A Phase 1, Open-label, Multicenter Study Evaluating the Safety and Tolerability, Biologic Activity, Pharmacodynamics, and Pharmacokinetics of Single and Repeated Escalating Intravitreal Doses of ICON-1 in Patients With Uveal Melanoma Who Are Planned to Undergo Enucleation or Brachytherapy
Phase: PHASE1
Conditions: Uveal Melanoma, Choroid Neoplasm
Sponsor: Iconic Therapeutics, Inc.

Protocol Title:  A Phase 1, Open-label, Multicenter Study Evaluating the Safety and Tolerability, 
Biologic Activity, Pharmacodynamics, and Pharmacokinetics of Single and Repeated Escalating 
Intravitreal Doses of ICON-1 in Patients with Uveal Melanoma Who are Planned to Undergo 
Enucleation or Brachytherapy 
 
Protocol date: 05 September 2016 
NCT Number: NCT02771340 
 

 
 
 
 
CLINICAL STUDY PROTOCOL 
 
PROTOCOL TITLE: 
A Phase 1, Open-label, Multicenter Study Evaluating 
the Safety and Tolerability, Biologic Activity, 
Pharmacodynamics, and Pharmacokinetics of Single 
and Repeated Escalating Intravitreal Doses of ICON-1 
in Patients with Uveal Melanoma Who are Planned to 
Undergo Enucleation or Brachytherapy 
PROTOCOL NUMBER: 
IT-003 
PHASE OF DEVELOPMENT: 
Phase 1 
INVESTIGATIONAL 
PRODUCT: 
human Immuno-conjugate 1 (ICON-1) 
INDICATION: 
Uveal Melanoma 
IND NUMBER: 
102,472 
SPONSOR: 
Iconic Therapeutics, Inc. 
7000 Shoreline Court 
Suite 270 
South San Francisco, CA 94080 
DATE OF PROTOCOL: 
Original: 17 March 2016 
Amendment 1: 05 September 2016 
 
Confidentiality Statement 
The information in this document is confidential and will not be disclosed to others without 
written authorization from Iconic Therapeutics, Inc., except to the extent necessary to obtain 
informed consent from persons who are potential participants in the trial or their legal guardians, 
persons participating in the conduct of the trial, appropriate institutional review boards or 
independent ethics committees, or duly authorized representatives of the United States Food and 
Drug Administration (FDA) or national regulatory authority. 

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1 
SPONSOR SIGNATURE PAGE 
This study will be conducted as outlined herein in accordance with current 
International Conference on Harmonisation (ICH) guidelines, Good Clinical Practices 
(GCPs), the Declaration of Helsinki, and complying with the obligations and 
requirements of the Sponsor as listed in Title 21 of the United States Code of Federal 
Regulations. 
 
Approved by: 
 
 
___________________________________ 
_________________________ 
Gabriela Burian, MD 
Chief Medical Officer 
Date 
 
 
 
___________________________________ 
_________________________ 
Debbi Kotlovker, MS 
Biostatistician 
Date 
 
 
 

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2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 1, Open-label, Multicenter Study Evaluating the Safety 
and Tolerability, Biologic Activity, Pharmacodynamics, and 
Pharmacokinetics of Single and Repeated Escalating 
Intravitreal Doses of ICON-1 in Patients with Uveal Melanoma 
Who are Planned to Undergo Enucleation or Brachytherapy 
 
Protocol Number: 
IT-003 
 
I have read and understand all sections of this protocol and commit to conducting the study as 
outlined herein in accordance with the current International Conference on Harmonisation (ICH) 
guidelines, Good Clinical Practices (GCPs) and the Declaration of Helsinki, and complying with 
the obligations and requirements of the Clinical Investigator and other requirements as listed in 
Title 21 of the United States Code of Federal Regulations and other applicable regulations.  
I agree to provide the Sponsor with accurate financial information to allow the Sponsor to submit 
complete and accurate certification and disclosure statements as required by applicable 
regulations. 
 
 
 
Principal Investigator’s Name (Printed) 
 
 
 
 
 
Principal Investigator’s Signature 
 
 
Date 
 

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3 
KEY ROLES AND CONTACTS 
Key roles and contact information may be updated by written notification to the clinical sites 
without a protocol amendment. 
Sponsor: 
 
Iconic Therapeutics, Inc. 
7000 Shoreline Court, Suite 270 
South San Francisco, CA 94080 
Phone: (650) 437-1000 
 
Medical Monitor: 
 
Wendy Murahashi, MD 
Medical Monitor 
Phone : (650) 208-4233 
 
Sponsor’s Responsible Medical 
Officer: 
 
Gabriela Burian, MD 
Chief Medical Officer 
Phone : (650) 437-1000 
 
 

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4 
PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 1, Open-label, Multicenter Study Evaluating the Safety and 
Tolerability, Biologic Activity, Pharmacodynamics, and 
Pharmacokinetics of Single and Repeated Escalating Intravitreal 
Doses of ICON-1 in Patients with Uveal Melanoma Who are Planned 
to Undergo Enucleation or Brachytherapy 
Protocol Number 
IT-003 
Study Phase 
Phase 1 
Study Sites 
Approximately 7-10 centers located in the United States 
Study Objectives 
Primary Objective 
 To evaluate the safety and tolerability of single and repeated 
escalating intravitreal injections of ICON-1 administered in 
patients with uveal melanoma who are planned to undergo 
enucleation or brachytherapy. 
Secondary Objectives 
 To assess the pharmacokinetics and pharmacodynamic effect 
of ICON-1 in patients with uveal melanoma. 
 To describe preliminary evidence of the biologic activity of 
ICON-1 as determined by changes in visual acuity, and tumor 
size 
Exploratory Objective 
 To explore the prognostic indicator of the genetic profile of 
the tumor in relation to Tissue Factor expression and response 
to ICON-1 therapy.    
 To describe preliminary evidence of the biologic activity of 
ICON-1 as determined by changes in tumor pathology, and 
proteomic analysis of vitreous humor. 
Study Design 
This is a phase 1, open-label, sequential-group, multicenter study to 
evaluate the safety and tolerability, biological activity, 
pharmacokinetics, and pharmacodynamic activity of single and 
repeated escalating intravitreal injections of ICON-1 in patients with 
primary uveal melanoma who are planned to undergo enucleation or 
brachytherapy.  

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Patients diagnosed with primary uveal melanoma involving the 
posterior uveal tract for which the selected treatment management 
plan is enucleation or brachytherapy may be screened for this study. 
Eligible patients will be assigned to one of three cohorts that will be 
enrolled consecutively:  
Cohort 1 (enucleation or brachytherapy): Single dose of 0.3 mg 
(300 µg/100 µl) ICON-1, (n=2)   
Cohort 2 (enucleation or brachytherapy): Two doses of 0.3 mg 
(300 µg/100 µl) ICON-1 each administered one week apart, 
(n=3)  
Cohort 3 (enucleation or brachytherapy): Two doses of 0.6 mg 
(300 µg/100 µl + 300 µg/ 100 µl) ICON-1 each administered 
one week apart, (n=5)   
Each dose level will be evaluated for clinical safety before escalating 
to the next cohort. Clinical and safety data will be reviewed by the 
IT-003 Safety Review Committee (SRC) comprised of at least one 
participating Clinical Investigator and the Iconic Therapeutics 
internal Safety Management Committee. The following ocular 
adverse events (even if non-serious) are considered Adverse Events 
of Special Interest (AESIs), and will be reported by the investigator to 
the sponsor and SRC as appropriate: 
 Ocular inflammatory event of CTCAE Grade ≥ 3 
 Vitreous or retinal hemorrhage event interfering with 
visualization of the tumor or retina of CTCAE Grade ≥ 2 
 Any acute onset treatment-emergent vision-threatening 
condition as assessed by the investigator 
Patient data will be evaluated by the SRC for the occurrence of ocular 
Dose Limiting Toxicity (DLT) events. An ocular DLT is defined as 
an ocular inflammatory adverse event of 3+ or more severity or a 
grade 2 or higher unexpected vitreous or retinal hemorrhage 
interfering with the visualization of the tumor or retina.   
All patients at a given dose level must complete their pre-procedure 
safety assessment after receiving their last dose of ICON-1 to enable 
evaluation of the safety of that dose level. For cohorts 1 and 2, if no 
patients experience a DLT, escalation to the next dose level will take 
place. If no patients experience a DLT in cohort 3, then cohort 3 will 
be considered the maximum administered dose (MAD). If one patient 
experiences a DLT in any cohort, an additional patient will be 
enrolled and evaluated at that dose level. For cohorts 1 and 2, if two 
or more patients experience a DLT in the original cohort or the 
expanded cohort, then enrollment in that cohort will be suspended 

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and any subsequent cohorts will not be enrolled. For cohort 3, if two 
or more patients experience a DLT in the original cohort or the 
expanded cohort, then enrollment in the cohort will be suspended and 
the IT-003 Safety Review Committee will examine the safety data to 
determine if changes are warranted.  
If an AESI occurs while the patient is at the study center and requires 
clinical management, the patient will remain at the study center 
according to the Investigator’s judgment. The patient will be 
managed according to the routine treatment practices of the study 
center. The patient will complete all subsequent study visits.  
All AESIs, serious adverse events, patient discontinuations and 
pregnancy reports must be reported to Iconic Therapeutics within 24 
hours of the investigator learning of the event. 
ICON-1 will be administered on Day 0 for all cohorts, and in addition 
on Day 7 for cohorts 2 and 3 only. Patients will return to the study 
center on Day 1 for a safety follow-up visit (all cohorts) and 1 day 
post Day 7 (cohorts 2 and 3 only). All patients will return to the clinic 
for safety, clinical, and imaging assessments prior to the scheduled 
surgical procedure. Patients will have their planned Standard of Care 
surgical procedure (enucleation or brachytherapy) as early as 4 days 
after the last ICON-1 treatment, and return to the study center 30 days 
post-procedure for follow-up safety assessments (and ocular 
assessments for brachytherapy patients) and end of study visit.  
Safety will be evaluated by means of occurrence of adverse events, 
clinical laboratory tests (serum chemistry, hematology, coagulation, 
and anti-drug antibody levels (ADA)), vital signs measurements, 
abbreviated physical examinations, slit-lamp biomicroscopy, 
intraocular pressure (IOP), and dilated ophthalmoscopy. 
Pharmacodynamic and biological activity will be measured by means 
of BCVA by ETDRS, spectral-domain optical coherence tomography 
(sdOCT), color fundus photography (CFP), fluorescein angiography 
(FA), ophthalmic ultrasound, and optionally (according to 
investigator judgment) indocyanine green (ICG) angiography and 
enhanced-depth imaging optical coherence tomography (EDI-OCT). 
Pharmacokinetic (PK) and Pharmacodynamic (PD) markers will be 
evaluated by means of measuring plasma concentrations of ICON-1, 
serum cytokine levels, circulating tissue factor (TF), 
immunophenotyping, and circulating tumor DNA (CTDNA).  
For enucleation patients: immediately following the enucleation 
procedure, vitreous humor will be aspirated for intraocular ICON-1 
and proteomic analysis of TF and cytokine levels. Following the 
clinical site’s standard of care pathology of the tumor, prepared slides 
and/or tumor block samples will be sent to a central laboratory for the 

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study for additional study-related pathology evaluation of the tumor 
(including ICON-1 binding, TF expression, protease activating 
receptors 2 (PAR2) expression, immune infiltrate, and alterations of 
the vasculature), genetic profiling, and Exome sequencing of the 
tumor. Genetic profiling of the tumor previously performed with fine 
needle aspiration of the tumor does not require repeated testing.   
For brachytherapy patients:  the plaque placement procedure and 
associated follow-up will be according to the standard of care at each 
site.  
Patients (or their legally authorized representative) may choose to 
withdraw from the study for any reason at any time without prejudice.  
Study assessments for an Early Termination Visit should be 
conducted in the event a patient discontinues from the study 
prematurely. 
Study Duration 
Enrollment is anticipated to take approximately 9 months and patient 
participation will be up to approximately 7-8 weeks including up to 7 
days for screening, and up to approximately 6-7 weeks for treatment 
and follow-up. 
Number of Subjects 
Up to 13 patients will be enrolled in the study 
Study Population 
Inclusion Criteria 
Patients must meet all of the following criteria to be included in the 
study: 
1. Verbal and written informed consent obtained from the subject or 
the subject’s legal representative (as applicable). 
2. Males or females of any race, ≥18 years of age. 
3. Clinical diagnosis of primary uveal melanoma involving the 
posterior uveal tract (choroid and/or ciliary body) in the study 
eye. Patients with metastatic disease are eligible. 
4. Planned enucleation or brachytherapy for primary uveal 
melanoma in the study eye.  
5. If a woman of childbearing potential (WOCBP) (i.e., not 
postmenopausal for at least 2 years or not surgically sterile), must 
have a negative serum pregnancy test at Screening, and must use 
adequate birth control if they have a non-surgically sterile male 
sexual partner throughout the study. Adequate methods of birth 
control include hormonal contraceptives, intrauterine 
contraceptive device (IUD), condom with spermicide, 
contraceptive sponge with spermicide, diaphragm with 
spermicide and cervical cap with spermicide. 

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Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from 
the study: 
1. Uveal melanoma in the study eye originating in the anterior uveal 
tract (iris). 
2. Chronic uncontrolled glaucoma or ocular hypertension in the 
study eye defined as an IOP >25mmHg regardless of concomitant 
treatment with IOP-lowering medications.  
3. Previous participation in an investigational study of ICON-1. 
4. Known serious allergy to fluorescein sodium or indocyanine 
green for injection in angiography.  
5. Use of two or more concomitant anticoagulant treatments (direct 
thrombin inhibitor class of drugs such as Coumadin (warfarin), 
Pradaxa (dabigatran), and Xarelto (rivaroxaban)). Aspirin is not 
considered an anticoagulant in this study. For patients receiving 
one chronic anticoagulant treatment (e.g., patients with a history 
of cardiovascular/cerebrovascular diseases [events] or 
hospitalization due to such conditions), the patient must have 
confirmation of stable clotting time using the appropriate test 
(Prothrombin Time (PT), International Normalized Ratio (INR) 
(e.g., Coumadin), or activated partial thromboplastin time (aPTT) 
(e.g., Pradaxa)) over the last 6 months from the patient’s treating 
physician. Some agents do not require PT/INR/aPTT monitoring 
(e.g., Eliquis (apixaban)).  
6. Hereditary or chronic hemorrhagic or coagulopathy conditions 
(i.e., hemophilia). 
7. Use of any investigational product or device within 30 days prior 
to Screening, or planned use of an investigational product or 
device during the study. 
8. History or presence of other concurrent conditions deemed by the 
Investigator to be likely to impact the subject’s clinical safety or 
to interfere with the interpretation of the study results, such as 
optic neuritis or atrophy (related to multiple sclerosis or other 
neurological disease), uveitis, or retinal vasculitis or other 
inflammatory intraocular conditions in the study eye. 
9. Presence of any other concurrent medical condition, including 
mental illness or substance abuse, deemed by the Investigator to 
be likely to interfere with a subject’s ability to provide informed 
consent, comply with monthly study visits and assessments, or 
interfere with the interpretation of the study results. 

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10. Woman who is pregnant or lactating. 
Study Eye 
Determination 
The study eye is defined as the eye that meets all of the inclusion 
criteria and none of the exclusion criteria.  
Investigational 
Product  
The investigational product is human Immuno-conjugate 1 (ICON-1). 
ICON-1 is a recombinant fusion protein that targets and binds to the 
aberrantly expressed Tissue Factor in retinal disease, tumors and 
supporting stroma (vasculature, infiltrating mononuclear cells). It is a 
dimeric antibody-like protein with a molecular weight of 157 kDa; 
each monomer has two functional domains joined by a linker. The 
targeting domain of ICON-1 is a mutated FVIIa protein conjugated to 
an Fc effector moiety of a human IgG1 immunoglobulin.   
ICON-1 is supplied in single-use glass vials containing 0.28 mL of a 
sterile solution of ICON-1 at a concentration of 3 mg/mL in 15 mM 
HEPES, 150 mM NaCl, 25 mM Arginine, pH 7.4 with 0.01% of 
Polysorbate-80 and 5 mM CaCl2. 
Test Article 
Administration 
Patients will be enrolled in one of three cohorts:  
 0.3 mg (300 µg/100 µl) ICON-1 administered on Day 0 
 0.3 mg (300 µg/100 µl) ICON-1 administered on Day 0 and 
Day 7 
 0.6 mg (300 µg/100 µl + 300 µg/100 µl) ICON-1 administered 
on Day 0 and Day 7  
Using aseptic technique, ICON-1 will be administered by first 
withdrawing vial contents through a 5-micron 19-gauge filter needle 
attached to a 1-cc tuberculin or Luer Lock syringe and then replacing 
the filter needle with a 30-gauge x ½ inch needle for intravitreal 
injection. Adequate topical anesthesia and broad-spectrum 
microbicide will be given prior to injection.   
IOP will be measured before and after each injection. For cohort 3, 
the second intravitreal injection will be administered the same day 
following stabilization of IOP to the pre-injection level (i.e., within 5 
mmHg of the pre-injection IOP) and a minimum of 30 minutes after 
the first injection. 
Study Endpoints 
Primary Endpoints 
Safety 
 Occurrence of ocular and systemic serious adverse events 
and adverse events 

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 Changes in standard clinical laboratory tests (serum 
chemistry, hematology, coagulation) and ADA levels 
 Changes in vital signs, and physical and ophthalmic 
examinations 
Secondary Endpoints 
Pharmacokinetics and Pharmacodynamic Markers 
 Plasma levels of ICON-1 following intravitreal injections of 
ICON-1  
 Change in circulating TF levels and serum cytokine levels 
following intravitreal injections of  ICON-1 
 Characterization of immunophenotyping patterns 
Pharmacodynamic and Biological Activity 
 Change in tumor size (thickness, volume) as assessed by 
imaging techniques (CFP, FA, sdOCT, ultrasound, ICG 
angiography, EDI-OCT) from baseline  
Exploratory Endpoints 
 Characterization of the genetic profile of the tumor (Type 1 
or Type 2), and associated changes in the tumor TF with 
ICON-1 treatment 
 Characterization of pathologic findings of the tumor (ICON-
1 staining of tumor structures, TF and PAR2 expression, 
characterization of the immune infiltrate, and alterations of 
the vasculature)  
 ICON-1 and proteomic analysis (TF and other cytokine 
levels) of the vitreous humor   
Statistical Analyses 
All patients who receive ICON-1 will be considered evaluable and 
will be included in the analysis. This study is exploratory and its 
sample size is not determined by statistical power considerations. 
There are no interim analyses planned; however, patient clinical and 
safety data will be examined on an ongoing basis to ensure patient 
safety and compliance with the dose escalation rules. 
 

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5 
TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................................... 1 
1 
SPONSOR SIGNATURE PAGE .................................................................................................... 3 
2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ................................................................... 4 
3 
KEY ROLES AND CONTACTS ................................................................................................... 5 
4 
PROTOCOL SYNOPSIS ................................................................................................................ 6 
5 
TABLE OF CONTENTS .............................................................................................................. 13 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 17 
7 
ETHICS ......................................................................................................................................... 21 
7.1 
Institutional Review Board ................................................................................................ 21 
7.2 
Ethical Conduct of the Study ............................................................................................. 21 
7.3 
Subject Information and Consent ...................................................................................... 22 
8 
INTRODUCTION ........................................................................................................................ 23 
8.1 
Background ....................................................................................................................... 23 
8.2 
Nonclinical Studies............................................................................................................ 28 
8.3 
Clinical Experience with ICON-1 ..................................................................................... 30 
8.4 
Study Rationale ................................................................................................................. 31 
9 
STUDY OBJECTIVES ................................................................................................................. 33 
9.1 
Primary Objective.............................................................................................................. 33 
9.2 
Secondary Objectives ........................................................................................................ 33 
9.3 
Exploratory Objective ....................................................................................................... 33 
10 INVESTIGATIONAL PLAN ....................................................................................................... 34 
10.1 
Overall Study Design and Plan ......................................................................................... 34 
10.2 
Study Sites ......................................................................................................................... 37 
10.3 
Discussion of Study Design .............................................................................................. 37 
10.4 
Appropriateness of Measurements .................................................................................... 37 
11 STUDY POPULATION ............................................................................................................... 39 
11.1 
Target Population .............................................................................................................. 39 
11.2 
Inclusion Criteria ............................................................................................................... 39 
11.3 
Exclusion Criteria .............................................................................................................. 39 
11.4 
Study Eye Determination .................................................................................................. 40 
12 STUDY TREATMENTS .............................................................................................................. 41 
12.1 
Study Drug Dosage and Administration ............................................................................ 41 
12.1.1 
Investigational Product (ICON-1) ..................................................................... 41 
12.1.2 
Test Article Administration............................................................................... 41 
12.2 
Study Drug Packaging, Labeling and Storage ................................................................... 41 
12.3 
Selection of Doses and Timing of Doses .......................................................................... 42 
12.4 
Criteria for Dose-Escalation and Stopping Rules .............................................................. 42 
12.5 
Measurement of Study Drug Compliance ......................................................................... 43 
12.6 
Study Drug Accountability ................................................................................................ 43 
12.7 
Prior and Concomitant Therapy ........................................................................................ 43 
12.8 
Other Study Supplies ......................................................................................................... 44 
13 TREATMENT ASSIGNMENT .................................................................................................... 45 
13.1 
Subject Identification Numbers ......................................................................................... 45 
13.2 
Enrollment and Method of Assigning Patients to Treatment Arms .................................. 45 
14 STUDY PROCEDURES .............................................................................................................. 46 
14.1 
Visit 1 (All cohorts): Screening (Day -7 through 0) .......................................................... 46 
14.2 
Visit 2 (All cohorts): Baseline (Treatment Day 0) ............................................................ 47 

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14.3 
Visit 3 (All cohorts): Day 1 ............................................................................................... 48 
14.4 
Visit 4 (Cohorts 2 and 3 only): Treatment Day 7 (±2 days) .............................................. 48 
14.5 
Visit 5 (Cohorts 2 and 3 only): 1 day post Day 7 treatment .............................................. 49 
14.6 
Visit 6 (All Cohorts): Procedure Assessments (On or 1 day prior to Surgical 
Procedure day) ................................................................................................................... 49 
14.7 
Visit 7 (All Cohorts): End of Study: 30 days ±5 days post Surgical Procedure ................ 51 
14.8 
Early Termination Visit ..................................................................................................... 51 
14.9 
Unscheduled Visits ............................................................................................................ 53 
14.10 Patient Withdrawal from Treatment or Study ................................................................... 53 
14.10.1 
Handling of Withdrawals .................................................................................. 53 
14.10.2 
Replacements .................................................................................................... 54 
14.10.3 
Sponsor or Regulatory Agency Termination of the Study ................................ 54 
15 STUDY ASSESSMENTS ............................................................................................................. 55 
15.1 
Informed Consent .............................................................................................................. 55 
15.2 
Eligibility Assessment ....................................................................................................... 55 
15.3 
Demographic Data ............................................................................................................. 55 
15.4 
Medical, Surgical, and Ocular History .............................................................................. 55 
15.5 
Prior and Concomitant Therapy ........................................................................................ 56 
15.6 
Vital Signs ......................................................................................................................... 56 
15.7 
Abbreviated Physical Examination ................................................................................... 56 
15.8 
Best-corrected Visual Acuity ............................................................................................ 56 
15.9 
Slit-lamp Biomicroscopy ................................................................................................... 56 
15.10 Intraocular Pressure ........................................................................................................... 57 
15.11 Dilated Ophthalmoscopy ................................................................................................... 57 
15.12 Color Fundus Photography ................................................................................................ 57 
15.13 Ophthalmic Ultrasound ..................................................................................................... 58 
15.14 Spectral-Domain Optical Coherence Tomography ........................................................... 58 
15.15 Enhanced Depth Imaging Optical Coherence Tomography .............................................. 58 
15.16 Fluorescein Angiography .................................................................................................. 58 
15.17 ICG Angiography .............................................................................................................. 59 
15.18 Clinical Laboratory Evaluations and Immunogenicity ...................................................... 59 
15.19 Pharmacokinetic and Pharmacodynamic Markers ............................................................ 60 
15.20 Proteomic Analysis of Vitreous......................................................................................... 60 
15.21 Tumor Pathology, Genetic Profiling and Exome Sequencing ........................................... 61 
15.22 Evaluation of Adverse Events ........................................................................................... 61 
15.22.1 
Definition of an Adverse Event......................................................................... 61 
15.22.2 
Serious Adverse Event ...................................................................................... 63 
15.22.3 
AE Severity ....................................................................................................... 63 
15.22.4 
Study Drug Causality ........................................................................................ 64 
15.22.5 
Adverse Events of Special Interest (AESIs) ..................................................... 64 
15.22.6 
Adverse Event Reporting Procedures ............................................................... 65 
15.22.7 
Reporting Serious Adverse Events to Regulatory Agencies ............................. 65 
15.22.8 
Pregnancy .......................................................................................................... 66 
15.22.9 
Overdose ........................................................................................................... 66 
15.22.10 Follow-up of Adverse Events............................................................................ 67 
15.22.11 Follow-up of Post-study Serious Adverse Events ............................................. 67 
16 STUDY ENDPOINTS .................................................................................................................. 68 
16.1 
Primary Endpoints ............................................................................................................. 68 
16.2 
Secondary Endpoints ......................................................................................................... 68 
16.3 
Exploratory Endpoints ....................................................................................................... 68 

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17 STATISTICAL ANALYSIS AND METHODS PLANNED ....................................................... 69 
17.1 
Statistical Analysis Plans ................................................................................................... 69 
17.2 
Analysis of the Conduct of the Study ................................................................................ 69 
17.3 
Handling of Dropouts or Missing Data ............................................................................. 69 
17.4 
Analysis of Treatment Arm Comparability ....................................................................... 69 
17.5 
Treatment Exposure .......................................................................................................... 69 
17.6 
Safety Analyses ................................................................................................................. 69 
17.7 
Biological Activity Analyses ............................................................................................. 70 
17.8 
Pharmacokinetic and Pharmacodynamic Markers Analyses ............................................. 70 
17.9 
Interim Analysis ................................................................................................................ 70 
17.10 Sample Size Determination ............................................................................................... 71 
18 DATA HANDLING AND RECORD KEEPING ......................................................................... 72 
18.1 
Case Report Forms and Source Documents ...................................................................... 72 
18.2 
Monitoring of the Study .................................................................................................... 72 
18.3 
Data Management.............................................................................................................. 73 
18.4 
Inspection of Records ........................................................................................................ 73 
18.5 
Study Record Retention ..................................................................................................... 74 
19 ADMINISTRATIVE CONSIDERATIONS ................................................................................. 75 
19.1 
Confidentiality ................................................................................................................... 75 
19.2 
Amendments to the Protocol ............................................................................................. 75 
19.3 
Protocol Deviations ........................................................................................................... 75 
19.4 
Study Reporting Requirements ......................................................................................... 76 
19.5 
Financial Disclosure .......................................................................................................... 76 
19.6 
Investigator Responsibilities ............................................................................................. 76 
19.7 
Clinical Trial Agreement ................................................................................................... 76 
19.8 
Policy for Publication and Presentation of Data ................................................................ 76 
20 REFERENCES .............................................................................................................................. 77 
21 APPENDICES .............................................................................................................................. 80 
21.1 
Appendix A:  Study Flowchart and Assessments – Cohort 1 (Patients Undergoing 
Enucleation or Brachytherapy) .......................................................................................... 81 
21.2 
Appendix B:  Study Flowchart and Assessments – Cohorts 2 and 3 (Patients 
Undergoing Enucleation or Brachytherapy) ...................................................................... 84 
 
 
 

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LIST OF IN-TEXT TABLES 
Table 1:  Toxicology and Immunogenicity Studies of ICON-1 .......................................28 
Table 2:  Summary of Preclinical Data Showing Anti-cancer Activity of 
ICON-1 ...................................................................................................30 
Table 3:  CTCAE Grading ................................................................................................63 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Signaling Pathways Involved in TF Expression ...............................................25 
Figure 2: Function of TF in Cancer Progression ..............................................................26 
Figure 3: Molecular Structure of ICON-1 ........................................................................27 
Figure 4: Study Design Schema .......................................................................................36 
 

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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
anti-drug antibody 
ADL 
Activities of Daily Living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AMD 
age-related macular degeneration 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BCVA 
best-corrected visual acuity 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFP 
color fundus photography 
CFR 
Code of Federal Regulations 
CMC 
circulating metastatic cells 
CNV 
choroidal neovascularization 
CO2 
carbon dioxide 
CPK 
creatine phosphokinase 
CrCl 
creatinine clearance 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRT 
Central Retinal Thickness 
CST 
central retinal subfield thickness 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTDNA 
Circulating tumor DNA 
DC 
dendritic cell 
DLT 
Dose Limiting Toxicity 
DMP 
Data Management Plan 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ERG 
electroretinography 
EDI-OCT 
enhanced depth imaging optical coherence tomography 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
fluorescein angiography 

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FAF 
fundus autofluorescence 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
g 
gram 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
Hct 
hematocrit 
Hgb 
hemoglobin 
ICON-1 
human Immuno-conjugate 1 (ICON-1) 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICGA 
Indocyanine green angiography 
ICH 
International Conference on Harmonisation 
IgG 
immunoglobulin G 
IHC 
immunohistochemistry 
INR 
International Normalized Ratio 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IUD 
intrauterine contraceptive device 
IVT 
intravitreal 
kg 
kilogram 
LDH 
lactic dehydrogenase 
Lin 
lineage markers 
MAb 
monoclonal antibody 
MAD 
maximum administered dose 
M-CSF 
macrophage colony-stimulating factor 
MCV 
mean corpuscular volume 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MDSC 
myeloid derived suppressor cell 
mg 
milligram 
mL 
milliliter 
MPV 
mean platelet volume 

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MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
ng 
nanogram 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect-level 
OM 
ocular melanoma 
OTC 
over-the-counter 
PAR2 
protease activating receptors 2 
PCV 
polypoid choroidal vasculopathy 
PD 
pharmacodynamics 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PT 
Prothrombin Time 
RBC 
red blood cell 
RDW 
red cell distribution width 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sdOCT 
spectral-domain optical coherence tomography 
SEER 
Surveillance, Epidemiology, and End Results 
SOC 
Standard-of-Care 
SRC 
Safety Review Committee 
TAM 
tumor-associated macrophage 
TCR 
Tissue-Cross-Reactivity 
TF 
tissue factor 
USPC 
uterine serous papillary adenocarcinoma 
UM 
uveal melanoma 
VEGF 
vascular endothelial growth factor 
VA 
visual acuity 
WBC 
white blood cell 
WOCBP 
women of child-bearing potential 
 
 
 
In this protocol, Sponsor duties refer to responsibilities that will be performed by the Sponsor, 
the Sponsor’s designee or the Sponsor’s designated CRO. In this protocol, Investigator refers to 

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the Principal Investigator or his/her designee who is responsible for performing study 
evaluations. 

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7 
ETHICS 
7.1 
Institutional Review Board  
The protocol, Investigator’s Brochure, informed consent form (ICF), advertisements to be used 
for patient recruitment, and any other written information provided to patients for this study, 
including all consent forms translated to a language other than the native language of the clinical 
site must be approved by the Investigator’s Institutional Review Board (IRB) or Ethics 
Committee (EC) before the study is initiated at a site. Documentation of this approval must be 
maintained by the clinical site and provided to the Sponsor (or designee) and must be made 
available during an inspection by the US Food and Drug Administration (FDA) or other 
regulatory agency inspectors. Prior to initiating the study, the Investigator will obtain written 
confirmation that the IRB is properly constituted and compliant with International Conference on 
Harmonisation (ICH) and Good Clinical Practice (GCP) requirements, and all applicable laws 
and local regulations. 
The study will not be initiated at your site until documentation confirming approval of the 
protocol, ICF, and any written materials supplied to the patient are received by the Sponsor or its 
designee. Approval documentation from the IRB/EC should be signed by the IRB/EC 
chairperson or designee, identify the IRB/EC by name and address, refer to the study protocol by 
title and/or protocol number and version or date, identify documents reviewed, and include the 
date of the review and approval or favorable opinion was granted.   
Appropriate reports on the progress of the study will be made to the IRB/EC and to the Sponsor 
(or designee) by the Investigator in accordance with applicable governmental regulations and 
local regulations, and in agreement with policies of the IRB/EC. The Investigator must provide 
written documentation of the following to the Sponsor (or designee): 
 IRB/EC periodic (e.g., semi-annually, annually) re-approval of the protocol as required 
by the site’s IRB 
 IRB/EC approvals of any amendments to the protocol or revisions to the ICF 
 IRB/EC receipt of safety and SAE reports, as appropriate 
 Any additional submissions (including an end of study report) required by the site’s 
IRB/EC. 
7.2 
Ethical Conduct of the Study 
This study will be conducted in compliance with GCP as described in FDA regulations (21 CFR 
parts 50, 54, 56, and 312), the ICH document “Guidance for Good Clinical Practice, E6 (R1),” 
and the principles of the World Medical Association Declaration of Helsinki – Ethical Principles 
for Medical Research Involving Human Subjects, including all amendments and Notes of 
Clarification. The Investigator is expected to comply with the requirements of the protocol, and 
will conduct all aspects of this study in accordance with all national, state, and local laws or 
regulations. 

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7.3 
Subject Information and Consent 
Written informed consent in compliance with FDA regulations (21 CFR 50.25), the ICH 
document “Guideline for Good Clinical Practice, E6 (R1),” and other applicable local regulations 
shall be obtained from each patient prior to entering the study or performing any study related 
procedure. An ICF template will be provided by the Sponsor (or designee) to clinical sites. The 
ICF will be submitted by the Investigator to his or her IRB/EC for review and approval prior to 
the start of the study. If any modifications to the content are proposed or made by the site, the 
ICF should be reviewed by the Sponsor (or designee) prior to IRB/EC submission. 
The investigator is responsible for obtaining written informed consent from each patient 
participating in the study. If there are any revisions to the ICF during the course of the study, all 
active participating patients must be re-consented using the revised ICF in a timely fashion.   
Informed consent must be obtained from the patient before any study related screening activity 
or treatment is undertaken that is not part of routine care. This includes, but is not limited to, the 
performance of diagnostic or therapeutic procedures and the administration of the first dose of 
the study treatment. All pertinent aspects of the study must be explained to the prospective 
patient and/or the patient’s legally authorized representative before signing the ICF. The patient 
and/or patient’s legally authorized representative will be informed that participation is voluntary 
and he/she can withdraw from the study at any time. The patient and/or patient’s legally 
authorized representative will be allowed to read the IRB/EC approved ICF. Once the 
Investigator or designee is assured the patient/patient’s legally authorized representative agrees 
to participate in the study, the patient/legally authorized representative will be asked to give 
consent by signing the ICF. The ICF must be signed and dated by the patient or by the patient’s 
legally authorized representative, and by the person who conducted the informed consent 
discussion, and witness (if required). The Investigator shall provide a copy of the signed and 
dated ICF to the patient/patient’s legally authorized representative. The original shall be 
maintained in the patient’s medical records at the site. This document should not be displayed or 
made accessible to any third party except the Sponsor, its designee or regulatory agency 
representatives. 
If a patient permanently revokes informed consent and declines further observation and/or 
contact, then this must be clearly documented in the patient’s chart and recording of further data 
will be discontinued. 

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8 
INTRODUCTION 
8.1 
Background 
Ocular melanoma (OM) is the second most common primary malignant melanoma in adults and 
leads to significant mortality and ocular morbidity [1]. About 95% of OM tumors can be 
described as Uveal Melanoma (UM), which develop in the melanocytes (pigment cells) of the 
eye and primarily affect the choroid, iris and ciliary body of the uveal tract [2,3]. Using data 
from the Surveillance, Epidemiology, and End Results (SEER) program the mean age-adjusted 
incidence of UM in the US is estimated to be 5.1 per million. An estimated 2,000 new cases of 
UM are diagnosed each year (2,4). In Europe the rate of new cases ranges from over 2 per 
million in Spain and Italy to over 6 per million in northern European countries [5,6]. 
Current Therapies and Unmet Therapeutic Need 
Standard-of-Care (SOC) for OM is currently radiation therapy or surgical removal of the eye 
(enucleation).  There are no chemotherapy agents or targeted biologics approved by the FDA for 
treatment of OM.  Small tumors (<10 mm in diameter and <2 mm in height) are often observed 
until growth is documented. Symptomatic patients with medium or large tumors usually receive 
some form of radiation, either plaque radiotherapy (brachytherapy) or proton beam radiation [2]. 
However, these radioactive therapies are highly invasive and lead to further complications 
including retinopathy, cataracts, glaucoma and significant vision loss. For large tumors 
enucleation is usually performed. Thus, there is a need for treatment of OM that avoids the loss 
of an eye or the acute and chronic complications of radiation, while still preserving sight. 
Neither radiation nor enucleation affects the rate at which metastatic disease occurs [7]. While 
local recurrence in the eye is rare, five- and ten-year rates of distant metastasis of 25 and 34 
percent have been reported [8] and nearly half of all ocular melanomas will eventually develop 
distant metastasis, primarily in the liver, with lung and bone marrow the other sites. Once 
metastases have occurred, median survival is between 6 and 12 months. In fact, approximately 
50 percent of all patients will die of metastatic disease within 10 years following diagnosis, 
despite early diagnosis of the primary tumor, successful local treatment, and close follow-up [9]. 
There is an urgent need for new therapeutic strategies for OM that are not only less or non-
invasive, but that also have a potential to slow the onset of metastases.  
Prognostic Markers in Uveal Melanoma 
Proper assessment of the extent of disease and propensity for metastasis is one of the major 
challenges in the current management of UM.  For example, UM is not only a localized ocular 
disease; circulating tumor cells (CTCs) have been observed as early as initial diagnosis [10].  In 
uveal melanoma patients, the presence of tyrosinase RNA in the peripheral blood was found to 
be associated with the stage of disease and predicted disease progression in patients with early as 
well as advanced melanoma [11,12,13]. In fact, the presence of tyrosinase or MelanA/MART1 
transcripts is an independent prognostic factor in patients with high-risk primary UM [14,15,16]. 
However, as with cutaneous melanoma [17], multiple markers will likely be needed to increase 
the sensitivity of tumor cell detection, i.e. micrometastasis, in UM. 

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The Molecular Pathogenesis of Uveal Melanoma 
Uveal melanoma harbors early activating mutations in GNAQ or GNA11 found in 80 percent of 
primary uveal melanomas [18].  Mutations in BRCA1-associated protein-1 (BAP1) and splicing 
factor 3B subunit 1 (SF3B1) occur later in tumor progression and are mutually exclusive [19]. 
Ciliary body tumor location has also been associated with monosomy 3 and gains in 
chromosome 8, both molecular markers of poor prognosis [20]. 
Uveal Melanomas Classification 
Type 1 Low Risk of Metastasis or Type 2 High Risk of Metastasis are based on gene expression 
profile. Genes that discriminate class 1 (low-risk) from class 2 (high-risk) include highly 
significant clusters of down-regulated genes on chromosome 3 and up-regulated genes on 
chromosome 8q [21]. Tumors have begun to be classified as having low (class 1) or high (class 
2) metastatic potential, depending on the expression of 15 genes [22]. 
Why Target Tissue Factor in Uveal Melanoma 
Tissue Factor is a 46kd 263 amino acid single chain transmembrane glycoprotein. Tissue Factor 
plays a key role in health and disease. In normal homeostasis it is involved in the initiation of 
coagulation via its external domain and mediation of pro-inflammatory pathways via extra and 
intracellular signaling. In tumor biology it has been shown to trigger angiogenesis, tumor growth 
and metastasis, and promote an inflammatory immune environment (via extra- and intracellular 
signaling).   
Two studies support the role of TF in UM. Direct evidence comes from Walker et al who 
showed TF was expressed at elevated levels in cell lines of uveal melanoma compared with 
normal uveal melanocytes by several techniques including Western blotting, RNAase protection 
and Reverse Transcription PCR [23].  In another study, Van Raamsdonk et al found that 83% of 
the 713 uveal melanomas they analyzed had somatic mutations in GNAQ or GNA11, both of 
which are genes coding for the alpha subunit of G proteins. They concluded that GNAQ and 
GNA11 are activated in a MET-PI3K-dependent manner, and are significant contributors to the 
development of UM [18]. Activation of the MET-P13K pathway has been shown to increase TF 
expression in cancer (Figure 1) [24]. 

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Figure 1: Signaling Pathways Involved in TF Expression 
 
(Figure 1 from Han et al. Journal of Hematology & Oncology 2014,7:54)  
Molecular Basis for Tissue Factor Signaling in Tumorigenesis and Metastasis 
1) TF regulates tumor cell proliferation and apoptosis. The TF/Vll complex initiates many of its 
activities by activation of Protease Activated Receptors (PAR2) (Figure 2). The TF/Vll/PAR2 
complex can lead to activation of enzymatic pathways (PKC, MAPK, P13K) regulating cell 
proliferation as well as inhibition of apoptosis by prevention of activation of caspase 3 [25]. 
2) TF promotes tumor angiogenesis and metastasis. Blood vessels in tumor tissues are essential 
for tumor progression and neovasculature is a prerequisite for blood-borne metastasis. 
TF/FVIIa/PAR2 induces the production of proangiogenic factors (VEGF) and migration 
promoting factors such as fibroblast growth factor 2 (FGF2), cysteine-rich 61 (Cyr61), CXCL1 
and IL-8 [26]. TF exhibits its pro-metastatic characteristics in part by initiating the pro-coagulant 
cascade in the tumor microenvironment, including thrombin formation, fibrin generation and 
platelet activation. This fibrin-platelet “clot” formation is essential for generating a shield around 
tumor cells to facilitate the spread of tumor cells and the escape of newly formed 
micrometastasis from natural killer (NK) cell-mediated cytolysis [27]. 

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Figure 2: Function of TF in Cancer Progression 
 
 
Immuno-oncology:  TF can modulate immune responses within the tumor microenvironment. 
Once thrombin is generated, it can directly cleave complement component C5 to produce C5a 
and C5b. C5a has a pro-tumor effect via recruiting myeloid derived suppressor cells to the tumor 
microenvironment, resulting in an immunosuppressive milieu [28]. 
Increased TF expression by cancer cells and supporting stroma leads to the secretion of a variety 
of chemokines, cytokines and to the accumulation of Type 2 macrophages (TAMs) within the 
tumor. Tumor-associated macrophages (TAMs) actively promote tumor growth by supporting 
the recruitment and development of myeloid derived suppressor cells (MDSCs). Tumor 
associated macrophages (Type 2 macrophages) produce high levels of IL-10, TGF-beta and low 
levels of IL-12. Type 1 macrophages produce low levels of IL-10 and high levels of IL-12.   
Myeloid derived suppressor cells (MDSCs) are characterized by the ability to suppress cytotoxic 
functions of T cells and NK cells - a key mechanism of tumor defense. MDSCs originate from 
myeloid progenitor cells and are immature cells that do not differentiate into granulocytes, 
macrophages, or dendritic cells (DCs).  
Figure 2. Function of TF in cancer progression. TF forms TF/FVIIa complex and subsequently induce PAR 
signaling using GPR alpha, beta, gamma (G protein coupled receptors). PKC is phosphorylated by activated PAR 
complex, which leads to p-PKC translocation. PAR can also induce MAPK and PI3K activation, both of which 
trigger pro-tumor effects, such as proliferation, angiogenesis and metastasis. Binding to activator protein (AP) can 
also induce c-Jun up regulation and in turn promote tumor progression. Moreover, TF binding to ABP-280 leads 
to actin modulation, resulting in tumor cells metastasis. As TF binds to integrin receptor and enhances the ability 
of migration, in turn leading to tumor cell angiogenesis and migration (From Han et al. Journal of Hematology & 
Oncology 2014, 7:54). 

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In general, human MDSCs are defined as CD11b-positive, CD33-positive, HLA-DR-negative or 
low, and lineage markers (Lin) (CD3, CD14, CD19, CD56) negative. Multiple tumor-derived 
factors secreted from the tumor and tumor stroma (tumor associated macrophages, fibroblasts 
and vascular endothelium) drive MDSC recruitment and differentiation. These tumor- derived 
factors include granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte 
colony-stimulating factor (G-SCF), macrophage colony-stimulating factor (M-CSF), IL-1𝛽, IL-6, 
VEGF, IL-13, IL-10, prostaglandin E2. Among these factors, GM-CSF and IL-6 may be most 
powerful in inducing MDSCs from bone marrow progenitors. GM-CSF is required for 
recruitment of MDSCs to the tumor microenvironment. Tumor-derived CXCR2 ligands (IL-8, 
CXCL1, CXCL2, CXCL5) also attract MDSCs to the tumor microenvironment [29]. 
ICON-1  
Iconic Therapeutics, Inc. has developed a therapeutic immunoprotein known as ICON-1 to target 
and bind TF. ICON-1 is a recombinant fusion protein, an antibody-like protein with a molecular 
weight of 157 kDa, that has two functional domains, one targeting and one effector domain 
joined by a linker (Figure 3). The targeting moiety of ICON-1 is a mutated factor VIIa protein 
and the Fc portion from a human IgG1 immunoglobulin is unchanged and maintains its effector 
function. The mutated VIIa is defective as a clotting signal but retains its specific high affinity 
for TF. When ICON-1 binds to TF expressed on the surface of cells, the Fc moiety is activated as 
it binds to the Fc receptor on NK cells, initiating cell-mediated cytotoxicity [30]. Secondary 
mechanisms of action that may be involved include complement activation and interference with 
TF intracellular signaling. 
Figure 3: Molecular Structure of ICON-1 
 
 
There are several mechanisms through which ICON-1 is thought to affect tumor growth and 
development. Early pre-clinical work demonstrated the ability of ICON-1 to cause antibody 
dependent cell mediated cytotoxicity of tumor target cells, and vascular endothelium. Other 
mechanisms under investigation include complement mediated cytotoxicity of targeted tissues 
and blockade of TF dependent internal signaling. The therapeutic potential of ICON-1 is derived 
via the FVIIa targeting moiety, ICON-1 binds to the TF expressed on the surface of endothelial 

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cells, tumor cells and tumor infiltrating macrophages interfering with TF’s intracellular signaling 
and their function of inducing angiogenesis and mediating inflammation. Secondly, the TF-
bound ICON-1 molecule, through its Fc effector region, signals the immune system to release 
natural killer (NK) cells and initiate cell-mediated cytotoxicity towards the tumor and its 
supporting stroma (vascular endothelium and infiltrating inflammatory cells). 
8.2 
Nonclinical Studies 
Several in vitro and in vivo studies support the characterization of the nonclinical 
pharmacodynamics, safety pharmacology, pharmacokinetics, and toxicology of ICON-1 in 
models of TF overexpression. 
A summary of the toxicology and immunogenicity studies conducted with ICON-1 via 
intravenous, intravitreal and subcutaneous administration are listed in Table 1. The intravitreal 
administration animal studies tested both single and repeated doses of ICON-1.  
Table 1:  Toxicology and Immunogenicity Studies of ICON-1 
Study Type 
Animal 
Model 
Number 
of 
Animals 
Route 
Dose 
Duration 
GLP; Tissue Cross 
Reactivity  
human  
≥3 
in 
vitro 
5, 30 μg/mL  
 
NA  
Exploratory  
mini-pig  
3 
IV 
3-24 μg/kg  
 
12 days  
Exploratory  
mini-pig  
3 
IVT 
510 μg  
12 days  
GLP; Single dose, 
PK  
mini-pig  
24 
IV 
6, 20, 60 μg/kg  
 
8 days  
  
GLP; Single dose  
rabbit  
9 
IVT 
150 μg  
8 days  
GLP; Repeat dose  
mini-pig  
24 
IVT 
60, 200, 600 μg  
94 days  
Potential 
immunogenicity 
monkey 
and dog 
6 
SC 
600 µg 
43 days 
 
Pharmacokinetic evaluations were conducted in the mini-pig from which a half-life and no-
observed-adverse-effect-level (NOAEL) were determined. Pharmacokinetics evaluation of 
ICON-1 after intravenous administration in the porcine species determined the half-life of ICON-
1 at 14.1 to 30.6 hours and the NOAEL of 60 μg/kg [data on file, Iconic Therapeutics]. 
ICON-1 was shown in vitro to have no effect on thrombin generation up to a concentration of 1 
micromolar [data on file, Iconic Therapeutics]. 

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A standard Tissue Cross-Reactivity (TCR) study was performed to determine if ICON-1 binds to 
normal human tissues and examine potential toxicities associated with ICON-1 administration.  
The findings from this study suggested that ICON-1 did not react with normal human tissues, 
when tested at the experimentally-determined optimal concentration (5 μg/mL) or at a 6-fold 
higher level. Staining was only observed in the positive control colon carcinoma tumor. Positive 
staining results may be indicative of potential toxicities associated with administration of ICON-
1 to humans in vivo. These findings confirm ICON-1 does not interact with normal tissue [data 
on file, Iconic Therapeutics]. 
Single intravitreal (IVT) administration of ICON-1 in the rabbit eye induced a mild ocular 
inflammatory response. Repeated dosing in the mini-pig induced a robust immune response and 
resulted in ocular inflammatory reactions, most evident after the second dose. The subcutaneous 
administration of ICON-1 in dogs and monkeys resulted in a robust immune response in anti-
drug antibodies in all animals, as early as 15 days after the drug administration. 
These nonclinical results indicated that a single IVT dose of up to 600 μg of ICON-1 was 
tolerable and safe in mini-pigs. The mutated FVIIa present in the ICON-1 molecule has minimal 
thrombin generation activity. The ocular reactions observed with the repeated IVT dose in mini-
pigs as well as the anti-drug antibody (ADA) response after subcutaneous administration in dogs 
and monkeys, suggested a species-specific immune response most likely due to the heterologous 
nature of the human protein in the three different species. 
These results were the basis of and supported the initiation of a single IVT ascending dose study 
of ICON-1 in humans, patients with CNV associated with wet AMD. 
Anti-cancer Activity of ICON-1 
TF is overexpressed in the pathological neovasculature of solid cancerous tumors and plays a 
role in tumor growth, tumor angiogenesis, metastasis, and thrombosis. Previous attempts to 
target TF have resulted in disruption of the clotting cascade, resulting in unacceptable safety 
profiles. ICON-1 has demonstrated activity against tumors by binding to TF, as well as 
preliminary safety data showing it does not disrupt normal clotting. 
Table 2 lists in vitro and in vivo nonclinical studies demonstrating the anti-cancer activity of 
ICON-1. The in vivo studies showed that ICON-1 was safe and effective when administered 
systemically. 
The in vitro studies suggest that part of the mechanism of action of ICON-1 is due to cell-
dependent cytotoxicity. Cocco et al [30] examined the response of chemotherapy-resistant 
primary uterine serous papillary adenocarcinoma (USPC) cell lines to ICON-1 treatment in 
chromium release assays. Using rituximab as a control, USPCs overexpressing TF were shown 
to be highly sensitive to ICON-1 as measured by cell-mediating killing (65.6% ± 3.7%; range 
57.5 - 77.0%, P< 0.001). In contrast, virtually no cytotoxicity against USPCs was observed in 
controls (controls = untreated, no ICON-1; rituximab treatment). 
When the molecule was tested in animal models of carcinoma, murine ICON-1 (delivered by an 
adenoviral vector) was shown to be effective in SCID-Hu and full murine models against 

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cutaneous melanoma, uterine, prostate and tongue carcinoma [31,32,33,34]. Adenoviral vector 
production of murine ICON-1 cause tumor regression in xenografts models.  
Table 2:  Summary of Preclinical Data Showing Anti-cancer Activity of ICON-1 
Year 
Author 
Type of cancer 
1999  
Hu et al [31]  
Tumor vasculature endothelial cells  
1999  
Wang et al [35] 
Human melanoma cells  
2000  
Hu and Garen [32] 
Human and mouse melanoma cells  
2001  
Hu and Garen [33] 
Tumor vasculature endothelial cells and mouse 
prostate cancer cells  
2010  
Hu and Li [34]  
Human tongue cancer cells  
2010  
Cocco et al [30] 
Uterine serous papillary carcinoma  
2010  
Cocco et al [36] 
Adenocarcinoma and squamous cell carcinoma of 
cervix 
 
8.3 
Clinical Experience with ICON-1 
In clinical studies conducted by Iconic Therapeutics, more than one hundred (100) patients have 
been administered ICON-1 as single doses, or repeated doses either as monotherapy or in 
combination with other therapies. A first-in-human Phase 1 study (IT-001) initiated in October 
2010 and completed in July 2012, evaluated administration of single doses of ICON-1 in 18 
patients with choroidal neovascularization (CNV) due to age-related macular degeneration (wet 
AMD). The study population included both treatment-naïve patients and patients previously 
treated with chronic anti-VEGF therapy. In an ongoing Phase 2, randomized, double-masked, 
active-controlled study (IT-002) in patients with CNV secondary to AMD, 88 patients have been 
enrolled. 
The Phase 1 study (IT-001) was an open-label, single intravitreal dose, dose-escalating design. 
There were no control groups in this study. Six patients each were enrolled in one of three 
different cohorts of ICON-1; 60 μg, 150 μg, and 300 μg. The three cohorts were enrolled 
sequentially employing a traditional 3+3 design. The planned maximum administered dose in 
this study was 300 μg ICON-1. The maximum tolerated dose (MTD) of ICON-1 would be 
identified as the maximum dose at which no more than 1 of 6 patients had a confirmed 
significant safety event (or 300 μg, the highest dose contemplated in the protocol). At the 
investigator’s discretion, treatment with bevacizumab (Avastin®) or ranibizumab (Lucentis®) 
therapy was allowed two weeks after injection of ICON-1 as rescue therapy. Patients could 
receive standard of care anti-VEGF therapy at any time thereafter. Patients were followed for 
safety and efficacy for 6 months following administration of ICON-1. The primary objectives of 
the study were to establish a preliminary safety profile of ascending doses of ICON-1 and to 
determine the MTD that can be administered by intravitreal injection as measured by the 

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occurrence of ocular and systemic adverse events. Ocular and systemic events were assessed by 
means of vital signs measurement, ophthalmic examinations, intraocular pressure measurement, 
and the presence of anti-ICON-1 antibodies.  
The administration of single intravitreal doses of ICON-1 was demonstrated to be safe and well 
tolerated in all three doses tested. There were no systemic or ocular dose-limiting toxicities and a 
maximum tolerated dose was not determined up to the maximum administered dose of 300 μg 
ICON-1. Most frequently reported adverse events were ocular (conjunctival hemorrhage [n=5], 
vitreous floaters [n=3], conjunctival edema [n=3], and signs of macular degeneration [n=3]) and 
commonly related to the injection procedure or the retinal signs of the underlying AMD. Only 
one adverse event, a case of vitritis in the 300 μg cohort was considered by the Investigator to be 
related to study drug. No retinal or choroidal abnormalities were noted on clinical examination or 
angiographically. There were no systemic adverse events reported. No significant systemic levels 
of ICON-1 or antibodies to ICON-1 were detected. Single dose administration of ICON-1 in the 
Phase 1 study demonstrated preliminary evidence of biologic activity and pharmacodynamic 
effect relevant to wet AMD; clinical improvement in BCVA, associated with a reduction in CRT 
(on OCT) and a decrease of CNV area of leakage (on FA) in some patients.  
The ongoing Phase 2 study (IT-002) is the first study to examine administration of repeated 
intravitreal doses of ICON-1. Eighty eight (88) patients ≥50 years of age with CVN secondary to 
AMD were enrolled in this study from approximately 49 centers located in the United States. 
The study was designed to test the safety of repeated intravitreal injections of 0.3 mg ICON-1 
administered as monotherapy or in combination with ranibizumab (Lucentis®) compared to 
ranibizumab monotherapy, and to test proof of concept by evaluating biologic activity and 
clinical outcomes of the three treatment arms. Patients will receive up to six (6) monthly 
intravitreal administrations of study treatment and followed for safety and efficacy through one 
month following administration of the last intravitreal treatment. Safety is evaluated by means of 
the occurrence of ocular and systemic adverse events, and changes in clinical laboratory tests, 
vital signs and ophthalmic evaluations. In addition, the pharmacokinetic and immunogenetic 
evaluation of the presence of ICON-1 in the systemic circulation is being performed. Biologic 
and pharmacodynamic effect is assessed by means of changes in visual acuity, qualitative and 
quantitative anatomic changes to the retina and CNV as measured by sdOCT, FA, fundus 
autofluorescence imaging (FAF) and CFP. 
Eighty six (86) patients received three or more doses of ICON-1 alone, in combination with 
Lucentis®, or Lucentis® alone. Thirteen SAEs in nine patients have been reported to date. There 
are currently no ocular or non-ocular safety events that led to study unmasking. No ocular or 
non-ocular safety signals have emerged to date and the study continues to be conducted as 
planned. 
8.4 
Study Rationale 
Uveal melanoma is a life-threatening and devastating disease characterized by poor overall 
survival and limited therapeutic options resulting in either the loss of an eye or complications 
leading to significant vision loss. Data from preclinical studies, and current and ongoing clinical 
studies in wet AMD (described above) supports investigating ICON-1 as a potentially less 

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invasive therapeutic option delaying the need for enucleation as well as possibly prolonging the 
onset of metastases.  
Patients scheduled for enucleation or brachytherapy as treatment of uveal melanoma provide an 
opportunity to examine the clinical safety of intravitreal administration of ICON-1 within a 
tumor environment. Examining the excised tissue after enucleation will allow confirmation of 
the extent of TF expression and whether intravitreally administered ICON-1 binds to TF 
expressed on uveal melanoma tumor cells and supporting stroma (target engagement).  The short 
term biologic response of ICON-1 binding will be examined with a comprehensive panel of in-
vitro and in-vivo outcome measures. This study may shed light on the ability of ICON-1 to 
produce cytotoxic damage to the tumor or inhibit tumor growth as shown in earlier pre-clinical 
models of tumor xenografts. 
The dose-escalating design and sample size for this study are based on the standard accepted 
clinical toxicity evaluation and are intended to establish a preliminary safety profile of ICON-1 
administered for the first time in patients with uveal melanoma and to provide preliminary 
evidence of biologic activity in support of additional studies.  

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9 
STUDY OBJECTIVES 
9.1 
Primary Objective 
The primary objective of this study is: 
 To evaluate the safety and tolerability of single and repeated escalating intravitreal 
injections of ICON-1 administered in patients with uveal melanoma who are planned to 
undergo enucleation or brachytherapy. 
9.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To assess the pharmacokinetics and pharmacodynamic effect of ICON-1 in patients with 
uveal melanoma. 
 To describe preliminary evidence of the biological activity of ICON-1 as determined by 
changes in visual acuity, and tumor size. 
9.3 
Exploratory Objective 
 To explore the prognostic indicator of the genetic profile of the tumor in relation to Tissue 
Factor expression and response to ICON-1 therapy. 
 To describe preliminary evidence of the biological activity of ICON-1 as determined by 
changes in tumor pathology, and proteomic analysis of vitreous humor. 

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10 INVESTIGATIONAL PLAN 
10.1 
Overall Study Design and Plan 
This is a phase 1, open-label, sequential-group, multicenter study to evaluate the safety and 
tolerability, biological activity, pharmacokinetics, and pharmacodynamic activity of single and 
repeated escalating intravitreal injections of ICON-1 in patients with primary uveal melanoma 
who are planned to undergo enucleation or brachytherapy.  
Patients diagnosed with primary uveal melanoma involving the posterior uveal tract for which 
the selected treatment management plan is enucleation or brachytherapy may be screened for this 
study. Eligible patients will be assigned to one of three cohorts that will be enrolled 
consecutively:  
Cohort 1 (enucleation or brachytherapy): Single dose of 0.3 mg (300 µg/100 µl) ICON-1, 
(n=2)   
Cohort 2 (enucleation or brachytherapy): Two doses of 0.3 mg (300 µg/100 µl) ICON-1 
each administered one week apart, (n=3)  
Cohort 3 (enucleation or brachytherapy): Two doses of 0.6 mg (300 µg/100 µl + 300 µg/ 
100 µl) ICON-1 each administered one week apart, (n=5)   
Each dose level will be evaluated for clinical safety before escalating to the next cohort. Clinical 
and safety data will be reviewed by the IT-003 Safety Review Committee (SRC) comprised of at 
least one participating Clinical Investigator and the Iconic Therapeutics internal Safety 
Management Committee. The following ocular adverse events (even if non-serious) are 
considered Adverse Events of Special Interest (AESIs), and will be reported by the investigator 
to the sponsor and SRC as appropriate: 
 Ocular inflammatory event of CTCAE Grade ≥ 3 
 Vitreous or retinal hemorrhage event interfering with visualization of the tumor or retina 
of CTCAE Grade ≥ 2 
 Any acute onset treatment-emergent vision-threatening condition as assessed by the 
investigator 
Patient data will be evaluated by the SRC for the occurrence of ocular Dose Limiting Toxicity 
(DLT) events. An ocular DLT is defined as an ocular inflammatory adverse event of 3+ or more 
severity or a grade 2 or higher unexpected vitreous or retinal hemorrhage interfering with the 
visualization of the tumor or retina.   
If an AESI occurs while the patient is at the study center and requires clinical management, the 
patient will remain at the study center according to the Investigator’s judgment. The patient will 
be managed according to the routine treatment practices of the study center. The patient will 
complete all subsequent study visits.  
All AESIs, serious adverse events, patient discontinuations and pregnancy reports must be 
reported to Iconic Therapeutics within 24 hours of the investigator learning of the event. 

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ICON-1 will be administered on Day 0 for all cohorts, and in addition on Day 7 for cohorts 2 and 
3 only. Patients will return to the study center on Day 1 for a safety follow-up visit (all cohorts) 
and 1 day post Day 7 (cohorts 2 and 3 only). All patients will return to the clinic for safety, 
clinical, and imaging assessments prior to the scheduled surgical procedure. Patients will have 
their planned surgical procedure (enucleation or brachytherapy plaque placement) as early as 4 
days after the last ICON-1 treatment, and return to the study center 30 days post-procedure for 
follow-up safety assessments (and ocular assessments for brachytherapy patients) and end of 
study visit.  
Safety will be evaluated by means of occurrence of adverse events, clinical laboratory tests 
(serum chemistry, hematology, coagulation, and plasma anti-drug antibody levels (ADA)), vital 
signs measurements, abbreviated physical examinations, slit-lamp biomicroscopy, intraocular 
pressure (IOP), and dilated ophthalmoscopy. Pharmacodynamic and biological activity will be 
measured by means of BCVA by ETDRS, spectral-domain optical coherence tomography 
(sdOCT), color fundus photography (CFP), fluorescein angiography (FA), ophthalmic 
ultrasound, and optionally (according to investigator judgment) ICG angiography, and enhanced-
depth imaging optical coherence tomography (EDI-OCT). Pharmacokinetic (PK) and 
Pharmacodynamic (PD) markers will be evaluated by means of measuring plasma concentrations 
of ICON-1, serum cytokine levels, circulating tissue factor (TF), immunophenotyping and 
circulating tumor DNA (CTDNA).  
For enucleation patients: immediately following the enucleation procedure, vitreous humor 
will be aspirated for intraocular ICON-1 and proteomic analysis of TF and cytokine levels. 
Following the clinical site’s standard of care pathology of the tumor, prepared slides and/or 
tumor block samples will be sent to a central laboratory for additional study-related pathology 
evaluation of the tumor (including ICON-1 binding, TF and PAR2 expression, immune infiltrate 
and alterations of the vasculature), genetic profiling, and Exome sequencing of the tumor. 
Genetic profiling of the tumor previously performed with fine needle aspiration of the tumor 
does not require repeated testing.     
For brachytherapy patients: the plaque placement procedure and associated follow-up will be 
according to the standard of care at each site.      
Patients (or their legally authorized representative) may choose to withdraw from the study for 
any reason at any time without prejudice.  Study assessments for an Early Termination Visit 
should be conducted in the event a patient discontinues from the study prematurely. 
 
 

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Figure 4: Study Design Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening (Day -7 to Day 0) and  
Baseline (Day 0) 
Intravitreal Injection(s) 
Sequential cohorts  
Cohort 1: 0.3 mg ICON-1 administered on Day 0 
Cohort 2: 0.3 mg ICON-1 administered on Day 0 and Day 7 
Cohort 3: 0.6 mg ICON-1 administered on Day 0 and Day 7 
(C1: n=2; C2: n=3; C3: n=5) 
Follow-up (From injection through pre-procedure assessments visit) and 
Scheduled Enucleation or Scheduled Brachytherapy 
DLT Review by  
IT-003 Safety Review Committee 
Review data through pre-procedure assessments visit in each cohort. 
0 DLTs in a cohort 
Escalate to the next cohort  
(as applicable) 
1 DLT in a cohort 
Enroll additional patient in 
cohort 
≥ 2 DLTs in a cohort 
Do not escalate to next cohort 
(as applicable) 
End of Study (30 days after surgical procedure) 
0 additional DLTs 
Escalate to the next cohort  
(as applicable)  
≥ 2 DLTs  
in original or expanded cohort 
Do not escalate to next cohort (as 
applicable) 
DLT Review by  
IT-003 Safety Review Committee 
Review data through pre-procedure assessments visit in cohort. 

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10.2 
Study Sites 
Approximately 7-10 centers located in the US will participate in this study.   
10.3 
Discussion of Study Design 
In this Phase 1 study ICON-1 will be intravitreally administered for the first time in patients with 
uveal melanoma. The starting dose of ICON-1 (300 µg/100 µl) is the maximum dose 
administered in the Phase 1 single IVT administration study, and the ongoing Phase 2 repeated 
IVT administration study in patients with CNV secondary to AMD. As this dose has been 
administered to approximately sixty (60) patients and found to be well tolerated to date, a cohort 
of two patients which may be expanded to three patients is thought to be sufficient to make a 
determination to escalate to the subsequent higher dose level of two doses of 0.3 mg (300 µg/100 
µl) ICON-1 administered one week apart.  The cohort size is increased (cohort 2; n=3, cohort 3; 
n=5), as the dose and volume is escalated in subsequent cohorts.  Each of these cohorts may be 
expanded by one patient in the event of a DLT. A toxicity rate of one third or less in a cohort is 
within the accepted clinically observed toxicity standards to establish a preliminary safety profile 
of ICON-1 administered in patients with uveal melanoma and to support additional studies. In 
this study, the maximum administered dose will not exceed 0.6 mg (300 µg/100 µl + 300 µg/100 
µl) ICON-1. 
Pharmacodynamic and biologic activity markers are utilized to explore preliminary evidence of 
activity with respect to target engagement (ICON-1 binding to TF in the tumor) as measured by 
tissue staining of the tumor and supporting stroma within the enucleated eye, assessment of 
immune infiltrate in the tumor, measurement of TF and PAR2 dependent cytokines/chemokines 
in blood, TF and cytokine levels in vitreous humor, and changes in tumor size and volume as 
well as changes in BCVA by ETDRS. Ophthalmic ultrasound is utilized to assess and measure 
changes in the size of the ocular tumor. Ophthalmic imaging including sdOCT, EDI-OCT, FA, 
ICGA, and CFP are utilized for measuring and evaluating changes in vasculature, in the 
anatomic layers of the retina, choroid, and ocular tumor and the associated pathology of the 
lesions (such as exudation).  
The study duration, including a one to two week dosing period prior to a scheduled enucleation 
or plaque placement procedure is considered an adequate period to assess safety, PK and 
preliminary pharmacodynamic and biologic activity without delaying or interfering with standard 
of care treatment for uveal melanoma. 
10.4 
Appropriateness of Measurements 
The primary aim for data analyses in this study is to assess the safety and tolerability of 
escalating doses of ICON-1 administered in patients with uveal melanoma. The choice of safety 
and biological activity parameters to be evaluated in this study reflect experience in preclinical 
studies, the Phase 1 study in patients with wet AMD, and the ongoing phase 2 study in patients 
with wet AMD. The PK and immunogenicity assessments in this study are used widely and are 
generally recognized as reliable, accurate, and relevant. Validated clinical bioanalytical assays 
will be used for this purpose. 

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Preliminary evidence of pharmacodynamic and biologic activity will be explored by measuring 
changes in BCVA via ETDRS, and tumor thickness, volume and vascularization via sdOCT and 
EDI-OCT, ophthalmic ultrasound, CFP, FA, and ICG angiography. Ophthalmic imaging 
modalities are routine assessments and are appropriate for documenting clinical findings of the 
retina, choroid, the ocular tumor and their vascularization at baseline and changes across the 
duration of the study for comparison.  

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11 STUDY POPULATION 
11.1 
Target Population 
The target population for this study is men and women age 18 years and older with a diagnosis of 
primary uveal melanoma involving the choroidal and/or ciliary body who are scheduled to 
undergo a standard of care enucleation procedure or brachytherapy.   
11.2 
Inclusion Criteria 
Patients must meet all of the following criteria to be included in the study: 
1. Verbal and written informed consent obtained from the subject or the subject’s legal 
representative (as applicable). 
2. Males or females of any race, ≥18 years of age. 
3. Clinical diagnosis of primary uveal melanoma involving the posterior uveal tract (choroid 
and/or ciliary body) in the study eye. Patients with metastatic disease are eligible. 
4. Planned enucleation or brachytherapy for primary uveal melanoma in the study eye. 
5. If a woman of childbearing potential (WOCBP) (i.e., not postmenopausal for at least 2 years 
or not surgically sterile), must have a negative serum pregnancy test at Screening, and must 
use adequate birth control if they have a non-surgically sterile male sexual partner 
throughout the study. Adequate methods of birth control include hormonal contraceptives, 
intrauterine contraceptive device (IUD), condom with spermicide, contraceptive sponge with 
spermicide, diaphragm with spermicide and cervical cap with spermicide. 
11.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Uveal melanoma in the study eye originating in the anterior uveal tract (iris). 
2. Chronic uncontrolled glaucoma or ocular hypertension in the study eye defined as an 
IOP >25mmHg regardless of concomitant treatment with IOP-lowering medications.  
3. Previous participation in an investigational study of ICON-1. 
4. Known serious allergy to fluorescein sodium indocyanine green for injection in 
angiography.  

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5. Use of two or more concomitant anticoagulant treatments (direct thrombin inhibitor 
class of drugs such as Coumadin (warfarin), Pradaxa (dabigatran), and Xarelto 
(rivaroxaban)). Aspirin is not considered an anticoagulant in this study. For patients 
receiving one chronic anticoagulant treatment (e.g., patients with a history of 
cardiovascular/cerebrovascular diseases [events] or hospitalization due to such 
conditions), the patient must have confirmation of stable clotting time using the 
appropriate test (Prothrombin Time (PT), International Normalized Ratio (INR) (e.g., 
Coumadin), or activated partial thromboplastin time (aPTT) (e.g., Pradaxa)) over the 
last 6 months from the patient’s treating physician. Some agents do not require 
PT/INR/aPTT monitoring (e.g., Eliquis (apixaban)).  
6. Hereditary or chronic hemorrhagic or coagulopathy conditions (i.e., hemophilia). 
7. Use of any investigational product or device within 30 days prior to Screening, or 
planned use of an investigational product or device during the study.  
8. History or presence of other concurrent conditions deemed by the Investigator to be 
likely to impact the subject’s clinical safety or to interfere with the interpretation of 
the study results, such as optic neuritis or atrophy (related to multiple sclerosis or 
other neurological disease), uveitis, or retinal vasculitis or other inflammatory 
intraocular conditions in the study eye. 
9. Presence of any other concurrent medical condition, including mental illness or 
substance abuse, deemed by the Investigator to be likely to interfere with a subject’s 
ability to provide informed consent, comply with monthly study visits and 
assessments, or interfere with the interpretation of the study results. 
10. Woman who is pregnant or lactating. 
11.4 
Study Eye Determination 
The study eye is defined as the eye that meets all of the inclusion criteria and none of the 
exclusion criteria. 

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12 STUDY TREATMENTS 
12.1 
Study Drug Dosage and Administration 
12.1.1 Investigational Product (ICON-1) 
The investigational product is human Immuno-conjugate 1 (ICON-1). ICON-1 is a recombinant 
fusion protein that targets and binds to the aberrantly expressed Tissue Factor (TF). It is a 
dimeric antibody-like protein; each monomer has two functional domains joined by a linker. The 
molecular weight is 157 kDa. The targeting domain of ICON-1 is a mutated FVIIa protein 
conjugated to an Fc effector moiety of a human IgG1 immunoglobulin.   
 
12.1.2 Test Article Administration 
Patients will be enrolled in one of three cohorts:  
 0.3 mg (300 µg/100 µl) ICON-1 administered on Day 0 
 0.3 mg (300 µg/100 µl) ICON-1 administered on Day 0 and Day 7 
 0.6 mg (300 µg/100 µl + 300 µg/100 µl) ICON-1 administered on Day 0 and Day 7 
Using aseptic technique, ICON-1 will be administered by first withdrawing vial contents through 
a 5-micron 19-gauge filter needle attached to a 1-cc tuberculin or Luer Lock syringe and then 
replacing the filter needle with a 30-gauge x ½ inch needle for the intravitreal injection. 
Adequate topical anesthesia and broad-spectrum microbicide will be given prior to injection.   
IOP will be measured before and after each intravitreal injection.  
For Cohort 3, the second intravitreal injection will be administered the same day following 
stabilization of IOP to the pre-injection level (i.e., within 5 mmHg of the pre-injection IOP) and 
a minimum of 30 minutes after the first injection.  
12.2 
Study Drug Packaging, Labeling and Storage 
ICON-1 will be provided by the Sponsor and is supplied in single-use glass vials containing 0.28 
mL of a sterile solution of ICON-1 at a concentration of 3 mg/mL in 15 mM HEPES, 150 mM 
NaCl, 25 mM Arginine, pH 7.4 with 0.01% of Polysorbate-80 and 5 mM CaCl2.  
Vials of ICON-1 will be shipped frozen on dry ice and should be stored frozen at ≤ -60ºC until 
just before use. Temporary storage is permitted at -20ºC for up to 60 days. ICON-1 vials should 
be thawed by leaving at room temperature for approximately 10-15 minutes prior to 
administration. Verify that the study drug is completely thawed by taking the vial and gently 
swirling it. ICON-1 may NOT be refrozen once it has been thawed. Time between thawing and 
administration should be as minimal as possible and should not exceed 4 hours. Vials of ICON-1 
are for single-use only. 

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12.3 
Selection of Doses and Timing of Doses  
The starting dose of ICON-1 was selected based on the results of preclinical efficacy and 
toxicology studies, a phase 1 study of single IVT administration and an ongoing phase 2 study of 
repeated IVT administration in patients with CNV secondary to AMD. The highest dose tested 
was 0.3 mg ICON-1 administered by intravitreal injection, and repeated doses up to 6 monthly 
doses per patient were found to be well tolerated in all patients to date. A maximum tolerated 
dose was not determined in the phase 1 study. In the phase 2 clinical study 300 µg/100 µl ICON-
1 is being administered intravitreally followed by 0.5 mg/50 µl ranibizumab after 30 minutes, a 
total injection volume of 150 µl. A total injection volume of 200 µl for cohort 3 is supported by a 
preclinical study in mini-pigs where three cycles of 600 µg ICON-1 were administered as two 
doses of 300 µg/100 µl each, two days apart (see Section 8.1 for information regarding the 
preclinical, Phase 1 and Phase 2 studies).  
12.4 
Criteria for Dose-Escalation and Stopping Rules 
Eligible patients will be assigned to one of three cohorts that will be enrolled consecutively:  
Cohort 1(enucleation or brachytherapy): Single dose of 0.3 mg (300 µg/100 µl) ICON-1, 
(n=2)   
Cohort 2 (enucleation or brachytherapy): Two doses of 0.3 mg (300 µg/100 µl) ICON-1 
each administered one week apart, (n=3)  
Cohort 3 (enucleation or brachytherapy): Two doses of 0.6 mg (300 µg/100 µl + 300 µg/ 
100 µl) ICON-1 each administered one week apart, (n=5)   
Each dose level will be evaluated for clinical safety before escalating to the next cohort. Clinical 
and safety data will be reviewed by the IT-003 Safety Review Committee comprised of at least 
one participating Clinical Investigator and the Iconic Therapeutics internal Safety Management 
Committee. Patients will be evaluated for the occurrence of ocular Dose Limiting Toxicity 
(DLT) events. An ocular DLT is defined as an ocular inflammatory adverse event of 3+ or more 
severity or a grade 2 or higher unexpected vitreous or retinal hemorrhage interfering with the 
visualization of the tumor or retina.  
All patients at a given dose level must complete their pre-procedure safety assessment after 
receiving their last dose of ICON-1, to enable evaluation of the safety of that dose level. For 
cohorts 1 and 2, if no patients experience a DLT, escalation to the next dose level will take place. 
If no patients experience a DLT in cohort 3, then cohort 3 will be considered the maximum 
administered dose (MAD).  
If one patient experiences a DLT in any cohort, an additional patient will be enrolled and 
evaluated at that dose level.  
For cohorts 1 and 2, if two or more patients experience a DLT in the original cohort or the 
expanded cohort, then enrollment in that cohort will be suspended, any subsequent cohorts will 
not be enrolled. For cohort 3, if two or more patients experience a DLT in the original cohort or 
the expanded cohort, then enrollment in the cohort will be suspended and the IT-003 Safety 
Review Committee will examine the safety data to determine if changes are warranted.  

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A maximum of three patients may be enrolled in cohort 1, a maximum of four patients may be 
enrolled in cohort 2, and a maximum of six patients may be enrolled in cohort 3. 
12.5 
Measurement of Study Drug Compliance 
All study treatment will be administered by the Investigator at each clinical site. The date and 
time of study treatment must be documented for each subject in the source record. Treatment 
assignment and dose must be documented in records with access restricted to authorized study 
personnel only.   
12.6 
Study Drug Accountability 
The Investigator or designee is responsible for maintaining accurate records of study drug 
supplies. Reasons for any departure from the expected dispensing regimen must be recorded. 
Study drug may not be used for any other purpose other than that described in the protocol. All 
study drug supplies and accountability records must be stored in a secure location with limited 
access restricted to authorized study personnel only. 
All vials of study drug will be recorded on a Drug Accountability Log accounting for all vials 
received, administered, not used, and destroyed. Drug Accountability will be performed by a 
Study Monitor during site visits. Once reconciled, study drug will be returned to the sponsor or 
destroyed at the site, as directed by the sponsor. If the study drug is to be destroyed at the site, it 
is the Investigator’s responsibility to ensure arrangements have been made for appropriate 
destruction according to applicable regulations, guidelines and procedures. Appropriate records 
of the destruction must be maintained. 
12.7 
Prior and Concomitant Therapy 
All medications (prescription, over-the-counter (OTC) and herbal) and nutritional supplements 
taken by a subject from 30 days prior to Screening through the completion of the study will be 
recorded. Changes in the dosing and/or frequency of concomitant medication must be captured 
with new start and stop dates indicating the previous and current doses/frequencies. 
Use of two or more concomitant anticoagulant treatments (direct thrombin inhibitor class of 
drugs such as Coumadin (warfarin), Pradaxa (dabigatran), and Xarelto (rivaroxaban)) is 
prohibited. Aspirin is not considered an anticoagulant treatment in this study. Concomitant 
treatment with one chronic anticoagulant (e.g., patients with a history of 
cardiovascular/cerebrovascular diseases [events] or hospitalization due to such conditions) is not 
prohibited. 
Use of treatment for concomitant metastatic disease is allowed during the study. 
Use of topical ocular anti-glaucoma medications is allowed during the study. 
Use of any investigational product or device within 30 days before Screening through the 
completion of the study is prohibited. 

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The Medical Monitor should be notified before prohibited medication or therapy is administered 
unless the safety of the patient requires immediate action. In the event of an emergency, any 
needed medications or therapies may be prescribed without prior approval but the Medical 
Monitor must be notified of the use immediately thereafter. The decision to administer a 
prohibited medication or therapy should be done with the safety of the patient as the primary 
consideration. If permissibility of a specific medication or therapy is in question, the Investigator 
should contact the Medical Monitor. 
12.8 
Other Study Supplies 
Additional supplies for administering study treatment intravitreal injections will include 1-cc 
tuberculin syringes, 5-micron 19-gauge x 1-1/2 inch filter needles for withdrawal of the study 
drug vial contents, and 30-gauge x ½ inch needles for intravitreal injections of ICON-1.  

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13 TREATMENT ASSIGNMENT 
13.1 
Subject Identification Numbers 
Patients will be enrolled in one of three cohorts following confirmation from the study Medical 
Monitor. Each patient will be assigned a unique Screening Number after informed consent is 
obtained. The Screening Number will be used as the Subject Number throughout the study.  
13.2 
Enrollment and Method of Assigning Patients to Treatment Arms 
This is an open-label, sequential-group, multicenter study. The Investigator will evaluate the 
inclusion and exclusion criteria to determine patient eligibility for entry into the study. When a 
potential patient is identified, the investigator must contact the Medical Monitor at Iconic 
Therapeutics to confirm availability in the cohort. 
The Sponsor, Investigator, research staff and participants will know the treatment that is being 
administered as well as the cohort assignment. Cohort 1 (single dose of 0.3 mg ICON-1) will be 
enrolled first, followed by cohort 2 (two doses of 0.3 mg ICON-1 administered one week apart), 
and then cohort 3 (two doses of 0.6 mg ICON-1 administered one week apart). Clinical and 
safety data will be reviewed by the IT-003 Safety Review Committee after all patients in a cohort 
have completed their pre-procedure safety assessment visit before enrolling patients into 
subsequent cohorts.   
 

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14 STUDY PROCEDURES 
The Study Flowchart and Assessments is presented in Section 21.1 (Appendix A). A detailed 
accounting of the assessments performed at each study visit is presented below.  An ICF must be 
signed and dated by the patient or the patient’s legally authorized representative, the person who 
conducted the informed consent discussion, and witness (if required) before any Screening 
assessments or treatment is undertaken that is not part of routine care. The Screening Number 
should be assigned to the patient after informed consent is obtained.  
The protocol-specified procedures for a given study visit may be split across 2 days within the 
visit-specific window (if applicable); however, for each visit all BCVA, ophthalmic exams and 
imaging must be performed on the same day and cannot be split across 2 or more days. 
14.1 
Visit 1 (All cohorts): Screening (Day -7 through 0) 
Screening must take place within 7 days prior to the intravitreal injection on Day 0 (Baseline 
Visit). Patients will undergo Screening assessments to determine if they are eligible to enroll in 
the study. If there is study drug available at the clinical site, Screening assessments to confirm 
eligibility may be performed on Day 0, prior to any intravitreal injection and any additional 
baseline specific assessments.  
The following procedures will be performed at Screening: 
 Obtain written informed consent 
 Obtain demographic data 
 Obtain medical and ocular history including surgical and medication history. Prior and 
concomitant medications taken within the last 30 days will be recorded. 
 Vital signs 
 Blood samples for clinical laboratory tests (serum chemistry, hematology and 
coagulation), prior to injection of Fluorescein and ICG dye (as applicable) 
 Blood sample for anti-drug antibody levels, prior to injection of Fluorescein and ICG dye 
(as applicable) 
 Blood sample for serum pregnancy test (women of child bearing potential only), prior to 
injection of Fluorescein and ICG dye (as applicable) 
 Abbreviated physical examination including height and weight 
 Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS-like charts (both eyes) 

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o Slit lamp biomicroscopy (both eyes) 
o IOP (both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o Color fundus photography (both eyes) 
o sdOCT (study eye only) 
o EDI-OCT optional according to investigator judgment (study eye only) 
o Ophthalmic ultrasound (study eye only) 
o Fluorescein angiography (both eyes) 
o ICG angiography optional according to investigator judgment (both eyes) 
14.2 
Visit 2 (All cohorts): Baseline (Treatment Day 0)  
Baseline assessments will be completed on Day 0. The following procedures will be performed: 
 Vital signs 
 Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP; cohorts 1 and 2: pre-injection (both eyes) and post injection (study eye only), 
cohort 3: pre-injection (both eyes) and post each injection (study eye only) 
o Dilated ophthalmoscopy (study eye only) 
 Blood sample (pre-injection and 4 hours ±1 hour after dose administration. For cohort 3, 
after the second injection) for pharmacodynamic assessment 
 Blood samples (pre-injection and 4 hours ±1 hour after dose administration. For cohort 3, 
after the second injection) for pharmacokinetic assessment 
 Administration of intravitreal injection(s)  
 Assessment of adverse events 
 Record concomitant medications 

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 Instruct patients to contact site study personnel immediately if their treated eye becomes 
red, sensitive to light, painful, or develops a change in vision. 
14.3 
Visit 3 (All cohorts): Day 1  
The following procedures will be performed at Day 1: 
 Vital signs 
 Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (study eye only) 
o Slit lamp biomicroscopy (study eye only) 
o IOP (study eye only) 
 Blood sample for pharmacodynamic assessment 
 Blood sample for pharmacokinetic assessment 
 Assessment of adverse events 
 Record concomitant medication 
14.4 
Visit 4 (Cohorts 2 and 3 only): Treatment Day 7 (±2 days) 
The following procedures will be performed at Day 7: 
 Vital signs 
 Perform the following ophthalmic procedures, prior to dose administration: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP; cohort 2: pre-injection (both eyes) and post injection (study eye only), 
cohort 3: pre-injection (both eyes) and post each injection (study eye only)  
o Dilated ophthalmoscopy (study eye only) 
o sdOCT (study eye only) 
o EDI-OCT optional according to investigator judgment (study eye only) 
o Ophthalmic ultrasound (study eye only)  

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 Blood samples for clinical laboratory tests (serum chemistry, hematology and 
coagulation) 
 Blood samples (pre-injection and 4 hours ±1 hour after dose administration. For cohort 3, 
after the second injection) for pharmacodynamic assessment 
 Blood samples (pre-injection and 4 hours ±1 hour after dose administration. For cohort 3, 
after the second injection) for pharmacokinetic assessment  
 Administration of intravitreal injection(s)  
 Assessment of adverse events 
 Record concomitant medication 
 Instruct patients to contact site study personnel immediately if their treated eye becomes 
red, sensitive to light, painful, or develops a change in vision. 
14.5 
Visit 5 (Cohorts 2 and 3 only): 1 day post Day 7 treatment 
The following procedures will be performed on the day after Day 7 treatment: 
 Vital signs 
 Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (study eye) 
o Slit lamp biomicroscopy (study eye) 
o IOP (study eye) 
 Blood sample for pharmacodynamic assessment 
 Blood sample for pharmacokinetic assessment 
 Assessment of adverse events 
 Record concomitant medication 
14.6 
Visit 6 (All Cohorts): Procedure Assessments (On or 1 day prior to Surgical 
Procedure day) 
The following procedures will be performed on or 1 day prior to the Surgical Procedure day: 
 Vital signs 

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 Perform the following ophthalmic procedures, (prior to Surgical Procedure): 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o Color fundus photography (both eyes) 
o sdOCT (study eye only) 
o EDI-OCT optional according to investigator judgment (study eye only) 
o Ophthalmic ultrasound (study eye only) 
o Fluorescein angiography (both eyes) 
o ICG angiography optional according to investigator judgment (both eyes) 
 Blood samples for clinical laboratory tests (serum chemistry, hematology, and 
coagulation) 
 Blood sample for pharmacodynamic assessment 
 Assessment of adverse events 
 Record concomitant medication 
Surgical Procedure will be performed ≥4 days after the last injection: 
The surgical procedure (enucleation or plaque placement) is scheduled independent of this 
study according to standard of care clinical management of uveal melanoma per patient’s 
treating physician and is not a study procedure. 
For Patients Undergoing Enucleation Only: After enucleation, the following samples will be 
obtained: 
 Vitreous humor aspirate for ICON-1 and proteomic analysis 
 A subset of pathology mounted slides and/or tumor block samples from the globe and 
tumor will be provided by the local pathology laboratory to the central laboratory for 
genetic tumor profiling and Exome sequencing 
 

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14.7 
Visit 7 (All Cohorts): End of Study: 30 days ±5 days post Surgical Procedure 
The following procedures will be performed 30 ±5 days after the Surgical Procedure: 
 Vital signs 
 Perform the following ophthalmic procedures (brachytherapy patients only): 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o Color fundus photography (both eyes) 
o sdOCT (study eye only) 
o Ophthalmic ultrasound (study eye only) 
 Abbreviated physical examination 
 Blood samples for clinical laboratory tests (serum chemistry, hematology, and 
coagulation) 
 Blood sample for anti-drug antibody levels 
 Blood sample for serum pregnancy test (women of child bearing potential only) 
 Assessment of adverse events 
 Record concomitant medication 
If follow-up is needed after the End of Study visit, it should occur as a post-study unscheduled 
visit at the discretion of the Investigator. Patients with an ongoing SAE at this visit will be 
followed until the event is resolved or stabilized as described in Section 15.22.10 
14.8 
Early Termination Visit 
Patients who discontinue study drug or withdraw from the study prematurely will undergo an 
Early Termination (ET) visit. At this visit, the following will be performed: 
 Vital signs 
 Blood samples for clinical laboratory tests (serum chemistry, hematology, and 
coagulation), prior to injection of Fluorescein and ICG dye (as applicable) 

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 Blood sample for anti-drug antibody levels, prior to injection of Fluorescein and ICG dye 
(as applicable) 
 Blood sample for serum pregnancy test (women of child bearing potential only), prior to 
injection of Fluorescein and ICG dye (as applicable) 
 Blood sample for pharmacodynamic assessment (collect only if Day 1 or 1 day post 
Day 7 treatment PD samples were not collected following injection on Day 0 or Day 7), 
prior to injection of Fluorescein and ICG dye (as applicable) 
 Blood sample for pharmacokinetic assessment (collect only if Day 1 or 1 day post Day 7 
treatment PK samples were not collected following injection on Day 0 or Day 7), prior to 
injection of Fluorescein and ICG dye (as applicable) 
 Abbreviated physical examination 
 Perform the following ophthalmic procedures (note: ocular assessments are performed 
only if early termination occurs prior to Surgical Procedure): 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o Color fundus photography (both eyes) 
o sdOCT (study eye only) 
o EDI-OCT optional according to investigator judgment (study eye only) 
o Ophthalmic ultrasound (study eye only) 
o Fluorescein angiography (both eyes) 
o ICG angiography optional according to investigator judgment (both eyes) 
 Assessment of adverse events 
 Record concomitant medication 
If follow up is needed after the early Termination visit, it should occur as a post-study 
unscheduled visit at the discretion of the Investigator. Patients with an ongoing SAE at this visit 
will be followed until the event is resolved or stabilized as described in Section 15.22.10.  

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14.9 
Unscheduled Visits 
Unscheduled visits may be necessary due to AEs or other reasons. The Investigator may examine 
a patient as often as is medically necessary while the patient is enrolled in the study. Any follow-
up that is performed to monitor patient safety should be recorded as an Unscheduled Visit. 
14.10 Patient Withdrawal from Treatment or Study 
14.10.1 Handling of Withdrawals 
Patients (or their legally authorized representative) may choose to withdraw from the study for 
any reason at any time without prejudice. The study assessments for the Early Termination Visit 
should be conducted in the event a patient discontinues from the study prematurely. If a patient 
withdraws from the study, he or she may not reenter the study. 
The Principal Investigator or the Sponsor may withdraw a patient from the study for any of the 
following reasons:  
 Adverse event 
 Prohibited therapy (patient requires concomitant medication or a medical procedure 
prohibited by the protocol) 
 Subject noncompliance (patient does not adhere to the requirements specified by the 
protocol) 
 Subject improper entry (patient was enrolled in the study but did not meet the eligibility 
criteria) 
 Subject withdrawal of consent 
 Pregnancy (patient becomes pregnant) 
 Lost to follow-up 
 Death 
At the time of withdrawal, the Principal Investigator should advise the patient of the other 
available options. When a patient is withdrawn from the study for any reason, the reason(s) for 
withdrawal will be recorded in the eCRF. For any patient who withdraws due to an AE, the 
reason for withdrawal must be recorded as an AE and not any other reason. Whenever possible, 
all patients who withdraw from the study prematurely will undergo assessments listed for the 
Early Termination visit.  
If a patient fails to return for a scheduled visit, it is the responsibility of the Principal Investigator 
or designee to document all efforts to contact the patient and to determine the reason the patient 
did not return. If a patient cannot be contacted with 3 documented telephone call attempts, 

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followed by a certified letter, and does not have a known reason for discontinuation (e.g., 
withdrawal of consent or an AE), the reason for discontinuation will be recorded as “lost to 
follow-up”. The date that the certified letter was mailed will be considered the date of study 
withdrawal. 
In the event of a patient death during the study, the date of death (as listed on the death 
certificate) will be used as the date of study withdrawal. 
It is vital to obtain follow-up data on any patient who is withdrawn due to an AE. In such cases, 
every effort must be made to undertake protocol-specified safety follow-up procedures.  
The Medical Monitor should be notified promptly when a patient is withdrawn. 
The Sponsor may terminate the study at any time for clinical or administrative reasons and may 
discontinue participation by an individual Investigator or site for poor enrollment or 
noncompliance. 
14.10.2 Replacements 
Patients who discontinue from the study prior to the pre-procedure safety evaluation following 
their last injection may be replaced. 
14.10.3 Sponsor or Regulatory Agency Termination of the Study 
Although the Sponsor intends to complete the study, the right is reserved to discontinue the study 
at any time for clinical or administrative reasons, or if required by the local regulatory authority. 

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15 STUDY ASSESSMENTS 
This section describes the study assessment procedures. See Study Flowchart and Assessments 
(Section 21.1 - Appendix A) for timing of each assessment. 
15.1 
Informed Consent 
Each site will be required to obtain IRB/EC approval of the ICF. Before any study specific 
procedures are performed, the investigator or designee will provide the subject or the subject’s 
legally authorized representative with a copy of the current IRB/EC approved ICF and allow 
adequate time for review and the opportunity to ask any questions regarding the study and/or 
ICF. The Investigator should answer all questions to the best of his ability and to the satisfaction 
of the subject or the subject’s legally authorized representative before performing any study visit 
assessments. The ICF should be signed and dated by the subject or subject’s legally authorized 
representative, the Investigator or his designee, and witness (where applicable) before any study 
specific procedures are performed. 
The consenting process must be conducted in accordance with ICH GCP and local regulatory 
and/or IRB/EC requirements. A copy of the signed and dated ICF should be given to the subject 
or the subject’s legally authorized representative and a copy should be maintained in the 
subject’s medical records. The consenting process should be documented in the subject’s source 
record including the names of persons participating in the discussions and a brief summary of 
what was discussed including questions and responses. 
If the protocol is amended or new safety information becomes available, and revisions are 
required to the ICF, the subject or subject’s legally authorized representative will be required to 
sign the updated IRB/EC approved ICF. 
If a subject or subject’s legally authorized representative withdraws consent at any time the date 
and time and details of the discussion should be recorded in the subject’s source record along 
with the names of the persons participating in the discussion.  
15.2 
Eligibility Assessment 
The Investigator must contact the study Medical Monitor when a potential patient is identified 
for the study to ensure there is space in the cohort. Screening assessments will be used to 
determine eligibility before enrolling a patient in the study cohort. 
15.3 
Demographic Data 
Demographic data will be recorded including date of birth, gender, race and ethnicity. 
15.4 
Medical, Surgical, and Ocular History 
Medical history will be recorded and should elicit all major illnesses, diagnoses, and surgeries 
for the patient. Ocular history will also be recorded and should be specific to which eye as 
appropriate. 

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15.5 
Prior and Concomitant Therapy 
Prior and Concomitant Therapy taken from 30 days prior to Screening through the last study visit 
will be recorded. The patient’s source record should include start and stop dates, dose, route, 
frequency, and indication. 
15.6 
Vital Signs 
Vital signs should be taken when the patient is adequately rested (after the patient has been 
resting in a seated position for at least 5 minutes). Vital signs measurements include blood 
pressure (systolic and diastolic in millimeter of mercury (mmHg)), heart rate (beats/minute), 
respiratory rate (breaths/minute), and temperature (◦C). 
15.7 
Abbreviated Physical Examination 
Abbreviated physical examination should include at a minimum assessments of general 
appearance, cardiovascular, respiratory, neck/HEENT (head, eyes, ears, nose and throat), and 
dermatologic. Height and weight will be measured at Screening only. Additional assessments 
should be completed at the judgment of the Investigator. 
15.8 
Best-corrected Visual Acuity 
Best-corrected visual acuity (BCVA) will be measured for each eye, pre-treatment prior to 
dilating eyes, using standard Early Treatment Diabetic Retinopathy Study (ETDRS)-like retro-
illuminated charts. BCVA will be recorded as the total letter score in each eye.  
Visual acuity testing will be performed by qualified site personnel, and should occur before any 
examination requiring contact with the eye. In order to provide standardization and well-
controlled measurements of BCVA during the study, all measurements at a single site must be 
consistently done using the same lighting conditions, correction, chart type, and measurement 
procedure for an individual patient throughout the study. 
A study specific refraction and BCVA testing protocol will be provided in a separate BCVA 
testing and imaging procedures manual. 
15.9 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy will be performed for each eye by qualified site personnel. Slit-lamp 
biomicroscopy, including magnification, will be performed without dilation of the pupil and 
consistent with standard clinical practice. The patient will be seated during the examination. This 
procedure should be conducted in the same manner for all patients and will include an 
assessment of each of the following as normal or abnormal: 
 Eyelids 
 Conjunctiva 
 Cornea 
 Anterior chamber 

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 Iris 
 Lens 
All abnormal findings that are clinically significant will be described. A change from normal to 
abnormal for any biomicroscopic variable will be considered clinically significant. 
15.10 Intraocular Pressure 
At each study visit IOP will be measured according to routine clinical practice using contact 
tonometry (e.g. Goldmann Applanation, Tono-Pen). It is recommended that the same instrument 
be used throughout the duration of the study for each patient. At injection visits, IOP will be 
measured in both eyes before the injection by qualified site personnel, and in the study eye only 
after intravitreal injection (in Cohort 3, IOP will be measured in the study eye following each of 
the two injections). Measurements will be recorded in mmHg (e.g., 19 mmHg). At the 1 day 
post-treatment visits, a single IOP measurement will be performed in the study eye only. At other 
study visits IOP will be measured in both eyes by qualified site personnel. Elevated IOP should 
be clinically managed in accordance with routine clinical care of the practice and in accordance 
with investigator judgment.    
The tonometer must be calibrated for accuracy before the first patient in the study at a given site 
undergoes the first examination, and continue to be performed in accordance with the 
manufacturer’s specifications until the last patient at the site has exited the study.   
15.11 Dilated Ophthalmoscopy 
A dilated fundus examination of the study eye will be performed pre-treatment in all patients by 
designated qualified site personnel. The following will be observed for the presence of 
abnormalities: 
 Vitreous body 
 Peripheral Retina 
 Macula 
 Choroid 
 Optic nerve 
All abnormal findings that are clinically significant will be described. A change from normal to 
abnormal for any ophthalmoscopic variable will be considered clinically significant. 
15.12 Color Fundus Photography 
Color fundus photography (CFP) for each eye will be performed to assess the retina and 
characteristics of the ocular tumor in the study eye. Color fundus photographs will be obtained 
using a digital fundus camera and will be performed by designated qualified site personnel. 
For detailed instructions regarding performance of CFP, please refer to the BCVA testing and 
imaging procedures manual provided separately. 

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15.13 Ophthalmic Ultrasound 
Ophthalmic ultrasound of the study eye will be performed to assess and measure (depth, width, 
and height) the ocular tumor from the external surface of the sclera. Ophthalmic ultrasound will 
be performed by designated qualified site personnel. 
For detailed instructions regarding collection of ultrasound measurements, please refer to the 
BCVA testing and imaging procedures manual provided separately. 
15.14 Spectral-Domain Optical Coherence Tomography 
Spectral-domain optical coherence tomography (sdOCT) imaging of the study eye will be 
performed to measure and assess cross-sectional images of the anatomic layers of the retina, the 
ocular tumor and associated pathological changes. sdOCT will be performed pre-treatment 
during visits in which ICON-1 is administered. sdOCT imaging will be obtained using a 
Spectral-Domain (High Definition) OCT device by designated qualified site personnel. 
Preferably the same machine will be used for initial and follow-up assessments of each patient.  
For detailed instructions regarding collection of sdOCT imaging, please refer to the BCVA 
testing and imaging procedures manual provided separately. 
15.15 Enhanced Depth Imaging Optical Coherence Tomography 
Enhanced depth optical coherence tomography (EDI-OCT) imaging of the study eye will be 
performed optionally, according to investigator judgment, to evaluate the structural changes of 
the choroid in the area of the tumor. 
EDI-OCT will be performed pre-treatment during visits in which ICON-1 is administered. EDI-
OCT imaging will be obtained using an EDI-OCT device by designated qualified site personnel. 
Preferably the same machine will be used for initial and follow-up assessments of each patient. 
For detailed instructions regarding collection of EDI-OCT imaging, please refer to the BCVA 
testing and imaging procedures manual provided separately. 
15.16 Fluorescein Angiography 
Fluorescein angiography (FA) imaging (after intravenous administration of Fluorescein dye) for 
each eye  will be performed to examine the circulation of the retina and characteristics of the 
ocular tumor in study eye according to standard FA image capture protocol. FA images will be 
obtained using a digital camera by designated qualified site personnel. 
For detailed instructions regarding collection of FA images, please refer to the BCVA testing and 
imaging procedures manual provided separately. 

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15.17 ICG Angiography 
Indocyanine green angiography (ICGA) imaging (after intravenous administration of 
Indocyanine Green dye) for each eye will be performed optionally, according to investigator 
judgment, to examine the blood vessels and connective tissue of the choroid and the ocular tumor 
in the study eye. ICGA images will be obtained using an infra-red sensitive camera by 
designated qualified site personnel. 
For detailed instructions regarding collection ICG imaging, please refer to the BCVA testing and 
imaging procedures manual provided separately. 
15.18 Clinical Laboratory Evaluations and Immunogenicity 
Blood samples for routine clinical laboratory tests and immunogenicity tests will be collected. 
The minimum tests to be performed include:  
 Hematology (complete blood count including white blood cell [WBC] count, WBC 
differential, red blood cell [RBC] count, hematocrit [Hct], hemoglobin [Hgb], mean 
corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular 
hemoglobin concentration [MCHC], red cell distribution width [RDW], platelet count, 
mean platelet volume [MPV], and C-reactive protein [CRP])  
 Serum chemistry profile (albumin, alkaline phosphatase, alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], blood urea nitrogen [BUN], calcium, serum chloride, 
carbon dioxide [CO2], creatinine, BUN/creatinine ratio, creatinine clearance [CrCl] using 
Cockcroft-Gault formula, creatine phosphokinase [CPK], direct and total bilirubin, 
triglycerides, gamma-glutamyl transferase [GGT], globulin, glucose, lactic 
dehydrogenase [LDH], phosphorus, potassium, sodium, total cholesterol, total protein, 
uric acid) 
 Serum pregnancy test for women of child bearing potential 
 Coagulation (PT, INR, fibrinogen, and activated partial thromboplastin time [aPTT]) 
 Immunogenicity (plasma anti-drug antibody [ADA]) 
Any abnormal test results determined to be clinically significant by the Investigator should be 
repeated at the discretion of the Investigator until the cause of the abnormality is determined, the 
value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. Clinical laboratory results should be initialed 
and dated by the Investigator and any abnormal results should be marked as clinically significant 
or not clinically significant. Clinically significant laboratory results should be recorded as an AE, 
preferably as a diagnosis where possible. 
Blood samples will be obtained to measure systemic levels of anti-drug antibodies. Blood 
samples for measurement of anti-drug antibodies will be drawn before the first intravitreal 
injection at Screening/Baseline before the intravitreal injection and at Week 2, Week 8 and the 
Early Termination visit (as applicable).  

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Female patients with a positive pregnancy test at Screening do not meet the eligibility criteria 
and may not enroll in the study. Women must have been in menopause for at least 2 years, or had 
a tubal ligation at least 1 year prior to Screening, or have had a total hysterectomy to be 
considered not of child bearing potential. 
It is the investigator’s responsibility to perform clinical laboratory assessments more frequently 
if clinically indicated.  
Hematology, serum chemistry, coagulation, and serum pregnancy tests will be performed by a 
central laboratory. ADA samples will be batch analyzed by a central bioanalytical laboratory. 
For detailed instructions regarding collection, storage and handling of clinical laboratory and 
immunogenicity samples, please refer to the Laboratory Manual provided separately. 
15.19 Pharmacokinetic and Pharmacodynamic Markers 
Blood samples for PK (plasma ICON-1 concentrations) and PD markers (including serum 
cytokine levels, circulating TF, immunophenotype patterns and CTDNA) analyses will be drawn 
from all study patients at pre-specified time points prior to and after administration of ICON-1.  
For all cohorts, blood samples for PK and PD analysis will be collected on Day 0 pre-injection 
and 4 hours ±1 hour post injection (for cohort 3 prior to the first injection and after the second 
injection), and on Day 1. For cohorts 2 and 3, blood samples for PK and PD analysis will also be 
collected on Day 7 prior to the first injection and 4 hours ±1 hour post injection (for cohort 3, 
prior to the first injection and after the second injection), and 1 day post Day 7 treatment. In 
addition, for all cohorts, a blood sample for PD markers will be collected prior to enucleation or 
plaque placement, as applicable.  
Blood samples for CTDNA will be collected along with the other PD marker samples on Day 0 
(all cohorts, pre-injection), Day 7 (cohorts 2 and 3 only, pre-injection), and prior to enucleation 
or plaque placement (all cohorts). 
A PK and PD sample will also be obtained at the Early Termination visit if Day 1 or 1 day post 
Day 7 treatment PK/PD samples were not collected following injection on Day 0 or Day 7, as 
applicable. 
For detailed instructions regarding collection, storage and handling of PK and PD samples, 
please refer to the Laboratory Instruction Manual provided separately. 
15.20 Proteomic Analysis of Vitreous  
For Patients Undergoing Enucleation Only:  Immediately following the enucleation 
procedure, vitreous humor aspirate will be collected for assessment of ICON-1 levels and 
proteomic analysis of TF and other cytokines, and will be sent to the central study laboratory. 
For detailed instructions regarding collection, storage, and handling of vitreous humor samples, 
please refer to the Laboratory Instruction Manual provided separately. 

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15.21 Tumor Pathology, Genetic Profiling and Exome Sequencing 
For Patients Undergoing Enucleation:  Following the enucleation procedure, the eye globe 
will be sent to the local site laboratory for pathology according to the clinical site’s standard of 
care practice. A subset of pathology slides and/or tumor block samples will be prepared by the 
local laboratory and sent to the study central laboratory for study-related assessments, including 
ICON-1 binding to TF within the tumor, TF and PAR2 expression, characterization of the 
immune infiltrate, and alterations of the vasculature, genetic profiling (Type 1 or Type 2), and 
Exome sequencing. Genetic profiling previously performed with fine needle aspiration of the 
tumor does not require repeated testing.  
A central laboratory designated for the study will perform the above testing for the provided 
slides and/or tumor block samples. For detailed instructions regarding specimens preparation, 
handling and shipping, please refer to the Laboratory Instruction Manual provided separately.  
For Patients Undergoing Plaque Placement:  If standard of care fine needle aspiration of the 
tumor is performed prior to plaque placement for genetic profile testing, the results of that testing 
will be recorded. 
15.22 Evaluation of Adverse Events 
Adverse events (AEs) will be monitored continuously during the study from the time that the 
subject has provided written informed consent through the subject’s last day of study 
participation. AEs may be reported spontaneously by the subject, discovered by Investigator or 
study staff through questioning, or observed through physical examination or other means. It is 
the responsibility of the Investigator to assess and document all AEs that occur during the course 
of the study, regardless of the causal relationship with the study drug.  
The following information will be collected for all AEs and recorded on the subject’s source 
document and AE eCRF: 
 Event description (diagnosis preferred, if unknown, record the signs/symptoms) 
 Onset and resolution dates 
 Severity (intensity) 
 Frequency (intermittency) 
 Relationship to study drug (causality) as determined by the Investigator 
 Seriousness 
 Action taken with study drug 
 Corrective action taken 
 Outcome 
15.22.1 Definition of an Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  

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An AE can therefore be: 
 Any unfavorable and unintended medical diagnosis, sign or symptom 
 Any new undesirable medical occurrence or unfavorable or unintended change in a pre-
existing condition that occurs during or after study treatment  
 Laboratory abnormality, vital sign or ophthalmic assessment that is assessed as clinically 
significant and different from baseline (e.g., requiring discontinuation of study treatment, 
specific treatment, or a change in subject management). If possible, changes in laboratory 
results or changes in vital signs that meet the definition of an AE should be reported as a 
medical diagnosis rather than as the abnormal value (e.g., “hypertension” rather than 
“blood pressure increased”).  
The following are special considerations when determining and reporting AEs: 
 Whenever possible, the Investigator should group signs or symptoms that constitute a 
single diagnosis under a single AE term (e.g., “cough, rhinitis, and sneezing” might be 
grouped together as “upper respiratory tract infection”).  
 Pre-existing conditions are not considered AEs unless the condition worsens (increase in 
frequency, severity or specificity) during or following study drug administration. 
Fluctuations in a pre-existing condition should be assessed by the Investigator, and those 
that fall within the limits of expected fluctuations for the disease state, and are not 
assessed as worsening of the disease, should not be considered AEs. Any change assessed 
as clinically significant worsening of the disease from baseline must be documented as an 
AE. 
 Elective surgery (including the planned enucleation surgery or brachytherapy, and 
associated inpatient hospitalization, as applicable) or routine diagnostic procedures are 
not considered AEs. However, an untoward medical event occurring during the pre-
scheduled elective surgery or diagnostic procedure should be recorded as an AE. 
 Death itself is not considered an AE; it is instead the outcome of an AE. 
 Pregnancy is not considered an AE, but it is an important medical event that must be 
followed up as described in Section 15.22.8. 
 For cohort 3, if the IOP in the study eye following the first intravitreal injection does not 
stabilize sufficiently to the pre-injection level (i.e., within 5 mmHg of the pre-injection 
IOP) to perform the second intravitreal injection, the change in IOP should be reported as 
an AE. 
 For cohort 3, elevated IOP in the study eye following the first intravitreal injection should 
be considered an AE if: (1) two or more follow-up IOP measurements are required to 
demonstrate stabilization to the pre-injection level (i.e., within 5 mmHg of the pre-
injection value), thereby delaying the time of the second intravitreal injection; or (2) 
interventional therapy is required to return IOP to within 5 mm Hg of the pre-injection 
value. 

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A treatment-emergent AE (TEAE) is any AE with an onset from any time after the patient has 
received study drug through 30 days after the last dose of study drug, whether or not it is 
considered causally related to the study drug.  
15.22.2 Serious Adverse Event 
All AEs will be assessed as either serious or non-serious. A serious adverse event (SAE) is any 
event that results in any of the following outcomes: 
 Death 
 Life-threatening (i.e., if in the view of the Investigator or Sponsor, the event’s occurrence 
placed the subject at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe).  
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
(Hospitalization for elective surgery for a pre-existing condition or for surgery planned 
before study entry is not considered an SAE.)  
 A persistent or significant disability/incapacity (permanent or substantial disruption of the 
subject’s ability to perform normal life functions). This definition is not intended to 
include experiences of relatively minor or temporary medical significance. 
 Congenital anomaly/birth defect (an AE that occurs in the child or fetus of a subject 
exposed to study drug prior to conception or during pregnancy). 
Important medical event or serious medical condition that does not meet any of the above criteria 
may be considered an SAE if, based upon appropriate medical judgment, it may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the outcomes listed 
above. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
15.22.3 AE Severity 
The severity of an AE should be determined by the intensity of the AE and will be assessed using 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03 (June 14, 2010) Eye Disorders section. 
Table 3:  CTCAE Grading 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*.  

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Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL**.  
Grade 4 
Life-threatening consequences; urgent intervention indicated.  
Grade 5 
Death related to AE.  
 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden  
15.22.4 Study Drug Causality 
The Investigator will assess the relationship of the AE to the study drug as either “Related” or 
“Not Related”. The following should be taken into consideration when assessing SAE causality: 
 Positive temporal relationship to study drug, such as if the study drug was withdrawn and 
the AE resolved or the event recurred after re-introduction. 
 If there is a reasonable possibility that the AE is associated with an underlying or 
concomitant illness. 
 Possible association with previous or concomitant therapy. 
 No temporal relationship to the study drug and/or a more likely alternative etiology 
exists. 
 If the AE is directly related to study procedures or lack of efficacy. 
15.22.5 
Adverse Events of Special Interest (AESIs) 
AESIs are events of medical and scientific concern specific to the investigational product, for 
which ongoing monitoring and rapid communications by the investigator to the sponsor and 
Safety Review Committee is appropriate. Ocular adverse events that qualify as an AESI (even if 
non-serious) include the following: 
 Ocular inflammatory event of CTCAE  Grade ≥ 3 
 Vitreous or retinal hemorrhage event interfering with visualization of the tumor or retina 
of CTCAE Grade ≥ 2 
 Any acute onset treatment-emergent vision-threatening condition as assessed by the 
investigator 
 

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15.22.6 Adverse Event Reporting Procedures 
The occurrence of AEs should be sought by non-direct questioning of the subject at each 
scheduled or unscheduled study visit. At each visit, study personnel should ask the following 
question: “Have you had any problems since your last visit?” AEs may also be detected when 
they are volunteered by the subject during and between visits or through physical examination, 
or other assessments. All AEs (serious and non-serious) reported by the subject will be reviewed 
by a qualified physician participating in the study and must be recorded on the subject’s source 
documents and AE eCRF. 
An AE that is classified as “serious” requires expeditious handling and reporting to the Sponsor 
or designee within 24 hours of site notification to comply with regulatory requirements.  
All SAEs and AESIs, whether or not related to study drug, must be reported immediately to the 
Sponsor or designee by entering the SAE/AESI information directly into the electronic data 
capture (EDC) system (AE eCRF) within 24 hours after the Investigator becomes aware of the 
event.  
Note that any SAEs that occur after the subject has provided written informed consent but before 
administration of study drug and are considered related to a protocol procedure must also be 
reported to the Sponsor or designee within 24 hours after the Investigator’s awareness of the 
event. 
Investigators should not wait to receive additional information to fully document an SAE before 
reporting the event to the Sponsor or designee. If only limited information is initially available, 
follow-up information regarding the SAE is required. Additional relevant information such as 
hospital records, laboratory test results, discharge summaries and/or autopsy reports should be 
provided as soon as these are available. These SAE follow-up documents should be uploaded 
into the EDC system for informational purposes; however, if a document cannot be uploaded, it 
should be submitted to Iconic Therapeutics Drug Safety: 
Safety Notification 
Email:  drugsafety@iconictherapeutics.com  
Fax:  650-246-9011 
(or email or fax number provided on Safety Notification Cover Sheet) 
 
15.22.7 Reporting Serious Adverse Events to Regulatory Agencies 
An AE, whether serious or non-serious, is considered “unexpected” if the event is not reported in 
the clinical safety section of the reference document (e.g., Investigator Brochure or Package 
Insert) or if the event is of greater severity or frequency than is reported in the reference 
document. 

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Expedited SAE reports are those SAEs that are both unexpected based on the reference 
document and considered related to the study drug (i.e., the relationship cannot be ruled out). 
The Sponsor will determine which SAEs qualify for expedited reporting.  
Reports of those SAEs that qualify for expedited reporting submitted to regulatory agencies in 
accordance with applicable local regulation (e.g., 21 Code of Federal Regulations [CFR] 312.32 
and, as applicable, European Union Directive 2001/83/EC and 2001/20/EC).  
Expedited reports will be also distributed to Investigators. Upon receiving such notices, the 
Investigator must review and retain the notice with the Investigator Brochure and immediately 
submit a copy of this information to the governing IRB/IEC in accordance with institutional 
guidelines and local regulations. 
15.22.8 Pregnancy 
Pregnancy alone is not an AE. However, any report of pregnancy that occurs in a female subject 
within 30 days after the subject’s last administration of study drug, and that becomes known to 
the Investigator, must be reported to the Sponsor even if the subject is withdrawn from study.  
If a subject or Investigator suspects that a subject may be pregnant prior to study drug 
administration, the study drug administration must be withheld until the results of blood serum 
pregnancy tests are available. If pregnancy is confirmed, the subject must not receive the study 
drug and must not be enrolled in the study. If pregnancy is suspected while the subject is 
receiving study treatment, the study drug must be withheld immediately until the result of a 
pregnancy testing is known. If pregnancy is confirmed, the study drug will be permanently 
discontinued and the subject withdrawn from the study. The Investigator must follow the 
pregnancy to conclusion, and collect data on both maternal and fetal outcome including follow-
up information regarding the course of the pregnancy and perinatal and neonatal outcomes.  
A Pregnancy Report form will be submitted to the Sponsor, at a minimum, initially and at the 
end of the pregnancy. The Investigator is also encouraged to submit to the Sponsor trimester 
follow up reports during the pregnancy. The outcome of the pregnancy and any complications 
occurring during the pregnancy or the delivery must be reported to the Sponsor. 
A miscarriage or spontaneous abortion will be considered an SAE, and will be reported to the 
Sponsor according to the procedure described in Section 15.22.5. 
15.22.9 Overdose 
Overdose is defined as any dose higher than the protocol prescribed dose of study drug. 
Occurrences of overdose leading to an AE will be reported on the AE eCRF. An overdose 
leading to an SAE will be reported to the Sponsor according to the procedure described in 
Section 15.22.5. 

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15.22.10 Follow-up of Adverse Events  
Patients with an ongoing SAE will be followed until the event is resolved, the significant 
changes return to baseline, the condition stabilizes, the event is no longer considered clinically 
significant by the Investigator, the patient withdraws consent, or the patient is lost to follow-up. 
This may imply that follow-up will continue after the patient has left the study and that 
additional investigation may be requested by the Sponsor. If the severity or relationship to study 
drug worsens for an ongoing SAE, a follow-up SAE report should be sent to the Sponsor within 
24 hours after the Investigator becomes aware of the change in status. 
All non-serious adverse events will be followed through the study exit visit. If a non-serious AE 
is first identified at the last scheduled study contact, the event will be recorded on the AE eCRF 
with the current status noted, but no further follow-up is required. 
15.22.11 Follow-up of Post-study Serious Adverse Events 
Should the Investigator become aware of a new SAE that occurs within 30 days after the last 
scheduled study contact and the event is determined by the Investigator to be related to the study 
drug, the SAE should be reported to the Sponsor and followed in accordance with the procedures 
described in this protocol. 

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16 STUDY ENDPOINTS 
16.1 
Primary Endpoints 
Safety as measured by: 
 Occurrence of ocular and systemic serious adverse events and adverse events 
 Changes in standard clinical laboratory tests (serum chemistry, hematology, coagulation) 
and ADA levels 
 Changes in vital signs and physical and ophthalmic examinations 
16.2 
Secondary Endpoints 
Pharmacokinetics and Pharmacodynamic Markers 
 Plasma levels of ICON-1 following intravitreal injections of ICON-1  
 Change in circulating TF and serum cytokine levels following intravitreal injections of  
ICON-1 
 Characterization of immunophenotyping patterns 
Pharmacodynamic and Biological Activity  
 Change in tumor size (thickness, volume) as assessed by imaging techniques (CFP, FA, 
sdOCT, ultrasound, ICG angiography, EDI-OCT) from baseline  
16.3 
Exploratory Endpoints 
 Characterization of the genetic profile of the tumor (Type 1 or Type 2), and associated 
changes in the tumor with ICON-1 treatment 
 Characterization of pathologic findings of the tumor (ICON-1 target engagement within 
the tumor, TF and PAR2 expression, characterization of immune infiltrate, and 
alterations of the vasculature) 
 ICON-1 and proteomic analysis (TF and other cytokine levels) of the vitreous humor  
 

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17 STATISTICAL ANALYSIS AND METHODS PLANNED 
17.1 
Statistical Analysis Plans 
This phase 1 study is exploratory and its sample size is not determined by statistical power 
considerations. Hence, no inferential testing will be performed. Data analysis for this study will 
be geared toward descriptive and graphical summaries. 
As descriptors of the three cohorts, univariate data summaries will be provided. For continuous 
endpoints, summary statistics will include number of patients, mean, median, standard deviation, 
minimum, and maximum. For categorical endpoints, summary statistics will include number of 
patients, frequency, and percentages. 
All patients who receive ICON-1 will be considered evaluable and will be included in the 
analysis. Exploratory analyses of the data not described in the following subsections may be 
conducted as deemed appropriate. The baseline evaluation will be defined as the last evaluation 
prior to the first study treatment. More details will be provided in the Statistical Analysis Plan 
(SAP). 
17.2 
Analysis of the Conduct of the Study 
The number of patients enrolled will be tabulated by study site and cohort. Patient disposition 
(the number of subjects enrolled, treated, and completing the study) will be tabulated by cohort. 
Subject discontinuations and reasons for discontinuation will be summarized. 
17.3 
Handling of Dropouts or Missing Data 
Patients who discontinue from the study prior to completing the one week safety evaluation 
following their last injection may be replaced. 
17.4 
Analysis of Treatment Arm Comparability 
Summary statistics of patient demographics, such as age, sex, and race will be provided by 
cohort to assess comparability. Other baseline characteristics such as genetic profile of the tumor 
may be summarized. 
17.5 
Treatment Exposure 
The total dose received will be summarized by cohort. The dose level, and number of doses 
received will also be summarized by cohort. Study drug administration data will be listed for 
each patient. 
17.6 
Safety Analyses 
Safety will be assessed through summaries of adverse events, changes in laboratory test results 
(serum chemistry, hematology, coagulation), and changes in vital signs and physical and 
ophthalmic examinations. Adverse events will be mapped using MedDRA. Systemic levels of 

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anti-drug antibodies (ADA) during the study will be collected for each patient. If there are 
sufficient numbers of patients exhibiting systemic levels of ADA, summary statistics by cohort 
will also be provided. 
All collected adverse event data will be listed by cohort, study site, and patient number. All 
Adverse Events of Special Interest (AESIs) occurring on or after intravitreal injection will be 
listed and summarized by cohort. All adverse events occurring on or after treatment on Day 0 
(treatment emergent adverse events, TEAEs) will be summarized by cohort. In addition, all 
serious adverse events, including deaths (if any), will be listed separately. Finally, all ocular 
adverse events will be listed and tabulated with events for the study and fellow eye summarized 
separately. 
Changes in laboratory data will be summarized by cohort.  
17.7 
Biological Activity Analyses 
Mean changes in tumor size and characteristics of pathologic tumor findings over time will be 
summarized for each patient. Mean changes in BCVA, retina and tumor thickness and volume, 
and areas of vascular leakage/ exudation over time will be summarized for each patient. 
Graphical displays of changes over time in ophthalmic ultrasound measures and ocular function 
may be constructed for each patient. Patient profiles, aggregating patient level data across many 
biological activity domains, may be used to explore joint biological effects in each patient. 
Vitreous humor (ICON-1, TF, and other cytokine levels) results over time will be summarized, if 
obtained. 
17.8 
Pharmacokinetic and Pharmacodynamic Markers Analyses 
Pharmacokinetic analyses will be conducted on data from patients who have received at least 1 
dose of ICON-1 and have at least one post-dose sample collected to allow estimation of the PK 
parameters. 
Individual (patient) plasma ICON-1 concentrations at each sampling time will be listed; 
corresponding summary statistics at each sampling time will be calculated for the ICON-1. 
Plasma ICON-1 versus time profiles (with concentrations on both a log and linear scale) will be 
plotted for each patient; corresponding summary time plots will likewise be constructed for 
cohort.  
When applicable, pharmacokinetic parameters will be calculated using non-compartmental 
techniques from plasma ICON-1 concentrations and will include the following parameters: t1/2, 
Cmax, Tmax, and AUC0-∞. Individual ICON-1 PK parameters will be listed for each patient, and 
summary statistics will be calculated for each cohort. 
17.9 
Interim Analysis 
No formal interim analysis is planned for this study. However, all individual patient data 
including safety data will be examined on an ongoing basis to ensure patient safety and to 
comply with the dose level escalation rules. 

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17.10 Sample Size Determination 
Up to 13 patients with uveal melanoma involving the posterior uveal tract will be enrolled from 
approximately seven to ten centers in the United States. Patients who discontinue before the one 
week safety evaluation following their last injection may be replaced. This study is exploratory 
and its sample size is not determined by statistical power considerations and no sample size 
calculations were performed. 

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18 DATA HANDLING AND RECORD KEEPING 
18.1 
Case Report Forms and Source Documents 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain detailed and accurate case histories of all study patients. Original data will be recorded 
in the subject’s source documents (which may include medical records, hospital charts, clinic 
charts/notes, diagnostics tests such as x-rays, laboratory tests and ECGs, and electronic 
recordings), and transcribed onto electronic case report forms (eCRFs) provided by the Sponsor. 
The Investigator agrees to maintain accurate source documentation as part of the case history for 
each subject. Recorded data should be updated/corrected in a manner that does not obliterate, 
destroy, or render illegible the previous entry (e.g., by drawing a single line through the incorrect 
entry and writing the revision next to the corrected data). An individual who has corrected an 
entry should make clear who made the correction and when, by adding his/her initials and the 
date of the correction. 
Designated site staff must complete the applicable eCRFs as soon as possible after each subject 
visit, and the eCRFs must be available for review at the next scheduled monitoring visit. 
Electronic case report form completion guidelines that describe how to appropriately enter data 
into eCRFs from the source documents will be provided to the study sites. If an item is not 
available or is not applicable, this should be indicated. Blank data fields should not be present 
unless otherwise directed. 
Prior to locking the clinical database, the Investigator must review and approve all completed 
eCRFs to verify their accuracy. 
18.2 
Monitoring of the Study 
Qualified individuals (CRAs or Study Monitors) designated by the Sponsor will follow the study 
closely, and monitor all aspects of the study according to ICH/GCP and standard operating 
procedures for compliance with applicable government regulations. The Principal Investigator 
(PI) agrees to allow the CRAs direct access to study drug accountability records and drug 
supplies, dispensing and storage areas, clinical files of the study patients (including original 
medical records) and the regulatory files. The PI also agrees to assist the CRAs if requested. The 
Principal Investigator and appropriate site staff are responsible for being present or available for 
consultation during routinely scheduled site visits conducted by the CRAs.  
The CRA will maintain necessary email, telephone, fax, and/or mail contact with the 
Investigators and study site personnel, and will visit the study sites at periodic intervals. The 
CRA will maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
Investigators and study site staff. During those visits, the CRA will compare the subject data 
entered in the eCRFs against original source documents at the clinical site, and evaluate the 
eCRFs for completeness and accuracy. Data that are modified on the eCRFs to resolve any 
discrepancies must be supported by the source documents. The review of subject medical records 

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will be performed in a manner to ensure that subject confidentiality is adequately maintained. 
Further details of the study monitoring will be outlined in a separate Monitoring Plan. 
18.3 
Data Management 
Data management for this study will be contracted to a Contract Research Organization (CRO) 
designated by the Sponsor. All data management procedures will be detailed in separate, 
specifically identified documents that collectively will be referenced as the Data Management 
Plan (DMP).  
The designated site personnel will transcribe the information required by the protocol onto the 
eCRFs that will be provided using a fully validated Electronic Data Capture (EDC) system 
conforming to FDA requirements for the capture of electronic data. The data will be checked for 
missing data or suspect errors upon entry against validation programs, and appropriate flags will 
be displayed on the eCRFs. The Investigator or designee will make the necessary corrections or 
verify the correctness of the data based on these flags. The database will be backed up regularly 
throughout the study by the CRO or EDC vendor.  
Study Monitors representing the Sponsor will review the eCRFs against the source 
documentation at the site for completeness and accuracy, and will discuss the need for further 
corrections with the Investigator or designee. In addition, computerized edit checks and manual 
review processes will also be performed by the CRO on an ongoing basis as outlined in the DMP 
until all data clarifications are resolved.  
In order to classify adverse events and concomitant medications, preferred terms will be assigned 
to the original terms entered on the eCRFs using MedDRA and WHO Drug dictionaries, 
respectively.  
After all data are entered and all data queries resolved, the Investigator must certify that the 
subject data are complete and accurate by applying an electronic signature to the eCRF study 
completion page. Once all eCRFs for the study are signed and the analysis populations are 
determined and documented, the clinical database will be locked. 
After the clinical database is locked, disks containing electronic copies of all applicable subjects’ 
eCRFs will be provided to each Investigator to be maintained on file by the Investigator. 
18.4 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspection(s) by providing direct access to all study records. The 
Investigator or study site may be audited by the Sponsor or its representatives and/or regulatory 
agencies at any time. In the event of an audit, the Investigator agrees to allow the Sponsor, 
representatives of the Sponsor, the FDA, or other regulatory agency access to all study records. 
The Sponsor will review case report form data and perform electronic edit checks on the data.  

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The Investigator should promptly notify the Sponsor of any audits scheduled by any regulatory 
authorities and promptly forward copies of any received audit reports to the Sponsor. 
18.5 
Study Record Retention 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical study must be retained by the Investigator. Original source documents 
for each subject should be included in this documentation. Study documentation should be 
retained by the Investigator until notified by the Sponsor in writing that retention is no longer 
necessary. In addition, the Investigator must notify the Sponsor of any change in the location, 
disposition or custody of the study documentation. Study documentation includes study records, 
subject charts/notes, subject medical records, laboratory tests, and paper or electronic recordings. 
It is the responsibility of the Sponsor to inform the Investigator/institution as to when this 
documentation no longer needs to be retained.  
Records containing subject medical information must be handled in accordance with the 
requirements of the applicable privacy rules and consistent with the terms of the subject 
authorization contained in the ICF for the study. Care should be taken to ensure that such records 
are not shared with any person or for any purpose not contemplated by the ICF. Furthermore, 
eCRFs and other documents to be transferred to the Sponsor should be completed in strict 
accordance with the instructions provided by the Sponsor, including the instructions regarding 
the coding of subject identities.  
Essential study documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study drug. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. Should the Investigator retire, relocate, or for other reasons withdraw from the 
responsibility of keeping the study records, custody must be transferred by the Investigator to 
another party who will accept the responsibility. The Sponsor must be notified in writing by the 
Investigator of the name and address of the new custodian and receive documented acceptance 
from the new custodian. If requested, the Investigator will provide the Sponsor, applicable 
regulatory agencies, and applicable IRB/IEC with direct access to original source documents. 
 

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19 ADMINISTRATIVE CONSIDERATIONS 
19.1 
Confidentiality 
All records identifying the patient will be kept confidential and to the extent permitted by the 
applicable laws and/or regulations will not be made publicly available. Patient names and other 
identifying information will not be supplied by the Sponsor. Only subject number and/or subject 
initials will be reported in the eCRF. If the patient name or other identifying information appears 
on any other document or study materials, the information must be deleted before a copy of the 
document is supplied to the Sponsor.   
The Investigator (or designee) is responsible to obtain from the patient or patient’s legally 
authorized representative, written permission to use protected health information per country-
specific regulations, such as the HIPAA in the United States. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to document this in the 
patient’s record. 
If the results of the study are published, the subject’s identity will remain confidential. The 
Investigator is responsible for maintaining a list enabling subject’s records to be identified. 
19.2 
Amendments to the Protocol 
Any changes or deviations in the protocol will be made as an amendment to the protocol and 
approved by the Sponsor and the IRB/EC before they are implemented. The Investigator or 
designee must notify the Sponsor or designee of any inadvertent protocol deviations upon their 
discovery, and document the deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the ICF will be amended and approved by the IRB/EC, and all patients on study must 
provide new informed consent. 
19.3 
Protocol Deviations 
The Investigator will not deviate from any tests, procedures, eligibility criteria, or the schedule of 
assessments described in the protocol except in the event of a medical emergency. The 
Investigator should contact the Medical Monitor with any questions concerning a subject who 
may not meet the entry criterion. Waivers for protocol eligibility will not be allowed for this 
study.  
All protocol deviations must be documented and explained in the subject’s source 
documentation, and should be reported to the Study Monitor. Protocol deviations should also be 
reported to the site IRB/EC in a timely manner and in accordance with the policies of the 
IRB/EC.  

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19.4 
Study Reporting Requirements 
The Investigator is responsible for submitting progress reports annually, or more frequently if 
required, to their IRB/EC and any applicable institutional committees in accordance with the 
policies of their IRB/EC and institutional committees respectively. The Investigator is 
responsible for maintaining copies of these reports and any acknowledgments from the IRB/EC 
or institutional committees. These reports must be available for review by the Study Monitor and 
any regulatory agency upon request. Any changes significantly affecting the conduct of the study 
and/or risk to the patients should be promptly reported to the Sponsor its designee, the IRB/EC 
and any applicable institutional committees. 
19.5 
Financial Disclosure 
Financial Disclosure Forms must be completed by the Principal Investigator and all Sub-
Investigators listed on the Form FDA 1572 who will directly be involved in the treatment or 
evaluation of patients in this study. 
19.6 
Investigator Responsibilities 
The Investigator should ensure that all persons involved in the conduct of the study are informed 
about the protocol, protocol amendments, study procedures, and any study-related duties. The 
investigator is responsible for assuring that study site staff are properly trained and credentialed 
to perform any delegated tasks. 
The Investigator is responsible for monitoring the safety of patients who have entered this study 
and for providing appropriate medical care. In addition, the Investigator is responsible for 
managing AEs that are serious or that cause the patient to withdraw before completing the study. 
Frequency of follow-up beyond that mandated in the protocol is left to the discretion of the 
Investigator.   
19.7 
Clinical Trial Agreement 
A fully executed (signed and dated by all applicable parties) Clinical Trial Agreement describing 
the responsibilities and terms of collaboration between Iconic Therapeutics and the study site is 
required prior to initiating the study. 
19.8 
Policy for Publication and Presentation of Data 
Iconic Therapeutics recognizes the importance of communicating medical study data and 
therefore encourages their publication in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Trial Agreement 
between Iconic Therapeutics and the institution of the Investigator. 

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20 REFERENCES 
1. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous 
and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The 
American College of Surgeons Commission on Cancer and the American Cancer 
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3. Shields, C. L., S. Kaliki, et al. American Joint Committee on Cancer classification of 
posterior uveal melanoma (tumor size category) predicts prognosis in 7731 patients. 
Ophthalmol. 2013;120(10):2066-2071. 
4. Stang, A. and K. H. Jockel. Trends in the incidence of ocular melanoma in the United 
States, 1974-1998. Cancer Causes Control. 2004; 15(1): 95-96; author reply 101-102. 
5. Stang, A., D. M. Parkin, et al. International uveal melanoma incidence trends in view of 
a decreasing proportion of morphological verification. Int J Cancer. 2005;114(1):114-
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6. Virgili, G., G. Gatta, et al. Incidence of uveal melanoma in Europe. Ophthalmol. 
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7. 28 CRN. The COMS randomized trial of iodine 125 brachytherapy for choroidal 
melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. 
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8. Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, 
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malignant cells by reverse transcriptase-polymerase chain reaction in long-term 
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29. Katoh H, Watanabe M. Myeloid-Derived Suppressor Cells and Therapeutic Strategies in 
Cancer Mediators of Inflammation.2015. Article ID 159269. 
30. Cocco E, Hu Z, Richter CE, Bellone S, Casagrande F, Bellone M, et al. hI-con1, a factor 
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21 APPENDICES 

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21.1 
Appendix A:  Study Flowchart and Assessments – Cohort 1 (Patients Undergoing Enucleation or Brachytherapy) 
Study Day 
Screening1 
 
Day -7 to 0 
Baseline 
Treatment 
Day 0 
Day 1 
NA for  
Cohort 1 
Procedure 
Assessments 
(On or 1 day 
prior to Surgical 
Procedure7 day) 
End of 
Study 
30 days ±5 
days post 
Surgical 
Procedure 
Early 
Termin-
ation 
Visit 
1 
2 
3 
42 & 52 
6 
7 
ET 
Demographic Data 
X 
 
 
 
 
 
 
Medical/Ocular/Surgical/ Medication 
History 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
 
X 
X 
X 
Serum Chemistry, Hematology and 
Coagulation Blood Samples 
X 
 
 
 
X 
X 
X 
Anti-drug Antibody levels (ADA) 
X 
 
 
 
 
X 
X 
Serum Pregnancy Test  
(WOCBP only) 
X 
 
 
 
 
X 
X 
Abbreviated Physical Exam 
X3 
 
 
 
 
X 
X 
Best-corrected Visual Acuity by 
ETDRS 
OU 
OU 
SE 
 
OU 
OU9 
OU10 
Slit Lamp Biomicroscopy 
OU 
OU 
SE 
 
OU 
OU9 
OU10 
Intraocular Pressure4 
 
Pre-injection 
Post-injection(s)  
OU 
 
OU 
SE 
SE 
 
OU 
 
OU9 
OU10 
Dilated Ophthalmoscopy 
OU 
SE 
 
 
OU 
OU9 
OU10 
Color Fundus Photography 
OU 
 
 
 
OU 
OU9 
OU10 
Spectral-domain Optical Coherence 
Tomography 
SE 
 
 
 
SE 
SE9 
SE10 

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Study Day 
Screening1 
 
Day -7 to 0 
Baseline 
Treatment 
Day 0 
Day 1 
NA for  
Cohort 1 
Procedure 
Assessments 
(On or 1 day 
prior to Surgical 
Procedure7 day) 
End of 
Study 
30 days ±5 
days post 
Surgical 
Procedure 
Early 
Termin-
ation 
Visit 
1 
2 
3 
42 & 52 
6 
7 
ET 
Enhanced Depth Imaging Optical 
Coherence Tomography  
(optional according to investigator 
judgment) 
SE 
 
 
 
SE 
 
SE10 
Ophthalmic Ultrasound 
SE 
 
 
 
SE 
SE9 
SE10 
Fluorescein Angiography 
OU 
 
 
 
OU 
 
OU10 
ICG Angiography 
(optional according to investigator 
judgment) 
OU 
 
 
 
OU 
 
OU10 
Pharmacodynamic Assessments  
(blood sample pre and post treatment) 
 
X5 
X 
 
X 
 
X6 
Pharmacokinetic Assessment 
(blood sample pre and post treatment) 
 
X5 
X 
 
 
 
X6 
Intravitreal Injection:  
COHORT 1 
 
X 
 
 
 
 
 
Scheduled Enucleation or Plaque 
Placement Procedure7 
(≥4 days after injection according to 
standard of care) 
 
 
 
 
X 
 
 
Mandatory Vitreous and Tumor 
Sample for Enucleation Patients8 
 
 
 
 
X 
 
 
Adverse Events 
 
X 
X 
 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
 
X 
X 
X 

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SE=Study Eye, OU=Both Eyes 
1 If there is study drug available at the clinical site, Screening assessments may be conducted on same day as Baseline visit (Day 0), prior to enrollment and 
intravitreal injection. Informed consent must be obtained before any study related screening activity or treatment is undertaken that is not part of routine care. 
2 Cohort 1 does not have Visit 4 or 5; the next visit after Visit 3 is Visit 6. 
3 Height and weight measured at Screening only. 
4 IOP measured using routine practice with a calibrated contact tonometer. For study eyes, IOP will be measured pre and post injection(s).   
5 Blood samples for PK and PD assessments will be drawn before and 4 hours ±1 hour post injection.  
6 At Early Termination, blood samples for PK and PD assessments will be drawn if Day 1 PK/PD blood samples were not collected following injection on Day 0.  
7 The surgical procedure is scheduled independent of this study according to standard of care clinical management of uveal melanoma per patient’s treating physician 
and is not a study procedure.   
8 Following enucleation, vitreous humor will be collected for ICON-1 and proteomic analysis of TF and other cytokine levels. In addition to the pathology standard 
procedures of the clinical site, the study-related pathology slides and/or tumor block sample will be prepared and shipped to a central study laboratory for additional 
evaluations of the tumor (TF expression, ICON-1 binding, immune infiltrate, genetic profiling, and Exome sequencing). Genetic profiling of the tumor previously 
performed with fine needle aspiration of the tumor does not require repeated testing.  
9 Ocular assessments for brachytherapy patients only. 
10 Ocular assessments at early termination visit only if early termination occurs prior to surgical procedure. 
 
 

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21.2 
Appendix B:  Study Flowchart and Assessments – Cohorts 2 and 3 (Patients Undergoing Enucleation or Brachytherapy) 
Study Day 
Screening1 
 
Day -7 to 0 
Baseline 
Treatment 
Day 0 
Day 1 
Treatment 
Day 7 
±2 days 
1 day post 
Day 7 
Treatment 
Procedure 
Assessments 
(On or 1 day 
prior to Surgical 
Procedure7 day) 
End of 
Study 
30 days ±5 
days post 
Surgical 
Procedure 
Early 
Termin-
ation 
Visit 
1 
2 
3 
4 
5 
6 
7 
ET 
Demographic Data 
X 
 
 
 
 
 
 
 
Medical/Ocular/Surgical/ 
Medication History 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry, Hematology and 
Coagulation Blood Samples 
X 
 
 
X 
 
X 
X 
X 
Anti-drug Antibody levels (ADA) 
X 
 
 
 
 
 
X 
X 
Serum Pregnancy Test  
(WOCBP only) 
X 
 
 
 
 
 
X 
X 
Abbreviated Physical Exam 
X2 
 
 
 
 
 
X 
X 
Best-corrected Visual Acuity by 
ETDRS 
OU 
OU 
SE 
OU 
SE 
OU 
OU9 
OU10 
Slit Lamp Biomicroscopy 
OU 
OU 
SE 
OU 
SE 
OU 
OU9 
OU10 
Intraocular Pressure3 
 
Pre-injection 
Post-injection(s)  
OU 
 
OU 
SE6 
SE 
 
OU 
SE6 
SE 
 
OU 
 
OU9 
OU10 
Dilated Ophthalmoscopy 
OU 
SE 
 
SE 
 
OU 
OU9 
OU10 
Color Fundus Photography 
OU 
 
 
 
 
OU 
OU9 
OU10 
Spectral-domain Optical Coherence 
Tomography 
SE 
 
 
SE 
 
SE 
SE9 
SE10 

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Study Day 
Screening1 
 
Day -7 to 0 
Baseline 
Treatment 
Day 0 
Day 1 
Treatment 
Day 7 
±2 days 
1 day post 
Day 7 
Treatment 
Procedure 
Assessments 
(On or 1 day 
prior to Surgical 
Procedure7 day) 
End of 
Study 
30 days ±5 
days post 
Surgical 
Procedure 
Early 
Termin-
ation 
Visit 
1 
2 
3 
4 
5 
6 
7 
ET 
Enhanced Depth Imaging Optical 
Coherence Tomography  
(optional according to investigator 
judgment) 
SE 
 
 
SE 
 
SE 
 
SE10 
Ophthalmic Ultrasound 
SE 
 
 
SE 
 
SE 
SE9 
SE10 
Fluorescein Angiography 
OU 
 
 
 
 
OU 
 
OU10 
ICG Angiography 
(optional according to investigator 
judgment) 
OU 
 
 
 
 
OU 
 
OU10 
Pharmacodynamic Assessments  
(blood sample pre and post treatment) 
 
X4 
X 
X4 
X 
X 
 
X5 
Pharmacokinetic Assessment 
(blood sample pre and post treatment) 
 
X4 
X 
X4 
X 
 
 
X5 
Intravitreal Injection:  
COHORT 2 
 
X 
 
X 
 
 
 
 
Intravitreal Injection:  
COHORT 3 
 
XX6 
 
XX6 
 
 
 
 
Scheduled Enucleation or Plaque 
Placement Procedure7   
(≥4 days after last injection according 
to standard of care) 
 
 
 
 
 
 
X 
 
 

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Study Day 
Screening1 
 
Day -7 to 0 
Baseline 
Treatment 
Day 0 
Day 1 
Treatment 
Day 7 
±2 days 
1 day post 
Day 7 
Treatment 
Procedure 
Assessments 
(On or 1 day 
prior to Surgical 
Procedure7 day) 
End of 
Study 
30 days ±5 
days post 
Surgical 
Procedure 
Early 
Termin-
ation 
Visit 
1 
2 
3 
4 
5 
6 
7 
ET 
Mandatory Vitreous and Tumor 
Sample for Enucleation Patients8 
 
 
 
 
 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
SE=Study Eye, OU=Both Eyes, XX=two injections 
1 If there is study drug available at the clinical site, Screening assessments may be conducted on same day as Baseline visit (Day 0), prior to enrollment and 
intravitreal injection. Informed consent must be obtained before any study related screening activity or treatment is undertaken that is not part of routine care. 
2 Height and weight measured at Screening only. 
3 IOP measured using routine practice with a calibrated contact tonometer. For study eyes, IOP will be measured pre and post injection(s).   
4 Blood samples for PK and PD assessments will be drawn before and 4 hours ±1 hour post injection (for cohort 3, after the second injection). 
5 At Early Termination, blood samples for PK and PD assessments will be drawn if Day 1 or 1 day post Day 7 treatment PK/PD blood samples were not collected 
following injection on Day 0 or Day 7.  
6 For Cohort 3, the study eye receives two study drug injections. The second study drug injection will occur following stabilization of IOP to within 5 mmHg of the 
pre injection measurement and ≥30 minutes after the first injection at the visit. 
7 The surgical procedure is scheduled independent of this study according to standard of care clinical management of uveal melanoma per patient’s treating physician 
and is not a study procedure.   
8 Following enucleation, vitreous humor will be collected for ICON-1 and proteomic analysis of TF and other cytokine levels. In addition to the pathology standard 
procedures of the clinical site, the study-related pathology slides and/or tumor block sample will be prepared and shipped to a central study laboratory for additional 
evaluations of the tumor (TF expression, ICON-1 binding, immune infiltrate, genetic profiling, and Exome sequencing). Genetic profiling of the tumor previously 
performed with fine needle aspiration of the tumor does not require repeated testing.  
9 Ocular assessments for brachytherapy patients only. 
10 Ocular assessments at early termination visit only if early termination occurs prior to surgical procedure.