Phase II Randomized Trial of Stereotactic Radiotherapy (SRT) Followed by Intravitreal Aflibercept Injection for Patients With Ocular Melanoma
Phase: PHASE2
Conditions: Uveal Melanoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University

Ph2 SRT and Aflibercept for ocular melanoma 
 
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THOMAS JEFFERSON UNIVERSITY 
Sidney Kimmel Cancer Center 
Phase II Randomized Trial of Radiotherapy Followed by intravitreal Aflibercept 
injection for patients with ocular melanoma 
Principal Investigator: 
Wenyin Shi, MD., PhD.  
Department of Radiation Oncology  
111 S 11 ST, Suite G301 
Philadelphia, PA 19107 
Phone: (215) 955-6702 
Fax: (215) 955-0412 
Co-Investigator(s): 
Thomas Jefferson University 
Lydia Komarnicky-Kocher  
Department of Radiation Oncology 111 S 11 ST, Suite G301 
Philadelphia, PA 19107 
Phone: (215) 955-6702 
Fax: (215) 955-0412 
 
Maria Werner-Wasik, MD  
Department of Radiation Oncology  
111 S 11 ST, Suite G301 
Philadelphia, PA 19107 
Phone: (215) 955-6702 
Fax: (215) 955-0412 
 
Voichita Bar Ad, MD 
Department of Radiation Oncology  
111 S 11 ST, Suite G301 
Philadelphia, PA 19107 
Phone: (215) 955-6702 
Fax: (215) 955-0412 
 
Wills Eye Hospital  
Carol Shields, MD  
Wills Eye Hospital 
840 Walnut Street, Suite 1440 
Philadelphia, PA 19107 
Phone: (877) 289-4557 
Fax: (215) 928-1140 
  
Sara Lally, MD Wills Eye Hospital 
840 Walnut Street, Suite 1440 
Philadelphia, PA 19107 

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Phone: (877) 289-4557 
Fax: (215) 928-1140 
 
Statistician: 
Inna Chervoneva, PhD 
Funding Sponsor: 
Regeneron 
IND/IDE Holder: 
Wenyin Shi, MD 
IND/IDE Number: 
140600 
Study Product: 
intravitreal Aflibercept Injection (IAI) 
Protocol IDs: 
JeffTrial # 11801 
PRC # 2018-078 
IRB Control # 18P.457 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document is confidential and the property of THOMAS JEFFERSON UNIVERSITY. 
No part of it may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from the study sponsor. 
 
Version Number: 
Version Date: 
1.0 
18DEC2017 
1.1 
09 March 2018 
2.0 
01 June 2018 
2.1 
25 June 2018 
3.0 
16 August 2018 
3.1 
08 April 2019 
3.2 
26 June 2020 
3.3 
24 June 2021 

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Table of Contents (This will be based on the headers in the body of the document. To update 
the table, hit Ctrl+A, and then F9.) 
 
Signature Page .......................................................................................................................... 8 
Statement of Compliance ........................................................................................................... 8 
List of Abbreviations ................................................................................................................... 9 
Study Summary ........................................................................................................................11 
1 
Introduction .........................................................................................................................14 
1.1 
Background Information ..............................................................................................14 
1.2 
Rationale for the Proposed Study ...............................................................................17 
1.3 
Correlative Studies ......................................................................................................18 
1.4 
Potential Risks and Benefits .......................................................................................18 
1.4.1 Potential Risks.........................................................................................................18 
1.4.2 Benefits ...................................................................................................................19 
2 
Study Objectives .................................................................................................................19 
2.1 
Objectives ...................................................................................................................19 
2.1.1 Primary ....................................................................................................................19 
2.1.2 Secondary ...............................................................................................................19 
2.2 
Endpoints/Outcome Measures ....................................................................................19 
2.2.1 Primary ....................................................................................................................19 
2.2.2 Secondary ...............................................................................................................19 
3 
Study Design ......................................................................................................................20 
3.1 
Number of Participants ...............................................................................................20 
3.2 
Duration of Therapy ....................................................................................................20 
3.3 
Duration of Follow Up .................................................................................................21 

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3.4 
Treatment Assignment Procedures .............................................................................21 
3.4.1 Randomization Procedures (if applicable) ...............................................................21 
3.4.2 Masking Procedures (if applicable) ..........................................................................21 
3.5 
Study Timeline ............................................................................................................21 
3.5.1 Primary Completion .................................................................................................21 
3.5.2 Study Completion ....................................................................................................21 
4 
Study Enrollment and Withdrawal .......................................................................................21 
4.1 
Eligibility Criteria .........................................................................................................21 
4.1.1 Inclusion Criteria ......................................................................................................21 
4.1.2 Exclusion Criteria ....................................................................................................22 
4.2 
Gender/Minority/Pediatric Inclusion for Research........................................................23 
4.3 
Strategies for Recruitment and Retention ...................................................................23 
4.4 
Participant Enrollment .................................................................................................23 
4.5 
Participant Withdrawal ................................................................................................23 
4.5.1 Reasons for Withdrawal ..........................................................................................23 
4.5.2 Handling of Participant Withdrawals and Participant Discontinuation of Study 
Intervention .........................................................................................................................24 
4.6 
Premature Termination or Suspension of Study ..........................................................24 
5 
Study Intervention ...............................................................................................................25 
5.1 
Study Product .............................................................................................................25 
5.2 
Study Product Description ...........................................................................................25 
5.2.1 Acquisition ...............................................................................................................25 
5.2.2 Formulation, Packaging, and Labeling .....................................................................25 
5.2.3 Product Storage and Stability ..................................................................................26 
5.3 
Dosage, Preparation, and Administration ....................................................................26 

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5.4 
Dose Modifications and Dosing Delays .......................................................................26 
5.5 
Study Product Accountability ......................................................................................27 
5.6 
Assessing Participant Compliance with Study Product Administration ........................27 
5.7 
Concomitant Medications/Treatments .........................................................................27 
5.8 
Dietary Restrictions .....................................................................................................27 
5.9 
Study Procedural Intervention(s) Description Radiation Therapy (Plaque 
brachytherapy) .......................................................................................................................27 
5.10 
Administration of Procedural Intervention ....................................................................29 
5.11 
Procedures for Training of Clinicians on Procedural Intervention ................................30 
5.12 
Assessment of Clinician and/or Participant Compliance with Study Procedural 
Intervention ............................................................................................................................30 
6 
Study Schedule ..................................................................................................................30 
6.1 
Pretreatment Period/Screening ...................................................................................30 
6.2 
Enrollment/Baseline ....................................................................................................31 
6.3 
Treatment Period ........................................................................................................31 
6.4 
Withdrawal Visit/Discontinuation of Therapy ...............................................................33 
7 
Study Procedures and Evaluations .....................................................................................33 
7.1 
Study Procedures/Evaluations ....................................................................................33 
8 
Evaluation of Safety ............................................................................................................34 
8.1 
Specification of Safety Parameters .............................................................................34 
8.1.1 Unanticipated Problems ..........................................................................................34 
8.1.2 Adverse Events .......................................................................................................34 
8.1.3 Serious Adverse Events ..........................................................................................35 
8.2 
Safety Assessment and Follow-Up .............................................................................36 
8.3 
Recording Adverse Events ..........................................................................................36 

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8.3.1 Relationship to Study Intervention ...........................................................................36 
8.3.2 Expectedness ..........................................................................................................37 
8.3.3 Severity of Event .....................................................................................................37 
8.3.4 Intervention .............................................................................................................37 
8.4 
Safety Reporting .........................................................................................................37 
8.4.1 Report to the TJU IRB .............................................................................................37 
8.4.2 Reporting to WEH IRB .............................................................................................38 
8.4.3 Reporting to SKCC DSMC ......................................................................................39 
8.4.4 Reporting to Funding Sponsor .................................................................................41 
8.4.5 Reporting to FDA .....................................................................................................42 
8.4.6 Reporting of Pregnancy ...........................................................................................43 
8.5 
Halting Rules ..............................................................................................................43 
9 
Study Oversight ..................................................................................................................43 
10 
Clinical Site Monitoring and Auditing ..............................................................................43 
11 
Statistical Considerations ...............................................................................................44 
11.1 
Study Hypotheses .......................................................................................................44 
11.2 
Statistical Analysis Plans ............................................................................................44 
11.3 
Sample Size Considerations .......................................................................................44 
11.3.1 
Replacement Policy .............................................................................................44 
11.3.2 
Accrual Estimates ................................................................................................44 
12 
Source Documents and Access to Source Data/Documents ..........................................45 
13 
Quality Control and Quality Assurance ...........................................................................46 
14 
Ethics/Protection of Human Participants .........................................................................46 
14.1 
Ethical Standard .........................................................................................................46 

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14.2 
Institutional Review Board ...........................................................................................46 
14.3 
Informed Consent Process ..........................................................................................46 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ..........................47 
14.5 
Participant Confidentiality............................................................................................47 
14.6 
Certificate of Confidentiality ........................................................................................47 
14.7 
Future Use of Stored Specimens and Other Identifiable Data .....................................47 
15 
Data Handling and Record Keeping ...............................................................................47 
15.1 
Data Management Responsibilities .............................................................................48 
15.2 
Data Capture Methods ................................................................................................48 
15.3 
Types of Data .............................................................................................................48 
15.4 
Study Records Retention ............................................................................................48 
15.5 
Protocol Deviations .....................................................................................................48 
16 
Study Finances ...............................................................................................................49 
16.1 
Funding Source ..........................................................................................................49 
16.2 
Conflict of Interest .......................................................................................................49 
16.3 
Participant Stipends or Payments ...............................................................................49 
17 
Publication and Data Sharing Policy ...............................................................................49 
18 
Literature References .....................................................................................................50 
Appendices ...............................................................................................................................52 
APPENDIX A: SCHEDULE OF EVENTS ..................................................................................53 
APPENDIX B: KPS SCORE ......................................................................................................55 
 

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Signature Page 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
Principal Investigator: 
Signed: 
 
Date:  
Name: 
Wenyin Shi, MD 
Title:  
Professor 
Statement of Compliance 
This study will be conducted in accordance with the International Conference on Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and Thomas Jefferson University research 
policies 
 
 
 

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List of Abbreviations 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IAI 
Intravitreal Aflibercept Injection 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PRC 
Protocol Review Committee 
QA 
Quality Assurance 
QC 
Quality Control 

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SAE 
Serious Adverse Event/Serious Adverse Experience 
SBRT 
Stereotactic Body Radiotherapy 
SKCC 
Sidney Kimmel Cancer Center 
SOP 
Standard Operating Procedure 
SRT 
Stereotactic Radiotherapy 
TJU 
Thomas Jefferson University 
UAP 
Unanticipated Problem 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Summary 
 
Title: 
Phase II Randomized Trial of Radiotherapy Followed by 
intravitreal Aflibercept injection for patients with ocular 
Melanoma 
 
Précis: 
Patients with localized ocular melanoma will be eligible to 
participate in this 2-arm randomized study. Patients in arm A 
will receive Radiation treatment (either Plaque brachytherapy 
or SRT to a total dose of 50Gy in 5 fractions) followed by an 
injection of intravitreal Aflibercept injection (IAI) at 4 months 
after completion of radiation treatment and repeat injections 
every 2 months afterwards for a total of 2 years (11 injections). 
Patients in arm B will receive the same radiation treatment 
followed by an injection of intravitreal Aflibercept injection (IAI) 
at 4 months after completion of radiation treatment and repeat 
injections every 4 months for a total of 2 years (6 injections). 
Primary endpoint will be safety. Secondary endpoints will 
include 2-year radiation maculopathy rate, radiation 
papilopathy rate, radiation glaucoma rate, local control, 
progression-free survival, and vision preservation rate. 
Objectives: 
 
Primary:  
Safety of therapy as defined by percent of patients with 
CTCAE v5.0 grade 3 or higher toxicity 
 
Secondary:  
2-year radiation maculopathy rate 
2-year radiation papilopathy rate 
2-year radiation glaucoma rate 
2-year local control 
2-year progression-free survival 
2-year vision preservation rate 

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Population: 
36 patients with localized uveal melanoma of one eye, male or 
female, age ≥18, who are otherwise fit to undergo radiation 
therapy and intravitreal injections 
Phase: 
II randomized 
Number of Sites: 
1 Jefferson Hospital for Neuroscience 
Description of 
Intervention: 
Patients will be randomly assigned to one of two different 
dosing intervals of injections of intravitreal Aflibercept, a novel 
anti-VEGF drug, after finishing radiation treatment of the eye. 
The dose of IAI administered will be identical in both arms at 2 
mg per injection. The first dose in both arms will be 
administered 4 months after the completion of radiation 
treatment. Patients in arm A will then receive one 2mg injection 
every 2 months for a total 2 years duration (11 injections total). 
Patients in arm B will receive one 2 mg injection every 4 
months for 2 years duration (6 total injections). 
Study Duration: 
30 months for patient enrollment window. Study will end 6 months 
after last enrolled patient completed the final study visit and study 
analysis (40 months after finishing radiation treatment) 
Participant 
Participation 
Duration: 
2.5 years 
Estimated Time to 
Complete 
Enrollment: 
30 months 

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Schematic of Study Design: 
Baseline 
 
Visit 1 
 
 
 
 
 
 
Visit 2  
(can be by  
Phone)  
Eligibility & 
Randomization 
 
 
 
Visit 3  
(inclusive of  
SOC XRT &  
2 Month Post  
XRT Exam)* 
 
 
 
Visit 4**  
(SOC) 
 
 
 
 
Visit 5-14*** 
 
 
 
 
 
 
Visit 15** 
 
 
 
* Plaque brachytherapy, or SRT (total of 5 treatments, every other day weekdays only, acceptable 
variation: every day treatment). All treatment should finish within 10 days (acceptable range: 14 days) 
Total 36 pts: Obtain informed consent. Screen potential subjects by inclusion and 
exclusion criteria; obtain history, document. 
ARM A 
Clinical examination, Ocular 
ultrasound, BCVA, OCT, 
intravitreal Aflibercept Injection 
Q2M. 
Visit 4 – 4 months post XRT Arm A & B 
Clinical examination Ocular Ultrasound, BVCA, OCT, first intravitreal Aflibercept 
Injection 
Final Assessments Arm A & B 
Clinical examination ocular Ultrasound, 
BCVA, OCT  
(26 months following XRT 
Randomize 1:1 
Arm B: 
intravitreal 
Aflibercept Q4m 
Arm A:  
intravitreal 
Aflibercept Q2m 
Plaque Brachytherapy or SRT treatment (50 Gy in 10 Gy fractions)  1st 
Aflibercept injection 4 months after radiation treatment. 
2 Month Post  XRT Clinical examination, Ocular Ultrasound, BCVA, OCT 
ARM B 
Clinical examination, Ocular 
ultrasound, BCVA, OCT Q 2 
months & intravitreal Aflibercept 
Injection Q4M. 

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** Acceptable range for each visit: ± 2 weeks 
***stratification: Fractionated SRT vs Radioactive plaque Brachytherapy 
1 Introduction 
1.1 Background Information 
Uveal tract melanoma is the most common adult primary intraocular malignancy and is 
the only known potentially lethal intraocular tumor(1). Most patients who develop uveal 
melanoma fall within the age range of 50-80 years, with median age at diagnosis of 58 
years. The majority of uveal melanomas arise in the choroidal and ciliary body, and are 
together designated as posterior uveal melanomas. Iris melanomas are less common, 
representing approximately 2-4% of all uveal tract melanomas, and tend to have a more 
benign natural history compared to posterior uveal melanomas. Iris melanomas tend to 
occur more commonly in young patients (age < 20 years), and may represent 
approximately 20% of all uveal melanomas in that age group(2). Unlike cutaneous 
melanoma, exposure to solar UV radiation has not been shown to be a reliable risk 
factor for development of uveal melanoma(3). However, other factors that have been 
linked to increased incidence of uveal melanoma include history of atypical cutaneous 
nevi, cutaneous freckles, and iris nevi (4). 
Uveal melanomas are often asymptomatic on presentation, and are frequently 
diagnosed on routine ophthalmologic evaluation. However, depending on location, 
patients may demonstrate local symptoms such as visual distortion, blurry vision, 
diplopia, ocular pain, or conjunctival injection (5). Typically, choroidal melanomas 
present as a mushroom-shaped sub-retinal mass and tumor growth can lead to retinal 
detachment and subsequent blindness. Melanomas arising in the ciliary bodies can lead 
to lens displacement causing visual distortion or elevation in ocular pressure as outflow 
maybe obstructed. Melanomas of the iris are usually visible as a pigmented lesion, and 
may also present with pupillary distortion, hyphema, or outflow obstruction leading to 
secondary glaucoma. Regardless of location, the vast majority of uveal melanomas are 
diagnosed clinically, without need for biopsy, with very high (>99%) accuracy (6). 
While local effects of tumor place the patient at risk for visual deficits or vision loss, the 
most common cause of death in these patients comes from metastatic dissemination of 
disease. Fortunately, at time of initial diagnosis, a minority (<4%) of patients have 
detectable metastatic disease burden (7). Uveal melanoma demonstrates a 
hematogenous route of spread, with the liver representing the most frequent site of 
initial metastasis (93%), followed by lung (24%), and bone (16%) (8). Spread to regional 
lymph nodes is uncommon given the lack of lymphatic supply from the uveal tract, 
however, may occur in cases where the tumor invades into the conjunctiva and 
metastasizes through those associated draining lymphatics to regional lymph nodes(9). 

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Incidence of metastatic development at 10 years from initial diagnosis is around 33%, 
25%, and 7% for melanomas of the ciliary body, choroid, and iris respectively (10). 
Overall mortality from ocular melanoma patients is approximately 19% at 5 years and 
35% at 10 years from diagnosis (11). After development of metastatic disease, 
however, prognosis becomes extremely poor, with 80% of patients dying within 1 year, 
and 90% dying within 2 years (12). 
The standard treatment for all uveal melanoma patients was historically enucleation. 
However, radiation treatment has now replaced enucleation as standard of care in 
patients with early stage disease. The main advantage of radiation over surgical 
treatment is eye preservation, and therefore potential for vision sparing. A landmark 
study investigating the efficacy of radiation therapy for definitive treatment of non- 
metastatic uveal melanoma was carried out by the Collaborative Ocular Melanoma 
Study group (COMS). In that trial, a total of 1317 patients were enrolled from 1989 – 
2003, and underwent randomization between surgical enucleation versus radiation 
therapy with plaque brachytherapy. Since the study was completed, the 12-year follow- 
up analysis has been published which has demonstrated no difference in overall 
survival, progression-free survival, or death with melanoma metastasis in the radiation 
group as compared to the enucleation group. The COMS study had led to the adoption 
of I-125 based plaque brachytherapy as the most commonly used form of radiation 
treatment for this disease (11, 12). 
In addition to brachytherapy, external beam radiation is a current standard of care for 
radiation treatment of uveal melanomas. One limitation of brachytherapy remains large 
tumor size. As tumor size increases, the ability of brachytherapy to adequately cover the 
entire tumor volume decreases. Typical upper bounds for tumor basal diameter and 
tumor thickness are around 22mm and 12 mm respectively for I-125 and 20mm and 
6mm respectively for Ru-106 when considering plaque brachytherapy(13). In addition to 
large tumor size, proximity of tumor to the optic disc is often a disqualification criteria for 
plaque brachytherapy, as the tumor would receive inadequate dose coverage. While 
notched plaques can allow treatment of some tumors close to the optic disc, tumors 
abutting, or within a few millimeters of the optic disc remain controversial and remains 
cautionary per the American Brachytherapy Society guidelines (13). For those patients 
who are poor candidates for plaque brachytherapy based on the above or any other 
factors, external beam radiation generally remains a safe treatment option. 
Early studies in external beam radiation therapy for these tumors was generally 
performed with proton-beam therapy. Proton therapy was pioneered by Gragoudas et al 
in the early 1980’s. They described their initial experience treating 76 uveal melanoma 
patients, who were otherwise not favorable brachytherapy candidates either due to 
proximity of tumor to the fovea or due to tumor size. Treatment planning included 
suturing of small tantalum markers to the sclera for tumor localization, and instructing 

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patients to maintain a fixed gaze to an LED light attached to the collimator for eye 
immobilization. Dose delivered was 70Gy fractionated over 5 consecutive days. Their 
results demonstrated excellent overall survival for patients with small tumors at 5-years 
comparable to plaque brachytherapy, but importantly, also demonstrated 5 year survival 
of over 55% for patients with large tumors who would otherwise not be suitable for 
vision-sparing treatment, while maintaining acceptable toxicity profiles (14). This study 
was followed by investigation of dose de-escalation which compared efficacy of 50 Gy 
delivered in 5 fractions to the previously used 70 Gy in 5 fractions in a group of 188 
patients with tumor close to (within 4 disc diameters) either the optic disc of macula. No 
difference was seen in local control or in development of metastatic disease between 
the two differing doses. However, patients treated with 50 Gy experienced significantly 
less visual field loss compared to those receiving 70 Gy, suggesting 50 Gy to be an 
effective and safe dose to use (15). 
Photon-based SRS treatment has also been reported in published experiences 
demonstrating comparable rates of local control in patients who are poor candidates 
from plaque brachytherapy due to unfavorable tumor characteristics. Sikuade et al 
reported their experience treating 106 pts with proton beam therapy (PBT) and 85 
patients treated with photon-based SRS using GammaKnife (GK) (16). Patients treated 
with EBRT had tumors that were either too large for brachytherapy (>16mm basal 
diameter or >6.5mm thick) or too close to the optic disc (<2.5 disc diameters). Patients 
who received protons were treated with similar set up to that described by Gragoudas et 
al, and were treated to a total dose of 53.1 CGE in 4 daily fractions. Patients treated 
with GK were treated to a total dose of 35 Gy in a single fraction. Eye immobilization in 
GK patients was achieved through retrobulbar anesthesia to temporarily paralyze the 
extraocular muscles. With median follow up time of 39 months, rates of radiation 
retinopathy were similar, and eye retention rates were high in both arms (95-98%). Post 
treatment visual acuity was slightly lower in the SRS arm compared to PBT arm (33% 
vs 55% with visual acuity >6/60), although this was confounded by a statistically higher 
number of patients with poor initial vision in the SRS arm as compared to the PBT arm. 
Another retrospective series described results of linac-based SRS treatment for 
posterior uveal melanomas treated to a total dose of 37-52Gy (Median dose 49 Gy). Of 
the 96 patients analyzed, 3 year and 5 year local control was excellent at 95% and 85% 
respectively (17). 
Although radiation treatment is highly effective in achieving local tumor control, radiation 
therapy may be associated with concerning treatment-related morbidity. The most 
common severe adverse effects of radiation therapy include retinopathy, papillopathy, 
cataract formation, glaucoma, and potentially, loss of serviceable vision (2, 18). The 
majority of these complications occur as late effects of treatment. The average time to 
onset of radiation papillopathy is approximately 18 months post-radiation treatment. The 
median time to development of optical coherence tomography (OCT)- evident radiation 
induced maculopathy is approximately 12 months, although may be seen as early as 4 

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months after completion of plaque-based brachytherapy (18). The development of OCT-
evident maculopathy is particularly important as this was found to significantly predict 
for subsequent loss of serviceable vision (18). Given this finding, radiation maculopathy 
and retinopathy are important toxicities to evaluate for and potentially mitigate. 
Inflammatory mediators and angiogenic factors are suspected to play a role in the 
pathogenesis of radiation maculopathy. In patients treated with plaques, it is found that 
prophylactic anti-VEGF agents can prevent and minimize radiation maculopathy (18, 
19). Previous experience with injection of intravitreal bevacizumab has been shown to 
reduce the 2-year cumulative incidence of OCT-evident maculopathy from 40% down to 
26% in those patients who underwent radioactive plaque brachytherapy alone versus 
plaque brachytherapy followed by 2 years of q4 month bevacizumab injections 
respectively (18). In this same study, the addition of intravitreal bevacizumab reduced 
the rate of clinically evident radiation retinopathy from 31% down to 16%, and reduced 
moderate vision loss from 57% down to 33% (18). 
In this study, we propose treatment of uveal melanoma patients with radiation treatment 
with the addition IAI with goal to reduce radiation-related vision-threatening toxicity. 
Aflibercept is a recombinant fusion protein composed of extracellular domains of human 
VEGF receptors 1 and 2 fused to the Fc portion of human IgG1. This drug is formulated 
as an iso-osmotic solution for intravitreal administration. We hypothesize intravitreal 
injection of aflibercept after radiation treatment for uveal melanoma will significantly 
reduce radiation induced ocular toxicity when delivered over a time period in which 
clinically meaningful toxicity including radiation papillopathy and retinopathy are known 
to develop. 
1.2 Rationale for the Proposed Study 
The patient population being selected for this study are those patients with non- 
metastatic uveal melanoma.  External beam radiation, with stereotactic technique, or 
brachytherapy can be used for eye preservation alternative to encleation. Radiation 
therapy to these tumors has well described risk of toxicity including radiation induced 
papillopathy and maculopathy, which may lead to deterioration in vision. VEGF and 
neovascularization is thought to play an important role in the development of these 
vision threatening toxicities. Therefore, we hypothesize that the addition of intravitreal 
Aflibercept, after completion of radiation therapy, will reduce the incidence of these 
adverse reactions. 
IAI is currently FDA approved for multiple ocular pathology indication including wet 
macular degeneration, diabetic maculopathy, and macular edema following retinal vein 
occlusion. It also has been reported to successfully treat post-radiation retinopathy (20-
22). The route of administration of this recombinant fusion protein is via intravitreal 
injection. In this manner, the systemic dose of IAI is negligible while at therapeutic levels 
within the globe. The dosage per injection for this study was chosen to match that of the 

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dosage of intravitreal Alfibercept in it’s currently FDA approved indications of 
2mg/injection. The dosing frequency of IAI in currently approved indications range from 
q1-2 months. One arm in the proposed trial will therefore use the injection frequency of 
q2 months. For the other arm, we will investigate a q4 month dosing regimen, to better 
align with current standard follow-up time frames for patients who undergo plaque 
brachytherapy without further therapy. 
1.3 Correlative Studies 
No planned correlative studies. 
1.4 Potential Risks and Benefits 
1.4.1 Potential Risks 
System Organ 
Class 
Very Common 
Common 
Uncommon 
Rare 
Immune System 
Disorders 
 
 
Hypersensitivity*** 
 
Eye Disorders 
Conjunctival 
hemorrhage, Eye 
pain 
Retinal pigment 
epithelial tear*, 
Detachment of the 
retinal pigment 
epithelium, 
Cataract, 
Cataract cortical, 
Cataract nuclear, 
Cataract 
subcapsular, 
Corneal erosion, 
Corneal abrasion, 
Intraocular 
pressure 
increased, Vision 
blurred, 
Vitreous floaters, 
Vitreous 
detachment, 
Injection site pain, 
Foreign body 
sensation in eyes, 
Lacrimation 
increased, Eyelid 
edema, 
Injection site 
hemorrhage, 
Punctate keratitis, 
Endophthalmitis**, 
Retinal 
detachment, 
Retinal tear, 
Uveitis, Iritis, 
Iridocyclitis, 
Lenticular 
opacities, Corneal 
epithelium defect, 
Anterior chamber 
flare, 
Corneal edema 
Cataract 
traumatic, Vitritis, 
Hypopyon 

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Conjunctival 
hyperemia, Ocular 
hyperemia 
*Conditions known to be associated with wet AMD. Observed in the wet AMD studies only. 
**Culture positive and culture negative endophthalmitis 
***During the post-marketing period, reports of hypersensitivity included rash, pruritis, urticaria, and 
isolated cases of severe anaphylactic/anaphylactoid reactions 
 
There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal 
use of VEGF inhibitors. 
1.4.2 Benefits 
We are investigating the hypothesis that the addition of IAI to radiation will reduce the 
incidence of several different potential side effects that are known to occur after 
radiation therapy. These side effects may directly or indirectly lead to deterioration in 
vision. Therefore, possible benefit for enrollment in this study is to receive IAI with goal 
to improve chance of maintaining functional visual acuity and minimizing other radiation 
related side effects. 
2 Study Objectives 
2.1 Objectives 
2.1.1 Primary 
To assess the percentage of patients able to successfully complete their prescribed 
treatment of radiation and/or IAI with an acceptable level of toxicity. 
2.1.2 Secondary 
To assess for reduction in the incidence of 2 year rates of radiation maculopathy, 
radiation papillopathy, functional vision preservation, radiation glaucoma, and to assess 
2 year local control and progression-free survival. 
An interim analysis is planned when all patients have completed 1 year of follow-up. 
2.2 Endpoints/Outcome Measures 
2.2.1 Primary 
Percent of patients who experience Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 grade ≥3 toxicity related to SRT and/or intravitreal Aflibercept. 
2.2.2 Secondary 

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 2-year rates of radiation maculopathy, defined as ophthalmoscopic detection of 
macular edema, retinal hemorrhage, retinal exudation, nerve fiber layer 
infarction, perivascular sheathing, and retinal or optic disc neovascularization 
 2-year rates of radiation papillopathy, defined as ophthalmoscopic detection of 
peripapillary encircling nerve fiber layer infarction, disc edema, or disc pallor 
 2-year rates of functional vision preservation defined as less than moderate 
vision loss (in pts with functional vision prior to study treatment). Moderate vision 
loss is defined as loss of 15 ETDRS letters or more of best-corrected visual 
acuity compared with presentation 
 2-year rates of radiation glaucoma. 
 2-year local control rate 
 2-year progression-free survival rate. 
3 Study Design 
This is a single center phase II, 2-arm, randomized clinical trial, investigating the 
addition of IAI in patients with non-metastatic uveal melanoma treated with radiation 
therapy (plaque brachytherapy or SRT). The patients will be treated on an outpatient 
basis. The first intravitreal injection of the study drug will occur 4 months after the 
completion of radiation treatment, and the remainder of the injections will be given over 
the following 2 years, at an interval specified by the randomization arm. Research 
subjects will be followed up every 2 months after completion of radiation, and will 
undergo an updated history and physical exam, including detailed eye exam and OCT 
exam which will be performed at Wills Eye Hospital. 
Wills Eye Hospital will be considered a research location under the single site (Thomas 
Jefferson University) for this trial. Both TJU IRB and WEH IRB will have oversight of this 
trial. 
3.1 Number of Participants 
36 pts, 18 in each arm 
3.2 Duration of Therapy 
FSRT will be given over 5 treatments every other day, weekday only (Acceptable range: 
all 5 treatment delivered no longer than 14 days).The plaque brachytherapy will be 
delivered over ~100 hr (acute time will base on the calculation). The first dose of IAI will 
be administered 4 months after the completion of SRT or plaque removal (acceptable 
range: ± 2 weeks) and then every 2 or 4 months from the first IAI dose (acceptable 
range ± 2 weeks) for a total of 2 years, depending on the randomization arm. Therefore, 
total duration of therapy will be 2 years and 2 months. 

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3.3 Duration of Follow Up 
On study follow-up will last for 2 months after last treatment with study drug. 
3.4 Treatment Assignment Procedures 
3.4.1 Randomization Procedures (if applicable) 
The type of radiation (plaque brachytherapy or SRT) is determined by treating 
physician. Patients will be randomized in a 1:1 fashion between the two arms of this 
study. Patients will be randomized upon enrollment (Baseline/Enrollment Visit) using 
RedCap which was developed by the study statistician. 
3.4.2 Masking Procedures (if applicable) 
No masking will be performed for this study. 
3.5 Study Timeline 
3.5.1 Primary Completion 
Primary completion will be reached once the final patient completes their last scheduled 
injection of intravitreal Aflibercept. 
3.5.2 Study Completion 
Study completion will be reached once the final patient completes their 2 month post- 
completion-of- IAI follow-up visit. 
4 Study Enrollment and Withdrawal 
4.1 Eligibility Criteria 
4.1.1 Inclusion Criteria 
Individuals must meet all of the following inclusion criteria in order to be eligible to 
participate in the study: 
1. Provide signed and dated informed consent form or have a Legally Authorized 
Representative (LAR) who can give consent 
2. Willing to comply with all study procedures and be available for the duration of 
the study 
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4. Must be a candidate for radiation therapy 
5. KPS≥60 
6. Diagnosed with uveal melanoma either clinically or pathologically on biopsy. 
7. Uveal melanoma of one eye only 
8. Localized uveal melanoma, with no evidence of metastasis 
9. Women of childbearing potential must have a negative urine or serum pregnancy 
test within 14 days prior to enrollment 
4.1.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation 
in this study: 
1. Tumor thickness more than 14 mm as measured by ultrasound 
2. Active collagen vascular disease 
3. Any contraindication to intravitreal injections including: elevated intraocular 
pressure, ocular or periocular infection, active intraocular inflammation, or other 
determined by treating physician. 
4. Known allergic reactions to components of intravitreal Aflibercept 
5. Patients with known hypercoagulable syndromes. 
6. Prior radiation to the eye or brain 
7. Life expectancy less than 6 months 
8. Blind in both eyes 
9. Deaf in both ears 
 
10. Patients are on or within 1 month of systemic anti-VEGF treatment 
11. Patients for whom enucleation is standard of care 
12. Pregnancy or active breastfeeding. Sexually active men* or women of 
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prior to the initial dose/start of the first treatment, during the study, and for at 
least 3 months after the last dose. Adequate contraceptive measures include 
stable use of oral contraceptives or other prescription pharmaceutical 
contraceptives for 2 or more menstrual cycles prior to screening; intrauterine 
device; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, 
foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly. 
*Contraception is not required for men with documented vasectomy. 
**Postmenopausal women must be amenorrheic for at least 12 months in order not to 
be considered of childbearing potential. Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation. 
4.2 Gender/Minority/Pediatric Inclusion for Research  
Pediatric (age <18 years) patients are excluded from this study. Both male and female 
patients are eligible for this study as are minority patients. The male to female ratio in 
this disease is about 1.3:1.The accrual will be monitored by the MDG quarterly and if 
enrollment does not reflect the known incidence, a plan to increase recruitment of 
women will be made. 
4.3 Strategies for Recruitment and Retention 
Patients will not receive direct financial compensation by enrollment into this study, 
however, the investigational drug will be supplied free-of-cost. Patients will be enrolled 
at Radiation Oncology at Thomas Jefferson University Hospital (TJUH). Patients will be 
retained in close follow-up at a frequency close to the standard of care for patients 
receiving plaque brachytherapy for treatment of their tumor, therefore, no significant 
additional burden of follow-up is anticipated through enrollment onto this study. 
4.4 Participant Enrollment 
All potential patients will be consented at Radiation Oncology at TJUH. Eligibility will be 
confirmed by the Principal Investigator or the listed Co-Investigators from TJUH. 
Randomization will occur at TJUH, and the study team at Wills Eye Hospital (WEH) will 
be alerted to the new enrolled participant as well as indicating which arm of the trial the 
participant was randomized to. 
Enrollment onto this study will only occur at TJUH. 
4.5 Participant Withdrawal 
4.5.1 Reasons for Withdrawal 

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Participants are free to withdraw from participation in the study at any time upon 
request. 
An investigator may terminate a study participant’s participation in the study if: 
 Any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
not be in the best interest of the participant. 
 The participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation. 
 Local progression of disease based on eye examination. 
 Non-compliance (missed 3 or more scheduled protocol visits, or determined by 
treating physicians) 
4.5.2 Handling of Participant Withdrawals and Participant Discontinuation of 
Study Intervention 
Even though subjects may be withdrawn prematurely from the study, it is imperative to 
collect at least survival data on such subjects throughout the protocol defined follow-up 
period for that subject (though careful thought should be given to the full data set that 
should to be collected on such subjects to fully support the analysis). Such data is 
important to the integrity of the final study analysis since early withdrawal could be 
related to the safety profile of the study drug. 
If a subject withdraws consent to participate in the study, attempts should be made to 
obtain permission to record at least survival data up to the protocol-described end of 
subject follow-up period. IT MUST BE A HIGH PRIORITY TO TRY TO OBTAIN AT 
LEAST SURVIVAL DATA ON ALL SUBJECTS LOST TO FOLLOW-UP AND TO NOTE 
WHAT METHODS WERE USED BEFORE ONE CAN STATE THE SUBJECT IS 
TRULY LOST TO FOLLOW-UP (three phone calls to subject, phone calls to next-of-kin 
if possible, certified letters). 
4.6 Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, 
will be provided by the suspending or terminating party to <investigator, funding agency, 
the Investigational New Drug (IND) /Investigational Device Exemption (IDE) sponsor 
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principal investigator will promptly inform the IRB and will provide the reason(s) for the 
termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to participants. 
 Insufficient adherence to protocol requirements. 
 Data that is not sufficiently complete and/or evaluable.  
 Determination of futility. 
5 Study Intervention 
5.1 Study Product  
intravitreal Aflibercept Injection 
5.2 Study Product Description 
Aflibercept is a recombinant fusion protein composed of extracellular domains of human 
VEGF receptors 1 and 2 fused to the Fc portion of human IgG1. This drug is formulated 
as an isosmotic solution for intravitreal administration. Aflibercept acts as a decoy 
receptor that binds VEGF-A and P1GF with higher affinity than their respective natural 
receptors, and therefore acts to reduce the effects of endogenous VEGF. This drug is 
FDA-approved for a number of indications including wet macular degeneration, diabetic 
maculopathy, and macular edema following retinal vein occlusion 
5.2.1 Acquisition 
The investigational drug will be supplied by the manufacturer, Regeneron. 
5.2.2 Formulation, Packaging, and Labeling 
2.0 mg aflibercept is formulated as a sterile liquid to a final concentration of 40 mg/mL 
IAI in 5% sucrose, 10 mM sodium phosphate pH 6.3, 0.03% polysorbate 20, and 40 mM 
NaCl. IAI 2.0 mg study drug will be supplied by Regeneron Pharmaceuticals Inc. in 
sealed, sterile 3 mL vials with a “withdrawable” volume of approximately 0.5 mL. Vials 
must be used only once (defined as entered with a needle). The volume of injection will 
be 0.05 mL for the 2 mg dose. For study drug in vials, the study drug will be withdrawn 
using aseptic technique. 
Study drug will be shipped to the site via overnight shipping using cold packs to 
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representative (e.g. pharmacist), will ensure that all study drugs are stored in a secured 
area, under recommended storage conditions and in accordance with applicable 
regulatory requirements. The shipping box is to be opened and stored immediately at 
the site in a refrigerator intended for investigational products at a temperature of 2° to 
8°C (35.6° to 46.4° F). 
When vials are removed from the refrigerator, the solution should be visually inspected 
and it should have no evidence of turbidity. If particulates, cloudiness, or discoloration 
are visible, the vial must not be used. Exposure of the material to temperatures outside 
these limits, except for warming prior to administration, is not recommended and may 
result in loss of activity. Records of actual storage conditions (i.e. temperature log) at 
the study site must be maintained; and must include a record of the dates, when the 
refrigerator was checked, the initials of person checking, and the temperature. 
5.2.3 Product Storage and Stability 
Study drug will be shipped at a temperature of 2° to 8°C (35.6° to 46.4° F) to the 
Investigational Drug Service (IDS) at regular intervals or as needed during the study. At 
the end of the study and following drug reconciliation and documentation, all unopened 
vials of study drug will be destroyed or returned to Regeneron Pharmaceuticals, Inc. or 
designee. During transportation from IDS to Shields Oncology at Wills Eye Hospital, a 
temperature of 2° to 8°C (35.6° to 46.4° F) will be maintained. 
5.3 Dosage, Preparation, and Administration  
Route of administration of aflibercept is through intravitreal injection. The dose per 
injection will be 2mg of active drug in each arm of the study. Frequency of dosing will 
depend on which arm the patient is randomized to. In arm A, patients will receive a 
single injection of 2mg intravitreal Aflibercept 4 months after the completion of radiation 
treatment, and then again every 2 months afterwards, for a total duration of 2 years (11 
injections total). In arm B, patients will receive a single injection of 2mg intravitreal 
aflibercept 4 months after the completion of radiation treatment, and then once every 4 
months afterwards, for a total duration of 2 years (6 injections total). After opening the 
vial, the drug should be administered under aseptic conditions. All injections of 
intravitreal aflibercept for both arms will occur at Shields Oncology in Wills Eye Hospital. 
5.4 Dose Modifications and Dosing Delays 
Dosage modifications are not allowed. If the patient experiences significant toxicity 
(grade 4 or 5 per CTCAE v5.0 criteria), the patient will discontinue the study 
intervention. Should the patient meet any exclusion criteria described in section 4.12 
while under treatment, the patient will similarly discontinue study intervention. The 
patient will continue to proceed with study-described follow-up every 2 months for a total 
of 2 years and 2 months. 

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5.5 Study Product Accountability 
All drug accountability records will be kept current. 
The investigator or delegated personnel will account for all opened and unopened vials 
of study drug. These records will contain the dates, quantity, and study medication 
 dispensed for each patient – or - 
 
 disposed of at the site per the site’s SOP for drug disposal. 
All accountability records will be made available for inspection by regulatory agency 
inspectors. 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, 
resolved, and documented prior to destruction of unused study drug. Drug destroyed on 
site will be documented in the study files. 
5.6 Assessing Participant Compliance with Study Product Administration 
Compliance with radiation therapy will be assessed through documentation of any 
missed treatments or unplanned treatment breaks. Compliance with IAI therapy will be 
through direct clinic administration of the drug. Missed or refused doses will be 
documented. 
5.7 Concomitant Medications/Treatments 
No specific concomitant medications will be routinely administered. Patients may 
continue to take all of their pre-enrollment medications for any other medical 
comorbidity, or any new medication which is prescribed to the patient. 
5.8 Dietary Restrictions 
No specific dietary restrictions are required. 
5.9 Study Procedural Intervention(s) Description Radiation Therapy 
(Plaque brachytherapy) 
Isotope utilized: I-125 seeds (model A IaI-125A) from IsoAid (Port Richey, FL). Planning 
System: EyePhysics 

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Gold plaque sizes: round plaques: 10 mm to 22 mm; notched: 18 mm, 20 mm, 22 mm. 
Associated dummy plaques are matched with each gold plaque. 
Procedure: The physician evaluates and determines the patient for appropriateness of 
plaque brachytherapy. Patient’s retinal diagram with tumor dimensions, distance from 
optic disc and fovea will be generated by Ocular Oncology Service at Wills Eye 
Hospital. 
 The tumor information will be entered into the EyePhysics planning system. 
Appropriate plaque size and shape will be determined. The plan will be generated. 
Plaque is custom made in the radiation lab where seeds are glued on the inner surface 
of the plaque according to the plan. 
The plaques will be implanted by Ocular Oncology Service at Wills Eye Hospital OR 
(usually on Thursday morning). The patient will be discharged after implant. 
Plaque will be removed promptly at prescribed time (within +/- 10% of prescribed dose). 
Dose prescribed: 70 Gy (acceptable range: +/-10%) is prescribed to a depth as 
determined by ocular exams and defined as the apex of the tumor. 2mm circumferential 
margin and 1mm apical margin are added to the tumor dimensions for adequate 
treatment coverage over approximately 4 days or approximately 100 hours based on 
the calculation. The implant may by necessity continue delivering dose for 5-7 days up 
to 170 hr if clinically indicated. Seed distribution may be full, posterior or radial based on 
tumor type and location.  Doses to following critical structures are calculated: optic disc, 
fovea, base dose at 1mm depth, lens, retina, opposite retina. 
Ideal Normal Tissue constraints: These doses vary widely based on location of plaque 
to these critical structures. As a result, these are not mandatory. 
Optic disc: < 70Gy Fovea: <70Gy 
Lens: 20Gy (acceptable based on location of plaque 65Gy) Base dose: < 400Gy 
Opposite Retina: <10 Gy 
Radiation Therapy: (SRT) 
Simulation 
Immobilization of the head will be through use of the BrainLab thermoplastic 3- piece 
mask system. The outer mask will have holes cut out around the bilateral eyes. The 
patient will undergo CT scan with Linac SRS protocol utilizing a custom localization 
block attached to the BrainLab CT board. The patient will be instructed to fix their gaze 

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on an attached LED light source for the duration of the CT scan, and for each treatment. 
CT simulation therapists will provide this coaching during time of simulation, and the 
machine therapists will reinforce this coaching at time of each treatment. 
Planning 
Planning will be performed using 3D-CRT or VMAT/IMRT technique, with prioritization 
on lowering dose delivered to the optic tract. 
 GTV will include all gross tumor. PTV will be a 2mm expansion off the GTV. No 
CTV will be defined. Prescription dose will be 50 Gy delivered over 5 fractions 
prescribed to the PTV delivered every other day (acceptable variation: every day 
treatment). All treatment should finish within 10 days (acceptable range: 14 days) 
PTV coverage should be ≥99%. 
Critical structures constraints: 
Contralateral eye max dose: 10 Gy 
Ipsilateral lens mean dose: 20 Gy (acceptable variation: 45 Gy) Brainstem; 20 Gy 
Chiasm: 10 Gy 
Contralateral optic nerve: 10 Gy 
Ipsilateral optic nerve (minus PTV) max dose: 55 Gy (keep it as low as possible) 
Treatment setup and delivery 
The patient will be setup on the linac treatment couch utilizing the ExacTrac image 
guidance system to align to the isocenter. The eye camera and gaze- fixation LED light 
will be turned on and the patient will be instructed to maintain gaze at the light source. 
The live eye image feed will be verified and monitored on the control panel in real time 
by both therapists and the treating physician. A cone-beam CT scan will be acquired on 
the first treatment day to verify set-up accuracy. Once setup is verified, the treatment 
will start, and the treating physician will monitor the live feed from the eye camera. A 
manual beam-pause will be issued in the event of gaze deviation, and will be resumed 
once gaze is refocused. 
5.10 Administration of Procedural Intervention 
Intravitreal Aflibercept therapy 

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Medication and dosage will be verified by the treating ophthalmologist prior to 
administration to check for correct dosage label and expiration. Once verified, the 
patient will undergo intravitreal injection of the drug under sterile conditions by the 
treating ophthalmologist, per standard protocol of intravitreal drug injection. The first 
injection of intravitreal aflibercept will occur 4 months after the completion of radiation  
therapy. The subsequent injection schedule will depend on the randomization arm as 
detailed in section 5.3 above. 
5.11 Procedures for Training of Clinicians on Procedural Intervention 
The administration of IAI will follow the policy and procedure guidelines already in 
practice by the treating ophthalmologist for intravitreal injections. The treating 
ophthalmologist will be instructed to follow the proper storage and handling guidelines 
per the manufacturer recommendations as described in section 5.2.2 and 5.2.3 above. 
5.12 Assessment of Clinician and/or Participant Compliance with Study 
Procedural Intervention 
Compliance for both radiation and IAI therapy will be assessed by direct observation of 
the treating physicians, given the nature of these interventions. 
6 Study Schedule  
6.1 Pretreatment Period/Screening 
 Obtain and document consent from potential participant on study consent form at 
Radiation Oncology (Thomas Jefferson University Hospital). 
 Review medical to determine eligibility based on inclusion/exclusion criteria. 
 Obtain pregnancy test via urine or blood b-HCG for women of childbearing 
potential within 14 days from enrollment. 
 Physical examination including eye exam to document baseline vision status, 
vital signs, and performance status using the KPS. 
 Vision status will be obtained during ophthalmic exam, including best corrected 
visual acuity (BCVA) 
 Perform optical coherence tomography (OCT) scan of eye. 
 Perform ultrasound of eye (ocular). 

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 Schedule study visits for individuals who are eligible and available for the 
duration of the study. 
 Provide potential participants with instructions needed to prepare for first study 
visit 
 SOC Labs: complete blood cell count (CBC) with differential, Day -30 to Day-1 of 
enrollment. 
 Review medications the patient is taking 
6.2 Enrollment/Baseline 
Enrollment/Baseline Visit (Visit 1, Day -30 to D1 prior to treatment) 
 Verify inclusion/exclusion criteria. 
 Obtain demographic information, medical history, medication history, alcohol, 
and tobacco use history. 
 Obtain randomization results. 
 Record results of physical and ocular examinations. 
6.3 Treatment Period 
Patients will receive radiation treatment in Radiation Oncology at Thomas Jefferson 
University. 
Treatment with IAI and visits with the ophthalmologist will occur at Wills Eye Hospital. 
Radiation Treatment: Plaque Brachytherapy or FSRT treatment (50Gy in 10Gy 
fractions). 
 Record adverse events as reported by participant or observed by investigator. 
 Plaque brachytherapy, continuously over 4 days (~100 hr), may be up to 7 days 
as determined by treating physician. 
 FSRT will be given, total of 5 treatments, every other day weekdays only 
(acceptable variation: every day treatment). All treatment should finish within 10 
days (acceptable range: 14 days) 
 Record participant’s compliance with radiation. 

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2 month follow-up – no Aflibercept. 
 Record adverse events as reported by participant or observed by investigator. 
 Obtain vital signs, KPS performance status 
 Perform physical examination and eye examination (including BCVA) 
 Obtain ultrasound of the eye + OCT scan. 
 Laboratory assessments as clinically indicated.  
Month 4 following RT: Administer 1st intravitreal dose of IAI for both arms.  
 Record adverse events as reported by participant or observed by investigator. 
 Obtain vital signs, KPS performance status. 
 Perform physical examination and eye examination (including BCVA). 
 Obtain ultrasound of the eye + OCT scan. 
 Laboratory assessments as clinically indicated.  
 Record participant’s compliance with intravitreal Aflibercept.  
Every two months following first Aflibercept injection starting at month 6 post RT 
and ending at month 24 post RT.(acceptable variation: ±2 weeks)  
 Record adverse events as reported participant or observed by investigator.  
 Obtain vital signs, KPS performance status 
 Perform physical examination and eye examination (including BCVA) 
 Obtain ultrasound of the eye + OCT scan. 
 Laboratory assessments as clinically indicated.  
Patients in Arm A (Aflibercept every 2 months) 
 IAI at each visit (month4, 6, 8, 10, 12, 14, 16, 18, 20, 22 ,24) 
 Record participant’s compliance with intravitreal Aflibercept 

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Patients in Arm B (Aflibercept every 4 months) 
 IAI on month 4, 8, 12, 16, 20, 24 only 
 Record participant’s compliance with intravitreal Aflibercept 
Final assessment (2 months after last Aflibercept injection) All patients (month 26 
± 1 w) 
 Record adverse events as reported by participant or observed by investigator. 
 Obtain vital signs, KPS performance status 
 Perform physical examination and eye examination 
 Obtain ultrasound of the eye + OCT scan. 
 Laboratory assessments as clinically indicated.  
**Patients will be recommended to continue with standard follow-up care with the 
treating ophthalmologist, including yearly physical exam, ocular exam, and yearly CXR 
and liver MRI for surveillance. Any local failures, or distant disease recurrence will be 
documented. Any patient death will also be recorded. 
6.4 Withdrawal Visit/Discontinuation of Therapy 
If the patient withdraws from the study early, patient should be encouraged to have an 
exit visit, with the following evaluations offered:  
 Record adverse events as reported by participant or observed by investigator. 
 Obtain vital signs, KPS performance status 
 Perform physical examination and eye examination 
 Obtain ultrasound of the eye + OCT scan. 
 Laboratory assessments as clinically indicated 
7 Study Procedures and Evaluations 
7.1 Study Procedures/Evaluations 

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Medical history: Should be obtained from both the electronic medical record (EMR) as 
well as from patient interview. Performance status should also be recorded. 
Medication history: Should include all medications the patient is currently taking 
(including prescription and over-the-counter medications). No specific medications are 
excluded for enrollment onto this study. The patient is not required to take any particular 
medications on this study, apart from the investigational drug, intravitreal Aflibercept, 
which will be administered as detailed in section 5 and 6 above. 
Physical exam: Should include assessment of the head and neck area, paying attention 
to any skin changes, swelling, and hair loss due to radiation therapy. Additionally, an 
eye exam (both eyes) will be performed including assessment of visual acuity, visual 
fields, conjunctival changes, periorbital edema, dry-eye, and extra-ocular movements. 
Radiographic studies: Include OCT scan, and ultrasound of the eye (ocular). 
Laboratory studies as clinically indicated. 
8 Evaluation of Safety 
8.1 Specification of Safety Parameters 
8.1.1 Unanticipated Problems 
Unanticipated problems (UAPs) include, in general, any incident, experience, or 
outcome that meets the following criteria: 
 unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
UAPs are considered to pose risk to participants or others when they suggest that the 
research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
8.1.2 Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a human 
participant, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the participant’s 
participation in the research, whether or not considered related to the participant’s 
participation in the research. 

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Progression of underlying malignancy will not be considered an AE if it is clearly 
consistent with the typical progression pattern of the underlying cancer (including time 
course, affected organs, etc.). Clinical symptoms of progression may be reported as 
AEs if the symptom cannot be determined as exclusively due to the progression of the 
underlying malignancy, or does not fit the expected pattern of progression for the 
disease under study. 
If there is any uncertainty about an AE being due only to progression of the underlying 
malignancy, it should be reported as an AE or SAE as outlined in section 8.1.3 
8.1.3 Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
 Results in death 
 Is life-threatening (places the participant at immediate risk of death from the 
event as it occurred) 
 Is disabling or incapacitating 
 Results in inpatient hospitalization or prolongation of existing hospitalization 
 Results in a persistent or significant disability or incapacity 
 Results in a congenital anomaly or birth defect  
 An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the participant or may require 
intervention to prevent one of the outcomes listed in this definition. 
Criteria for Serious Sight-Threatening Ocular Adverse Events 
 
Criteria for serious sight-threatening ocular AEs include the following: 
 AE causes a decrease in BCVA of >30 letters (compared with the most recent 
assessment of BCVA). 
 AE causes a decrease in VA to the level of light perception or worse. 
 AE requires surgical intervention (eg, vitreous tap or biopsy with IVT injection of 
anti-infectives, laser or retinal cryopexy with gas) to prevent permanent loss of 
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 AE is associated with severe intraocular inflammation (ie, 4 + anterior chamber 
cell/flare or 4 + vitritis) 
 In the opinion of the investigator, AE may require medical intervention to prevent 
permanent loss of sight 
8.2 Safety Assessment and Follow-Up 
The PI will follow adverse events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day 
of study participation. At each study visit, the investigator (or designee) will inquire 
about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization. 
8.3 Recording Adverse Events 
The following subsections detail what information must be documented for each 
adverse event occurring during the time period specified in Section 8.2 Safety 
Assessment and Follow-Up.  
8.3.1 Relationship to Study Intervention 
The relationship to study intervention or study participation must be assessed and 
documented for all adverse events. Evaluation of relatedness must consider etiologies 
such as natural history of the underlying disease, concurrent illness, concomitant 
therapy, study-related procedures, accidents, and other external factors.  
The following guidelines are used to assess relationship of an event to study 
intervention: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event 
onset. 
b. An alternate etiology has been established. 

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8.3.2 Expectedness 
The PI is responsible for determining whether an AE is expected or unexpected. An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the intervention. Risk 
information to assess expectedness can be obtained from preclinical studies, the 
investigator’s brochure, published medical literature, the protocol, or the informed 
consent document. 
8.3.3 Severity of Event 
Adverse events will be graded for severity according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  
8.3.4 Intervention 
Any intervention implemented to treat the adverse event must be documented for all 
adverse events. 
8.4 Safety Reporting  
The Thomas Jefferson University clinical team coordinating the trial will be responsible 
for reporting adverse events and unanticipated problems as described in the following 
sections. 
8.4.1 Report to the TJU IRB 
8.4.1.1 Unanticipated Problems 
All incidents or events that meet criteria for unanticipated problems (UAPs) as defined in 
Section 8.1.1 Unanticipated Problems require the creation and completion of an 
unanticipated problem report form (OHR-20). 
UAPs that pose risk to participants or others, and that are not AEs, will be submitted to 
the TJU IRB on an OHR-20 form via the eazUP system within 5 working days of the 
investigator becoming aware of the event. 
UAPs that do not pose risk to participants or others will be submitted to the TJU IRB at 
the next continuing review. 
8.4.1.2 Adverse Events 
Grade 1 AEs will be reported to the TJU IRB at the time of continuing review.  
Grade 2 AEs will be reported to the TJU IRB at the time of continuing review. 
8.4.1.3 Serious Adverse Events 

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SAEs will be reported to the TJU IRB on OHR-10 forms via the electronic reporting 
system (eSAEy) according to the required time frames described below. 
Grade 3-4 AEs that are unexpected and deemed to be at least possibly related to the 
study will be reported to the TJU IRB within 2 working days of knowledge of the event. 
Grade 3-4 AEs that are deemed unrelated to the study will be reported to the TJU IRB 
within 5 working days. 
Grade 5 AEs will be reported to the TJU IRB within one working day of knowledge of the 
event. 
All SAEs will be submitted to the TJU IRB at continuing review, including those that 
were reported previously. 
8.4.2 Reporting to WEH IRB 
8.4.2.1 Unanticipated Problems 
Unanticipated problems (UAPs) that pose risk to participants or others, and that are not 
AEs, will be submitted to the WEH IRB via memo/letter detailing the incident, concerns, 
and proposed resolution within 5 working days of the investigator becoming aware of 
the event. 
UAPs that do not pose risk to participants or others will be submitted to the WEH IRB at 
the next continuing review. 
8.4.2.2 Adverse Events  
 
Grade 1 AEs will be reported to the WEH IRB at the time of continuing review. Grade 2 
AEs will be reported to the WEH IRB at the time of continuing review. 
8.4.2.3 Serious Adverse Events  
SAEs occurring outside of Wills Eye Hospital will be reported to WEH IRB via the Form- 
3A according to the required timeframes described below. 
Any serious and unexpected adverse reaction that is probably or definitely related to the 
research 
Grade 3-4 AEs occurring at Wills Eye Hospital must be reported to WEH IRB within 48 
hours via Form-3B 
Grade 5 AEs that are unanticipated must be reported to WEH IRB within 24 hours via 
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Grade 5 AEs not related to the research must be reported to WEH IRB within 5 days via 
Form-3B. 
All SAEs will be submitted to the WEH IRB at continuing review, including those 
reported previously. 
8.4.3 Reporting to SKCC DSMC 
All AEs and SAEs, safety and toxicity data, and any corrective actions will be submitted 
to the DSMC per the frequency described in the SKCC DSMP. The report to the SKCC 
DSMC will also include any unanticipated problems that in the opinion of the PI should 
be reported to the DSMC. 
For expedited reporting requirements, see table below:                                            
DSMC AE/SAE Reporting Requirements 

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8.4.4 Reporting to Funding Sponsor 
All reports to the funder will be submitted by the Thomas Jefferson University clinical 
team. 
All SAEs, regardless of assessment of causal relationship to study drug, must be 
reported to Regeneron within 15 days 
Information not available at the time of the initial report must be documented in a follow- 
up report. Substantiating data such as relevant hospital or medical records and 
diagnostic test reports may also be requested. 
Deaths 
Any AE that results in death is considered an SAE. Deaths that occur from the time the 
patient signs the ICF until 30 days after dosing will be reported to the appropriate IRB 
and to Regeneron Pharmacovigilance and Risk Management (or designee) within 24 
hours of learning of the death. 
Any available autopsy reports and relevant medical reports will be sent to Regeneron 
Pharmaceuticals, Inc. as soon as possible. 
To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com 
Fax: (914) 345-7476 
SAE hotline: (914) 593-1504 
Pregnancy and Other Events that Require Accelerated Reporting 
The following events will be reported to Regeneron Pharmaceuticals, Inc. within 24 
hours of learning of the event: 
1. Overdose: Accidental or intentional overdose of the study drug or concomitant 
medication, whether or not it is considered an AE. 
2. Pregnancy: Although it is not considered an AE, the investigator will report to 
Regeneron Pharmaceuticals, Inc., any pregnancy occurring in a female patient or 
female partner of a male patient, during the study or within 30 days following the 
last dose of study drug. The investigator will follow the pregnancy until delivery, 
or longer. If the pregnancy continues to term (delivery), the health of the infant 
will also be reported to Regeneron Pharmaceuticals, Inc. 
 

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These AEs will be reported to: 
Medical.safety@regeneron.com Fax: (914) 345-7476 
SAE hotline: (914) 593-1504 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study will be reported to Regeneron 
Pharmaceuticals Inc. within 30 days. All SAEs leading to a patient’s withdrawal from the 
study will be reported. To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com Fax: (914) 345-7476 
SAE hotline: (914) 593-1504 
8.4.5 Reporting to FDA 
All reports to the FDA will be submitted by the Thomas Jefferson University clinical 
team. All reports to the FDA will be submitted using the MedWatch 3500A form. 
7 Calendar-Day Telephone or Fax Report: 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the investigator to be possibly 
related to the use of intravitreal Aflibercept. An unexpected adverse event is one that is 
not already described in the prescribing instruction. 
Such reports are to be telephoned or faxed to the FDA within 7 calendar days and 
Regeneron within 24 hours of first learning of the event. Each telephone call or fax 
transmission should be directed to the FDA new drug review division in the Center for 
Drug Evaluation and Research or in the product review division for the Center for 
Biologics Evaluation and Research, whichever is responsible for the review of the IND. 
15 Calendar-Day Written Report: 
The Sponsor-Investigator is also required to notify the FDA and all participating 
investigators, in a written IND Safety Report, of any serious, unexpected AE that is 
considered possibly related to the use of intravitreal Aflibercept. An unexpected adverse 
event is one that is not already described in the prescribing information. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32. All safety reports previously filed with the IND 
concerning similar events should be analyzed. The new report should contain 
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Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, Regeneron, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a MedWatch 3500A Form but 
alternative formats are acceptable (e.g. summary letter). 
8.4.6 Reporting of Pregnancy 
If pregnancy is noted during any part of enrollment from time of screening to time of 
radiation therapy completion, the patient must be immediately removed from therapeutic 
intervention and PI must be informed. No information is available regarding safety of IAI 
in pregnant women or their fetuses. However, per manufacturer recommendations, 
patients who are breast feeding should not undergo intravitreal Aflibercept therapy as 
IgG1s may be excreted in breast milk. Additionally, the manufacturer recommends 
pregnant women not use intravitreal Aflibercept, and that all women of childbearing age 
agree to use adequate contraception for at least 3 months following last dose of 
intravitreal Aflibercept. 
See Section 8.4.3 for information on how to report pregnancy to Regeneron. 
8.5 Halting Rules 
Enrollment should be halted if greater than 40% of patients experience treatment 
related any ≥Grade 3 toxicity and safety review must convene prior to further 
enrollment. 
9 Study Oversight 
In addition to the PI’s responsibility for oversight, study oversight will be under the 
direction of the SKCC’s Data and Safety Monitoring Committee (DSMC). The SKCC 
DSMC operates in compliance with a Data and Safety Monitoring Plan (DSMP) that is 
approved by the NCI.  
10 Clinical Site Monitoring and Auditing 
Clinical site monitoring and auditing is conducted to ensure that the rights of human 
participants are protected, that the study is implemented in accordance with the protocol 
and/or other operating procedures, and that the quality and integrity of study data and 
data collection methods are maintained. Monitoring and auditing for this study will be 
performed in accordance with the SKCC’s Data and Safety Monitoring Plan (DSMP) 
developed by the SKCC Data and Safety Monitoring Committee (DSMC). The DSMP 
specifies the frequency of monitoring, monitoring procedures, the level of clinical site 
monitoring activities (e.g., the percentage of participant data to be reviewed), and the 
distribution of monitoring reports. Some monitoring activities may be performed 

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remotely, while others will take place at the study site(s). Appropriate staff will conduct 
monitoring activities and provide reports of the findings and associated action items in 
accordance with the details described in the SKCC DSMP. 
11 Statistical Considerations  
11.1 Study Hypotheses 
We hypothesize that the percent of patients who experience CTCAE v5.0 grade ≥3 
toxicity related to SRT and/or IAI will be significantly lower than 40%. 
11.2 Statistical Analysis Plans 
For the primary analysis, the null hypothesis that the rate of toxicity related to radiation 
and/or IAI is 40% will be tested using one-sided exact binomial test with alpha 0.05. 
Since the primary endpoint is patient tolerability, the two arms will be combined for the 
primary analysis. For the secondary analysis, the 2-year rates of radiation maculopathy, 
radiation papillopathy, functional vision preservation (in pts with functional vision prior to 
study treatment), radiation glaucoma, and local control will be estimated separately in 
each arm with the corresponding exact binomial 90% confidence interval. The 
progression-free survival in the combined two arms of the study will be analyzed using 
the Kaplan-Meier estimator. 
It is not expected that two dosing regimens would produce different levels of toxicity. 
However, to evaluate this possibility, the rate of toxicity with the corresponding exact 
binomial 90% confidence interval will be also estimated separately in each arm. 
11.3 Sample Size Considerations 
The sample size of 33 patients provides 80% to reject the null hypothesis that toxicity 
rate is 40% if the true toxicity rate is 20%, assuming the one-sided exact binomial test 
with alpha 0.05. A total of 36 pts will be enrolled to account for drop off and 
unanalyzable subjects. 
11.3.1 Replacement Policy 
Patients prematurely withdrawn from the study can be replaced, if needed, to ensure an 
adequate number of evaluable patients. The investigator, (in cooperation with the study 
statistician, if applicable) will decide whether or not to replace withdrawn patients. 
Patient withdrawn before finishing FSRT and first injection of intravitreal aflibercept will 
be replaced. 
11.3.2 Accrual Estimates 

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2 pts a month 
12 Source Documents and Access to Source Data/Documents 
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6, and regulatory and institutional requirements for the protection 
of confidentiality of participant information. Study staff will permit authorized 
representatives of SKCC and regulatory agencies to examine (and when required by 
applicable law, to copy) research records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety, progress and data validity.  

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13 Quality Control and Quality Assurance 
The investigator will allocate adequate time for monitoring activities by the TJU SKCC. 
The Investigator will also ensure that the medical monitor or other compliance or quality 
assurance reviewer is given access to all the above noted study-related documents and 
study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate 
space to conduct the monitoring visit. 
14 Ethics/Protection of Human Participants  
14.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research, as drafted by the US National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 
1979) and codified in 45 CFR Part 46 and/or the ICH E6.  
14.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the IRB for review and approval. Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the 
changes are implemented in the study.  
14.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation. Extensive 
discussion of risks and possible benefits of study participation will be provided to 
participants and their families, if applicable. A consent form describing in detail the study 
procedures and risks will be given to the participant. Consent forms will be IRB- 
approved, and the participant is required to read and review the document or have the 
document read to him or her. The investigator or designee will explain the research 
study to the participant and answer any questions that may arise. The participant will 
sign the informed consent document prior to any study-related assessments or 
procedures. Participants will be given the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. They may withdraw consent 
at any time throughout the course of the study. A copy of the signed informed consent 
document will be given to participants for their records. The rights and welfare of the 
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care will not be adversely affected if they decline to participate in this study. The 
consent process will be documented in the clinical or research record. 
Regeneron will have the right to review and comment on the informed consent form. 
14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
This study is intended to investigate treatment outcomes of adults with uveal melanoma, 
and therefore children (age <18 years) are excluded from this study. No minority group 
is excluded from this study. Both men and women are eligible for enrollment, however, 
pregnant or breast-feeding women are excluded due to concern for risk to fetus. 
14.5 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to any study information relating to participants. 
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all 
study documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) for the study participants. 
The clinical study site will permit access to such records. 
14.6 Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
obtained from the NIH. This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research 
records to refuse to disclose identifying information on research participation in any civil, 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, 
state, or local level. By protecting researchers and institutions from being compelled to 
disclose information that would identify research participants, Certificates of 
Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
14.7 Future Use of Stored Specimens and Other Identifiable Data  
The collected data will be analyzed at end of the study for publication. 
15 Data Handling and Record Keeping 

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The investigators are responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. All source documents must be completed in a neat, 
legible manner to ensure accurate interpretation of data. The investigators will maintain 
adequate case histories of study participants, including accurate case report forms 
(CRFs), and source documentation. 
The data will be entered into REDCap on password protected computers on internal 
network drives. Full imaging reports will remain as part of the EMR, however, 
documentation of disease and treatment related AEs will be coded into RedCap. 
The data will be entered into RedCap by the Thomas Jefferson University clinical team. 
15.1 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff 
under the supervision of the investigator. All source documents and laboratory reports 
must be reviewed by the study team and data entry staff, who will ensure that they are 
accurate and complete. Unanticipated problems and adverse events must be reviewed 
by the investigator or designee. 
15.2 Data Capture Methods 
As noted in section 15.1, data will be recorded and stored in RedCap on a password 
protected internal network drive. Data will be entered into RedCapat the end of each 
patient follow-up visit or when results from any relevant imaging return. 
15.3 Types of Data 
Data that will be collected will include: Safety (CTCAE v5.0 toxicity data); KPS 
performance status; physical exam findings including skin/periocular reactions and vital 
signs; ocular exam findings including visual acuity and visual field testing; imaging 
reports from OCT scan, and eye ultrasounds. 
15.4 Study Records Retention 
Study records will be maintained for at least 5 years after completion of study. 
15.5 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Procedures requirements. The noncompliance may be on the 
part of the participant, the investigator, or study staff. As a result of deviations, 
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All deviations from the protocol must be addressed in study participant source 
documents and promptly reported to the IRB and other regulatory bodies according to 
their requirements.  
16 Study Finances 
16.1 Funding Source 
Regeneron is providing a grant and study drug to Wills Eye and Thomas Jefferson 
University. 
16.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by a properly constituted Conflict of Interest Committee 
with a Committee-sanctioned conflict management plan that has been reviewed and 
approved by the study sponsor prior to participation in this study. All Jefferson 
University Investigators will follow the TJU Conflicts of Interest Policy for Employees 
(107.03). 
16.3 Participant Stipends or Payments 
Participants will not receive any payment for participation in this study. 
17 Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. It requires scientists to 
submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital 
archive PubMed Central upon acceptance for publication. 
The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a clinical trials registration policy as a condition for publication. The ICMJE 
defines a clinical trial as any research project that prospectively assigns human 
participants to intervention or concurrent comparison or control groups to study the 
cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral 
treatments, process-of-care changes, and the like. Health outcomes include any 
biomedical or health-related measures obtained in patients or participants, including 
pharmacokinetic measures and adverse events. The ICMJE policy requires that all 
clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is 

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sponsored by the National Library of Medicine. Other biomedical journals are 
considering adopting similar policies. The ICMJE does not review specific studies to 
determine whether registration is necessary; instead, the committee recommends that 
researchers who have questions about the need to register err on the side of 
registration or consult the editorial office of the journal in which they wish to publish. 
U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or 
FDAAA), Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or 
designated principal investigator) register and report results of certain "applicable 
clinical trials:" 
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product subject to FDA regulation; 
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA 
regulation (other than small feasibility studies) and pediatric postmarket surveillance 
studies. 
NIH grantees must take specific steps to ensure compliance with NIH implementation of 
FDAAA. 
18 Literature References 
1. Krantz BA, Dave N, Komatsubara KM, Marr BP, Carvajal RD. Uveal melanoma: 
epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol. 
2017;11:279-89. 
2. Shields CL, Kaliki S, Furuta M, Mashayekhi A, Shields JA. Clinical spectrum and 
prognosis of uveal melanoma based on age at presentation in 8,033 cases. 
Retina. 2012;32(7):1363-72. 
3. Schwartz LH, Ferrand R, Boelle PY, Maylin C, D'Hermies F, Virmont J. Lack of 
correlation between the location of choroidal melanoma and ultraviolet-radiation 
dose distribution. Radiat Res. 1997;147(4):451-6. 
4. Weis E, Shah CP, Lajous M, Shields JA, Shields CL. The association of 
cutaneous and iris nevi with uveal melanoma: a meta-analysis. Ophthalmology. 
2009;116(3):536-43 e2. 
5. Eskelin S, Kivela T. Mode of presentation and time to treatment of uveal 
melanoma in Finland. Br J Ophthalmol. 2002;86(3):333-8. 
6. Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular 
Melanoma Study. COMS report no. 1. Archives of ophthalmology. 
1990;108(9):1268-73. 
7. Collaborative Ocular Melanoma Study G. Assessment of metastatic disease 
status at death in 435 patients with large choroidal melanoma in the 

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Collaborative Ocular Melanoma Study (COMS): COMS report no. 15. Archives of 
ophthalmology. 2001;119(5):670-6. 
8. Finger PT, Kurli M, Reddy S, Tena LB, Pavlick AC. Whole body PET/CT for initial 
staging of choroidal melanoma. Br J Ophthalmol. 2005;89(10):1270-4. 
9. Dithmar S, Diaz CE, Grossniklaus HE. Intraocular melanoma spread to regional 
lymph nodes: report of two cases. Retina. 2000;20(1):76-9. 
10. Shields CL, Furuta M, Thangappan A, Nagori S, Mashayekhi A, Lally DR, et al. 
Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. 
Archives of ophthalmology. 2009;127(8):989-98. 
11. Collaborative Ocular Melanoma Study G. The COMS randomized trial of iodine 
125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and 
prognostic factors: COMS report No. 28. Archives of ophthalmology. 
2006;124(12):1684-93. 
12. Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, 
et al. Development of metastatic disease after enrollment in the COMS trials for 
treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group 
Report No. 26. Archives of ophthalmology. 2005;123(12):1639-43. 
13. American Brachytherapy Society - Ophthalmic Oncology Task Force. Electronic 
address pec, Committee AO. The American Brachytherapy Society consensus 
guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma. 
Brachytherapy. 2014;13(1):1-14. 
14. Gragoudas ES, Goitein M, Verhey L, Munzenreider J, Urie M, Suit H, et al. 
Proton beam irradiation of uveal melanomas. Results of 5 1/2-year study. 
Archives of ophthalmology. 1982;100(6):928-34. 
15. Gragoudas ES, Lane AM, Regan S, Li W, Judge HE, Munzenrider JE, et al. A 
randomized controlled trial of varying radiation doses in the treatment of 
choroidal melanoma. Archives of ophthalmology. 2000;118(6):773-8. 
16. Sikuade MJ, Salvi S, Rundle PA, Errington DG, Kacperek A, Rennie IG. 
Outcomes of treatment with stereotactic radiosurgery or proton beam therapy for 
choroidal melanoma. Eye (Lond). 2015;29(9):1194-8. 
17. Furdova A, Sramka M, Chorvath M, Kralik G, Krasnik V, Krcova I, et al. 
Stereotactic radiosurgery in intraocular malignant melanoma--retrospective 
study. Neuro Endocrinol Lett. 2014;35(1):28-36. 
18. Shah SU, Shields CL, Bianciotto CG, Iturralde J, Al-Dahmash SA, Say EA, et al. 
Intravitreal bevacizumab at 4-month intervals for prevention of macular edema 
after plaque radiotherapy of uveal melanoma. Ophthalmology. 2014;121(1):269-
75. 
19. Mashayekhi A, Rojanaporn D, Al-Dahmash S, Shields CL, Shields JA. Monthly 
intravitreal bevacizumab for macular edema after iodine-125 plaque radiotherapy 
of uveal melanoma. European journal of ophthalmology. 2014;24(2):228-34. 
20. Karagiannis D, Kontomichos L, Georgalas I, Peponis V, Antoniou E, Parikakis E. 
Glioma-associated radiation retinopathy treated successfully with aflibercept. 
Ther Clin Risk Manag. 2019;15:937-41. 

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21. Pooprasert P, Young-Zvandasara T, Al-Bermani A. Radiation retinopathy treated 
successfully with aflibercept. BMJ Case Rep. 2017;2017. 
22. Fallico M, Reibaldi M, Avitabile T, Longo A, Bonfiglio V, Chronopoulos A, et al. 
Intravitreal aflibercept for the treatment of radiation-induced macular edema after 
ruthenium 106 plaque radiotherapy for choroidal melanoma. Graefes Arch Clin 
Exp Ophthalmol. 2019;257(7):1547-54. 
 
Appendices 
The following documents are officially affiliated with the protocol and will be submitted to the IRB 
as a part of the protocol. As such, changes to these items require a protocol amendment. 
Appendix A: Schedule of Events 
Appendix B: KPS Score 
 
 
 

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APPENDIX A: SCHEDULE OF EVENTS 
Procedures Screening 
(D -30 to -
1) 
Visit 
1 
RT1 
Visit 
2 
M23 
Visit 
3 
M43 
 
Visit 
4-13 
M6 – 
243 
Visit 
14 
M263, 
9 
Withdrawal 
Visit/ 
Discontinuation 
of Therapy 
Signed 
Informed 
Consent8 
X 
 
 
 
 
 
 
 
Eligibility and 
Randomization8 
X 
 
 
 
 
 
 
 
Review of 
Medical 
History5 
X 
 
 
 
 
 
 
 
Physical Exam 
including vital 
signs 
X 
 
X 
X 
 
X 
X 
X 
Karnofsky 
Performance 
Status 
X 
 
X 
X 
 
X 
X 
X 
Ophthalmic 
Exam 
(including 
BCVA) 
X 
 
X 
X 
 
X 
X 
X 
Ocular 
Ultrasound 
X 
 
X 
X 
 
X 
X 
X 
OCT 
X 
 
X 
X 
 
X 
X 
X 
Review of 
Concomitant 
Medications10 
X 
X 
X 
X 
 
X 
X 
X 
Adverse Events 
Assessment 
 
X 
X 
X 
 
X 
X 
X 
CBC w/diff 
X7 
 
 
 
 
 
X 
 
CMP, LFTs 
 
 
 
 
 
 
X 
 
Pregnancy Test 
(for WOCBP 
only)6 
X 
 
 
 
 
 
 
 
Radiation 
Treatment 
(FSRT or 
Plaque 
brachytherapy)1 
 
X 
 
 
 
 
 
 
IAI (Arm A)2 
 
 
 
X11 
 
X 
 
 
IAI (Arm B)4 
 
 
 
X11 
 
X 
 
 
Note: BCVA – best corrected visual acuity. 
 

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1. FSRT, total of 5 treatments, every other day, weekdays only (acceptable variation: every day 
treatment). FSRT should finish within 10 days (acceptable range: 14 days). Plaque 
brachytherapy: total implant time is 4 days (~100 hr up to 170 hr), may be up to 7 days per 
treating physician.  
2. Months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 after finishing SRT, acceptable variation ±1 
weeks. 
3. Acceptable variation ± 2 weeks. 
4. Months 4, 8, 12, 16, 20, 24, after finishing SRT, acceptable variation ±1 weeks 
5. Medical history includes demographics, alcohol use, and tobacco use. 
6. Blood or urine pregnancy test must be done within 14 days of enrollment. 
7. Screening labs must be done within 30 days of enrollment. 
8. Informed Consent and confirmation of eligibility will only occur at Radiation Oncology at Thomas 
Jefferson University Hospital. 
9. Patients will be recommended to continue with standard follow-up care with the treating 
ophthalmologist, including yearly physical exam, ocular exam, and yearly CXR and liver MRI for 
surveillance. Any local failures, or distant disease recurrence will be documented. Any patient 
death will also be recorded. 
10. Must include all medications that patient is currently taking (including prescription and over-the-
counter medications). 
11. Arm A & B: Administer 1st intravitreal dose of Aflibercept 4 months after radiation (acceptable 
variation ± 2 weeks.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B: KPS SCORE