-1305 (immunogenicity) 
• To assess the duration of response in distinct expansion groups of subjects with advanced 
solid tumours in CLEVER-1 positive subjects from selected tumour types at a selected dose 
• To assess progression free survival in subjects who receive at least 1 dose of FP-1305 
• To assess the overall survival in subjects who receive at least 1 dose of FP-1305 
• To determine the safety and tolerability of FP-1305 during repeated dosing in each tumour 
type at a selected dose 
3.9 Exploratory Objectives for Part III 
• To measure cytokine concentration in the peripheral blood 
• To measure immune cell profile in circulation 
• To assess if treatment elicits a change in LDH, and oxLDL, CRP, CA-125 (OC subjects), 
CA19-9 (PDAC, gallbladder cancer, cholangiocarcinoma, gastric adenocarcinoma subjects), 
AFP (HCC subjects), CEA (CRC, ER+ BC, gastric adenocarcinoma subjects), CA-15-3 (ER+ 
BC subjects) levels or other relevant markers pre- and post-treatment  
3.10 Outcome Measures 
Part I 
Primary outcome measure  
• Tolerable dose(s) will be determined by the TITE-CRM based on the occurrence/non-
occurrence of dose limiting toxicities in the trial subjects according to definitions in Section 
4.1. 
Secondary outcome measures 
• The PK profile of a single dose (during Cycle 1) and repeated doses (during Cycles 1-5) of 
FP-1305 will be determined by repeated measurements of the drug concentration in the 
circulation. Peak concentration (Cmax), trough concentration (Cmin), AUC, clearance, 
volume of distribution, and terminal half-life (t1/2) for each dose level will be determined. 
• Immunogenicity will be evaluated by assessing anti-drug antibodies in the circulation 
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• The ORR to the treatment will be determined by tumour imaging according to RECIST 1.1. 
The CBR is the proportion of subjects that have a complete response, partial response, or 
stable disease. The irORR will also be calculated. 
Exploratory outcome measures 
• CLEVER-1 on circulating monocytes will be determined by flow cytometry. The proportion 
of circulating CD14+ monocytes binding labelled FP-1305 prior to treatment and their mean 
fluorescence intensity (MFI) will be used to define CLEVER-1 positivity. CLEVER-1 in 
tumour samples (if available) prior to treatment will be identified with immunohistochemistry 
and reported as positive cells / mm2 of sample. The MFI of CLEVER-1 positive cells will be 
correlated to the number of CLEVER-1 positive cells in the tumour sample if the number is 
available.    
• The proportion of circulating monocytes binding labelled FP-1305 and another CLEVER-1 
binding antibody prior to and during the treatment at selected time points and their MFI will 
be reported.  
• Potential predictive genetic, cellular and other markers will be associated with FP-1305 
clinical activity as determined by ORR and irORR. This includes but is not limited to the 
correlation of response and immune cell profile, cytokine/chemokine profile and the 
proportion of CLEVER-1-positive monocytes, CD4, CD8, their ratio and regulatory T-cells 
in the circulation and in tumour specimens prior to treatment and in circulation during the 
first cycle of treatment. 
• The proportion of lymphocyte subsets (CD4, CD8, their ratio, NK-cells, B-cells and 
regulatory T-cells, and macrophage HLA expression and myeloid derived suppressor cell 
populations in circulation will be analysed at given time points with flow cytometry and 
plotted against the scheduled sampling time. The level of circulating cytokines and 
chemokines (including but not necessarily limited to IFN, IL-1, IL-2, IL-4, IL-6, 
IL-8/CXCL8, IL-10, IL-12p70, IL-13 and TNF alpha, IP-10/CXCL10, Eotaxin/CCL11, 
MCP-1/CCL2, MIP-1/CCL3, MIP-1/CCL4) will be analysed by multiplex assays prior to 
and during the treatment. Aggregated data (mean and median) from each dose level will be 
presented using descriptive statistics. 
• LDH, LDL and oxLDL, CRP, CA-125 (OC subjects), CA19-9 (PDAC,  cholangiocarcinoma 
subjects), CEA (CRC subjects) and AFP (HCC subjects) levels prior to and during the 
treatment will be measured from blood. 
• The ORR to the treatment will be determined by tumour imaging according to RECIST 1.1. 
The CBR is the proportion of subjects that have a CR, PR, or SD. The irORR will also be 
calculated. Results from each tumour type will be reported separately. 
• The duration of response is measured from the time of initial response until documented 
tumour progression, death, or dropout. 
• Progression free survival as the time from subject allocation into the trial until documented 
disease progression according to RECIST 1.1 or death will be measured in the population that 
has been dosed at least once. 
• Overall survival is defined as the time from subject allocation into the trial until death from 
any cause and will be measured in the population that has been dosed at least once. Data will 
be censored on the last documented data that the subject has been alive. 
 

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Part II 
Primary outcome measures 
• Safety and tolerability will be defined by physical examination, adverse events and by safety 
laboratory tests. Adverse events are collected, graded and reported according to the NCI-
CTCAE version 5.0. MedDRA terminology will be used to classify, record, manage, and 
analyse the data. Tolerability of new dose(s) will be determined based on the occurrence/non-
occurrence of DLT during 28 days following the first dose of FP-1305 in subjects evaluable 
for DLT assessment in Part II. 
• The response (ORR, CBR, and irORR separately) to the treatment will be determined by 
tumour imaging according to RECIST 1.1 based on images obtained by Cycle 7. Results from 
each tumour type, dose level and dosing frequency will be reported separately.  
Secondary outcome measures 
• The PK profile of a single dose (during Cycle 1) and repeated doses (during Cycles 2-5) of 
FP-1305 will be determined by repeated measurements of the drug concentration in the 
circulation. Peak concentration (Cmax), trough concentration (Cmin), AUC, clearance, 
volume of distribution, and terminal half-life (t1/2) for each dose level will be determined. 
Results from each tumour type will be reported separately. 
• Immunogenicity will be evaluated by assessing anti-drug antibodies in the circulation 
periodically during treatment and follow-up. Results from each tumour type will be reported 
separately. 
• Potential genetic, cellular and other predictive markers will be associated with FP-1305 
clinical activity as determined by ORR, CBR and irORR. This includes but is not limited to 
the correlation of response and immune cell profile, cytokine/chemokine profile and the 
proportion of CLEVER-1-positive monocytes, CD4, CD8, their ratio and regulatory T-cells 
in the circulation and in tumour specimens prior to treatment and in circulation during the 
first cycle of treatment. 
• The duration of response is measured from the time of initial response until documented 
tumour progression, death, or dropout. 
• Safety and tolerability will be defined by physical examination, adverse events and by safety 
laboratory tests. Adverse events are graded and reported according to the NCI-CTCAE 
version 5.0. MedDRA terminology will be used to classify, record, manage, and analyse the 
data. 
Exploratory outcome measures 
• CLEVER-1 on circulating monocytes will be determined by flow cytometry. The proportion 
of circulating CD14+ monocytes binding labelled FP-1305 prior to treatment and their MFI 
will be used to define CLEVER-1 positivity. CLEVER-1 in tumour samples (if available) 
prior to treatment will be identified with immunohistochemistry and reported as positive cells 
/ mm2 of sample. The MFI of CLEVER-1 positive cells will be correlated to the number of 
CLEVER-1 positive cells in the tumour sample if the number is available.    
• The proportion of circulating monocytes binding labelled FP-1305 and another CLEVER-1 
binding antibody prior to and during the treatment at selected time points and their MFI will 
be reported.  
• sCLEVER-1 and its blockage will be determined by measuring the amount of sCLEVER-1 
with immunoassay prior to treatment and during the treatment.  
• CD8 positive cells within the tumour stroma prior to treatment will be identified with 
immunohistochemistry and reported as positive cells / mm2 of sample. The subjects will be 

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grouped according to response (CR/PR/SD/Progressive disease) and the mean number of 
CD8 positive cells according to each group will be reported. 
• Progression free survival as the time from subject allocation into the trial until documented 
disease progression according to RECIST 1.1 or death will be measured in the population that 
has been dosed at least once. 
• Overall survival is defined as the time from subject allocation into the trial until death from 
any cause and will be measured in the population that has been dosed at least once. Data will 
be censored on the last documented data that the subject has been alive.  
• The proportion of lymphocyte subsets (CD4, CD8, their ratio, NK-cells, B-cells and 
regulatory T-cells), and possibly macrophage HLA expression and myeloid derived 
suppressor cell populations in circulation will be analysed at given time points with flow 
cytometry and plotted against the scheduled sampling time. The level of circulating cytokines 
and chemokines (including but not necessarily limited to IFN, IL-1, IL-2, IL-4, IL-6, 
IL-8/CXCL8, IL-10, IL-12p70, IL-13 and TNF alpha, IP-10/CXCL10, Eotaxin/CCL11, 
MCP-1/CCL2, MIP-1 /CCL3, MIP-1/CCL4) will be analysed by multiplex assays prior to 
and during the treatment.  
• LDH, LDL, oxLDL, and CRP, as well as the following tumour specific markers CA-125 (OC 
subjects), CA19-9 (PDAC, gallbladder cancer, cholangiocarcinoma, gastric adenocarcinoma 
subjects), CEA (CRC, ER+ BC, gastric adenocarcinoma subjects), AFP (HCC subjects), CA-
15-3 (ER+ BC subjects) levels prior to and during the treatment will be measured from blood. 
Part III 
Primary outcome measure 
• The response (ORR CBR and irORR separately) to the treatment will be determined by 
tumour imaging according to RECIST 1.1 based on images obtained by Cycle 7. Results from 
each tumour type will be reported separately. 
Secondary outcome measures  
• The population PK of FP-1305 will be determined by measurements of the drug concentration 
in the circulation between Cycles 1 and 5. Results from each tumour type will be reported 
separately. 
• Immunogenicity will be evaluated by assessing anti-drug antibodies in the circulation 
periodically during treatment and follow-up. Results from each tumour type will be reported 
separately. 
• The duration of response is measured from the time of initial response until documented 
tumour progression, death, or dropout. 
• Progression free survival as the time from subject allocation into the trial until documented 
disease progression according to RECIST 1.1 or death will be measured in the population that 
has been dosed at least once. 
• Overall survival is defined as the time from subject allocation into the trial until death from 
any cause and will be measured in the population that has been dosed at least once. Data will 
be censored on the last documented data that the subject has been alive.  
• Safety and tolerability will be defined by physical examination, adverse events and by safety 
laboratory tests. Adverse events are graded and reported according to the NCI-CTCAE 
version 5.0. MedDRA terminology will be used to classify, record, manage, and analyse the 
data 

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Exploratory outcome measures 
• The proportion of lymphocyte subsets (CD4, CD8, their ratio, NK-cells, B-cells and 
regulatory T-cells), and macrophage HLA expression and myeloid derived suppressor cell 
populations in circulation will be analysed at given time points with flow cytometry and 
plotted against the scheduled sampling time. The level of circulating cytokines and 
chemokines (including but not necessarily limited to IFN, IL-1, IL-2, IL-4, IL-6, 
IL-8/CXCL8, IL-10, IL-12p70, IL-13 and TNF alpha, IP-10/CXCL10, Eotaxin/CCL11, 
MCP-1/CCL2, MIP-1 /CCL3, MIP-1/CCL4) will be analysed by multiplex assays prior to 
and during the treatment.  
• LDH, LDL, oxLDL, and CRP, as well as the following tumour specific markers CA-125 (OC 
subjects), CA19-9 (PDAC, gallbladder cancer, cholangiocarcinoma, gastric adenocarcinoma 
subjects), CEA (CRC, ER+ BC, gastric adenocarcinoma subjects), AFP (HCC subjects) and 
CA-15-3 (ER+ BC subjects) levels prior to and during the treatment will be measured from 
blood. 
4 
TRIAL DESIGN  
This is a prospective, three-part (see Figure 1) open label, Phase I/II dose-finding and separate cohorts 
expansion trial to determine the safety, tolerability and efficacy of CLEVER-1 antibody FP-1305 in 
subjects with cutaneous melanoma, pancreatic ductal adenocarcinoma, ovarian cancer, colorectal 
adenocarcinoma, hepatocellular carcinoma, gallbladder cancer, cholangiocarcinoma, uveal 
melanoma, gastric (including GE junction) adenocarcinoma, ER+ breast cancer and anaplastic 
thyroid cancer. The enrolment period for Part I lasted for 13 months. It is estimated that the enrolment 
period for both Part II and III would be 24 months for either part. For each subject, the trial will 
consist of a screening period (maximum 28 days), treatment phase with FP-1305 (one year with 
potential to continue longer), and a post-treatment period for safety assessment (maximum 4 weeks). 
Survival data will be collected beyond the subject’s active participation in the trial. The collection of 
the survival data of a subject is limited to 2 years from the first IMP dose (at 1 year and 2 years after 
the first IMP dose). The maximal total duration of the trial is estimated to be 6 years. In case it would 
be beneficial for a study subject to continue the treatment beyond one year (as judged by an 
investigator), the treatment can be continued within this protocol and the survival data will be 
collected for 1 year after the last IMP dose (see 8.7.1).  
 
Part I of the trial will involve the identification of tolerable doses amongst four predefined doses. 
This will be based on the occurrence of DLTs with an acceptable (target) DLT rate of 20%. It is 
estimated that in total 30 subjects in 2-4 countries will be accrued from all disease groups to be 
investigated. The highest dose that can be tolerated based on the target (maximum tolerated dose) 
will first be determined using an efficient, adaptive dose-finding design, a modified time-to-event 
continual reassessment method (TITE-CRM), which allows for more accurate determination of the 
highest tolerated dose and shorter trial duration than conventional dose-finding designs. An early 
stopping rule will be incorporated to allow the trial to stop early or insert a lower dose if there is an 
unacceptable level of DLT at the lowest dose (level 0; 0.3 mg/kg). The lower reserve dose levels are 
0.1 mg/kg and 0.05 mg/kg as shown in Table 4. The de-escalation reserve dose levels will be utilised 
if there is strong evidence to suggest that the MTD is lower than 0.3 mg/kg and may be utilised also 
if more data on safety, PK and/or PD markers is required for dose selection for Part II. The 20 mg/kg 
dose may be utilized based on MTD or receptor occupancy and other PD markers. 
 
The decision on the number and timing of the doses via intravenous infusion was guided by 
nonclinical studies. The initial FP-1305 dose level (Dose Level 0; Table 4) is 0.3 mg/kg every 

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minimum of three weeks, the Data Monitoring Committee (DMC) evaluates whether reserve doses 
are required before the dose for Part II can be selected. If deemed necessary, reserve dose(s) will be 
utilised. In addition, three additional subjects per dose level may be enrolled to any tested dose level 
to gather more data. If subjects are allocated to two or more dose levels in Part I, randomisation to 
the selected doses will be utilized.  
 
The decision of using more dose levels will be made by the DMC on the basis of the data collected 
from the subjects. It is estimated that approximately 30 evaluable subjects in total in Part I will be 
enrolled. At the end of Part I, the DMC utilises the receptor occupancy, changes in immune function, 
PK, PD and/or ORR data to determine the dose or doses for further investigation in Part II. Further 
decisions about Part II dose levels can be made based on cumulative data collected throughout the 
study. 
 
In addition, the DMC may also recommend to include additional subjects on certain dose levels to 
ensure sufficient data is available for optimal dose selection for the Part II. 
 
Subjects with HCC may potentially exhibit decreased antibody (FP-1305) clearance, due to a 
possibility that the liver endothelium’s lysosomal compartment is diseased. Based on investigators 
best decision, and consultation of Medical Monitor, the first subject enrolled with HCC during Part 
I or in Part II may be administered with a dose one level lower than the highest tested dose or the 
phase II recommended dose. In Part II the first subject with HCC and underlying liver cirrhosis may 
be administered one level lower than the recommended dose level for the first dose. The 
recommended dose should be administered from the second dose (Cycle 2) forward if no toxicity 
appeared. After this, additional subjects with HCC that are enrolled should be dosed at the 
recommended dose level, if no toxicity has appeared for the first subject with HCC during the first 
cycle of treatment (3 weeks) with the lower dose level. 
  
Part II of the trial will involve expansion groups of subjects by tumour type. The following tumour 
types will be selected for cohort expansion after the data of the first part of the trial has been reviewed: 
advanced hepatocellular carcinoma, cholangiocarcinoma and gallbladder cancer, pancreatic ductal 
adenocarcinoma, ovarian cancer, colorectal adenocarcinoma, cutaneous melanoma, uveal melanoma, 
gastric adenocarcinoma (including GE junction), ER+ breast cancer and anaplastic thyroid cancer. 
Each cohort will contain 10 subjects in Part II (10 at each dose level with random allocation within 
the same dosing schema Q3W, Q2W or Q1W. In addition, new dose level(s) 30 mg/kg and possibly 
also 45 and 100 mg/kg that include more than one tumour type will be tested for tolerability and 
safety. The data from both Part I and Part II will be used to define CLEVER-1 positivity in each 
tumour type. In Part III, subjects will be enrolled in tumour types that have demonstrated preliminary 
anti-tumour activity based on the CBR. Up to a total sample size of 700 subjects in all parts will be 
enrolled in approximately 20-30 sites in 5-8 countries. Subjects in Part III are stratified by disease 
type as in Part II and may be stratified by CLEVER-1 positivity. In Part II and Part III, cohorts for a 
particular tumour type may be opened sequentially or not opened at all i.e., if there is a strong signal 
for efficacy in cutaneous melanoma, that cohort may be opened first. Each cohort of subjects with a 
certain tumour type will be analysed for efficacy after 10 subjects have been treated with the dose(s) 
selected for Part II. The decision of continuing the cohort for Part III will be based on the results 
obtained from this analysis supported by the statistical rule to continue the cohort. Cohorts with best 
efficacy signal at any dose level may be advanced to Part III. However, it may not be meaningful to 
advance all Part II cohorts at any dose level with a minimal and clinically not meaningful signal of 
efficacy into Part III. 
 

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Figure 1A displays the trial pathway including dose escalation and expansion phases. Figure 1B 
displays how the initial design of the TITE-CRM will work in the absence of any DLT in Part I. Once 
a DLT is observed, subsequent dose decisions will be made with the usage of the TITE-CRM. This 
will take into account all accumulated DLT information–both partial (<9 weeks) and complete 
(9 weeks). 
 
In this study protocol, the study drug is administered Q3W intervals. Based on the analysis of the 
PK, receptor occupancy and PD during the Q3W administration, it was deemed necessary to study 
more frequent dosing. With Protocol Addendum, Q2W and Q1W dosing intervals are implemented 
into Part II and possibly also to Part III if deemed appropriate. The purpose is to investigate the 
tolerability, safety, PD and preliminary efficacy of more frequent dosings infusion (Q2W and Q1W). 
Scientific justification and details of conducting of Q2W and Q1W dosings have been presented in 
the FP-1305 Investigator’s Brochure and Protocol Addendum, respectively 
4.1 Dose Limiting Toxicity  
DLT evaluable subjects include:  
• Part I: All subjects  
• Part II: The first three (or six if there is one DLT in the first three) subjects in the following  
cohorts 
o Q3W cohorts at dose levels that have not previously been tested in Part I 
o Q2W cohorts at each new dose level for the Q2W schema 
o Q1W cohorts at each new dose level for the Q1W schema   
• Part III: DLT not applicable 
 
DLT assessment period in Part II is shorter than in Part I, justified by the safety and tolerability data 
collected during the trial and enabling prompt dose escalation as a part of the  3+3 design of Part II.     
• Part I: 63 days (9 weeks) following the first dose of FP-1305 
• Part II: 28 days (4 weeks) following the first dose of FP-1305 
 
A DLT is defined as a drug related AE  Grade 3 according to NCI-CTCAE version 5.0 occurring 
during the DLT assessment period and related to FP-1305. The following are exceptions to the rule: 
• Grade 3 infusion reactions that resolve within 8 hours from the onset of the reaction are not 
defined as a DLT 
• Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate antiemetic and other 
supportive care are not defined as a DLT 
• For thrombocytopenia, haemorrhage is required to qualify grade 3 toxicity as DLT; Grade 4 
thrombocytopenia is DLT regardless of haemorrhage  
• For neutropenia DLT is as follows,  
o Any neutropenic fever 
o Grade 3 neutropenia persisting > 5 days or Grade 4 neutropenia  
• For toxicity judged to be consistent with an acute infusion-related reaction or cytokine release 
syndrome, DLT will be defined as follows (Sehn 2012):  
o Grade 4 drug-related AE or  
o Grade 3 drug-related AE that cannot be resolved by infusion rate reduction or interruption, 
or supportive care.  
• An AE which, in the opinion of the Investigator, is attributed to a study subject’s underlying 
disease will not be considered a DLT.  

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In addition, the following are considered DLTs (occurring during the DLT assessment period and 
related to FP-1305): 
• Grade ≥2 ALT or AST increase accompanied with bilirubin elevation >2x ULN if baseline 
value was normal; >2 x baseline if baseline value was abnormal   
• Dose delay of the 2nd cycle due to drug-related toxicity of >14 days 
A serious adverse event (SAE) may be considered a DLT according to this section. The severity of 
the AEs will be codified according to the NCI-CTCAE version 5.0. If the subject has an event that 
meets the DLT criteria otherwise, but it is not considered to be drug related, then the reason needs to 
be clearly documented. The sites are requested to report the DLTs via electronic case report form 
(eCRF) immediately within 24 h an event meets the DLT criteria. In case the eCRF cannot be updated 
with the DLT (e.g. technical issue), sites are to email to Medical Monitor immediately within 24 h 
stating a suspected DLT has occurred. The SAE reporting according to Section 11.4 is required in 
any case to all events that meet the SAE criteria. 
4.2 Stopping and Dose Escalation Rule(s)  
4.2.1 DLT at the Initial Dose after the First Infusion (Part I) 
If the first subject experiences DLT at initial dose after first infusion, the trial will be halted, and the 
TITE-CRM will be updated accordingly. Reserve dose levels (-1 or -2) will be used based on the new 
information. 
4.2.2 DLTs during the DLT Assessment Period at the First Dose Level (Part I) 
A repeated dosing will be initiated at the first dose with the first subject if no DLTs have been 
observed during the observation period. The second subject in this cohort can be dosed with the same 
dose after three weeks of the initial dose (Figure 1) if the first subject did not experience DLT after 
the first infusion. 
 
If one subject has DLT at the initial dose level during the DLT assessment period, recruitment to any 
cohort will be halted and the TITE-CRM will be updated with the new information and used to guide 
the decisions. Subjects in any cohort may continue receiving additional repeated doses if they have 
not experienced DLT while on repeated dosing and their accumulated time within the DLT 
assessment period will be taken into account by the TITE-CRM model. 
4.2.3 Predefined Dose Escalation Rules for TITE-CRM (Part I) 
Dose escalation is allowed to the next level after two subjects are treated with FP-1305 without DLT 
even if the full DLT assessment period is not completed. Dose escalation to further dose levels is not 
allowed until at least two subjects have been observed for the full DLT period. For example, dose 
escalation can be performed from dose level 0 to dose level 1 even if the full DLT period is not 
completed. However, dose escalation to level 2 is not allowed until two subjects have had the full 9-
week DLT assessment either on level 0 or on level 1 and two subjects on level 1 has been dosed and 
followed up for a minimum of three weeks after the first dose. Similarly, the dose cannot be escalated 
from the third (Level 2) to the fourth level (Level 3) before the full DLT period of nine weeks is 
reached altogether from two previous dose levels (A. two subjects at the second (Level 1) dose level 
or B. two subjects at the third (Level 2) dose level or C. one subject at the second (Level 1) and one 
at the third (Level 2) dose level). New subjects will be enrolled to the particular dose level (Level 0, 
1, or 2) to replace subjects that have not completed the full DLT of nine weeks at the first (Level 0), 
second (Level 1) or the third (Level 2) dose level. The enrolment of replacing subjects can be 
conducted without delays. If there is DLT in any subject at any level during the DLT assessment 

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period, no new subject will be dosed at any dose until the TITE-CRM has been updated. Dosing of 
the already dosed subjects may continue receiving additional repeated doses if they have not 
experienced DLT while on repeated dosing and TITE-CRM allows that. Recommendation from the 
TITE-CRM will be used to guide decisions on the dosing level of the next subject during dose 
escalation and to guide the MTD decision after completion of Part I. The third and the fourth subject 
at the highest dose level can be allocated into the trial when two subjects at this level have been 
observed for the full 9-week DLT period. 
4.2.4 DLTs during the DLT Assessment Period after the Dose has been Escalated (Part I) 
If the dose levels below the dose that demonstrate unacceptable DLT do not demonstrate DLT, the 
repeated dosing will be conducted at those dose levels. If an acceptable DLT level has been observed 
at the repeating dose levels, these levels are right doses for expansion cohorts from the DLT 
perspective. Immune function, PK and PD data will be used to determine if the dose is suitable for 
Part II. If none of the tested dose levels (including reserve dose levels -1 and -2 shown in Table 4) 
demonstrate acceptable safety, the trial will be halted until the Sponsor has amended the protocol or 
decided to stop the trial. 
4.2.5 Delayed Toxicities That Occur after the Full DLT Assessment Period (For Part I 
subjects and Part II subjects that are in cohorts investigating new exposure levels)   
Rules for enrolment halt are applied to all Part I subjects and in Part II to the first six study subjects 
in a cohort that is  exploring a new level of exposure for the first time (i.e. Q2W and Q1W frequencies, 
and Q3W doses that  have not been tested in Part I). This is to ensure the safety of the study subjects 
during dose exploration in case of potential AEs that occur after the defined DLT period, which could 
provide a signal to limit the dose. If two DLT evaluable subjects within a particular dose or dosing 
frequency i.e., in a specific dose escalation cohort have delayed AEs after the DLT assessment period, 
that would otherwise have been determined as DLTs during the period, enrolment to that cohort and 
all cohorts that have higher exposure is halted until the DMC has evaluated the cases and made the 
decision how to proceed. The rule applies only to a specific dose/cohort i.e., one delayed DLT in  a 
cohort testing a certain level of exposure (dose & frequency) is not summed up with another delayed 
DLT from another dosing scheme. For example, one delayed DLT in 1 mg/kg Q1W and one delayed 
DLT in 10 mg/kg Q2W do not sum up to two delayed DLTs and contribute to this rule. In case two 
delayed DLTs occur in the first 6 subjects (DLT evaluable patients) at a particular dose e.g., at 10 
mg/kg Q2W, the DMC meeting will be scheduled to evaluate has a maximum tolerated dose been 
achieved. Delayed DLT occurring beyond the first 6 subjects will be monitored, followed up and 
presented to the DMC during scheduled meetings. The enrolment halt described above refers to a 
temporary hold not to dose any new subjects at the dose level that is under DMC evaluation, or any 
higher dose level. Subjects already receiving the dose, or higher dose, that have not experienced a 
DLT may continue receiving the drug until DMC resolution or further guidance. Trial activities at 
lower doses are not affected and can continue as normal. As this enrolment halt is envisaged by the 
protocol, therefore no substantial amendment informing about the halt will be submitted in these 
situations. Further actions will be taken according to the DMC recommendation as necessary. 
4.3 Dose Escalation to 30, 45 and 100 mg/kg Doses (Q3W, Part II) 
Dose level 30 mg/kg and possibly 45 mg/kg and 100 mg/kg are included to investigate further 
tolerability, safety, receptor occupancy and efficacy in Part II of the study. 3 + 3 design (with 
additional safety margins/sentinel dosing between first three subjects) will be utilized to investigate 
these additional dose levels, and if tolerated, dose levels will be expanded to 10 subjects. To ensure 
safety at high doses the 30 mg/kg Q3W dose level will finish enrolment of all 10 subjects before the 

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dose can be escalated to 45 mg/kg Q3W. Similarly, the 45 mg/kg Q3W dose level will finish 
enrolment of all 10 subjects before the dose can be escalated to 100 mg/kg Q3W. These cohorts of 
ten patients exploring higher doses may consist of subjects with different cancer types of interest. 
Schedule of assessments in these dose levels is the same as Part II schedule (Table 2). In addition to 
standard Part II assessments the first three patients undergoing 45mg/kg and 100mg/kg will undergo 
24h monitoring in hospital after the first dose. 
4.3.1 Enrolment of Subjects (30 - 100 mg/kg Q3W) and Dose Escalation (Part II) 
To ensure the safety of the study subjects, the first three subjects at and above the 30 mg/kg dose 
level will be enrolled stepwise after each has cleared their 28 day DLT observation period.  The 
detailed rules for enrolling the first three subjects on a dose level are described below (4.3.2). If any 
of the first three subjects dosed at the 30 mg/kg dose level has a DMC verified DLT (see Section 4.1 
for DLT definition) within 28 days from the first IMP administration, an additional three subjects 
will be enrolled on the 30 mg/kg dose level. If a maximum of one of the six subjects experiences a 
DLT at 30 mg/kg dose level, up to ten subjects will be included in the 30 mg/kg dose level after 
which the trial can proceed to the next dose level. If at least two of the first three subjects or two of 
the six subjects experience a DMC verified DLT at the 30 mg/kg dose level, then the MTD has  been 
reached,  enrolment to the 30 mg/kg dose level will be placed on hold and dose escalation is 
terminated. The MTD is defined as the highest dose level, in which the first six subjects were treated 
with a maximum of one subject experiencing a DLT. Subjects on treatment who have not experienced 
DLT at that dose level may continue receiving the treatment and the DMC will  decide regarding the 
treatment continuation and possible dose level de-escalation for these particular and DLT 
experienced subjects. The doses 45 and 100 mg/kg Q3W have the same 3 + 3 dosing rules as 
described for 30 mg/kg, and if at least two of the first three subjects or two of the six subjects has a 
DLT, then the MTD has been reached, enrolment to the dose level will be placed on hold, and dose 
escalation is terminated. If MTD is achieved at the dose level of 30mg/kg Q3W, a reserve de-
escalation dose level of 20 mg/kg Q3W may be investigated with the same 3+3 design approach. 
4.3.2 Dosing Rules (30 - 100 mg/kg) (Q3W, Part II) 
Sentinel dosing will be applied for 30-100mg/kg dosing. The second subject on a particular dose 
level can receive the first dose only after the first subject has been followed up for 28 days (additional 
precaution compared to traditional 3+3 model) after the first dose, and has not demonstrated any 
DLT. The third subject may receive the first dose after the second subject has been followed up for 
28 days after the first dose and and neither of the subjects have demonstrated any DLTs. DLT 
evaluable subject will have at least one dose of IMP and have at least 28 days of follow-up after IMP 
infusion. If these criteria are not met, the subject will be replaced. Once three evaluable subjects have 
received at least one dose and have been followed up at for 28 days with no DLTs, all remaining 
subjects on the dose level may be enrolled without any hold. If any of the first three subjects cannot 
be followed for the full 28-day DLT observation period for reasons other than DLT, the subject may 
be replaced in order to obtain the required tolerability information of 28 days from the first IMP 
infusion, before the remaining subjects on the dose level may be enrolled. The replaced subject will, 
however, count towards thecohort of 10 subjects. The same rules will apply for the other dose levels. 
5 
ELIGIBILITY  
Subjects registered onto this trial must fulfil all the common inclusion and exclusion criteria and 
fulfil their disease specific inclusion and exclusion criteria. 

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5.1 Inclusion and Exclusion Criteria 
5.1.1 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in the clinical 
trial: 
1) Written Informed Consent 
2) Aged ≥ 18 years male or female 
3) Tumour sample should be collected during screening period. If a recent tumour biopsy obtained 
within six months before the date of consent is available (or older, as agreed on a case by case 
basis with the sponsor), that may be used. At the discretion of the sponsor, the tumour sample 
may be optional for certain subjects in Part III 
4) Life expectancy > 12 weeks 
5) Histologically confirmed advanced (inoperable or metastatic) malignancies in which (according 
to the view of the investigator) no curative, effective or suitable treatment options exist.   
o Hepatocellular carcinoma  
o Gallbladder cancer or intra- or extrahepatic cholangiocarcinoma 
o Colorectal adenocarcinoma  
o Serous poorly differentiated (Grade 3) ovarian adenocarcinoma or undifferentiated 
ovarian cancer  
o Pancreatic ductal adenocarcinoma  
o Immunotherapy (IO) resistant cutaneous melanoma (progression during programmed cell 
death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) or CTLA-4 antibody 
therapy)  
o Uveal melanoma in Parts II and III 
o Gastric adenocarcinoma (including adenocarcinoma of the distal esophagus / GE 
junction) in Parts II and III 
o ER+ breast cancer in Parts II and III 
o Anaplastic thyroid cancer in Parts II and III 
6) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
7) Measurable disease in Parts II and III 
8) Adequate bone marrow, liver and kidney function defined as 
 
Blood white blood cell  ≥ lower limit of normal  
 
Blood neutrophil count ≥ 1x109/L 
 
Blood platelet count ≥ 100x109/L, for HCC ≥ 50x109/L  
 
Blood haemoglobin ≥ 9.0 g/dL 
 
Creatinine clearance > 40 mL/min calculated by Cockcroft-Gault formula 
 
AST ≤ 3 X ULN (≤ 5 x ULN when HCC or hepatic metastases are present) 
 
ALT ≤ 3 X ULN (≤ 5 x ULN when HCC or hepatic metastases present) 
 
Bilirubin ≤ 1.5 X ULN 
 
Albumin ≥ 3.0 g/dL 
The most recent measurements taken during the screening period must be within the required 
limits for the patient to be considered eligible (i.e. criteria met once during the screening period 
are not sufficient if there are more recent measurements available that are not within the 
required limits.  It is however acceptable to repeat measurements if the initial measurements or 
subsequent measurements taken during the screening period are not within the required limits; 
the patient is eligible providing that the newest measurements are within the required limits). 
However, once a subject is out of the screening period, and has had eligibility confirmed and 

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been enrolled, the pre-dose laboratory assessments are not subjected to inclusion criteria limits, 
but only for investigators assessment of subject safety. 
9) Women of child-bearing potential must have a negative pregnancy test in serum prior to trial 
entry 
10) Women of child-bearing potential and men who have partners of child-bearing potential must be 
willing to practise highly effective contraception for the duration of the trial and for three months 
after the completion of treatment 
5.1.2 Exclusion Criteria 
1) Less than 21 days since the last dose of intravenous anticancer chemotherapy or less than five 
half-lives from a small molecule targeted therapy or oral anticancer chemotherapy before the first 
IMP administration  
2) Any immunotherapy within preceding 6 weeks from the first IMP administration 
3) Investigational therapy or major surgery within 4 weeks before the first IMP administration 
4) Active clinically serious infection > Grade 2 NCI-CTCAE version 5.0 (   Appendix 5 - Common 
Toxicity Criteria Gradings) within preceding 2 weeks before the first IMP administration 
5) Brain metastases 
6) Subject has not recovered from the previous therapies to Grade  1 severity as classified by the 
NCI-CTCAE version 5.0 (except Grade  2 alopecia, neuropathy or thyroid disorders) 
7) Pregnant or lactating women 
8) History of second malignancy except for non-melanotic skin cancer, cervical carcinoma in situ 
or superficial bladder cancer, or any other malignancy treated previously with curative intent and 
more than three years without relapse  
9) Evidence of severe or uncontrolled systemic diseases, congestive cardiac failure  New York Heart 
Association (NYHA) class ≥ 2 (   Appendix 7 - NYHA classification), Myocardial Infarction 
(MI) within 6 months or laboratory finding that in the view of the investigator makes it 
undesirable for the subject to participate in the trial  
10) Any medical condition that the Investigator considers significant to compromise the safety of the 
subject or that impairs the interpretation of IMP toxicity assessment 
11) Confirmed human immunodeficiency virus infection  
12) Symptomatic cytomegalovirus infection 
13) Subjects with active auto-immune disorder (except type I diabetes, celiac disease, 
hypothyroidism requiring only hormone replacement, vitiligo, psoriasis, or alopecia) 
14) The subject requires systemic corticosteroid or other immunosuppressive treatment 
15) Subjects with organ transplants 
16) Subjects in dialysis  
17) Use of Live (attenuated) vaccines for 30 days prior to the start of study treatment, during 
treatment, and until last visit 
18) Subject is unwilling or unable to comply with treatment and trial instructions 
19) Subjects with known hypersensitivity to the IMP or any of the pharmaceutical ingredients 
5.1.3 Specific Additional Exclusion Criteria for HCC 
1) Any ablative therapy (Radio Frequency Ablation or Percutaneous Ethanol Injection) for HCC 
(this should not exclude subjects if target lesion(s) have not been treated and occurred > 6 weeks 
prior trial entry)  
2) Hepatic encephalopathy  
3) Ascites refractory to diuretic therapy 
4) Child-Pugh score  7 

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6 
SCREENING AND CONSENT  
6.1 Informed Consent 
It is the responsibility of the Investigator to obtain a written informed consent from each subject prior 
to performing any trial related procedure. A Patient Information and Consent Document is provided 
to facilitate this process. Investigators must ensure that they adequately explain the aim, trial 
treatment, anticipated benefits and potential hazards of taking part in the trial to the subject. The 
Investigator should also stress that the subject is completely free to refuse to take part or withdraw 
from the trial at any time. The subject should be given ample time (e.g. 24 hours) to read the Patient 
Information and Consent Document and to discuss their participation with others outside of the site 
research team. The subject must be given an opportunity to ask questions which should be answered 
to their satisfaction. The right of the subject to refuse to participate in the trial without giving a reason 
must be respected. 
 
If the subject expresses an interest in participating in the trial, they should be asked to sign and date 
the latest version of the Patient Information and Consent Document. The Investigator must then sign 
and date the form. A copy of the Patient Information and Consent Document should be given to the 
subject, a copy should be filed in the hospital notes, and/or in the Investigator Site File (ISF). Once 
the subject is entered into the trial, the subject’s trial number should be entered on the Information 
and Consent Document maintained in the ISF.  
 
Details of the informed consent discussions should be recorded in the subject’s medical notes; this 
should include the date consent was given and the short name of the trial or protocol code. 
Throughout the trial, the subject should have the opportunity to ask questions about the trial and any 
new information that may be relevant to the subjects’ continued participation should be shared with 
them in a timely manner. On occasion, it may be necessary to re-consent the subject, in which case 
the process above should be followed and the subject’s right to withdraw from the trial respected. 
 
Details of all subjects consented onto the trial should be recorded on the Patient Screening and 
Enrolment Log, and with the subject’s prior consent their General Practitioner should also be 
informed that they are taking part in the trial according to the local requirements. A General 
Practitioner Letter is provided electronically for this purpose. 
6.2 Screening  
During the screening period, a subject’s eligibility for the trial is determined by evaluation of the 
exclusion and inclusion criteria. A signed informed consent (see Section 6.1) must be present before 
starting any screening procedures.  
 
Subjects will undergo a medical history review as part of the screening assessment.  
 
The parameters listed below are collected and recorded into the eCRF during the screening period. 
Local laboratory parameters are analysed according to standard practice e.g. plasma/serum (the same 
method should be used throughout the study). All screening procedures must occur within 28 days 
before the IMP is administered.  
• Informed consent 
• Demographic data (age, race, and sex) 
• Inclusion/Exclusion criteria 

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• Medical history (current diseases including their treatment history and other relevant medical 
history) 
• Weight 
• Concomitant medications, vaccinations and interventional procedures (including herbal 
products) taken within 28 days prior to the signed consent or during the screening period 
• ECOG performance status 
• A targeted physical examination covering the major body systems (e.g. general appearance, 
head [ear, nose and throat], cardiovascular, eyes, respiratory, abdomen, urogenital, 
musculoskeletal, neurological, lymph nodes and skin) 
• Vital signs (blood pressure, heart rate, body temperature and respiratory rate) 
• Electrocardiography (ECG) 
• Cytomegalovirus (CMV) infection status (If a subject has no symptoms, the blood test is not 
needed. However, if an investigator is unsure, then the test should be performed.) 
• Blood sampling for 
o Human immunodeficiency virus (HIV) serology 
o Hepatitis B and C virus (immunochemical or nucleic acid test) 
o Complete blood count (CBC: white blood cells, neutrophils, lymphocytes, 
thrombocytes, haemoglobin) 
o Comprehensive metabolic panel (CMP): (glucose, calcium, sodium, potassium, 
chloride, creatinine, ALT, alkaline phosphatase (ALP), AST, creatine kinase (CK), total 
bilirubin, albumin) 
o Endocrine panel: cortisol, lipase, pancreas-specific amylase, thyroid stimulating 
hormone, parathyroid hormone (PTH), free thyroxine (T4), free triiodothyronine (T3), 
troponin 
• Serum pregnancy test (women of child-bearing potential only) 
• Tumour biopsy must be less than 6 months old from the date of consent or taken during the 
screening period. An archival block, if available, can be used to complement the obtained biopsy. 
See the Laboratory Manual for sample procurement and handling procedures. 
• Brain imaging (computerized tomography (CT)). Routine diagnostic image (CT/ magnetic 
resonance imaging (MRI)) can be used if available. The brain scan within six weeks prior to the 
1st dose is acceptable. 
• AE assessment. Photographs to document visible AEs should be considered.  
 
A subject may be re-screened if he/she fails screening but later fulfils the eligibility criteria. If the 28 
day screening period has been exceeded, the subject must be re-consented to the trial and a new 
subject's trial number is created for the subject.  
 
7 
TRIAL ENTRY 
In Part I, the screening of a subject can only be started when there is an open slot in a cohort, and it 
has been communicated in writing to which site the available slot has been allocated. 
Communications regarding the opening of upcoming cohorts and the allocation of slots to sites will 
be sent to all active investigators/sites to ensure transparency. The trial should not be discussed with 
a potential subject until a slot has been confirmed for that particular subject. Once a slot or slots has 
been secured by a particular subject or to the site, the signed informed consent will be obtained (see 
Section 6.1) and a subject number will be given to the subject(s). The eligibility of each subject will 
be verified by the Medical Monitor. After the eligibility check and Medical Monitor’s enrolment 

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confirmation, any change in the subject eligibility criteria needs to be reported in the eCRF and the 
suitability of the subject to enter the study treatment must be carefully evaluated and confirmed by 
the investigator prior to Cycle 1 dosing. Other hospitals may also refer subjects to the trial, but the 
screening must occur at the investigative site. During Part I of the trial, confirmation that the TITE-
CRM is up to date is required; if DLT information about the assigned subjects is missing from the 
TITE-CRM, new subjects cannot be dosed until all missing safety data is entered into the system. 
Once confirmed that the TITE-CRM is up to date, the initial dose of the subject may be determined. 
If the randomisation is applied during Part I the dose will be provided by system that handles the 
randomisation. Once assigned, the subject numbers for any screening failures, non-treated, non-
evaluable, or discontinued subjects will not be re-used. After Part I has been completed, data has 
been analysed and the dose has been selected to Part II, TITE-CRM will not be used any more. 
However, all subjects entering the trial can be administered the IMP only after the Medical Monitor 
has verified the subject’s eligibility. 
 
8 
TREATMENT DETAILS 
8.1 Investigational Medicinal Product 
The IMP is FP-1305 (bexmarilimab). Further details can be found in the latest version of the 
Pharmacy Manual and Investigator’s Brochure. 
8.1.1 Dosage Form and Composition 
The IMP is clear to opalescent solution intended for intravenous application. Each 10 mL glass vial 
contains 250 mg of FP-1305 in histidine buffer containing stabilising excipients. The concentration 
of FP-1305 in the formulation is 25 mg/mL. Each vial is packed into a carton box. Further details of 
packaging and labelling can be found in the latest version of the Pharmacy Manual. 
8.1.2 Instructions for Storage 
The IMP must be stored in a secure area according to local regulations at 2-8 °C. Further details can 
be found in the latest version of the Pharmacy Manual. 
8.1.3 Instructions for Handling the Investigational Medicinal Product 
The Investigator or other designated trial personnel will maintain a log of all IMP received, 
dispensed, destroyed, and/or returned. Drug supplies will be inventoried and accounted throughout 
the trial. Detailed instructions for the handling of the IMP are given in the Pharmacy Manual. 
8.2 Trial Treatment 
Once the subject has been confirmed to be eligible for the trial by the Simbec-Orion Medical Monitor, 
the treatment period can start. The Investigator or other designated trial personnel will administer 
FP‐1305 I.V. (peripheral or central venous line) on D1 of each cycle. The infusion rate, duration of 
infusion, total volume infused, and any interruption in administration will be recorded as source data 
and will be transferred on the appropriate eCRF page.  
8.2.1 First Infusion 
• The first FP‐1305 infusion should be administered I.V. at an initial rate of 50 mL/h for the first 
30 minutes.  
• In the absence of a hypersensitivity reaction, the infusion rate may be increased gradually as per 
the instructions given in the Pharmacy Manual. Infusion rate will be limited based on the dosing 
level and volume of saline utilised.  

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• If a hypersensitivity reaction develops, the infusion should be temporarily stopped for up to 3 
hours. Upon resolution of the subject’s symptoms, the infusion can resume at one-half the rate 
previously associated with hypersensitivity. 
• If the subject’s symptoms do not resolve within 3 hours, the administration of FP‐1305 should be 
discontinued for this cycle. 
• If a second infusion reaction develops despite a reduced infusion rate, the administration of FP‐
1305 should be discontinued for this cycle. 
All subjects in Part I dose-escalation cohorts must be closely monitored for safety for the first 24 
hours after the first IMP infusion at the trial site hospital. Subjects in the dose-expansion cohorts in 
Part I and in Part II  must be monitored for a minimum of 6 hours after the first IMP administration. 
However, first three subjects testing new doses or dosing frequencies in Part II should be closely 
monitored for safety for the first 24 h after the first IMP infusion at the trial site hospital. In Part III, 
all subjects must be monitored for minimum of 4 hours after the first IMP infusion. Any subject who 
is deemed at risk of tumour lysis syndrome or any other safety concern by the judgement of the 
treating investigator may be hospitalized for a longer period. 
8.2.2  Subsequent Infusions 
• Subsequent infusions may be administered at the highest rate that was well tolerated in the 
preceding cycle, for the first 30 minutes 
• In the absence of a hypersensitivity reaction, the infusion rate can be doubled every 30 minutes, 
to the maximum infusion rate allowed for the dosing level as per instructions given in the 
Pharmacy Manual  
• If a hypersensitivity reaction develops, subjects will be pre-medicated prior to each treatment 
cycle with: 
• Acetaminophen 1000 mg per os 12 h and 30 min prior to the planned infusion time 
• Antihistamine (Diphenhydramine 50 mg equivalent) per os 12 h and 30 min prior to the planned 
infusion time 
• Glucocorticoid (Hydrocortisone 100 mg equivalent) I.V. 30 min prior to the planned infusion 
time 
• Variance based on institutional practice is acceptable once discussed with the Sponsor. In 
addition, the guidelines under First Infusion (Section 8.2) should be followed for the first 
subsequent infusion. 
After the second infusion (Cycle 2), the Part I subjects and in Part II the first three subjects testing 
new doses or dosing frequencies must be monitored for safety at the clinical facility for a minimum 
of 6 hours. Other subjects in Part II and subjects in Part III must be monitored for safety for a 
minimum of 2 hours after the second infusion. 
After Cycle 2 the IMP may be administered in the outpatient setting and the subjects must be 
monitored for safety for a minimum of 2 hours prior to discharge until the end of the treatment. In 
any part of the trial, post-dose observation will be longer if deemed appropriate.  
8.3 Treatment Schedule 
The treatment period is divided into cycles. Each cycle in Q3W dosing lasts three weeks (21 days). 
The IMP will be administered on Day 1 of each cycle (Q3W) for up to one year with the possibility 
to extend the treatment beyond one year according to routine clinical practice (see Section 8.7.1). If 
the IMP infusion cannot be administered as scheduled the IMP infusion must be administered as soon 
as possible. The IMP administration day is counted as Day 1 of the cycle (for delays see Section 8.7). 
 

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Protocol Addendum implements more frequent dosings (Q2W and Q1W). Protocol Addendum 
requires all relevant national approvals in the countries concerned prior to implementation.  
8.4 Assessments during Treatment Period  
The assessments during the trial are described in the following chapters and also in Table 1 (Part I), 
Table 2 (Part II) and Table 3 (Part III). Before each IMP administration, a pre-dose physical 
evaluation is conducted. AEs will be collected during the whole treatment period starting after the 
signing of the Informed Consent.  
8.4.1 Parameters Collected during Pre-Dose Evaluation in Part I  
In Part I the pre-dose assessment is done in every cycle for the 1 -year treatment period if not 
otherwise stated. Pre-Dose assessments maybe taken also up to three days before the Day 1 in each 
cycle. 
• Height (only in Cycle 1) 
• Weight 
• Vital signs (blood pressure, heart rate, body temperature and respiratory rate).  
• A physical examination covering the major body systems (general appearance, head [ear, nose 
and throat], cardiovascular, eyes, respiratory, abdomen, urogenital, musculoskeletal, 
neurological, lymph nodes and skin) 
• ECG (in Cycles 1, 2, 4, 6, and every second cycle thereafter; the ECG must be performed also 
always if clinically indicated) 
• ECOG performance status 
• Urine dipstick test 
• PK sampling (only in Cycles 1, 2, 3, 4 and 5) 
• Anti-drug antibody (ADA) sampling (on Cycles 1, 2, 4, 6, and every second cycle thereafter, or 
if clinically indicated) 
• Blood samples  
o CBC 
o CMP 
o Endocrine panel (cortisol, lipase, amylase (pancreas specific) in Cycles 1, 4 and 8; 
thyroid stimulating hormone, PTH, free thyroxine (T4), free triiodothyronine (T3) on 
each cycle) 
o Hepatitis B and C virus (quantitative assessment in Cycles 1, 2, 4 and 6 if tested initially 
positive) 
o LDH 
o LDL 
o AFP (HCC subjects) 
o CRP 
o CA-125 (OC subjects) 
o CA19-9 (PDAC, gallbladder cancer, cholangiocarcinoma subjects) 
o CEA (CRC subjects) 
• Research blood samples 
o Receptor occupancy and monocytes (RO assay) (only in Cycles 1, 2, 3, and 4) 
o OxLDL (only in Cycles 1, 2, 3, and 4) 
o Flow cytometry (TBNK cells and CD127 FOXP3 Assay) (only in Cycles 1, 2, 3, and 4) 
o Cytokine and chemokine panel (only in Cycles 1, 2, 3, and 4) 
o Blood sample for PBMC isolation (only in Cycles 1 and 4) 
• Imaging  

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o MRI/CT (The same imaging method (CT, MRI) per subject must be used throughout 
the trial. The first scan (C1) must be less than 6 weeks old prior the first dose (routine 
diagnostic image can be used). Cycles 1, 4, 7, 10, and every third cycle thereafter, up to 
one year. The images have to be taken as close as possible ( 10 days) to the initial 
schedule even if there are missed IMP doses. If the treatment extends beyond one year, 
18- (± 1 month) and 24- (± 1 month) month images from the first dose are mandatory to 
take if not routinely taken at these timepoints. 
• AE assessment; photographs to document visible AEs should be considered  
• Concomitant medications and interventional procedures (including herbal products) 
8.4.2 Parameters Collected during Pre-Dose Evaluation in Part II 
In Part II the pre-dose assessment is done in every cycle for the 1 -year treatment period if not 
otherwise stated. Pre-Dose assessments maybe taken also up to three days before the Day 1 in each 
cycle. 
• Height (only in Cycle 1) 
• Weight 
• Vital signs (blood pressure, heart rate, body temperature and respiratory rate).  
• A targeted physical examination covering the major body systems (e.g. general appearance, head 
[ear, nose and throat], cardiovascular, eyes, respiratory, abdomen, urogenital, musculoskeletal, 
neurological, lymph nodes and skin) 
• ECG (in Cycles 1, 2, 4, 6, and every second cycle thereafter; the ECG must be performed also 
always if clinically indicated) 
• ECOG performance status 
• Urine dipstick test 
• PK sampling (only in Cycles 1, 2, 3 and 4) 
• ADA sampling (on Cycles 1, 2, 4, 6, and every second cycle thereafter, or if clinically indicated) 
• Blood samples  
o CBC 
o CMP 
o Endocrine panel (cortisol, lipase, pancreas-specific amylase , thyroid stimulating 
hormone, PTH, free thyroxine (T4), free triiodothyronine (T3), troponin) 
o Hepatitis B and C virus (quantitative assessment in Cycles 1, 2, 4 and 6 if tested initially 
positive) 
o LDH 
o LDL Cholesterol 
o AFP (HCC subjects) 
o CRP 
o CA-125 (OC subjects) 
o CA19-9 (PDAC, gallbladder cancer, cholangiocarcinoma, gastric adenocarcinoma 
subjects) 
o CEA (CRC, ER+ BC, gastric adenocarcinoma subjects) 
o CA-15-3 (ER+ BC subjects) 
• Research blood samples 
o At selected sites and cohorts only: Blood sample for RO and PBMC isolation (only on 
Cycles 1 and 2) 
o Blood sample for PBMC isolation when ‘Blood sample for RO and PBMC’ is not 
collected (only in Cycles 1 and 2) 
o sCLEVER-1 RO sample (Cycles 1, 2 and 3) 

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o OxLDL (only in Cycles 1, 2, 3, and 4) 
o Flow cytometry (TBNK cells, CD127 FOXP3 Assay and PD-1 T-Helper Assay) (only 
in Cycles 1, 2, 3 and 4) 
o Cytokine and chemokine panel (only in Cycles 1, 2, 3 and 4) 
o Circulating tumour deoxyribonucleic acid (ctDNA) requires genetic consent (only in 
Cycles 1, 2 and 3) 
• Serum or urine pregnancy test (women of child-bearing potential only) 
• Imaging  
o MRI/CT (The same imaging method (CT, MRI) per subject must be used throughout 
the trial. The first scan (C1) must be less than 6 weeks old prior the first dose (routine 
diagnostic image can be used). Cycles 1, 4, 7, 10, and every third cycle thereafter, up to 
one year. The images have to be taken as close as possible ( 10 days) to the initial 
schedule even if there are missed IMP doses. If the treatment extends beyond one year, 
18- (± 1 month) and 24- (± 1 month) month images from the first dose are mandatory to 
take if not routinely taken at these timepoints. 
• AE assessment; photographs to document visible AEs should be considered  
• Concomitant medications and interventional procedures (including herbal products) 
8.4.3 Parameters Collected during Pre-Dose Evaluation in Part III 
In Part III the pre-dose assessment is done in every cycle for the 1 -year treatment period if not 
otherwise stated. Pre-Dose assessments maybe taken also up to three days before the Day 1 in each 
cycle. See also Table 3 and the Laboratory Manual. 
• Height (only in Cycle 1) 
• Weight 
• Vital signs (blood pressure, heart rate, body temperature and respiratory rate).  
• A targeted physical examination covering the major body systems (e.g. general appearance, head 
[ear, nose and throat], cardiovascular, eyes, respiratory, abdomen, urogenital, musculoskeletal, 
neurological, lymph nodes and skin) 
• ECG (only in Cycle 5; the ECG must be performed also always if clinically indicated) 
• ECOG performance status 
• PK sampling for population PK 
o For subjects with odd trial numbers (group A) at Cycle 1 
o For subjects with even trial numbers (group B) at Cycle 4 
• Subjects with odd trial numbers (group A) only in Cycle 1.  
• Subjects with even trial numbers (group B) only in Cycle 4. 
• ADA sampling is done only in Cycles 1, 2, 5, 8 and every third cycle thereafter, or if clinically 
indicated. 
• Blood samples  
o CBC 
o CMP 
o Endocrine panel (cortisol, lipase, pancreas-specific amylase , thyroid stimulating 
hormone, PTH, free thyroxine (T4), free triiodothyronine (T3), troponin) 
o Hepatitis B and C virus (quantitative assessment in Cycles 1, 2, 4 and 6 if tested initially 
positive) 
o LDH 
o LDL Cholesterol 
o AFP (HCC subjects) 

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o CRP 
o CA-125 (OC subjects) 
o CA19-9 (PDAC, gallbladder cancer, cholangiocarcinoma, gastric adenocarcinoma 
subjects) 
o CEA (CRC, ER+ BC, gastric adenocarcinoma subjects) 
o CA-15-3 (ER+ BC subjects) 
• Research blood samples 
o OxLDL (only in Cycles 1, 2, 3 and 4) 
o Flow cytometry (TBNK cells, CD127 FOXP3 Assay and PD-1 T-Helper Assay) (only 
in Cycles 1 and 2) 
o Cytokine and chemokine panel (only in Cycles 1 and 2) 
o Blood sample for PBMC isolation (only in Cycles 1 and 4) 
o ctDNA requires genetic consent (only in Cycles 1, 2 and 3)  
• Serum or urine pregnancy test (women of child-bearing potential only) 
• Tumour Imaging  
o MRI/CT (The same imaging method (CT, MRI) per subject must be used throughout 
the trial. The first scan (C1) must be less than 6 weeks old prior the first dose (routine 
diagnostic image can be used). Cycles 1, 4, 7, 10, and every third cycle thereafter, up to 
one year. The images have to be taken as close as possible ( 10 days) to the initial 
schedule even if there are missed IMP doses. If the treatment extends beyond one year, 
18- (± 1 month) and 24- (± 1 month) month images from the first dose are mandatory to 
take if not routinely taken at these timepoints 
• AE assessment; photographs to document visible Aes should be considered  
• Concomitant medications and interventional procedures (including herbal products) 
8.4.4 Samples Collected and Parameters Analysed during and after IMP Administration in 
Part I 
During or after the IMP infusion, parameters for safety and blood samples are collected as follows 
(see also Table 1 and the Laboratory Manual): 
• 
Vital signs (blood pressure, heart rate, body temperature and respiratory rate)  
o Cycles 1-3: During infusion, 3 additional readings e.g., every 20 minutes for 1 hour. 
However, the third additional measurement should be performed after the IMP infusion 
has completed; therefore, if the infusion lasts more than 1 hour, then the third additional 
measurement may be more than 20 minutes after the second additional measurement. 
For the subsequent infusions vital signs are to be measured only before and after IMP 
infusion. 
o in Cycle 1 at 5 hours (+/- 2 hours) after IMP infusion completion 
• 
PK sampling (only in Cycles 1, 2 and 4) 
o 0 h after all IMP has been administered, 1 h (+/- 5 mins), 5 h (+/- 30 mins), D2 (+/- 4 
h), D3 (+/- 4 h) D4 (+/- 4 h), D5 (+/- 8 h), and D8 (+/- 24 h) after IMP administration 
• Tumour biopsy (only in Cycle 2) 
o Should be obtained within 10 days after the IMP administration. See the Laboratory 
Manual for sample procurement and handling procedures. 
• 
ECG (only in Cycles 1 and 4) 
o 0 h after the infusion and PK sampling 
• Blood samples (only in Cycle 1) 
o CBC on D5 (+/- 4 h) 
o CMP on D5 (+/- 4 h) 

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• Research blood samples 
o Receptor occupancy and monocytes (RO assay) (only in Cycles 1 and 2) D2 (+/- 4 h), 
D8 (+/- 24 h) and D15 (+/- 24 h) 
o Flow cytometry (TBNK cells and CD127 FOXP3 Assay) (only in Cycles 1 and 2) D2 
(+/- 4 h), D8 (+/- 24 h) and D15 (+/- 24 h) 
o Cytokine and chemokine panel (only in Cycles 1 and 2) D8 (+/-24 h) and D15 (+/- 24 
h) 
o  Blood sample for PBMC isolation (only in Cycle 1) D5 (+/- 4 h) 
• AE assessment. NOTE: AE assessments should be conducted each time the subject is visiting 
the hospital. Photographs to document visible Aes should be considered. 
8.4.5 Samples Collected and Parameters Analysed during and after IMP Administration in 
Part II 
During or after the IMP infusion, parameters for safety and blood samples are collected as follows 
(see also Table 2 and the Laboratory Manual): 
• Vital signs (blood pressure, heart rate, body temperature and respiratory rate)  
o Cycles 1-3: 20 minutes after the start of the infusion, 40 minutes after the start of the 
infusion and at 1 h after the start of the infusion or at the end of the infusion (immediately 
after flushing the line), whichever occurs later.For the subsequent infusions vital signs 
are to be measured only before and after IMP infusion. 
o in Cycle 1 at 5 hours (+/- 2 hours) after IMP infusion completion  
• PK sampling (only in Cycles 1 and 2) 
o 0 h after all IMP has been administered, 1 h (+/- 5 mins), 5 h (+/- 30 mins), D2 (+/- 4 
h), D3 (+/- 4 h) D4 (+/- 4 h), D5 (+/- 8 h), and D8 (+/- 24 h)  
• Tumour biopsy (only in Cycle 2 and if any new lesions) 
o Cycle 2 biopsy should be obtained within 10 days after the IMP administration. See the 
Laboratory Manual for sample procurement and handling procedures. 
o Biopsy from new lesions is recommended if assessed feasible by the investigator 
considering the location of the lesions and condition of the subject. 
• ECG (only in Cycles 1 and 4) 
o 0 h after the infusion and PK sampling 
• Blood samples  
o CBC on D5 (+/- 8 h) (only in Cycle 1) 
o CMP on D5 (+/- 8 h) (only in Cycle 1) 
o CMP on D8 (+/- 24h) (only in Cycles 2 and 3) 
• Research blood samples 
o At selected sites and cohorts only: Blood sample for RO and PBMC isolation (only in 
Cycle 1) D2 (+/- 4 h), D8 (+/- 24 h) and D15 (+/- 24 h) 
o Blood sample for PBMC isolation when ‘Blood sample for RO and PBMC’ is not 
collected (only in Cycle 1) D2 (+/- 4 h), D8 (+/- 24 h) and D15 (+/- 24 h) 
o sCLEVER-1 RO sample (only in Cycles 1 and 2) D2 (+/- 4 h), D8 (+/- 24 h) and D15 
(+/- 24 h)  
o Flow cytometry (TBNK cells, CD127 FOXP3 Assay and PD-1 T-Helper Assay) (only 
on Cycles 1 and 2) D2 (+/- 4 h), D8 (+/- 24 h) and D15 (+/- 24 h) 
o Cytokine and chemokine panel (only on Cycles 1 and 2) D8 (+/-24 h) and D15 (+/- 24 
h) 
• AE assessment. NOTE: AE assessments should be conducted each time the subject is visiting 
the hospital. Photographs to document visible AEs should be considered. 

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8.4.6 Samples Collected and Parameters Analysed during and after IMP Administration in 
Part III 
• During or after the IMP infusion, parameters and blood samples are collected as follows (see 
also Table 3): 
• 
Vital signs (blood pressure, heart rate, body temperature and respiratory rate)  
o Cycles 1-3: 20 minutes after the start of the infusion, 40 minutes after the start of the 
infusion and at 1 h after the start of the infusion or at the end of the infusion (immediately 
after flushing the line), whichever occurs later.For the subsequent infusions vital signs 
are to be measured only before and after IMP infusion. 
• PK sampling for population PK 
o For subjects with odd trial numbers (group A) PK sampling will be at Cycle 1 Day 2 
(+/- 2 h), at Cycle 1 Day 5 (+/- 24 h), at Cycle 2 Day 1 four hours (+/- 2 h) after all IMP 
has been administered, and at Cycle 4 D3 (+/- 24 h)  
o 
For subjects with even trial numbers (group B) PK sampling will be at Cycle 1 Day 1 
four hours (+/-2 h) after all IMP has been administred, at Cycle 1 Day 3 (+/- 24 h), at 
Cycle 2 Day 2 (+/- 2 h), and at Cycle 4 Day 5 (+/- 24 h)  
• Tumour biopsy (only in Cycle 2 and if any new lesions) 
o Cycle 2 biopsy should be obtained within 10 days after the IMP administration. See the 
Laboratory Manual for sample procurement and handling procedures. 
o Biopsy from new lesions is recommended if assessed feasible by the investigator 
considering the location of the lesions and condition of the subject. 
• Blood samples  
o CMP on D5 (+/- 8 h) (only in Cycle 1) 
o CMP on D8 (+/- 24h) (only in Cycles 2 and 3) 
• Research blood samples (Cycle 1 only) 
o Flow cytometry (TBNK cells, CD127 FOXP3 Assay and PD-1 T-Helper Assay) on D8 
(+/- 24 h) and D15 (+/- 24 h) 
o Cytokine and chemokine panel on D8 (+/- 24 h) and D15 (+/- 24 h) 
o Blood sample for PBMC isolation on D8 (+/- 24 h) 
• AE assessment. NOTE: AE assessments should be conducted each time the subject is visiting 
the hospital. Photographs to document visible AEs should be considered. 
8.4.7 Tumour Assessment  
Tumour assessment is done at the treating site according to RECIST 1.1 (Eisenhauer et al. 2009; 
Appendix 1 - RECIST Criteria) and Immune-related response criteria (Appendix 2 - Immune-related 
Response Criteria). MRI/CT (chest, abdomen and pelvis) slice thickness must be 5 mm or less. In 
case of suspicion of pseudoprogression and subjective stable disease (no clinical deterioration) a 
second tumour evaluation should be carried out at least 4 weeks after the first response evaluation 
even if the subject has been deemed to discontinue from the study. For evaluable subjects, the 
response will be reported in each cohort as the numbers of subjects who have CR, PR, SD, or 
progressive disease as well as irCR, irPR, irSD, or ir-progressive disease.  
8.5    Assessments during the Post-Treatment Period 
The post-treatment period starts once the subject has completed the treatment period or stopped the 
treatment permanently (see Section 10.4). Once it has been decided that a subject will permanently 
stop treatment, a Follow-up Visit should be performed 4 weeks (+/- 1 week) after their last dose of 
IMP.  If the last IMP dose was >5 weeks at the time of the decision, the Follow-up Visit should be 
performed as soon as possible. If the subject discontinued the treatment period due to AEs, the subject 

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must be followed up until the AEs have resolved or no change is the AE status is observed over the 
period.  
• Vital signs (blood pressure, heart rate, body temperature and respiratory rate).  
• A targeted physical examination covering the major body systems (e.g. general appearance, head 
[ear, nose and throat], cardiovascular, eyes, respiratory, abdomen, urogenital, musculoskeletal, 
neurological, lymph nodes and skin) 
• ECG (in Part I and II) 
• ECOG performance status 
• ADA sampling  
• Blood samples  
o CBC 
o CMP 
o LDH 
o LDL Cholesterol 
o AFP (HCC subjects) 
o CRP 
o CA-125 (OC subjects) 
o CA19-9 (PDAC, gallbladder cancer, cholangiocarcinoma, gastric adenocarcinoma 
subjects) 
o CEA (CRC, ER+ BC, gastric adenocarcinoma subjects) 
o CA-15-3 (ER+ BC subjects) 
• Serum pregnancy test (women of child-bearing potential only) 
• AE assessment. Photographs to document visible AEs should be considered.  
• Concomitant medications and interventional procedures (including herbal products) 
8.6 Sample Collection 
8.6.1 Tumour Paraffin Blocks  
Tumour biopsy samples will be collected according to the schedule shown in Table 1, Table 2 or 
Table 3, and following the instructions in the Central Laboratory Services Manual. As indicated, 
tumour biopsy may be collected also if any new lesions are present. Biopsy from new lesions is 
recommended only if assessed feasible by the investigator considering the location of the lesions and 
condition of the subject. Tumour paraffin blocks or cut slides thereof with a notification that the 
sample contains tumour cells will be sent to the central laboratory for CLEVER-1 assessment by e.g. 
immunohistochemistry. Other biomarkers and gene expression may be analysed and genetic analysis 
may be conducted with appropriate methods. 
The blocks collected prior to consent will be returned to the study site on request and latest after the 
trial has ended. The genetic analyses are optional for all subjects entering the trial and will involve a 
separate subject consent procedure. Consenting to genetic sampling is not a prerequisite to 
participating in the main trial. Tumour samples collected due other reasons (e.g. unscheduled biopsy 
or another informative sample for clinical reasons) may be analysed for scientific purpose when 
available.  
8.6.2 Blood Samples 
Blood samples will be collected at defined time points (see Table 1, Table 2 and Table 3 as well as 
the Central Laboratory Services Manual) and for additional research and development related to FP-
1305, cancer treatment and disease pathology. PBMCs will be isolated from the blood samples. These 
cells may also be used for the extraction of ribonucleic acid (RNA)/DNA i.e, genetic analyses may 

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be conducted from these samples. The genetic analyses are optional for all subjects entering the trial 
and will involve a separate subject consent procedure. The subjects that give genetic consent will 
also have blood collected for ctDNA samples and subsequent analysis. Consenting to genetic 
sampling is not a prerequisite to participating in the main trial. RNA/DNA samples will be destroyed 
at latest 10 years after completion of this trial. If the subject withdraws the consent, the sample will 
be destroyed without undue delay. The samples will be sent to the central laboratory and will be 
analysed in Europe and the US. Specific details about blood sample collection, preparation and 
storages are provided in the Laboratory Manual. In addition, blood samples will be collected for local 
analyses e.g. for safety monitoring purposes. Auto-antibodies against liver can be considered in 
immune-related AEs.  
8.7 Dose Modifications, Infusion Delays, Missed Doses and Special Cases  
IMP infusion will be prepared based on the subject’s predose weight at each cycle (if not available, 
the most recent weight should be used). No visit specific dose adjustments are allowed for FP-1305, 
except for weight change adjustments. However, the maximum amount of FP-1305 in one IMP 
infusion is 10 g and cannot be exceeded irrespective of the weight-based dose. Guidance will be 
provided in the Pharmacy Manual to ensure calculated doses do not exceed this limit. If the IMP 
cannot be administered at the scheduled visit for any reason, the IMP must be administered as soon 
as possible, below here are instructions for Q3W schema. Instructions for Q2W and Q1W schemas 
are in Protocol Addendum.  
• If the delay is 1 to 7 days, the procedures based on the current visit should be performed, and 
the subsequent visit will follow 21 days from the date of the infusion that occurred.  
• If the delay is more than 7 days, the dose is considered missed, and the next per protocol visit 
should be brought forward and performed as soon as possible. Note, that the tumour images 
are still to be taken at every scheduled time point  
o (e.g. if there is an eight day delay for Cycle 4 Day 1, Cycle 4 IMP is considered a 
missed dose. The infusion given eight days after the original schedule in this case is 
Cycle 5 IMP dose and the related Cycle 5 procedures should be performed. In 
addition, tumour imaging of Cycle 4 should be done.) The subsequent visit will follow 
21 days from the date of the infusion that just occurred.  
o Cycle 2 is an exception: every effort should be made to ensure that Cycle 2 is not 
delayed. In unavoidable delay, Cycle 2 IMP administration and the related Cycle 2 
procedures should be performed as soon as possible.  
 
Subjects that miss two consecutive scheduled doses (more than 49 days from the previous dose) will 
discontinue the treatment and enter the follow-up period unless specific consultation and agreement 
occurs between the investigator, the Medical Monitor and the Sponsor justify continued trial therapy. 
These decisions must be carefully documented. 
 
Additionally, intra-subject dose change may occur to the recommended Part II/Part III dose after it 
has been determined. This decision must be carefully documented.  
8.7.1 Treatment beyond One Year 
In case that, as judged by the investigator, it would be beneficial to continue the treatment beyond 
one year, the protocol allows the treatment according to normal clinical practice, in order to allow 
the treatment continuation of the study subjects, provided that the clinical development and 
manufacturing of FP-1305 continues and it is not available via other routes. If the treatment is 
continued beyond one year, the following procedures/assessments will be done: 

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• FP-1305 infusion every three weeks  
• Collection of weight, vital signs, physical examinations, ECOG, CBC, and CMP pre-dose for 
every infusion during the second year of treatment 
• All available clinical routine images will be utilized. 18- (± 1 month) and 24- (± 1 month) 
month images from the first dose are mandatory to take if not routinely taken at these 
timepoints 
• Collection of treatment related adverse events 
• Collection of survival data (limited to 1 year from the last IMP dose if the treatment has been 
continued beyond one year)  
8.7.2 Treatment Hold in Complete Response 
If a study subject meets the irRECIST criteria for a confirmed complete response, the treatment can 
be placed on hold. The subject should complete follow-up visit but continues in the trial without 
treatment (FP-1305). Surveillance is conducted using routine good medical care and the results with 
AE evaluation will be reported to the Sponsor. The treatment with FP-1305 can be continued if the 
disease progresses (Trial duration and Treatment extension beyond one year definitions shall apply) 
and the trial is still ongoing. The decision of re-initiation must be agreed between the investigator, 
the Medical Monitor and the  Sponsor and carefully documented to justify the decision. A written 
informed consent for treatment re-initiation will be obtained before the treatment can be started. The 
subject will enter to the study using the same subject number as before discontinuation. Relevant 
medical data received post study completion/ discontinuation will be collected in the eCRF once the 
subject has given the written consent for the re-initiation. The following pre-dose assessments will 
be performed prior to the re-initiation: 
• CT/MRI scan 
• ADA 
• Vital signs, physical examinations, ECOG, CBC, and CMP 
Once the treatment has been reinitiated, ‘Treatment Beyond One Year’ procedures will apply to each 
cycle. Tumour imaging will be performed at 2, 4, 6, 9, 12, 18 and 24 months timepoints after re-
initiation of the treatment and ADA will be collected at the end of the treatment and if clinically 
indicated. The subject will receive the dose used in the study at the time of the re-initiation, even if 
the subject was previously on another dose. Once it has been decided that a subject will permanently 
stop treatment, a Follow-up Visit should be performed 4 weeks (+/- 1 week) after their last dose of 
IMP. If the last IMP dose was >5 weeks at the time of the decision, the Follow-up Visit should be 
performed as soon as possible. 
8.8 Possible Toxicities 
There is no experience about using FP-1305 in humans. Thus, the possible toxicities are based on the 
mode of action (MoA) of the drug and other drugs in this class as well as on a nonclinical toxicity 
study conducted in monkeys. The following toxicities can be possible: 
 
Infusion reactions: These typically develop within 30 minutes to two hours after the initiation of the 
drug infusion, although symptoms (headache, pruritus, throat irritation, flushing, rash, urticaria, 
hypertension, and pyrexia) may be delayed for up to 24 hours. Most reactions occur after the first or 
the second exposure to the agent, but between 10 and 30 percent occur during the subsequent 
treatments. In general, the likelihood of an infusion reaction declines with each subsequent course of 
therapy. Proper management should take place in case these types of reactions occur (see 
Section 8.9.1 for general advice for treatment). 
 

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Cytokine release syndrome/Cytokine storm: The cytokine-release syndrome resembles type 1 
hypersensitivity reaction and may be clinically indistinguishable. The symptoms are generally mild 
to moderate in severity and usually occur within the first couple of hours after starting the infusion, 
predominantly with the first infusion. Based on the antibody properties (no complement binding 
activation, no Fc-gamma receptor binding) and the lack of increased cytokine release in cytokine 
release assay in vitro, rapid onset cytokine storm is not expected (see Section 8.2.1 and Section 8.9.1 
for general advice for treatment). 
 
Immune-related adverse events: These are dependent on the MoA properties of the used drugs. 
Whenever agents that potentiate the immune system activation are used, there is a possibility that the 
immune system also attacks the healthy tissues. The onset of these events depends on the agents used, 
but the most widely experience is obtained from the immune checkpoint inhibitors (CTLA-4 or PD-
[L] 1 targeting agents). The symptoms typically develop relatively late (weeks to months) during the 
course of the agent administration. Usually they are mild to moderate in intensity. With PD-1 therapy, 
the incidence of severe (Grade 3 to 4) events is low. They most commonly involve the skin, the GI 
tract, and the endocrine organs. 
 
Based on the MoA properties, FP-1305 is predicted to induce immune cell activation. This activation 
might lead to immune-related adverse reactions. Thus, special attention should be given to fever, 
diarrhoea, colitis, transaminase or total bilirubin elevations, signs and symptoms of nephritis, renal 
dysfunction, endocrinopathies, hyperglycaemia, changes in the thyroid function, or rash. Study 
subjects may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel 
habits, and hypotension, or nonspecific symptoms which may resemble symptoms caused by e.g. 
brain metastasis or the underlying disease. However, since FP-1305 is suspected to only induce direct 
tumour effects, the likelihood of irAEs is expected to be low. 
 
Tumour lysis syndrome: Tumour lysis syndrome is an oncologic emergency that develops most often 
in patients with non-Hodgkin’s lymphoma or acute leukaemia, its frequency is increasing among 
patients who have tumours that used to be only rarely associated with this complication. The onset 
may vary, but after Rituximab (EU)/Rituxan (US) therapy it occurs after 12-24 hours of the first 
infusion. It occurs when tumour cells release their contents into the bloodstream, either spontaneously 
or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalaemia, 
hyperphosphatemia, and hypocalcaemia. These electrolyte and metabolic disturbances can progress 
to clinical toxic effects, including renal insufficiency, cardiac arrhythmias, seizures, and death due to 
multiorgan failure. Hyperphosphatemia with calcium phosphate deposition and/or the precipitation 
of uric acid in the renal tubules can also cause acute kidney injury. 
With the emergence of new effective and targeted anticancer drugs or new combinations of drugs, 
tumour lysis syndrome has also been observed in patients with cancers that were previously rarely 
associated with this complication. At least one case of tumour lysis syndrome has been observed with 
anti-CSF1R therapy. It is possible that also FP-1305 can cause tumour lysis syndrome because it can 
direct cytotoxic T-cells to kill tumour cells. FP-1305 may also impair macrophage phagocytosis 
function, a MoA that may predispose to tumour lysis syndrome if a massive anti-tumour effect is 
achieved. 
 
Increased fibrosis in response to liver injury: Fibrosis of the liver is an excessive accumulation of 
scar tissue that results from ongoing inflammation and liver cell death that occurs in most types of 
chronic liver diseases. Nodules, abnormal spherical areas of cells, form as dying liver cells are 
replaced by regenerating cells. This regeneration of cells causes the liver to become hard. Fibrosis 

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refers to the accumulation of tough, fibrous scar tissue in the liver. Preclinical models have 
demonstrated that CLEVER-1 expressing endothelial cells and macrophages may remove products 
of oxidative stress, thereby preventing low-level continuous injury and scarring. Since FP-1305 most 
likely impairs this function it is possible that the risk of fibrosis of the liver may increase if a patient 
has a condition that induces liver injury. 
8.9 Management of Toxicities 
All AEs should be graded according to Section 11.3.1 and proper action taken based on the clinical 
findings and grading.  
 
In the following, when a limit for a laboratory parameter in plasma is indicated and the local practice 
is to have the test in serum, the equivalent value should be considered, and vice versa.   
 
FP-1305 should be withheld for any of the following adverse event at least possibly related to FP-
1305: 
1) 
Grade 2 pneumonitis (see Section 8.9.2.1) 
2) 
Grade 2 or 3 colitis (see Section 8.9.2.2) 
3) 
Grade 2 nephritis (see Section 8.9.2.3) 
4) 
Grade 2 liver enzyme elevations (see Section 8.9.2.4) 
5) 
Grade 2 or 3 endocrinopathy (see Section 8.9.2.5) 
6) 
Grade 2 fibrosis due to liver injury (see Section 8.9.4) 
7) 
Any other severe or Grade 3 treatment-related adverse reaction 
8) 
Prolonged (> 2 weeks) Grade 2 or intolerable Grade 2 toxicity 
 
FP-1305 must be permanently discontinued for any of the following adverse event at least possibly 
related to FP-1305: 
1) 
Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone 
replacement therapy and/or immunosupressants) 
2) 
Grade 3 or 4 infusion reaction (see Section 8.9.1) 
3) 
Grade 3 or 4 pneumonitis or Grade 2 recurring pneumonitis (see treatment in Section 8.9.2.1) 
4) 
Grade 4 colitis (see Section 8.9.2.2) 
5) 
Grade 3 or 4 nephritis (see Section 8.9.2.3) 
6) 
Grade 3 or 4 hepatitic failure (see Section 8.9.2.4) 
7) 
Grade 4 endocrinopathy (see Section 8.9.2.5) 
8) 
Grade 3 or 4 fibrosis due to liver injury (see Section 8.9.4) 
9) 
Inability to reduce the corticosteroid dose to 10 mg or less of prednisone or equivalent per day 
within 6 weeks from the initiation of the continuous corticosteroid 
10) Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone 
replacement therapy and/or immunosupressants) that do not recover to Grade 0-1 within 
6 weeks after the last dosing of FP-1305 and that are considered clinically significant 
11) Any haematological or non-haematological Grade 3 treatment-related adverse reaction that 
recurs 
8.9.1 Infusion Reactions 
In case of an infusion reaction, the following documentation should be recorded 
1) 
Pre-infusion assessment (i.e., the drugs administered, doses, number of previous infusions of 
the agent, and infusion rates) 
2) 
Initial symptoms and course of progression 

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3) 
Time when the infusion was initiated and time when the infusion reaction began  
4) 
Intervention, timing, and subject response 
5) 
Time of symptom resolution 
Infusion reactions are generally not considered to be DLT, but this judgement should be conducted 
after each case. Severe (Grade 3 or 4) reactions should be reported within 24 hours to the Sponsor. 
 
Grade 1 infusion reaction (Mild reaction; no infusion interruption or intervention necessary) 
Monitor the subject closely or treatment according to the local practise. Consider prophylactic 
medication (e.g., paracetamol a.k.a. acetaminophen and diphenhydramine) for next administration. 
 
Grade 2 infusion reaction (Moderate reaction leading to infusion interruption but responsive to 
symptomatic treatment): Interrupt the infusion but maintain vascular access with normal saline. 
Paracetamol (a.k.a. acetaminophen) and diphenhydramine (or other antihistamine according to local 
practises) usage is recommended or treatment according to the local practise. However, 
diphenhydramine (50 mg) and ranitidine (50 mg diluted in 5% dextrose to 20 mL) given together for 
anaphylaxis are superior to diphenhydramine given alone. Vital sign assessment should be 
periodically repeated until the subject is stable. Once the symptoms are totally resolved, the infusion 
may be restarted at maximum 50% of the previous infusion rate. If the symptoms do not recur during 
30 minutes of infusion of this slower rate, the infusion rate may be increased to the normal rate. If 
symptoms recur, the infusion must be stopped, and the amount infused should be reported. 
Prophylactic medication for the next administration is highly recommended and the infusion rate 
should be adjusted (see Section 8.2.1 and Section 8.2.2).  
 
Grade 3 or 4 infusion reaction (A prolonged reaction that does not rapidly respond to symptomatic 
treatment, with possible recurrence of symptoms following initial improvement, hospitalization 
indicated for the clinical sequelae, or life-threatening requiring pressor or ventilatory support): 
Interrupt the infusion but maintain a vascular access with normal saline. Epinephrine should be 
considered depending on the severity of the reaction. Corticosteroids may be given IV or orally; oral 
administration is sufficient in less severe anaphylactic events. Vital sign assessment should be 
periodically repeated until the subject is stable. The administration of FP-1305 is permanently 
discontinued. 
8.9.2 Immune Related Adverse Events 
The aetiology of symptoms that may suggest an irAEs should always be investigated in order to rule 
out symptoms due to infection or disease progression. Systemic use of corticosteroids is generally 
prohibited (see Section 10.2) because a decrease in immune cells in circulation is observed after 
initiation of corticosteroid treatment and it may counteract the effect of the IMP. Thus, it needs to be 
carefully evaluated, if the continuation in the study is beneficial for the subject. In such cases, 
investigator should consult the Sponsor and Medical Monitor for subject continuation. 
8.9.2.1 Immune-Mediated Pneumonitis 
Monitor subjects for signs and symptoms of pneumonitis. A CT should be performed to confirm 
diagnosis. Corticosteroids should be administered at a dose of 1 to 2 mg/kg/day prednisone 
equivalents for Grade 2 or greater pneumonitis. Upon improvement to Grade 1 or less, initiate 
corticosteroid taper and continue to taper over at least 1 month. Permanently discontinue FP-1305 
for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold FP-1305 until the 
resolution for moderate (Grade 2) pneumonitis. If Grade 2 pneumonitis recurs FP-1305 must be 
permanently discontinued. 

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8.9.2.2 Immune-Mediated Colitis 
Monitor subjects for immune-mediated colitis. Subjects with Grade 3 or Grade 4 diarrhoea as well 
as those with Grade 2 diarrhoea with blood in the stools should be evaluated for the presence of 
colitis. Diagnosis with endoscopy should be considered. Administer corticosteroids at a dose of 1 to 
2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life- 
threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone 
equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days 
duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose 
to 1 to 2 mg/kg/day prednisone equivalents. Upon improvement to Grade 1 or less, initiate 
corticosteroid taper and continue to taper over at least 1 month. Withhold FP-1305 for Grade 2 or 3 
immune-mediated colitis. Permanently discontinue FP-1305 for Grade 4 colitis or for recurrent colitis 
upon restarting the drug. 
 
Consider adding an agent or other immunosuppressant agents, such as an anti-TNF antibody therapy, 
for the management of immune-mediated colitis unresponsive to systemic corticosteroids within 3 to 
5 days or recurring after symptom improvement. If other immunosuppressive agents are needed for 
the management of immune-mediated colitis, FP-1305 should be permanently discontinued. 
8.9.2.3 Immune-Mediated Nephritis and/or Renal Dysfunction 
Corticosteroids should be used (initial dose of 1 to 2 mg/kg/day prednisone or equivalent) for Grade 
2 or greater nephritis (creatinine 2 - 3 x above baseline). Upon improvement to Grade 1 or less, 
initiate corticosteroid taper and continue to taper over at least 1 month. Withhold FP-1305 for 
moderate (Grade 2) nephritis, and permanently discontinue FP-1305 for severe (Grade 3) or life-
threatening (Grade 4) nephritis. 
8.9.2.4 Immune-Mediated Hepatitis and/or Liver Dysfunction 
Liver tests should be periodically performed (according to the schedule). If immune-mediated 
hepatitis is suspected, corticosteroids should be used (initial dose of 1 to 2 mg/kg/day prednisone or 
equivalent followed by a taper) for Grade 2 or greater transaminase elevations (Grade 2 transferase 
levels >3.0 - 5.0 x ULN if baseline value was normal; >3.0 - 5.0 x baseline if baseline value was 
abnormal) or bilirubin elevations (Grade 2 >1.5 – 3.0 x ULN if baseline value was normal; >1.5 – 
3.0 x baseline if baseline value was abnormal).  
 
Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 
1 month. In steroid refractory subjects, the use of mycophenolate mofetil 500-1000mg twice a day 
may be considered and FP-1305 should be permanently discontinued. A liver biopsy should be 
considered to confirm the diagnosis. 
 
In case of suspected immune-mediated hepatitis related to FP-1305 withhold FP-1305 for moderate 
(Grade 2) liver enzyme elevation, and permanently discontinue FP-1305 for severe (Grade 3) or life-
threatening (Grade 4) hepatic failure if the increase is not clearly related to cancer progression in the 
liver.  
8.9.2.5 Immune-Mediated Endocrinopathies 
Subjects should be monitored for clinical signs and symptoms of endocrinopathies. Subjects may 
present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and 
hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or 

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underlying disease. Unless an alternate aetiology has been identified, signs or symptoms of 
endocrinopathies should be considered immune-related. 
 
Withhold FP-1305 for symptomatic hypothyroidism and initiate thyroid hormone replacement if 
needed. Withhold FP-1305 for symptomatic hyperthyroidism and initiate antithyroid medication if 
needed. If an acute inflammation of the thyroid is suspected, corticosteroids (initial dose of 1 to 2 
mg/kg/day prednisone equivalents) should be considered. Upon improvement, administration of 
FP-1305 can be resumed after corticosteroid taper. FP-1305 must be permanently discontinued for 
life-threatening (Grade 4) hyperthyroidism or hypothyroidism. Monitoring of thyroid function should 
be continued to ensure appropriate hormone replacement is utilised. 
  
Withhold FP-1305 for symptomatic Grade 2 adrenal insufficiency and initiate physiologic 
corticosteroid replacement if needed. FP-1305 must be permanently discontinued for severe (Grade 
3) or life-threatening (Grade 4) adrenal insufficiency. Monitoring of adrenal function and hormone 
levels should be continued to ensure that appropriate corticosteroid replacement is utilised. 
 
Withhold FP-1305 for symptomatic Grade 2 or 3 hypophysitis, and initiate hormone replacement as 
needed. If an acute inflammation of the pituitary gland is suspected, corticosteroids (initial dose of 1 
to 2 mg/kg/day prednisone or equivalent) should be considered. Upon improvement, administration 
of FP-1305 can be resumed after corticosteroid taper. FP-1305 must be permanently discontinued for 
life-threatening (Grade 4) hypophysitis. Monitoring of pituitary function and hormone levels should 
be continued to ensure appropriate hormone replacement is utilised. 
 
Withhold FP-1305 for symptomatic diabetes, and initiate insulin replacement as needed. FP-1305 
must be permanently discontinued for life-threatening (Grade 4) diabetes. Monitoring of blood sugar 
should be continued to ensure appropriate insulin replacement is utilised.  
 
Adequate evaluation should be performed to confirm aetiology of symptoms related to irAEs. 
Consultation of endocrinologist is recommended when endocrinopathy is suspected. 
8.9.3 Tumour Lysis Syndrome 
Tumour lysis syndrome is generally not considered to be DLT. The syndrome should be reported in 
24 hours to Sponsor if Grade 3 or Grade 4. 
 
When there is a suspicion of a tumour lysis syndrome (plasma phosphate level >4.5 mg/dL (1.5 
millimole per litre (mmol/L), plasma potassium level >6.0 mmol/L, and plasma albumin corrected 
calcium <7.0 mg/dL (1.75 mmol/L) or ionized calcium <1.12 (0.3 mmol/L), treatment with 
intravenous fluids and phosphate binders should be initiated. Rasburicase, a recombinant urate 
oxidase enzyme, should be considered if serum creatinine levels increase 2.0–2.9 fold from the 
baseline. If the increase is higher, rasburicase treatment should be started immediately. When subjects 
are treated with rasburicase, the blood samples used for the measurement of the uric acid level must 
be placed on ice to prevent ex vivo breakdown of the uric acid by rasburicase and thus obtaining a 
spuriously low level. 
 
The administration of FP-1305 can be continued when a tumour lysis syndrome occurs, especially 
when cancer is responding to the treatment. However, prophylactic medication (allopurinol 300 to 
800 mg/day in divided doses) may be considered, and proper intravenous hydration should be 
ensured. 

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8.9.4 Increased Fibrosis in Response to Liver Injury 
Subjects should be continuously monitored with laboratory analyses and physical assessment to 
ensure adequate liver function. FP-1305 should be withheld when Grade 2 (NCI-CTCAE version 
5.0) AST, ALT or total bilirubin elevation is detected, and there is no evidence for cancer progression 
in the liver or other IMP non-related medical cause that might explain the increase. The IMP 
administration can be reinitiated when the liver enzyme values decrease to Grade <2 after 
discontinuation of FP-1305. If the adverse reaction recurs, indicating causal relationship to FP-1305, 
it must be permanently discontinued. 
 
FP-1305 must be permanently discontinued if Grade 3-4 (NCI-CTCAE version 5.0) AST, ALT or 
total bilirubin elevation is detected in the absence of cancer progression in the liver or other IMP 
non-related medical cause that might explain the increase. For subjects with liver metastasis who 
begin treatment with Grade 2 AST or ALT, FP-1305 must be permanently discontinued when AST 
or ALT increases by ≥3 times from the baseline and lasts for at least 1 week in the absence of cancer 
progression or other IMP non-related medical cause that might explain the increase. 
 
Proper diagnosis of the liver injury is encouraged. 
8.10 Treatment beyond RECIST defined disease progression 
In case of suspicion of pseudoprogression and subjective stable disease (no clinical deterioration),  a 
second tumour evaluation should be carried out at least 4 weeks after the first  response evaluation 
even if the subject has been deemed to discontinue from the study. 
Subjects treated with FP-1305 may continue treatment beyond initial RECIST 1.1 defined 
progressive disease, assessed by the investigator, as long as they meet the following criteria 
(assessment of the criteria must be recorded in the source data): 
1) Investigator-assessed clinical benefit 
2) Tolerance of study treatment 
3) Stable or improved ECOG performance status 
4) Treatment beyond progression will not delay an imminent intervention to prevent 
seriouscomplications of disease progression (e.g., central nervous system (CNS) metastases) 
A follow-up scan should be performed after 4 weeks to determine whether there has been a decrease 
in the tumour size or continued progressive disease. The assessment of clinical benefit should be 
balanced by clinical judgment as to whether the participant is clinically deteriorating and unlikely to 
receive any benefit from continued treatment with FP-1305. If the investigator feels that the subject 
continues to receive clinical benefit by continuing treatment, the subject should remain on the trial 
and continue to receive monitoring. For the subjects who continue study therapy beyond progression, 
further progression is defined as an additional 10% increase in tumour burden with a minimum 5 mm 
absolute increase from the time of the initial progressive disease. This includes an increase in the 
sum of diameters of all target lesions and/or the diameters of new measurable lesions compared to 
the time of initial progressive disease. FP-1305 treatment should be discontinued permanently upon 
documentation of further progression. 
8.11 Treatment Compliance  
The Investigator and the trial personnel should ensure that each subject receives the right dose of 
FP-1305 as scheduled. 
 

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9 
SUPPORTIVE TREATMENT 
See Section 10.1 and Section 10.2 for allowed and prohibited interventions, respectively. 
 
10    CONCOMITANT INTERVENTIONS / MEDICATIONS  
10.1 Allowed Interventions 
The subject’s regular medication for other diseases 
Palliative radiotherapy to bone metastases and non-target lesions on RECIST 
Scheduled biopsies of the tumour 
Corticosteroids with minimal absorption (topical, inhaled or intranasal) may be used if on a stable 
dose  
All other interventions/medications/vaccines not listed in the prohibited interventions 
10.2 Prohibited Interventions 
Continuous use of immunosuppressive drugs 
Systemic chemotherapy 
Systemic corticosteroids other than replacement therapy (primary or secondary adrenal 
insufficiency) or used for treatment for infusion reaction,or as instructed in this protocol 
Other investigational agents 
Radiotherapy to the primary tumour or target lesions 
Major surgery unless vital indication 
Live (attenuated) vaccines 
 
Medication that is necessary for the subject must not be stopped. Otherwise, prohibited interventions 
must be stopped prior to treatment with FP-1305 as defined in the exclusion criteria (Section 5.1); or 
at least five half-lives prior to treatment with FP-1305 if no definition is given in Section 5.1.  
 
If a subject requires treatment with systemic corticosteroids (oral or I.V.) after treatment with FP-
1305 has been started this must be discussed and approved in advance (in written) by the Medical 
Monitor or the Sponsor (except for FP-1305 treatment related adverse effects as indicated in this 
protocol and emergency cases e.g. spinal cord compression and progressing brain metastases in 
which steroids are needed immediately as assessed by the Investigator). 
10.3 Contraception and Pregnancy 
Women of childbearing potential (i.e. not post-menopausal or surgically sterilised) must use highly 
effective methods of contraception (e.g. combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation;  progestogen-only hormonal contraception 
associated with inhibition of ovulation; intra-uterine device (IUD); intrauterine hormone-releasing 
system (IUS) or vasectomised partner) to prevent pregnancy or abstain* from heterosexual activity 
for the duration of the trial and for at least 3 months following treatment discontinuation. In addition, 
barrier contraception (with or without spermicide) may be used but this should not be considered as 
an adequate form of contraception on its own. 
*Abstinence must be in line with the preferred and usual lifestyle of the subject. [Periodic abstinence 
(such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception]. 
 

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Fertile men whose partners could be of childbearing potential should routinely use a condom during 
the study and for 3 months thereafter. The partner, if not pregnant, should also use a reliable form of 
contraception such as the oral contraceptive pill or an IUD. 
 
Refer to Section 11.4.1 if a pregnancy is reported, either that of a female participant, or the partner 
of a male participant. 
 
Female participants should not breast feed during the treatment period and for at least 3 months after 
the last infusion of the IMP. 
10.4 Trial Subject Withdrawal/Discontinuation  
Administration of the IMP and the subject´s participation in the study must be discontinued for any 
of the following reasons: 
1) Withdrawal of informed consent 
2) In the case of any clinical AE, laboratory abnormality or illness leading to the conclusion by the 
investigator that participation into the trial is not the best interest of the subject 
3) In the occurrence of toxicities as defined in Section 8.9 
4) Pregnancy 
5) Termination of the trial by the Sponsor  
6) Loss of ability to freely provide informed consent  
7) Inability to comply with protocol 
8) Disease progression (for treatment beyond RECIST defined disease progression see  Section 8.10) 
9) Dosing delays greater than the maximum allowed dosing delays as defined in Section 8.7 
All trial subjects should comply with the protocol specified follow-up procedures as outlined in 
Section 8.5. The only exception to this requirement is a withdrawal of informed consent for all trial 
procedures or when a subject has lost the ability to consent freely. All data collected until the 
withdrawal of informed consent will be analysed and included into trial data. 
10.5 COVID-19 Vaccination  
The outcome of the risk assessment conducted by Faron and the study team is that a COVID‑19 
vaccine given to a trial subject is considered as a simple concomitant medication with no interaction 
that requires advice on timing of the vaccine or any other aspect. 
 
Treatment with FP-1305 during an ongoing round of vaccination will not, as far as Faron and the 
study team are aware of, compromise the efficacy of any COVID-19 vaccines. The study team will 
continue to review and monitor any update in terms of COVID‑19 vaccine interaction with molecules 
targeting macrophages. 
 
Investigators should follow the study protocol, local prescribing guidance and policies when 
considering if vaccination against COVID-19 is appropriate for subjects participating in this study. 
 
11    ADVERSE EVENT REPORTING 
11.1 Reporting Requirements 
The collection and reporting of Adverse Events (AEs) will be in accordance with International 
Conference on Harmonisation (ICH) GCP, European Union, and national regulations and 
requirements. The definitions of different types of AE are listed in Appendix 4 - Definition of 
Adverse Events25. 

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In summary, the AE collection should comply with the following principles: 
1) care should be exercised to collect AEs 
2) follow-up period of 4 weeks (+/- 1 week; until follow-up visit) after the last dose does not have 
exceptions for AE collection. In circumstances where follow-up visit will not be performed, the 
follow-up period for AE reporting is 4 weeks from last dose of IMP. 
3) if the study subject discontinues from the study, also collection of new AEs is discontinued at the 
follow-up visit, with the exception of follow-up for the IMP-related AEs (see Section 11.6). 
Survival information should be collected at 1 year and 2 years after the first IMP dose directly 
from the subject/caregiver or hospital records, or at 1 year after the last IMP dose if the 
treatment has been continued beyond one year 
4) survival data collection after the last dose is not subjected for active AE collection 
5) if an investigator becomes aware of a Serious Adverse Drug Reaction after the subject’s 
discontinuation, or during the survival data collection period after treatment, this event should 
be reported immediately per the standard SAE reporting practices (see Section 11.4) 
11.2 Definition of Adverse Event 
An AE is any untoward medical occurrence in a study subject or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. 
 
An AE can therefore be any unfavourable and unintended sign (including abnormal laboratory 
findings), symptom or disease temporally associated with the use of an investigational medicinal 
product, whether or not related to the investigational medicinal product. 
11.3 Adverse Events 
It is the responsibility of the Investigator to collect all AEs (both serious and non-serious) derived by 
observation, by spontaneous unsolicited reports of subjects, and, where appropriate, by routine open 
questioning. 
 
As this is a first in human trial, all medical occurrences which meet the definition of an AE 
(Section 5)) should be recorded. Disease progression will be recorded as an AE/SAE in this study. 
  
Any pre-existing conditions or abnormal laboratory findings present at screening should be recorded 
in the medical history and should not be recorded as an AE unless the condition worsens by at least 
one CTC grade during the trial.  
 
Abnormal laboratory findings (e.g., biochemistry, haematology, urinalysis) or other abnormal 
assessments (e.g., vital signs) that are judged by the Investigator as clinically significant will, if 
certain requirements are met, be recorded as AEs or SAEs. Clinically significant abnormal laboratory 
findings or other abnormal assessments that meet the definition of an AE or SAE and are detected 
during the study or are present at screening and significantly worsen following the start of the study, 
will be recorded as AEs or SAEs. However, clinically significant abnormal laboratory findings or 
other abnormal assessments that are associated with the disease being studied (unless judged by the 
Investigator as more severe than expected for the subject’s condition), or that are present or detected 
at the start of the study and do not worsen, will not be recorded as AEs or SAEs. The Investigator 
will exercise their medical and scientific judgment in deciding whether an abnormal laboratory 
finding, or other abnormal assessment is clinically significant. 
 

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The Investigator should assess the seriousness and causality (relatedness to the study medication) of 
all AEs experienced by the subject and this should be documented in the source data. The trial site is 
responsible for providing full details of AEs/SAEs in the electronic data capture system in the 
designated eCRF forms continuously during the trial.  
11.3.1 Grading of Adverse Event Severity    
AEs will be reviewed using the NCI-CTCAE version 5.0 (see    Appendix 5 - Common Toxicity 
Criteria Gradings). For AEs not specifically graded by the NCI-CTCAE criteria, the criteria in 
Table 5 will apply. For each episode, the highest severity grade attained should be reported. 
Table 5: 
Grading of Adverse Event Severity 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living* 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living** 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
 
*Instrumental activities of daily living refer to: preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.  
**Self-care activities of daily living refer to: bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.  
Note: A severe AE is not necessarily a serious AE. For example, a headache may be severe in intensity, but would not 
be classified as serious unless it met one of the SAE criteria (see list in Appendix 4 - Definition of Adverse Events) 
11.3.2 Relationship of Adverse Event to Study Medication 
The Investigator will assess the causality/relationship between FP-1305 and the AE and record that 
assessment in the source data. Causality will be assessed as: 
• Not related: AE is obviously explained by another cause; OR the time of occurrence of AE is 
not reasonably related to administration of the IMP 
• Possibly related: Study drug administration and AE occurrence are reasonably related in time; 
AND AE is explained equally well by causes other than the IMP 
• Probably related: Study drug administration and the occurrence of the AE are reasonably related 
in time; AND the AE is more likely explained by exposure to the IMP than by other mechanisms 
11.4 Serious Adverse Events  
The Investigator must report AEs that meet the definition of an SAE (see    Appendix 4 - Definition 
of Adverse Events for definition) immediately, or within 24 hours of the trial site becoming aware 
of the SAE.  
 
The AEs defined as serious and which require reporting as an SAE must be reported using either an 
electronic SAE Form in the eCRF (primary) or a paper SAE Form (back-up method; contact details 
in the form and on the second page of this protocol). If the trial site personnel are unable to complete 

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the electronic SAE form within 24 h after receiving information about the event, the initial reporting 
must be done on the paper SAE report and emailed or fax to Simbec-Orion Pharmacovigilance 
(within 24 h of awareness). The trial site should report the event in the electronic SAE form of the 
eCRF as soon as possible after that.   
 
The Investigator Site Staff Signature and Task Delegation Log at each trial site will clearly show 
delegation of responsibilities regarding SAE reporting. A medically qualified person at the trial site 
identified on the delegation log with this responsibility must assess the SAE. The Principal 
Investigator or delegated sub-investigators are responsible for the SAE reporting procedures at the 
site during the trial and must always sign-off on each SAE (regardless of whether reported using the 
electronic or paper form) as soon as possible even if other site staff have reported the event on behalf 
of the investigators. 
 
For all SAEs where important or relevant information is missing, active follow-up must be 
undertaken. The follow-up information of the SAEs must be reported following the same procedure 
as for the initial reporting. The follow-up report should describe if the SAE has resolved or is 
continuing, how it was treated, and whether the subject continued the IMP or whether the IMP 
administration was permanently discontinued. 
11.4.1 Monitoring Pregnancies for Potential Serious Adverse Events 
Any pregnancy that occurs in a female subject or the partner of a male subject during the trial, must 
be reported on the Pregnancy Notification Report form in the eCRF (preferred way) or a paper-based 
form (back-up; contact details on the form and on the second page of this protocol) and must be 
immediately sent to Simbec-Orion Pharmacovigilance or within 24 hours of the time the information 
is known.  
 
Pregnancies must be immediately reported and should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal and/or new-born complications for up to three 
months after the birth/termination or if needed, within 1 year after birth where possible and 
appropriate. Pregnancy in itself is not regarded as an AE.  
 
Consent to report information regarding these pregnancy outcomes should be obtained from the 
mother. Once consent has been obtained, pregnancy outcomes must be collected for females who 
took the IMP and the female partners of any males who took the IMP on the Pregnancy Outcome 
form in the eCRF (preferred way) or a paper-based form (back-up; contact details on the form and 
on the second page of this protocol) and should be sent to Simbec-Orion Pharmacovigilance 
immediately or within 24 hours of the time the information is known.  
 
If the pregnancy outcome meets the SAE definition also complete an SAE Form as detailed in 
Section11.4. It is important to monitor the outcome of any pregnancies of subjects in order to provide 
SAE data on congenital anomalies, birth defects or spontaneous abortion. 
11.5 Adverse Events of Special Interest 
Potential autoimmunity has been reported in study subjects after receiving FP-1305. Four study 
subjects have had hepatic involvement, with a different clinical presentation and associated AE 
reporting terminology. Some of these events have been graded life-threatening (more details provided 
in the IB).  

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An Adverse Event of Special Interest (AESI) is an AE that requires reporting on an expedited basis 
(The Investigator must report AEs that meet the definition of an AESI immediately, or within 24 
hours of the trial site becoming aware of the AESI to Simbec-Orion Pharmacovigilance and on the 
eCRF), regardless of the seriousness, expectedness, or relatedness of the AE to the administration of 
the IMP. 
In this protocol, the below listed are considered AESIs for FP-1305: 
1. Drug induced liver injury defined by Hy’s law as: 
• Grade ≥ 2 alanine aminotransferase (ALT) or aspartate transaminase (AST) increase 
accompanied with 
• Bilirubin elevation > 2 x upper limit of normal (ULN) if baseline value was normal; 
> 2 x baseline if baseline value was abnormal, without findings of cholestasis or any 
other reason explaining the combination of increased aminotransferase and serum 
total bilirubin 
2. Any new or worsening of existing autoimmunity after the administration of FP-1305 
All AESIs will be followed until recovery or resolution or until the investigator assesses the event to 
be stable. AESIs will follow the same reporting timeline as that of SAE to pharmacovigilance team. 
11.6 AE/SAE Recording and Reporting Period  
Details of all AEs will be recorded from the date of consent until the AEs have resolved or no change 
in the AE status is observed during the post-treatment follow-up period (until Follow-up Visit has 
been conducted). In circumstances where follow-up visit will not be performed, the follow-up period 
for AE reporting is 4 weeks from last dose of IMP. If the subject is discontinued from the treatment, 
the subject must be followed up for open AEs until the AE has resolved, or no change in subject 
status is observed over the follow-up period. However, all IMP related Grade 3 or 4 AEs must be 
followed until resolution to Grade 2 or better (for grading see Section 11.3.1). 
 
The investigator is not required to actively monitor subjects for adverse events occurring after the 
Follow-up Visit has been conducted; however, serious adverse drug reactions occurring after the 
follow-up period to a subject that has received one or more doses of the IMP should be reported to 
the Sponsor per the standard SAE reporting process (see Section 11.4) within 24 hours of the 
investigator or site team member becoming aware of them.   
 
Concomitant medications and procedures associated with Serious Adverse Drug Reactions that occur 
after subject has withdrawn/discontinued (i.e. after Follow-up Visit) will only be recorded in SAE 
narrative, and not in the other eCRF pages.   
11.7 Reporting to Competent Authorities and Independent Ethics Committees 
According to the applicable requirements and Safety Management Plan, any AE that meets the 
criteria of a Suspected Unexpected Serious Adverse Reaction (SUSAR) is subject to expedited 
reporting to the Competent Authorities and IEC(s)/ IRB(s). The reference safety information (RSI) 
section in the Investigator’s Brochure will be used to assess the expectedness of an SAE. 
 
The Development Safety Update Reports (DSUR) will be provided to the Competent Authorities and 
IEC(s) /IRB(s) responsible for the trial annually. The DSUR will include information on SUSARs, 
SARs (serious adverse reactions) and other relevant safety findings. 

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The relevant Competent Authorities and IEC(s)/IRB(s) will be immediately notified if a significant 
safety issue is identified during the course of the trial.   
11.8 Safety Reporting to Investigators 
Details of all SUSARs and any other significant safety issues which arise during the course of the 
trial and any consequences they may have on the trial will be reported to Principal Investigators. If 
applicable the Investigator will report the SUSAR or significant safety issue to their IEC/IRB. A copy 
of any such correspondence should be filed in the ISF. 
 
12    DATA HANDLING AND RECORD KEEPING  
12.1 Data Collection  
All relevant data related to safety and efficacy including laboratory values and clinical parameters 
should be recorded in the medical records and be captured in the eCRF system. The site is responsible 
for completing the eCRF forms in a timely manner. All data on the eCRFs must be verifiable in the 
source data/hospital or patient records, unless eCRF data are declared as source data. 
12.2 Archiving 
It is the responsibility of the Principal Investigator to ensure all essential trial documentation and 
source records (e.g. signed Patient Information and Consent Documents, Investigator Site Files, 
Pharmacy Files, patients’ hospital notes, copies of eCRFs etc.) are stored in secure archives for 25 
years after the end of the trial. However, these documents should be retained for a longer period if 
required by applicable legal requirements. The Sponsor’s approval is required prior to transfer or 
destruction of the documents. 
 
13    QUALITY MANAGEMENT 
This trial is to be conducted according to the ICH harmonised tripartite guideline for good clinical 
practice E6(R2) and the European Union directive 2001/20/EC to ensure that the rights, safety and 
well-being of trial subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki (Appendix 3 - WMA Declaration of Helsinki), and that the clinical trial data 
are credible. 
For the trial to start, all required documentation must be approved by the relevant ethical committees 
and Competent Authorities, in accordance with local legal requirements. The Sponsor must ensure 
that all ethical and legal requirements have been met before the first subject is enrolled in the trial. 
 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, receive 
approval from the appropriate personnel, and receive ethical committee/competent authority approval 
prior to implementation (if appropriate). 
 
Administrative changes (not affecting the subject benefit/risk ratio) may be made without the need 
for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
13.1 Site Set-up and Initiation 
All sites will be required to sign a contractual agreement with the Sponsor prior to participation. In 
addition, all participating Investigators will be asked to sign the necessary agreements and supply a 

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current curriculum vitae to the Sponsor or representative of the Sponsor.  All members of the site 
research team that will perform study specific activities will also be required to sign the “Site Staff 
Signature and Task Delegation Log”. Prior to commencing recruitment, all sites will undergo a 
process of initiation.  Key members of the site research team will be required to be trained by the 
Sponsor, or a representative of the Sponsor, covering aspects of the trial design, protocol procedures, 
AE reporting, collection and reporting of data and record keeping. The investigators are responsible 
for ensuring that appropriate training relevant to the study is given to the medical, nursing and other 
personnel involved in the study.  The investigators will also ensure that any information relevant to 
the conduct of the study is forwarded to the sub-investigators and other relevant study centre 
personnel.  Sites will be provided with an Investigator Site File and a Pharmacy File containing 
essential documentation, instructions, and other documentation required for the conduct of the trial.  
The Sponsor or representative of the Sponsor must be informed immediately of any change in the 
site research team.   
13.2 On-Site Monitoring  
A separate Site Monitoring and Management Plan is available where full details of the monitoring 
activities are described. The trial is conducted according to the GCP and quality standards. Monitors 
must ensure that the required documentation and trial site training has been done before the site can 
start enrolling subjects. During the treatment phase, the site(s) will be monitored to ensure protocol 
adherence and to verify the source data. Any issues in compliance will be reported to the Sponsor. 
 
By participating into this trial, the Investigator(s) and the site(s) conducting this trial will permit trial-
related monitoring, audits, Institutional Review Board or equivalent review, and regulatory 
inspection(s) and provide direct access to source data/documents. A reasonable time must be given 
for the site(s) to prepare for such activities. 
13.3 Audit and Inspection 
The Investigator will permit trial-related monitoring, audits, ethical review, and regulatory 
inspection(s) at their site, providing direct access to source data/documents.  
 
Sites are also requested to notify the Sponsor of any relevant regulatory authority inspections.   
13.4 Notification of Serious Breaches 
The sites and the Sponsor of the trial will report any serious breaches or protocol/ICH-
GCP deviations in accordance with the local laws and current regulations. A “serious breach” is a 
breach which is likely to effect to a significant degree: 
1) The safety and rights of a subject. 
2) The reliability and robustness of the data generated in the clinical trial. 
Where the Sponsor is investigating whether or not a serious breach has occurred, sites are also 
requested to cooperate with the Sponsor in providing sufficient information to report the breach to 
the relevant Competent Authorities and IEC(s)/IRB(s) where required and in undertaking any 
corrective and/or preventive action.   
 
14    END OF TRIAL DEFINITION 
The end of trial will be the date the overall survival data of the last subject has been collected. 
 

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The Sponsor will notify relevant Competent Authorities and IEC(s)/IRB(s) that the trial has ended at 
the appropriate time and will provide them with a summary of the clinical trial report within 
12 months of the end of trial.  
 
The Sponsor reserves the right to stop the trial at any time on the basis of new information regarding 
safety or efficacy (e.g., discovery of an unexpected, significant or unacceptable risk to the subjects 
enrolled in the trial), or if trial progress is unsatisfactory (e.g., failure to enrol subjects at an acceptable 
rate), or for other valid reasons (e.g., Sponsor decides to suspend or discontinue development of the 
drug). After such a decision is made, the Investigator must inform all on-trial subjects within 1 week. 
All delivered trial materials must be collected and all eCRF pages completed to the extent possible. 
 
15    STATISTICAL CONSIDERATIONS 
This is an adaptive study conducted in 3 parts with separate objectives. For each part there will be a 
separate statistical analysis plan (SAP) which includes the full details of the analyses of the endpoints 
of that part. The SAPs can also have sequel documented subversions in case there are analyses 
conducted intermittently during some part.  
15.1 Trial Population 
The trial subject population includes subjects who have advanced (inoperable or metastatic) 
cutaneous melanoma, pancreatic ductal adenocarcinoma, ovarian cancer, colorectal adenocarcinoma, 
hepatocellular carcinoma, gallbladder cancer, cholangio-carcinoma, uveal melanoma, gastric 
(including GE junction) adenocarcinoma, ER+ breast cancer and anaplastic thyroid cancer without 
standard treatment options available and who adhere to the trial inclusion and exclusion criteria. 
 
For the purpose of analyses the following populations are defined: 
 
Safety population: Includes all subjects who have received any amount of FP-1305 
 
DLT evaluable population: Includes all subjects in Part I who have received at least one dose of 
FP-1305 and followed up for at least three weeks. Any subject that withdraws, discontinues from the 
trial or dies not related to treatment prior to the end of the 9-week DLT assessment period will be 
replaced. 
 
Efficacy evaluable population: Includes all subjects who have received at least one dose of FP-1305 
for the first time and has tumour imaging conducted at the baseline, and at least once during the 
treatment or progress or die due to their disease before the first tumour imaging post FP-1305 
administration. 
 
Subjects that re-initiate the treatment: Includes all subjects that have received at least one dose of 
FP-1305 after re-initiation of the therapy and has tumour imaging conducted at the baseline, and at 
least once during the treatment or progress or die due to their disease before the first tumour imaging 
post FP-1305 administration will be analysed for efficacy after the re-initiation in a separate cohort. 
15.2 Objectives and Outcome Measures  
These are detailed in full in Section 3. 

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15.3 Analyses of Outcome Measures 
15.3.1 Primary Outcome (Part I) 
The final model determined MTD, which is the dose level with DLT probability estimated to be 
closest to the acceptable percentage (target DLT rate) of subjects experiencing a DLT, will be 
reported with its associated probability of DLT and 90% probability interval. All tolerable doses to 
be considered will be the MTD and doses below it. The recommended dose for Parts II and III will 
be selected based on the assessment of changes in immune function, PK and PD data. 
15.3.2 Primary Outcome (Part II) 
ORR, CBR and irORR will be reported as the proportion of subjects of all evaluable subjects within 
each tumour type cohort and dose. The 90% confidence intervals for ORR, CBR and irORR will be 
calculated. Simon’s Two-Stage design will be used to evaluate efficacy and decide whether the cohort 
can be further expanded or not for Part III.   
15.3.3 Primary Outcome (Part III) 
ORR, CBR and irORR will be reported as the proportion of subjects of all evaluable subjects within 
each tumour type cohort. The 90% confidence intervals for ORR, CBR and irORR will be calculated. 
Duration of response is measured from the time of initial response until documented tumour 
progression, death or dropout. 
15.3.4 Secondary and Exploratory Outcomes 
15.3.4.1 Monocytes CLEVER-1 positivity 
The proportion of CLEVER-1-positive monocytes in the blood total monocyte population will be 
measured by flow cytometry from blood samples collected over time during the first four cycles. 
Results will be reported with descriptive statistics. Also explorative statistical analyses will be 
conducted for the flow cytometry data, if feasible. 
15.3.4.2 sCLEVER-1 
sCLEVER-1 and its occupancy by FP-1305 in the blood will be measured by immunoassay over time 
during the first cycles. Results will be reported with descriptive statistics. Also explorative statistical 
analyses will be conducted for the data, if feasible. 
15.3.4.3 Pharmacokinetic Parameters 
The serum concentration of FP-1305 will be determined by a validated method according to the 
assessment schedules. The concentrations will be summarized by visit and the sampling time using 
descriptive statistics by the dose level. Only subjects who have received the whole dose at each 
infusion will be used for the repeated PK analysis. The mean concentration will be plotted against 
the scheduled sampling times. A tabulated summary with descriptive statistics will be given. 
15.3.4.4 Immunogenicity 
Anti-human FP-1305 antibodies will be assessed analysed by a validated method. Immunogenicity 
results will be summarized by listing of all available immunogenicity data. The frequency of 
positivity will be given by dose and cohort. The correlation of AEs and immunogenicity may be 
examined. 

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15.3.4.5 Safety 
Safety and tolerability will be reported through the assessment of observed adverse events in the 
subjects. The number of cases and the number of subjects that these cases occurred in will be reported 
for each event. Drug-related events are reported in a separate table. In addition, both DLTs and drug-
related serious adverse events are reported separately in a tabular format, and their seriousness will 
be assessed based on the NCI-CTCAE classification. AEs are also to be evaluated stratified by dose 
level and by disease group. 
15.4 Analysis of Efficacy Parameters 
The proportion of CLEVER-1-positive monocytes in the blood total monocyte population will be 
measured by flow cytometry from blood samples collected over time during the first four cycles. The 
results will be reported with descriptive statistics. 
 
Tumour samples collected before and during the treatment will be stained for CLEVER-1. The 
proportion of CLEVER-1 positive TAMs will be analysed by immunohistochemistry. Macrophage 
mannose receptor and/or other markers may be used to determine the total content of TAMs. The 
proportion of CLEVER-1 positive cells prior to and during the treatment will be reported using 
descriptive statistics. The correlation between circulating CLEVER-1-positive monocytes and 
CLEVER-1 expression in tumour macrophages will be calculated before and during the treatment. 
The correlation of the parameters obtained during Cycle 1 with ORR, CRB and irORR rates will also 
be calculated for subjects included into the ORR/CBR/irORR analysis. The results will be 
summarized using descriptive statistics. If feasible, exploratory statistical analyses will also be used 
to describe the associations.   
 
The proportion of lymphocyte subsets (CD4, CD8, their ratio, NK-cells, B-cells and regulatory T-
cells), and macrophage HLA expression and myeloid derived suppressor cell populations in 
circulation will be analysed at given time points with flow cytometry and plotted against the 
scheduled sampling time. The level of circulating cytokines and chemokines (these may include but 
are not limited to the following IFN, IFN, IL-1, IL-1, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, 
IL-8/CXCL8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-18, IL-21, IL-22, IL-23, IL-27, IL-31, 
TNF alpha, TNF beta, GM-CSF, Eotaxin/CCL11, GRO alpha/CXCL1, IP-10/CXCL10, MCP-
1/CCL2, MIP-1/CCL3, MIP-1/CCL4, RANTES/CCL5, SDF-1/CXCL12) will be analysed by 
multiplex assays pre- and post-treatment. Aggregated data (mean and median) from each dose level 
will be presented using descriptive statistics by tumour type cohort. 
ORR, CBR and irORR will be reported as the proportion of subjects of all evaluable subjects within 
each tumour type cohort. The 95% confidence intervals for the ORR, CBR and irORR will be 
calculated. 
 
The change in LDH, LDL and OxLDL, CRP, CA-125 (OC subjects), CA19-9 (PDAC, gallbladder 
cancer, cholangiocarcinoma, gastric adenocarcinoma subjects), CEA (CRC, ER+ BC, gastric adeno-
carcinoma subjects), CA-15-3 (ER+ BC subjects) and AFP (HCC subjects) levels in the subjects pre- 
and post-treatment will be reported with descriptive statistics. 
 
The correlation of the response according to RECIST 1.1 defined responses (CR/PR/SD/PD) with 
the immune cell profile, the level of circulating cytokines and chemokines, CLEVER-1 on circulating 
monocytes, and possible genetic analyses during the first four cycles of treatment will be reported 
using descriptive statistics. If feasible, exploratory statistical analyses will also be used to describe 
the associations. 

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The receptor occupancy of FP-1305 on the circulating monocytes during Part I and in some subjects 
during Part II will be analysed using flow cytometry and will be plotted against scheduled sampling 
times. Aggregated data (mean and median) from each dose level will be presented by tumour type 
cohort. The results will be summarized using descriptive statistics. 
 
Free sCLEVER-1 in the circulation will be measured with immunoassay. 
Overall survival data, including but not limited to the six-month, one-year and two-year survival rates 
will be reported for each cohort, and will be analysed using the Kaplan-Meier method and cox-
modelling where appropriate. 
 
Progression free survival including but not limited to the six-month, one-year and two-year survival 
rates will be reported for each tumour type cohort and will be analysed using the Kaplan-Meier 
method and cox-modelling where appropriate. 
15.5 Planned Interim Analysis 
There is no predefined interim analysis. Interim analyses on safety and efficacy or on PK, 
immunogenicity, and selected biomarkers may be provided on ongoing basis prior to completion of 
the trial in order to expedite conclusions and to support trial presentations or publications. 
15.6 Planned Main Analyses  
Part I 
The main analysis for determining the recommended dose to be expanded upon will take place once 
all subjects in part I have been recruited to trial and have been followed-up for the 9-week DLT 
assessment period.  
 
Part II 
Each cohort will be analysed when ten evaluable subjects have been accrued and treated with the 
selected dose. Subjects from Part I can be included into the cohort of ten subjects if they have been 
treated with the selected dose. 
 
Part III 
Each cohort that is continued after the analysis of Part II will be analysed when 29 evaluable subjects 
have been accrued and treated with optimal dose or until the required 4 responders are reached. The 
cohort can continue accruing subjects if the stopping rule is not met. The final analysis of each cohort 
is when the particular cohort has been considered complete. 
15.7 Power Calculations  
The operating characteristics of the TITE-CRM will be assessed to assure the design is well calibrated 
for determining the MTD. Fine-tuning of the model to tailor to the trial’s requirements will be aided 
with the use of the Dose-Transition Pathways, which maps out in advance how the model will 
recommend doses for all permutations of DLT outcomes for the initial subjects (Yap et al, 2017). 
Details of the TITE-CRM is presented in the corresponding statistical analysis plan. Part II and Part 
III are based on adaptive Simon’s Two-Stage design, with the following assumptions Type I error 
rate (α; one-sided) 0.05, power 0.80, response probability in the palliative treatment 5% (alternative 
option for these subjects) and response in the trial treatment 20%, 10 subjects in each cohort with at 
least one subject that demonstrates clinical benefit (CBR by RECIST 1.1 criteria) in the Part II is 
needed to conclude that the cohort may be expanded. Additionally, data from Part II will be used to 
determine CLEVER-1 positivity in each of the cohorts. If it is possible that cohorts can be divided in 

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the CLEVER-1 positive and CLEVER-1 negative groups, both subgroups will be expanded in Part 
III so that 10 subjects in each group are recruited. In case there are 10/10 non-responders in either of 
the subgroups, then the recruitment will continue only in the other subgroup with responders. The 
recruitment can continue within that subgroup until the planned maximum of 29 subjects (or until the 
required 4 subjects that demonstrate clinical benefit are reached). If the subgroups cannot be defined, 
the Part III continues with the original cohorts having 1 responder in the cohort. In case there are 
clearly more negative than positive subjects in some cohort, and also clear difference in the response, 
the DMC will evaluate the data and decide further cohort expansions. 
 
If the desirable response is obtained in Part III of the trial the cohort(s) may be further expanded. 
 
16    ACCESS TO SOURCE DATA AND RELATED DOCUMENTS 
By participating into this trial, the Investigator(s) and the site(s) conducting this trial will permit trial-
related monitoring, audits, Institutional Review Board or equivalent review, and regulatory 
inspection(s) and provide direct access to source data/documents. A reasonable time must be given 
for the site(s) to prepare for such activities. 
 
17    TRIAL ORGANISATIONAL STRUCTURE 
17.1 Sponsor 
The Sponsor of the trial is Faron Pharmaceuticals. The Sponsor may delegate duties to trial sites and 
to contract research organizations. 
17.2 Data Monitoring Committee 
The DMC will be composed, as a minimum, of the designated investigators and other specialists with 
relevant expertise and independent of the trial will be invited to be members of the committee. Key 
supportive roles in coordinating the meetings and producing the required data include the Sponsor’s 
Chief Medical Officer and Simbec-Orion’s (CRO) Medical Expert and Study Statistician. 
The committee will formally review toxicity and other relevant data including the recommendation 
from TITE-CRM at any time DLT has been observed and after completion of the Part I and further 
on in Part II according to 3+3 design.The DMC will issue recommendations to dose-escalation and 
optimal dose(s). 
If applicable, the committee may recommend to  
• stop dose escalation, for example if a plateau in biomarker changes has been identified, or 
• add one or more dose escalation cohort(s) if the highest dose is reached in the absence of DLT 
and a plateau in biomarker changes has not been identified or  
• add one or more intermediate dose level(s) 
• add three additional subjects to one or more dose levels below the MTD / highest tested dose level 
to obtain more data to inform dose selection for Part II and III, and when deemed necessary, 
recommend to add even further subjects to any defined dose level(s) in Part I   
• increase the post-dose monitoring time for the study subjects 
• discontinue enrolment in a cohort to ensure the best benefit of the subjects  
• modify dosing for ongoing subjects if indicated by accumulated data 
All decisions will be documented in the form of minutes. Addition of new dose escalation cohorts 
will require the competent authority approval if this new cohort is higher than the maximum dose in 
the protocol. 

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17.3 Finance 
The Sponsor will make contracts with trial sites and contract research organizations.  
 
18    ETHICAL CONSIDERATIONS  
The trial will be performed in accordance with the recommendations guiding physicians in 
biomedical research involving human subjects, adopted by the 18th World Medical Association 
General Assembly, Helsinki, Finland, June 1964, amended at the 64th World Medical Association 
General Assembly, Fortaleza, Brazil, October 2013 (website: https://www.wma.net/policies-
post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-
subjects/; Appendix 3 - WMA Declaration of Helsinki). 
 
The trial will be conducted in accordance with the the European Union directive 2001/20/EC, data 
protection regulation (Regulation (EU) 2016/679), local laws, and the ICH GCP E6(R2). This trial 
will be carried out under a Clinical Trial Authorisation in accordance with local regulations. The 
protocol will be submitted to and approved by the corresponding ethical committees.  
 
Before any subjects are enrolled into the trial, the Principal Investigator at each site is required to 
obtain corresponding approval. Sites will not be permitted to enrol subjects until written confirmation 
of approval is received.  
 
It is the responsibility of the Principal Investigator to ensure that all subsequent amendments gain the 
necessary local approval. This does not affect the individual clinicians’ responsibility to take 
immediate action if thought necessary to protect the health and interest of individual subjects. 
Evaluation of the anticipated benefits and risks of the IMP and with regards to the participation of a 
subject is conducted reqularly. This evaluation is performed, at a minimum, annually in association 
with the IB annual update/review, if accumulated data does not indicate a need for more frequent 
evaluation.  
 
19    CONFIDENTIALITY AND DATA PROTECTION 
Personal information of the study subjects collected during the trial will be processed in accordance 
with the Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 
on the protection of natural persons with regard to the processing of personal data and on the free 
movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation, 
GDPR) and all applicable local laws.  
 
All trial findings and documents will be regarded as confidential. The Investigator and members of 
their research team must not disclose any information without prior written approval from the 
Sponsor. The Investigator must maintain documents not for submission to the Sponsor in strict 
confidence. In the case of specific issues and/or queries from the Regulatory Authorities, it will be 
necessary to have access to the complete trial records, provided that subject confidentiality is 
protected.  
 
Subjects will be identified on the eCRF and other documents submitted to the Sponsor or Sponsor’s 
representative by their trial subject number. Documents that identify the subject must not to be 
submitted to the Sponsor and must be maintained in confidence by the Investigator. 
 

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The Investigators (and appropriately authorised staff) will be given access to an online web-based 
electronic data-capture system that is compliant with US Food and Drug Administration Title 21 
Code of Federal Regulations Part 11. This system is specifically designed for the collection of clinical 
data in electronic format. Access rights to the electronic data-capture system will be carefully 
controlled and configured according to each individual’s role throughout the trial. Only the 
Investigator and authorised staff will be able to enter and correct data in the eCRF. 
 
The eCRF should be completed for each subject included in the trial and should reflect the latest 
observations on the subjects participating in the trial. Therefore, the eCRF is to be completed as soon 
as possible during or immediately after the subject’s visit or assessment. The Investigator must verify 
that all data entries in the eCRF are accurate and correct. If some assessments cannot be done, or if 
certain information is unavailable, not applicable or unknown, the Investigator should indicate this 
in the eCRF. 
 
Computerised data-check programs and manual checks will identify any data discrepancies for 
resolution. Corresponding queries will be generated in the system and the site will be informed online 
about new issues to be resolved. All discrepancies must be resolved online directly by the Investigator 
or by staff authorised to do this by Delegation of Authority. 
 
The Investigator will be required to electronically sign off the clinical data recorded in the eCRF. 
 
20    PUBLICATION POLICY  
Any manuscript, abstract or other publication or presentation of results or information arising in 
connection with the trial (including any ancillary trial involving trial subjects) must be prepared in 
conjunction with the trial Sponsor and must be submitted to the Sponsor for review and comment at 
least 45 days prior to submission for publication or presentation. No single centre or groups of centres 
may publish individually. The Sponsor will review the communications for accuracy to avoid 
potential discrepancies with submissions to health authorities, verify that confidential information is 
not accidentally disclosed, and provide any relevant supplementary information. The Sponsor’s 
comments on the proposed publication shall be considered in good faith by the authors. The Sponsor 
may delay such submission by a maximum of 90 days if it reasonably believes that publication of 
results may compromise its intellectual property rights or may insist that such information or data is 
removed from the proposed publication. Publication of the results will not include confidential 
information without the permission of the Sponsor. 
 
The original eCRF pages and all data generated during the trial under this protocol will become the 
property of the Sponsor. 
 
The Sponsor may announce quality-assured summary data in order to comply with the requirements 
of financial regulatory authorities, while ensuring so far as possible that such announcements will 
not compromise the Investigators’ ability to publish the data in appropriate scientific forums. 
Authorship of communications arising from the trial-related data and subsequent analysis may 
include members from the contributing site(s) including basic research laboratories and Sponsor’s 
personnel. 
 

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21    REFERENCE LIST  
Algars A, Irjala H, Vaittinen S, Huhtinen H, Sundstrom J, Salmi M, Ristamaki R, et al. Type and location of 
tumour-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients. Int J 
Cancer 2012;131:864-873. 
 
Ammar A, Mohammed RA, Salmi M, Pepper M, Paish EC, Ellis IO, Martin SG. Lymphatic expression of 
CLEVER-1 in breast cancer and its relationship with lymph node metastasis. Anal Cell Pathol (Amst) 
2011;34:67-78. 
 
Balkwill FR, Capasso M, Hagemann T. The tumour microenvironment at a glance. J Cell Sci 2012;125:5591-
5596. 
 
Butler JM, Kobayashi H, Rafii S. Instructive role of the vascular niche in promoting tumour growth and tissue 
repair by angiocrine factors. Nat Rev Cancer 2010;10:138-146. 
 
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22    APPENDIX 1 - RECIST CRITERIA  
The following contains excerpts from the RECIST version 1.1 plus trial specific instructions.  
A free copy of the revised guidelines is available from https://recist.eortc.org/recist-1-1-2/ 
http://www.eortc.be/recist/default.htm  
(Eisenhauer et al., 2009) 
 
Measurability of Tumour Lesions at Baseline 
Only patients with measurable disease at baseline should be included in Parts II and III. Measurable 
disease is defined by the presence of at least one measurable lesion. At baseline, tumour lesions will 
be categorised as follows:  
• Measurable 
• Non-measurable 
Measurable lesions are those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) with a minimum size of 10 mm by CT scan (CT scan slice thickness no 
greater than 5 mm), 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with callipers should be recorded as non-measurable) and 20 mm by chest X-ray. For 
malignant lymph nodes to be considered pathologically enlarged and measurable, a lymph node must 
be ≥15 mm in short axis when assessed by a CT scan (at baseline and during treatment, only the short 
axis will be measured and followed). 
 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to >15 mm short axis) and truly non-measurable lesions.  
 
Lesions considered to be truly non-measurable include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging techniques, and 
cystic lesions. 
 
Tumour lesions that are situated in a previously irradiated area are not considered measurable. 
The term "evaluable" in reference to measurability is not recommended and will not be used because 
it does not provide additional meaning or accuracy.  
 
All measurements should be recorded in metric notation using callipers (or a ruler) if clinically 
assessed. All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of treatment.  
 
Specifications by Methods of Measurements 
The same method of assessment and the same technique should be used to characterise each identified 
and reported lesions at baseline, during treatment and at the post-treatment assessment. Image-based 
evaluation is preferred to evaluation by clinical examination when both methods have been used to 
assess the anti-tumour effect of a treatment. CT is the best currently available and reproducible 
method for measuring target lesions selected for response assessment. Investigators should utilise the 
best available CT imaging technique available to them for determining response and PFS of patients 
participating in the MATINS trial. 
 

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24    APPENDIX 3 - WMA DECLARATION OF HELSINKI  
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical 
principles for medical research involving human subjects, including research on identifiable human material and 
data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied with 
consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA 
encourages others who are involved in medical research involving human subjects to adopt these principles. 
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my 
first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient’s 
best interest when providing medical care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including those 
who are involved in medical research. The physician’s knowledge and conscience are dedicated to the fulfilment of 
this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the causes, development and 
effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best proven interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect 
their health and rights. 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence 
over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to 
self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for 
the protection of research subjects must always rest with the physician or other health care professionals and never 
with the research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving human subjects 
in their own countries as well as applicable international norms and standards. No national or international ethical, 
legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in 
this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the environment. 
12. Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and 
scientific education, training and qualifications. Research on patients or healthy volunteers requires the supervision 
of a competent and appropriately qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to participation in 
research. 
14. Physicians who combine medical research with medical care should involve their patients in research only to the 
extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the patients who serve 
as research subjects. 

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15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must be 
ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
 
Medical research involving human subjects may only be conducted if the importance of the objective outweighs the 
risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of predictable risks and 
burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to them and 
to other individuals or groups affected by the condition under investigation. 
 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed and 
documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are confident that the risks 
have been adequately assessed and can be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive outcomes, 
physicians must assess whether to continue, modify or immediately stop the study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being wronged or 
of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities 
of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group should stand 
to benefit from the knowledge, practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a 
thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, 
as appropriate, animal experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be clearly described and justified 
in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved and should indicate how the principles 
in this Declaration have been addressed. The protocol should include information regarding funding, sponsors, 
institutional affiliations, potential conflicts of interest, incentives for subjects and information regarding provisions 
for treating and/or compensating subjects who are harmed as a consequence of participation in the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the concerned 
research ethics committee before the study begins. This committee must be transparent in its functioning, must be 
independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take 
into consideration the laws and regulations of the country or countries in which the research is to be performed as 
well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
 
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information 
to the committee, especially information about any serious adverse events. No amendment to the protocol may be 
made without consideration and approval by the committee. After the end of the study, the researchers must submit 
a final report to the committee containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal 
information. 

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Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no individual capable of giving 
informed consent may be enrolled in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, 
post-study provisions and any other relevant aspects of the study. The potential subject must be informed of the right 
to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well as to the methods used to 
deliver the information. 
 
After ensuring that the potential subject has understood the information, the physician or another appropriately 
qualified individual must then seek the potential subject’s freely-given informed consent, preferably in writing. If 
the consent cannot be expressed in writing, the non-written consent must be formally documented and witnessed. 
 
All medical research subjects should be given the option of being informed about the general outcome and results of 
the study. 
27. When seeking informed consent for participation in a research study the physician must be particularly cautious if 
the potential subject is in a dependent relationship with the physician or may consent under duress. In such situations 
the informed consent must be sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek informed 
consent from the legally authorised representative. These individuals must not be included in a research study that 
has no likelihood of benefit for them unless it is intended to promote the health of the group represented by the 
potential subject, the research cannot instead be performed with persons capable of providing informed consent, and 
the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to the consent of the legally 
authorised representative. The potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for example, unconscious 
patients, may be done only if the physical or mental condition that prevents giving informed consent is a necessary 
characteristic of the research  group. In such circumstances the physician must seek informed consent from the 
legally authorised representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving subjects with a 
condition that renders them unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee. Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research. The refusal of a 
patient to participate in a study or the patient’s decision to withdraw from the study must never adversely affect the 
patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data contained in 
biobanks or similar repositories, physicians must seek informed consent for its collection, storage and/or reuse. There 
may be exceptional situations where consent would be impossible or impracticable to obtain for such research. In 
such situations the research may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven 
intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
 
Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than 
the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an 
intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best 
proven intervention. 
 
Extreme care must be taken to avoid abuse of this option. 

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Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-
trial access for all participants who still need an intervention identified as beneficial in the trial. This information 
must also be disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible database before 
recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication and 
dissemination of the results of research. Researchers have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of their reports. All parties should 
adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest 
must be declared in the publication. Reports of research not in accordance with the principles of this Declaration 
should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known interventions have 
been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally 
authorised representative, may use an unproven intervention if in the physician’s judgement it offers hope of saving 
life, re-establishing health or alleviating suffering. This intervention should subsequently be made the object of 
research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where 
appropriate, made publicly available. 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-
human-subjects/; 
 
 

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25    APPENDIX 4 - DEFINITION OF ADVERSE EVENTS  
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
 
An AE can therefore be any unfavourable and unintended sign (including abnormal laboratory 
findings), symptom or disease temporally associated with the use of an investigational medicinal 
product, whether or not related to the investigational medicinal product. 
 
Serious Adverse Event (SAE) 
Any untoward medical occurrence or effect that at any dose:  
1) Results in death  
2) Is life-threatening [1] 
3) Requires hospitalisation [2] or prolongation of existing inpatients’ hospitalisation 
4) Results in persistent or significant disability or incapacity  
5) Is a congenital anomaly/birth defect 
6) Or is otherwise considered medically significant by the Investigator [3] 
Comments:  
The term severe is often used to describe the intensity (severity) of a specific event. This is not the 
same as serious, which is based on patients/event outcome or action criteria. 
[1] Life threatening in the definition of an SAE refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
 
[2] Hospitalisation is defined as an unplanned, formal inpatient admission, even if the hospitalisation 
is a precautionary measure for continued observation. Thus, hospitalisation for protocol treatment 
(e.g. line insertion), elective procedures (unless brought forward because of worsening symptoms) 
or for social reasons (e.g. respite care) are not regarded as an SAE. 
 
[3] Medical judgment should be exercised in deciding whether an AE is serious in other situations. 
Important AEs that are not immediately life threatening or do not result in death or hospitalisation 
but may jeopardise the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above, should be considered serious. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An SAE that is suspected to be associated with the use of the IMP and unexpected i.e. the nature, or 
severity of the event is not consistent with the applicable product information. 
 
 

Faron Pharmaceuticals Ltd. 
MATINS Protocol v11 
 
FP-1305 25 mg/mL concentrate for solution for infusion 
page 107 (109) 
 
CONFIDENTIAL 
 
26    APPENDIX 5 - COMMON TOXICITY CRITERIA GRADINGS 
Toxicities will be recorded according to the NCI-CTCAE version 5.0.  The full CTCAE document is 
available on the National Cancer Institute (NCI) website, the following address was correct when 
this version of the protocol was approved: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm;