A Phase 2 Study Using Stereotactic Ablative Radiation Therapy and Ipilimumab in Patients With Oligometastatic Melanoma
Phase: PHASE2
Conditions: Liver Metastases, Lung Metastases, Recurrent Melanoma, Stage IV Melanoma, Tumors Metastatic to Brain
Sponsor: Ohio State University Comprehensive Cancer Center

IRB Protocol Number: 2013C0096 
IRB Approval Date: 07/15/2019 
Protocol Version 06/12/2019 
 
 
 
1 
Ohio State University 
 
A phase 2 study using stereotactic ablative radiation therapy and ipilimumab in 
patients with oligometastatic melanoma 
 
Primary Investigator: 
Jose Bazan M.D. 
Department of Radiation Oncology 
James Cancer Hospital & Solove Research Institute 
460 W. 10th Avenue  
2nd Floor 
Columbus, OH 43210 
Phone: (614) 293-8415 
Fax: (614) 366-8707 
Email: Jose.Bazan2@osumc.edu 
 
 
 
Bristol-Myers Squibb, Co. 
 
Study Product: 
IPILIMUMAB 
Protocol Number: 
CA184-236 
OSU Number: 
OSU- 12182 
FDA IND Number and Status;     IND 119222 - EXEMPT 
Date: 
06/12/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB Protocol Number: 2013C0096 
IRB Approval Date: 07/15/2019 
Protocol Version 06/12/2019 
 
 
 
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CONFIDENTIAL 
Table of Contents 
 
STUDY SUMMARY  ..................................................................................... 11 
 
1  INTRODUCTION  ..................................................................................... 14 
1.1  SPECIFIC AIMS ......................................................................... 14 
1.2  BACKGROUND AND RATIONALE  ........................................... 14 
1.2.1  The role of CTLA-4 and ipilimumab in melanoma ......... 15 
1.2.2  The role of radiation therapy in melanoma .................... 17 
1.2.3  The role of SABR in melanoma .................................... 17 
1.2.4  The potential synergism of ipilimumab and SABR ........ 18 
1.2.5  Hypothesis .................................................................... 18 
1.3  INVESTIGATIONAL AGENT ...................................................... 20 
1.4  PRECLINICAL DATA  ................................................................ 20 
1.4.1  Pharmacology of Ipilimumab ......................................... 20 
1.4.2  Pre-Clinical Toxicology of Ipilimumab  .......................... 20 
1.4.3  Preclinical data on combination with radiation therapy . 21 
1.5  CLINICAL DATA TO DATE ........................................................ 21 
1.5.1  Human Pharmacokinetics of Ipilimumab  ...................... 21 
1.5.2  Clinical Safety with Ipilimumab  .................................... 23 
1.5.3  Clinical Efficacy of Ipilimumab in Melanoma ................. 32 
1.6  OVERALL RISK/BENEFIT ASSESSMENT ................................ 36 
 
2  STUDY OBJECTIVES ............................................................................. 38 
2.1  PRIMARY OBJECTIVES ............................................................ 38 
2.2  SECONDARY OBJECTIVES ...................................................... 38 
2.3  EXPLORATORY/CORRELATIVE OBJECTIVES ....................... 38 
 
3  STUDY DESIGN ...................................................................................... 39 
3.1  GENERAL DESIGN .................................................................... 39 
3.1.1  Screening  ..................................................................... 39 
3.1.2  Treatment  .................................................................... 39 
3.1.3  Reinduction ................................................................... 40 
3.1.4  Follow-up ...................................................................... 40 
3.2  PRIMARY STUDY ENDPOINTS ................................................ 41 
3.3  SECONDARY STUDY ENDPOINTS .......................................... 41 
3.4  CORRELATIVE/EXPLORATORY STUDY ENDPOINTS ........... 41 
 
4  SUBJECT SELECTION AND WITHDRAWAL ........................................ 44 
4.1  INCLUSION CRITERIA .............................................................. 44 
4.2  EXCLUSION CRITERIA  ............................................................ 46 
4.3  GENDER/MINORITY/PEDIATRIC INCLUSION FOR RESEARCH .....48 

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4.4  SUBJECT RECRUITMENT AND SCREENING ......................... 48 
4.5  EARLY WITHDRAWAL OF SUBJECTS ..................................... 48 
4.5.1  When and How to Withdraw Subjects ........................... 48 
4.5.2  Data Collection and Follow-up for Withdrawn Subjects 49 
5  STUDY DRUG.......................................................................................... 50 
5.1  DOSE CALCULATIONS ............................................................. 50 
5.2  STORAGE, PREPARATION, AND ADMINISTRATION ............. 50 
5.3  DOSE MODIFICATION .............................................................. 51 
5.4  DISCONTINUATION OF STUDY THERAPY ............................. 52 
5.5  IMMUNE-RELATED ADVERSE EVENTS (irAEs) REACTIONS 
       AND IMMUNE-MEDIATED ADVERSE REACTIONS: 
       DEFINITION, MONITORING, AND TREATMENT ...................... 55 
5.6  PROHIBITED AND RESTRICTED THERAPIES DURING THE  
       STUDY ....................................................................................... 60 
5.7  METHOD FOR ASSIGNING SUBJECTS TO TREATMENT  
       GROUPS .................................................................................... 61 
5.8  SUBJECT COMPLIANCE MONITORING .................................. 61 
5.9  PRIOR AND CONCOMITANT THERAPY .................................. 61 
 
6  STUDY PROCEDURES ........................................................................... 61 
6.1  TREATMENT OVERVIEW ......................................................... 61 
6.2  SCREENING .............................................................................. 62 
6.3  STEREOTACTIC ABLATIVE RADIATION THERAPY ............... 62 
6.3.1  Radiation Therapy......................................................... 62 
6.3.2  Fractionated, Total Dose and Radiation Therapy Planning ...63 
6.3.3  Field Definition .............................................................. 63 
6.3.4  Dose Considerations ..................................................... 63 
6.3.5  Dosimetry ...................................................................... 63 
6.4  INTERRUPTION AND DISCONTINUATION .............................. 65 
6.5  VISIT SCHEDULE ...................................................................... 65 
6.5.1  Pre-Study Clinical Laboratory Tests & Procedures ....... 65 
6.5.2  On-Study Clinical Laboratory Tests & Procedures ........ 66 
6.5.3  Follow-up Clinical Laboratory Tests & Procedures ....... 66 
6.6  STUDY PROCEDURES BY VISIT & TREATMENT CYCLE……66 
6.7  STUDY MATERIALS .................................................................. 67 
6.8  SAFETY ASSESSMENTS .......................................................... 67 
6.9  ADVERSE EVENTS ................................................................... 67 
6.10  EFFICACY ASSESSMENTS .................................................... 69 
6.10.1  Definition of Measurable/Non-Measurable and Index/       Non-
Index Lesions .......................................................................... 70 
6.10.2  mWHO criteria for response ...........................................71 
6.10.3  Definition of Tumor Response Using irRC .................. 73 
 
7  STATISTICAL PLAN ............................................................................... 76 
7.1  SAMPLE SIZE DETERMINATION ............................................. 76 

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7.2  STATISTICAL METHODS .......................................................... 76 
7.3  SUBJECT POPULATION(S) FOR ANALYSIS ........................... 78 
7.4  INTERIM ANALYSIS…………………………………………………78 
 
8  STUDY CALENDAR…………………………………………………………..78 
 
9  IPILIMUMAB …………………………………………………………………..78 
9.1  IDENTIFICATION ....................................................................... 78 
9.2  PACKAGING AND LABELING ................................................... 79 
9.3  STORAGE, HANDLING, AND DISPENSING ............................. 79 
9.3.1  Storage ......................................................................... 79 
9.3.2  Handling and Disposal .................................................. 79 
9.3.3  Dispensing .................................................................... 79 
9.4  DRUG ORDERING AND ACCOUNTABILITY ............................ 79 
9.4.1  Initial Orders ................................................................. 79 
9.4.2  Re-Supply ..................................................................... 80 
9.5  IPILIMUMAB ACCOUNTABILITY ............................................... 80 
9.6  IPILIMUMAB DESTRUCTION .................................................... 81 
 
 
10  ADVERSE EVENT REPORTING ........................................................... 81 
10.1  COLLECTION OF SAFETY INFORMATION ............................ 81 
10.1.1  Serious Adverse Events .............................................. 81 
10.1.2  Nonserious Adverse Events ........................................ 82 
10.2  ASSIGNMENT OF ADVERSE EVENT INTENSITY AND          
         RELATIONSHIP TO INVESTIGATIONAL PRODUCT .............. 82 
10.3  COLLECTION AND REPORTING ............................................ 83 
10.3.1  Serious Adverse Events  ............................................. 83 
10.3.2  Handling of Expedited Safety Reports ........................ 85 
10.3.3  Nonserious Adverse Events ........................................ 86 
10.3.4  Pregnancy ................................................................... 86 
10.3.5  Other Safety Considerations  ...................................... 87 
10.4  DATA & SAFETY MONITORING COMMITTEE ....................... 89 
 
11  DATA HANDLING AND RECORD KEEPING ....................................... 89 
11.1  CONFIDENTIALITY .................................................................. 89 
11.2  INFORMED CONSENT ............................................................ 90 
11.3  SOURCE DOCUMENTS .......................................................... 90 
11.4  CASE REPORT FORMS .......................................................... 90 
11.5  MONITORING AND AUDIT ...................................................... 91 
11.6  RECORDS RETENTION .......................................................... 91 
 
12  ETHICAL AND REGULATORY CONSIDERATIONS ............................ 92 
12.1  INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
         COMMITTEE (IRB/IEC) ............................................................ 92 

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13  TISSUE/SPECIMEN COLLECTION & CORRELATIVE ANALYSIS ..... 93 
13.1  BACKGROUND ........................................................................ 93 
13.2  SCREENING FOR ELIGIBILITY ............................................... 93 
13.3  PLANNED CORRELATIVE ANALYSES .................................. 93 
13.4  SPECIMEN COLLECTION ....................................................... 93 
13.5  CORRELATIVE STRATEGY .................................................... 95 
13.6  CONFIDENTIALITY/STORAGE ............................................... 96 
 
14  STUDY FINANCES  ............................................................................... 97 
14.1  FUNDING SOURCE ................................................................. 97 
14.2  CONFLICT OF INTEREST ....................................................... 97 
14.3  SUBJECT STIPENDS OR PAYMENTS  .................................. 97 
 
15  PUBLICATION PLAN  ........................................................................... 97 
 
16  REFERENCES ....................................................................................... 98 
 
Appendix I:  ECOG Performance Status Scale ........................................ 101 
Appendix II:  Study Schedule .................................................................... 102 
Appendix III:  Comparison between WHO criteria and the irRC………...105 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
ADCC  
antibody-dependent cellular cytotoxicity 
AE 
 
adverse events 
ALC  
Absolute lymphocyte count 
ACTH  
Adrenocorticotropic hormone level 
ALT 
 
alanine aminotransferase  
ANC  
absolute neutrophil count 
APC  
antigen-presenting cells 
AST  
aspartate aminotransferase  
AUC  
area under the curve 
 
BMS  
Bristol-Myers Squibb  
BORR  
best overall/objective response rate 
BW 
 
body weight 
 
CBC  
complete blood count 
CDCC  
complement-dependent cellular cytotoxicity 
CI 
 
confidence interval 
CHO  
Chinese hamster ovary cell 
CL 
 
systemic clearance 
CTLA-4 
cytoxic T lymphocyte antigen 4 
cm 
 
centimeter 
Cmax  
maximum concentration 
Cmin  
minimum concentration 
CMP  
comprehensive metabolic panel  
COMPTV 
center of mass of the planned target volume 
CR 
 
complete response 
CRF  
case report form 
CT 
 
computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events  
CTV  
clinical target volume 
 
DCR  
disease control rate 
DMSO 
dimethyl sulfoxide  
DNA  
deoxyribonucleic acid 
DSMC 
Data and Safety Monitoring Committee 
DTIC  
dacarbazine  
 
ECL  
electrochemiluminescent  
ECOG  
Eastern Cooperative Oncology Group 
ESR  
expedited safety report 
EU 
 
European Union 
 

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FDA  
Food and Drug Administration 
FSH  
follicle stimulating hormone 
 
GCP  
Good Clinical Practice 
g/dL  
grams per deciliter 
GI 
 
gastrointestinal  
g/L 
 
grams per liter 
GTV  
gross tumor volume 
Gy 
 
Gray 
 
 
HCG  
human chorionic gonadotropin  
HepB  
hepatitis B 
HepC  
hepatitis C 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
 
human immunodeficiency virus 
HLA  
human leukocyte antigen 
HLA-DR 
human leukocyte antigen-disease resistance 
hr 
 
hours 
HR 
 
high risk 
HRT  
hormone replacement therapy 
 
IB 
 
investigational brochure 
ICH 
 
International Conference on Harmonisation   
IDO 
 
indoleamine 2,3-dioxygenase 
IEC 
 
International Education Council 
IgG1  
human immunoglobulin G 
IMRT  
intensity modulated radiation therapy 
IND 
 
investigational new drug 
Ipi 
 
ipilimumab 
ir 
 
immune-related 
irAE 
 
immune-related adverse effects 
irBOR  
immune-related best overall response  
irCR  
immune-related complete response 
irPD  
immune-related progressive disease 
irPR  
immune-related partial response 
irRC  
immune-related response criteria  
irSD  
immune-related stable disease 
irSPD  
immune-related sum of product diameter 
IRB 
 
investigational review board 
ITT 
 
insulin tolerance test 
ITV 
 
intensive therapy unit 
IU/L 
 
International Unites per liter 
IV 
 
intravenous 
 

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kg 
 
kilogram 
 
L 
 
liter 
LDH  
lactate dehydrogenase 
LFT 
 
liver function test 
 
mAb  
monoclonal antibody 
mcg/mL 
micrograms per milliliter 
mg 
 
milligram 
mg/dL  
milligrams per deciliter 
mg/kg  
milligrams to kilograms 
mg/kg/day 
milligrams per kilogram per day 
mg/m2  
milligrams per metered square 
mIU/mL 
milli international units per milliliter 
mL 
 
milliliter 
MLC  
multi-leaf collimator 
mL/h  
milliliters per hour 
mL/h/kg 
milliliters per hours per kilogram 
mL/min 
milliliter per minute 
mm 
 
millimeter 
mmHg 
millimeters of mercury 
MRI 
 
magnetic resonance imaging 
MR 
 
magnetic resonance 
mRNAs  
micro ribonucleic acids 
MV 
 
megavoltage 
Mwho  
modified World Health Organization 
 
 
NCA  
non-compartmental analysis 
NCI 
 
National Cancer Institute 
NYHA  
New York Heart Association 
 
OAR  
organs at risk 
OR 
 
overall response 
OS 
 
overall survival 
OSUCCC 
Ohio State University Comprehensive Cancer Center 
 
PAP 
PET/CT 
positron emission tomography-computed tomography 
PFS  
progression-free survival  
PHA  
 
PHI 
 
protected health information 
PI 
 
primary investigator  
PK 
 
pharmacokinetic  
PPK  
population pharmacokinetics  
PR 
 
partial response  

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PS 
 
performance status 
PSA  
prostate-specific antigen 
PSMA  
prostate-specific membrane antigen 
PTV  
planned target volume 
 
q3w 
 
every three weeks 
 
RECIST 
response evaluation criteria in solid tumors 
RP2D  
recommended phase II dose 
RTOG  
Radiation Therapy Oncology Group 
 
SABR  
stereotactic ablative radiation therapy 
SAE  
serious adverse event 
SD 
 
stable disease 
SPD  
sum of the products of diameters 
SRS  
slow-reacting substance 
SUSAR 
suspected, unexpected serious adverse reaction 
SWOG 
Southwest Oncology Group 
 
TA 
 
tumor assessment 
TAA  
tumor-associated antigen  
TMA  
tissue microarray 
 
ug/mL  
microgram per milliliter 
uL 
 
microliter 
ULN  
upper limit of normal  
USP  
acetic acid solution 
 
Vss 
 
volume of distribution at steady-state 
 
WBC  
white blood cell 
WOCBP 
women of childbearing potential  
 

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Study Summary 
Title 
A phase II study using stereotactic ablative radiation therapy 
(SABR) and ipilimumab in patients with oligometastatic melanoma 
Short Title 
SABR and ipilimumab in oligometastatic melanoma 
Protocol Number 
OSU #12182 
IRB # 2013C0096 
Phase 
2 
Methodology/Study 
Design 
Phase II, single-arm, open label, non-randomized study with 
stereotactic ablative radiation therapy and ipilimumab as outlined 
in the treatment plan. We will perform a phase II trial with a 
primary endpoint of progression-free survival. 
Study Duration 
24 months 
Study Center(s) 
Single center 
Objectives 
Primary Objectives: 
• To determine the progression-free survival of the     
combination of SABR and ipilimumab in patients with 
oligometastatic melanoma using mWHO criteria 
 
Secondary and Correlative Objectives: 
• To determine the progression-free survival of the     
combination of SABR and ipilimumab in patients with 
oligometastatic melanoma using irRC criteria 
• To evaluate the tolerability and safety of the combination 
• To evaluate of response rate based on mWHO & irRC 
criteria 
• To evaluate the local control rate 
• To evaluate the overall survival rate 
• To determine the effect of SABR and ipilimumab on 
changes in blood and serum markers:  absolute lymphocyte 
count, T-cell activation markers, T-cell suppression 
markers, T-helper cells and related cytokines, T-reg 
markers, co-stimulatory molecules, and serum cytokines 
• To 
determine 
the 
association 
between 
response, 
progression-free survival and genomic DNA mutations in 
key melanoma genes and tumor antigen expression 
Number of 
Subjects 
32 
 

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Diagnosis and 
Main Inclusion 
Criteria 
Male and female patients > 18 years old with Stage IV melanoma 
 
Key Inclusion Criteria: 
• Confirmed melanoma with metastatic disease confined 
to an area amenable to SABR (lung, liver, bone, brain, 
adrenal, nodal station outside the regional lymph 
drainage of the primary)   
• 1-3 sites of metastatic disease to be targeted by SABR 
• Normal end organ function  
• Measurable disease by CT 
• ECOG PS of 0 - 2  
 
Study Product, 
Dose, Route, 
Regimen 
Ipilimumab will be administered on week 1 at a dose of 3 mg/kg.  
Subsequent cycles of ipilimumab will be given every three weeks 
(week 4, 7, & 10). 
 
SABR will be delivered between the second and third doses of 
ipilimumab(week 5-6) using the following suggested schedules:  
18 Gy x 3 to lung, 10 Gy x 5 to liver, 6 Gy x 6 to nodal stations, 
12 Gy x 3 to adrenal, 18 Gy x 1 to bone, and 24 Gy x 1, 18 Gy x 
1, 15 Gy x 1 to < 2.0 cm, 2.0-3.0 cm, and >3 cm brain 
metastases, respectively. 
Duration of therapy: Patients will receive at least 12 weeks of 
therapy and will be observed for toxicity for 90 days after the last 
ipilimumab infusion.  Patients will remain on study until evidence 
of progression or death.  
Duration of 
administration 
 
12 weeks 
Reference therapy 
NA 

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Statistical 
Methodology 
Overall, this study will require 32 evaluable patients. We estimate 
that we will accrue 1-2 patients per month.  Thus, the minimum 
study duration will be 16 months and the maximum is 32 months.  
 
Current literature and experience with maintenance therapy in this 
patient population shows that we can expect that this treatment 
regimen will not be considered promising in this patient population 
if at most 15% of patients are progression-free and alive at 6 
months. For this agent to be considered promising in this patient 
population, we would expect an improvement in the 6-month PFS 
rate to at least 35% with this regimen in this patient population. 
Constraining the Type I and II error rates to 10% each, a 2-stage 
phase II Simon minimax study design will require 32 evaluable 
patients to test these hypotheses regarding the 6-month PFS rate 
with ipilimumab when given in combination with the stereotactic 
ablative radiation therapy in this patient population.  
 

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1.0 INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures.  
1.1 Specific Aims 
For nearly 30 years melanoma has been treated with chemotherapy agents like 
dacarbazine with a very modest benefit.  A relative revolution in the treatment options for 
patients with metastatic melanoma has occurred over the last several years as promising 
targeted agents and immunotherapies have shown impressive disease stabilization rates.  
In order to turn impressive disease stabilization rates into actual long term disease 
control, additional therapeutic advances are needed.  The immunotherapy agent 
ipilimumab is an exciting new agent which is being tested in a host of settings in 
melanoma to determine how to achieve a maximum benefit in disease control.  We aim 
to improve the exciting advances in melanoma care afforded by ipilimumab by enhancing 
response rates and disease control with an aggressive local treatment like SABR 
(Stereotactic Ablative Radiation Therapy).  This is important because overall response 
rates for melanoma immunotherapy remain low in metastatic disease and disease control 
rates stand at between 20 and 35% with overall survival measured in months1. 
 
The objectives of this study are: 
 
Primary Objectives: 
• To evaluate the 6-month progression-free survival of the combination of SABR 
and 3 mg/kg ipilimumab in patients with oligometastatic melanoma using mWHO 
criteria 
 
Secondary Objectives: 
• To evaluate the 6-month progression-free survival of the combination of SABR and 
3 mg/kg ipilimumab in patients with oligometastatic melanoma using irRC criteria 
 
• To evaluate the tolerability and safety of the combination 
• To evaluate the response rate based on mWHO & irRC criteria2 
• To evaluate the local control rate 
• To evaluate the overall survival rate 
Correlative Objectives: 
•   To determine the effect of SABR and ipilimumab on changes in blood and serum 
markers:  absolute lymphocyte count, T-cell activation markers, T-cell suppression 
markers, T-helper cells and related cytokines, T-reg markers, co-stimulatory 
molecules, and serum cytokines 

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•   To determine the association between response, progression-free survival and 
genomic DNA mutations in key melanoma genes and tumor antigen expression 
1.2 Background and Rationale 
The regulatory pathways that limit the immune systems surveillance and response 
to melanoma are becoming increasingly well characterized. Cytotoxic T-lymphocyte–
associated antigen 4 (CTLA-4) is molecule with a checkpoint function that down-
regulates pathways of T-cell activation3. Ipilimumab is a fully human monoclonal 
antibody (IgG1) that blocks CTLA-4, and thereby promotes antitumor immunity4-5.  
Ipilimumab has shown impressive activity in patients with metastatic melanoma when 
it has been used as monotherapy in phase 2 studies6-8 and a pivotal, recently reported 
phase III study1.  This study evaluated whether ipilimumab with or without the gp100 
vaccine improves overall survival, as compared with gp100 alone, among patients 
with metastatic melanoma who had undergone previous treatment.  Ipilimumab was 
dosed at 3 mg/kg body weight.  The median overall survival was 10 months for patients 
treated with ipilimumab and 6.4 months for the gp100 vaccine alone.  Ipilimumab-
treated patients had an 11% overall response rate and a 28% disease control rate.  
Ipilimumab was granted FDA approval for the treatment of metastatic melanoma in 
2011 based largely on the survival benefit found by this trial. 
 
1.2.1. The role of CTLA-4 and ipilimumab in melanoma 
 
Activated T-cells and antibodies targeting tumor-associated antigens (TAAs) have 
commonly been detected in blood from patients with various types of cancer9 supporting 
an active role for a host immune response against cancers.  In melanoma, T-cell infiltrates 
in primary melanoma have prognostic significance10,  and T-cell infiltrates within regional 
nodal metastases predict benefit in patients treated with neoadjuvant interferon-α-2b 
therapy11-12.  
 
Two signals are required for full T-cell activation 13-14.  The first is initiated by T-cell 
receptor binding to TAAs presented by antigen presenting cells (APCs) via major 
histocompatibility complexes I and II. The second signal is launched when the principal 
co-stimulatory receptor on the T cell, CD28, binds to B7 ligand subtypes CD80 and CD86 
on the APC.  The resulting dual signaling induces cytokine release and T-cell proliferation 
which triggers and then amplifies the immune response.  In response to T-cell activation, 
CTLA-4 is upregulated and competes with CD28 for CD80 and CD86 binding on APCs 
but with significantly higher affinity, therefore downregulating the T cell response (Fig. 
1)14.  CTLA-4, therefore, downregulates T-cell responses and APC function, resulting in 
a decreased immune response to TAAs and immune tolerance 13, 15.  CTLA-4 signaling 
contributes to the immunosuppressive function of regulatory T cells 16.  CTLA-4 is the 
main negative regulator of T-cell-mediated antitumor immune responses and therefore 
represents a critical immunity checkpoint, controlling both the duration and the intensity 
of an immune response 13, 15, 17. 
 

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Figure 1.1. Ipilimumab mechanism of action 14. 
 
 
Ipilimumab (Yervoy, BMS-734016, MDX-010, MDX-CTLA4 Bristol-Myers Squibb) 
is a fully human, antagonistic monoclonal antibody directed against CTLA-418. It promotes 
durable objective responses in patients with metastatic melanoma1, 19. It is approved by 
FDA to treat patients with unresectable or metastatic melanoma.  
 
The safety and efficacy of Ipilimumab were investigated in a randomized (3:1:1), 
double-blind, double-dummy study that included 676 randomized patients with 
unresectable or metastatic melanoma previously treated with one or more of the following: 
aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin 1. Of these 676 
patients, 403 were randomized to receive Ipilimumab at 3 mg/kg in combination with an 
investigational peptide vaccine with incomplete Freund’s adjuvant (gp100), 137 were 
randomized to receive Ipilimumab at 3 mg/kg, and 136 were randomized to receive gp100 
alone. The study enrolled only patients with HLA-A2*0201 genotype; this HLA genotype 
facilitates the immune presentation of the investigational peptide vaccine. The study 
excluded patients with active autoimmune disease or those receiving systemic 
immunosuppression for organ transplantation. Ipilimumab /placebo was administered at 
3 mg/kg as an intravenous infusion every 3 weeks for four doses. Gp100/placebo was 
administered at a dose of 2 mg peptide by deep subcutaneous injection every 3 weeks 
for four doses. Assessment of tumor response was conducted at weeks 12 and 24, and 
every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 
24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, 
respectively. 
 
The major efficacy outcome measure was overall survival (OS) in the Ipilimumab 
+ gp100 arm compared to that in the gp100 arm. Secondary efficacy outcome measures 
were OS in the Ipilimumab + gp100 arm compared to the Ipilimumab arm, OS in the 

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Ipilimumab arm compared to the gp100 arm, best overall response rate (BORR) at week 
24 between each of the study arms, and duration of response. Of the randomized 
patients, 61%, 59%, and 54% in the Ipilimumab +gp100, Ipilimumab, and gp100 arms, 
respectively, were men. Twenty-nine percent were ≥65 years of age, the median age was 
57 years, 71% had M1c stage, 12% had a history of previously treated brain metastasis, 
98% had ECOG performance status of 0 and 1, 23% had received aldesleukin and 38% 
had elevated LDH level. Sixty-one percent of patients randomized to either Ipilimumab-
containing arm received all 4 planned doses. The median duration of follow-up was 8.9 
months.  
 
1.2.2. The role of radiation therapy in melanoma 
 
Historically radiation therapy has played several important roles in the 
management of melanoma: definitive treatment of primary lesions in patients too frail to 
undergo resection, palliative treatment of distant metastatic lesions and local recurrences, 
elective treatment of regional nodes at high risk for subclinical disease, and adjuvant 
treatment after resection of the primary lesion or metastatic regional nodes.  It is estimated 
that radiation therapy is indicated in at least 23% of melanoma patients, though this 
modality is frequently under utilized20.  The under utilization of radiation therapy occurs, 
in part, because of the long-held belief that melanoma is a radioresistant malignancy.  In 
vitro studies have demonstrated a wide shoulder on the cell survival curve for many 
melanoma cell lines which suggests that melanoma has a large capacity for repair of 
sublethal damage.  One way to overcome melanoma’s intrinsic ability to repair sublethal 
damage is to deliver high-dose fractions of radiation therapy.  In the past the potential 
enhancement of cell kill using high-dose fractionation had to be weighed against potential 
increases in late normal tissue complications.   
The immune system plays a complex role in cancer control, and emerging 
evidence suggests that even in cell lines that in vitro are relatively radioresistant in vivo 
are sensitive due to the supportive anti-tumor effects of the immune system21.  Various 
mechanisms of action have been postulated including increased T cell infiltration after in 
vivo radiation therapy, increased TNF alpha22, induction of IL-1 alpha23, and induction of 
IL-623. 
 
1.2.3  The role of SABR in melanoma: 
 
SABR is an advanced radiation therapy technique which delivers a high dose of 
photon-based radiation therapy to a tumor target with a high degree of conformality, thus 
minimizing the dose to nearby healthy tissues.  SABR uses image-guided radiation 
therapy techniques like daily pretreatment kilovoltage or megavoltage CT scans and 
various forms of motion management to deliver high doses of radiation therapy to a tumor 
target in 1-5 total ablative treatments.  SABR has become an exciting byproduct of recent 
advances in linear accelerator design and improvements in the physics of motion 
management.  Most large cancer centers now have a robust experience treating brain, 
lung, liver, and skeletal metastases with SABR.  Indeed, the local control rates from SABR 
to metastases in the lung has been so exciting that several of national clinical trials are 

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now enrolling or in development to compare the efficacy of SABR to that of invasive 
surgical resection (RTOG 1021)24-25.   
 
SABR was first applied to melanoma metastases to the vertebral bodies and brain 
with encouraging outcomes26-29.  Aggressive targeting of individual melanoma sites of 
metastasis via SABR to the lungs and liver has been reported by Stinauer who treated 28 
metastatic lesions in 17 patients using a SABR regimen of 40-50 Gy in 5 total fractions or 
42-60 Gy in 3 total fractions30.  The local control of metastases treated was 88% at 18 
months and the median overall survival was 22.2 months. 
 
The importance of aggressive local disease control and its ability to improve 
survival in melanoma was recently highlighted by the SWOG 9430 trial31.  This phase II 
trial in 77  patients with oligometastatic melanoma examined the value of an attempted 
complete surgical resection of all sites of disease.  They found a median overall survival 
of 21 months compared with 6.2 months in patients involved in cooperative group 
systemic therapy alone trials.  Likewise, they found a median relapse-free survival of 5 
months compared with the historical baseline of 1.7 months on cooperative group 
systemic agent alone trials.  This trial suggests that aggressive treatment of 
oligometastatic disease may prolong survival.  The potential advantages of using SABR 
as the local control method are that SABR is non-invasive and requires minimal recovery 
time. 
 
1.2.4  The potential synergism of ipilimumab and SABR: 
 
Ipilimumab and SABR are a particularly intriguing pair for concurrent treatment and 
potential synergism of effect.  The underlying hypothesis is that radiation therapy, 
particularly radiation therapy using high doses per fraction, causes uncontrolled 
melanoma cell death and causes additional antigens to be presented in per-tumoral tissue 
during the uncontrolled cell death.  The additional antigen presentation enhances the 
effect of immunotherapies like ipilimumab.  Radiation therapy clearly affects various 
aspects of the immune system:  a recent high profile publication32 highlighted the 
induction of the abscopal effect by radiation therapy and conversely, the importance of 
immune function on the ablative properties of high dose per fraction radiation therapy33.  
Subsequently, a number of publications have hypothesized a role for the combination of 
immune-modulating drugs like ipilimumab and radiation therapy34-40. 
 
1.2.5 Hypothesis: 
 
We hypothesize that hypo-fractionated radiation therapy causes aberrant cell death 
processes which may result in additional antigen presentation.  When combined with 
ipilimumab the additional antigen presentation may incite a more robust immune 
response.   

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1.3 Investigational Agent 
 
Ipilimumab is a fully human monoclonal immunoglobulin (IgG1κ) specific for human 
cytotoxic T lymphocyte antigen 4 (CTLA-4, CD152), which is expressed on a subset of 
activated T cells.  The proposed mechanism of action for ipilimumab is T-cell potentiation 
through interference of the interaction of CTLA-4 with B7 (CD80 or CD86) molecules on 
antigen presenting cells, with subsequent blockade of the inhibitory function of CTLA-4.  
Ipilimumab consists of four polypeptide chains; two identical heavy chains primarily 
consisting of 447 amino acids each with two identical kappa light chains consisting of 215 
amino acids each linked through inter-chain disulfide bonds.   
 
1.4 Preclinical Data 
1.4.1 Pharmacology of Ipilimumab 
 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody 
(mAb).  In vitro studies were performed with ipilimumab to demonstrate that it is specific 
for CTLA-4, actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any 
cross-reactivity with human B7.1, B7.2 negative cell lines, and stains the appropriate cells 
without non-specific cross-reactivity in normal human tissues, as demonstrated by 
immunohistochemistry.  Ipilimumab does cross-react with CTLA-4 in non-human primates 
including cynomolgus monkeys. 
 
Ipilimumab was originally produced and purified from a hybridoma clone.  
Subsequently, a transfectoma (CHO cell) has been generated that is capable of 
producing more ipilimumab on a per cell basis than the hybridoma.  Material from the 
transfectoma will be utilized in this and future ipilimumab clinical studies.  Biochemical, 
immunologic and in vivo preclinical primate assessments demonstrated similarity 
between hybridoma and transfectoma-derived ipilimumab. 
 
1.4.2 Pre-Clinical Toxicology of Ipilimumab 
 
Complete information on the pre-clinical toxicology studies can be found in the 
Ipilimumab Investigator Brochure (IB).  Non-clinical toxicity assessments included in vitro 
evaluation for the potential of ipilimumab to mediate complement-dependent cellular 
cytotoxicity (CDCC) or antibody-dependent cellular cytotoxicity (ADCC), and toxicology 
assessments in cynomolgus monkeys alone and in the presence of vaccines. 
 
The in vitro studies demonstrated that ipilimumab did not mediate CDCC of PHA- or 
(CD)3-activated human T cells.  However, low to moderate ADCC activity was noted at 
concentrations up to 50 ug/mL.  These data are consistent with the requirement of high 
levels of antigen expression on the surface of target cells for efficient ADCC or CDCC.  

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Since ipilimumab is a human IgG1, an isotype generally capable of mediating CDCC and 
ADCC, the lack of these activities is likely due to a very low expression of CTLA-4 on 
activated T cells.  Therefore, these data suggest that ipilimumab treatment would not 
result in depletion of activated T cells in vivo.  Indeed, no depletion of T cells or T cell 
subsets were noted in toxicology studies in cynomolgus monkeys. 
 
 
No mortality or signs of toxicity were observed in three independent 14-day 
intravenous toxicology studies in cynomolgus monkeys at multiple doses up to 
30 mg/kg/dose.  Furthermore, ipilimumab was evaluated in sub-chronic and chronic 
toxicology studies in cynomolgus monkeys with and without Hepatitis B (HepB) Vaccine 
and Melanoma Vaccine.  Ipilimumab was well tolerated alone or in combination in all 
studies.  There were no significant changes in clinical signs, body weight values, clinical 
pathology values or T cell activation markers.  In addition, there were no significant 
histopathology changes in the stomach or colon. 
1.4.3 Preclinical data on combination with radiation therapy 
 
Currently, there is no data on the combination of Ipilimumab with radiation in 
preclinical studies. A study evaluated the efficacy of a different CTLA-4 antibody (9H10) 
in combination of radiation treatment 41. Radiation treatment consists of 12 Gy in two daily 
fractions. The CTLA-4 antibody was administered 1, 4 and 7 days after radiation 
treatment. Combination treatment showed significant inhibition of the tumor growth 
compared to radiation treatment combined with control antibody treatment 41. 
 
1.5 Clinical Data to Date 
1.5.1 Human Pharmacokinetics of Ipilimumab 
 
The pharmacokinetics of ipilimumab was studied in 499 patients with unresectable or 
metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg administered once every 
3 weeks for four doses. Peak concentration (C max), trough concentration (Cmin), and 
area under the curve (AUC) of ipilimumab were found to be dose proportional within the 
dose range examined. Upon repeated dosing of ipilimumab administered every 3 weeks, 
ipilimumab clearance was found to be time-invariant, and minimal systemic accumulation 
was observed as evident by an accumulation index of 1.5-fold or less. Ipilimumab steady-
state concentration was reached by the third dose. The following mean (percent 
coefficient of variation) parameters were generated through population pharmacokinetic 
analysis: terminal half-life of 14.7 days (30.1%); systemic clearance (CL) of 15.3 mL/h 
(38.5%); and volume of distribution at steady-state (Vss) of 7.21 L (10.5%). The mean 

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(±SD) ipilimumab Cmin achieved at steady-state with the 3 mg/kg regimen was 21.8 
mg/mL (±11.2). 
Specific Populations: Cross-study analyses were performed on data from patients with 
a variety of conditions, including 420 patients with melanoma who received single or 
multiple infusions of ipilimumab at doses of 0.3, 3, or 10 mg/kg. The effects of various 
covariates on ipilimumab pharmacokinetics were assessed in population pharmacokinetic 
analyses. 
 
Ipilimumab CL increased with increasing body weight; however, no dose adjustment 
of ipilimumab is required for body weight after administration on a mg/kg basis. The 
following factors had no clinically meaningful effect on the CL of ipilimumab: age (range 
26 to 86 years), gender, concomitant use of budesonide, performance status, HLA-
A2*0201 status, positive anti-ipilimumab antibody status, prior use of systemic anticancer 
therapy, or baseline lactate dehydrogenase (LDH) levels. The effect of race was not 
examined as there were insufficient numbers of patients in non-Caucasian ethnic groups. 
Renal Impairment: Creatinine clearance at baseline did not have a clinically important 
effect on ipilimumab pharmacokinetics in patients with calculated creatinine clearance 
values of 29 mL/min or greater. 
Hepatic Impairment: Baseline AST, total bilirubin, and ALT levels did not have a clinically 
important effect on ipilimumab pharmacokinetics in patients with various degrees of 
hepatic impairment. 
 
Pharmacokinetic (PK) profiles for ipilimumab have been analyzed. The primary 
objective of Protocol MDX010-015 was to determine the safety and PK profile of single 
and multiple doses of ipilimumab derived from a transfectoma or hybridoma cell line. 
Mean plasma concentrations of ipilimumab administered at doses of 3 mg/kg (hybridoma-
derived drug product); 2.8 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, and 20 mg/kg 
(transfectoma-derived drug product) demonstrated approximate dose proportionality. 
Equimolar doses of hybridoma-derived and transfectoma-derived drug product had 
comparable PK profiles. The range of mean volume of distribution at steady state (Vss) 
across cohorts 2.8, 3, 5, 7.5, 10, 15, and 20 mg/kg, was 57.3 to 82.6 mL/kg, indicating 
drug distribution was mostly limited to the intravascular space. The clearance was low 
(range 0.11 to 0.29 mL/h/kg) and reflective of the half-life (range 297 to 414 h), which is 
consistent with the long terminal disposition phase of ipilimumab. There was moderate 
variability in the PK parameters among subjects, with CV of 11% to 48% in AUC(0-21d), 
20% to 59% in CL, and 17% to 46% in Vss. 
 
Ipilimumab was originally produced and purified from a hybridoma clone. Ipilimumab 
drug substance is currently manufactured using Process B. A new drug substance 
manufacturing process (Process C) has been developed utilizing a higher producing sub-
clone of the current Master Cell Bank, and modified cell culture and purification steps. 
The new drug substance manufacturing process is intended to replace the current drug 

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substance manufacturing process. The biocomparability of Process C relative to Process 
B was assessed in Study CA184087. 
PK in Phase 1 Study CA184087 (Process B and Process C)  
 
The PK of ipilimumab was assessed when manufactured by a newer process C 
relative to current process B as an IV infusion (1.5-hr), in subjects with advanced 
melanoma (CA184087). Upon meeting eligibility criteria, subjects were randomized (1:1) 
to receive either ipilimumab Process B (Arm A, reference) or ipilimumab Process C (Arm 
B, test) at a dose of 10 mg/kg IV administered over 90 minutes every 3 weeks on Days 
1, 22, 43, and 64 (Weeks 1, 4, 7, and 10) during induction therapy. Randomization was 
stratified by baseline body weight (BW) and LDH values since both were identified as 
potential covariates in a population PK assessment. 
 
The primary endpoint of PK data at week 4 demonstrated that the PK of Process B 
and Process C are biocomparable as the 90% CIs for the ratio of geometric means of 
AUC(0-21d) and Cmax - both adjusted or not adjusted for covariates - were entirely 
contained with the pre-specified equivalence interval (80 - 125%). 
Population Pharmacokinetics 
 
The population pharmacokinetics (PPK) of ipilimumab was developed with 420 
subjects (1767 serum concentrations) with advanced melanoma in phase 2 studies 
(CA184007, CA184008, and CA184022).16,17,18 Subsequently, the final PPK model was 
evaluated by an external model validation dataset from CA184004 (79 subjects with 328 
serum concentration data). The PPK analysis demonstrated that PK of ipilimumab is 
linear and exposures are dose- proportional across the tested dose range of 0.3 to 10 
mg/kg, and the model parameters are time-invariant. The ipilimumab CL of 15.3 mL/h 
from PPK analysis is consistent with that determined by PK analysis as assessed in 
MDX010-15 as 12.8 mL/h for a dose of 2.8 mg/kg and 15.7 mL/h for a dose of 10 mg/kg. 
The terminal half-life and Vss of ipilimumab calculated from the model were 14.7 days, 
and 7.21 L, which are consistent with that determined by non-compartmental analysis 
(NCA). Volume of central and peripheral compartment were found to be 4.16 and 3.22 L, 
respectively, suggesting that ipilimumab first distributes into plasma volume and 
subsequently into extracellular fluid space. Clearance of ipilimumab was found to 
increase with increase in body weight, supporting dosing of ipilimumab based on a weight 
normalized regimen. Other covariates had effects that were either not statistically 
significant or were of minimal clinical relevance. 
1.5.2 Clinical Safety with Ipilimumab 
Overview of Clinical Trials Experience 
 
Because clinical trials are conducted under widely varying conditions, the adverse 
reaction rates observed cannot be directly compared with rates in other clinical trials or 

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experience with therapeutics in the same class and may not reflect the rates observed in 
clinical practice. 
 
The clinical development program excluded patients with active autoimmune disease 
or those receiving systemic immunosuppression for organ transplantation. Exposure to 
ipilimumab 3 mg/kg for four doses given by intravenous infusion in previously treated 
patients with unresectable or metastatic melanoma was assessed in a randomized, 
double-blind clinical study (MDX010-20). One hundred thirty-one patients (median age 
57 years, 60% male) received ipilimumab as a single agent, 380 patients (median age 56 
years, 61% male) received ipilimumab with an investigational gp100 peptide vaccine 
(gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide 
vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). 
Ipilimumab was discontinued for adverse reactions in 10% of patients. 
 
The most common adverse reactions (≥5%) in patients who received ipilimumab at 3 
mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. 
 
Table 1 presents selected adverse reactions from MDX010-20, which occurred in at 
least 5% of patients in the ipilimumab-containing arms and with at least 5% increased 

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incidence over the control gp100 arm for all-grade events and at least 1% incidence over 
the control group for Grade 3–5 events. 
 
 
 
 
 
 
 
 
 
 
 

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Table 1: 
Selected Adverse Reactions in MDX010-20 
 
Percentage (%) of Patientsa 
 
YERVOY 3 mg/kg 
n = 131 
YERVOY 3mg/kg  
+ gp100  
n = 380 
gp100 
n = 132 
System 
Organ 
Class/Preferred 
Term 
Any 
Grade 
Grade 
3-5 
Any 
Grade 
Grade 3-
5 
Any 
Grade 
Grade 
3-5 
Gastrointestinal 
Disorders 
 
 
 
 
 
 
Diarrhea 
32 
5 
37 
4 
20 
1 
Colitis 
8 
5 
5 
3 
2 
0 
Skin 
and 
Subcutaneous 
Tissue Disorders 
 
 
 
 
 
 
Pruritus 
31 
0 
21 
<1 
11 
0 
Rash 
29 
2 
25 
2 
8 
0 
General Disorders 
and Administration 
Site Conditions  
 
 
 
 
 
 
Fatigue 
41 
7 
34 
5 
31 
3 
− 
a Incidences presented in this table are based on reports of adverse events 
regardless of causality. 
− 
Source: Yervoy Prescribing Information, Bristol-Myers Squibb, March 2011. 
 
 

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Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-
mediated adverse reactions from MDX010-20: 
Table 2: 
Severe to Fatal Immune-mediated Adverse Reactions in 
MDX010-20 
 
Percentage (%) of Patients  
 
YERVOY 3 mg/kg 
n = 131 
YERVOY 3 mg/kg + 
gp100  
n = 380 
Any Immune-mediated Adverse 
Reaction  
15 
12 
Entercolitis a,b 
7 
7 
Hepatotoxicity a 
1 
2 
Dermatitis a 
2 
3 
Neuropathy a 
1 
< 1 
Endocrinopathy 
4 
1 
Hypopituitarism 
4 
1 
Adrenal insufficiency 
0 
1 
Other 
 
 
Pneumonitis 
0 
< 1 
Meningitis 
0 
< 1 
Nephritis 
1 
0 
Eosinophilia c 
1 
0 
Pericarditis a,c 
0 
< 1 
− 
a Including fatal outcome 

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− 
b Including intestinal perforation 
− 
c Underlying etiology not established 
− Source: Yervoy Prescribing Information, Bristol-Myers Squibb, March 2011. 
 
CA184024 evaluated the addition of 10 mg/kg ipilimumab to dacarbazine in patients 
with previously-untreated, metastatic melanoma. A total of 502 patients were randomized 
to receive up to 8 cycles of dacarbazine 850 mg/m2 q3w, with either ipilimumab 10 mg/kg 
or placebo for cycles 1-4 and as maintenance after completion of chemotherapy. 
Ipilimumab AEs were consistent with previous studies and predominately affected skin, 
gastrointestinal (GI) tract, liver, and the endocrine system. Events were managed with 
established 
guidelines 
and 
were 
generally 
responsive 
to 
dose 
interruption/discontinuation, corticosteroids and/or other immunosuppresants. Select 

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adverse events associated with the mechanism of action of ipilimumab, regardless of 
attribution by the investigator, are shown in Table 3.  

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Table 3: 
CA184024 Select Adverse Events 
 
Ipilimumab 
+ 
DTIC 
n = 247 
Placebo 
+ 
DTIC 
n = 251 
Total 
Grade 3 - 4 
Total 
Grade 3 - 4 
% Patients 
Dermatologic 
 
 
 
 
 
Pruritis 
29.6 
2.0 
8.8 
0 
 
Rash 
24.7 
1.2 
6.8 
0 
Gastrointestinal 
(GI) 
 
 
 
 
 
Diarrhea 
36.4 
4.0 
24.7 
0 
 
Colitis 
4.5 
2.0 
0.4 
0 
 
GI perforation 
0 
0 
0 
0 
Hepatic 
 
 
 
 
 
Increased ALT 
33.2 
21.9 
5.6 
0.8 
 
Increased AST 
29.1 
18.2 
5.6 
1.2 
Endocrine 
 
 
 
 
 
Hypothyroidism 
1.6 
0 
0.4 
0 
 
Autoimmune 
thyroiditis 
0.8 
0 
0 
0 
 
Hyperthyroidism 
0.4 
0 
0.4 
0 
 
Hypophysitis a 
0 
0 
0 
0 
 
a (0.4%) hypophysitis was reported on Day 364. 

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Safety Profile of Ipilimumab at a Dose of 10 mg/kg (Phase 2 data) 
 
The safety profile of ipilimumab at a dose of 10 mg/kg was characterized in a total of 
325 subjects who received multiple doses of 10 mg/kg ipilimumab as monotherapy in the 
4 completed melanoma studies (CA184004, -007, -008, and -022). Overall, the incidence 
of Grade 3/4 AEs attributable to study drug was 31%. The target organ system, the 
incidence and the severity of the most commonly observed irAEs are displayed in Table 4. 
Table 4: 
Summary of irAE Safety Data for 10 mg/kg in Melanoma 
 
Total 
Low-grade 
(Grade 1 - 2) 
(%) 
High-grade 
(Grade 3 - 4) 
(%) 
Median Time 
to Resolution 
of 
Grade 2 - 4 
irAEs 
(weeks) 
All irAEs 
72.3 
46.2 
25.2 
- 
Skin 
(eg, 
rash, 
pruritus) 
52.0 
49.2 
2.8 
6.14 
GI 
(eg, 
colitis, 
diarrhea) 
37.2 
24.9 
12.3 
2.29 
Liver 
(eg, 
LFT 
elevations) 
8.0 
0.9 
6.8 
4.0 
Endocrine 
(eg, 
hypophysitis, 
hypothyroid) 
6.2 
3.7 
2.5 
20.1 
 
 
Overall, the 10 mg/kg had an acceptable safety regimen, while being the most active 
dose. The study drug related deaths across the program are in Section 5 of the 
investigators brochure. 
 
Across clinical studies that utilized ipilimumab doses ranging from 0.3 to 10 mg/kg, 
the following adverse reactions were also reported (incidence less than 1% unless 

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otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory 
distress syndrome, renal failure, and infusion reaction. 
 
Based on the experience in the entire clinical program for melanoma, the incidence 
and severity of enterocolitis and hepatitis appear to be dose-dependent. 
Immunogenicity 
 
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding 
antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This 
assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence 
of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity 
or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies 
against ipilimumab detected. 
 
Because trough levels of ipilimumab interfere with the ECL assay results, a subset 
analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 
6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for 
binding antibodies against ipilimumab. 
 
Immunogenicity assay results are highly dependent on several factors including 
assay sensitivity and specificity, assay methodology, sample handling, timing of sample 
collection, concomitant medications, and underlying disease. For these reasons, 
comparison of incidence of antibodies to ipilimumab with the incidences of antibodies to 
other products may be misleading. 
Pregnancy Outcomes 
 
Based on animal data, ipilimumab may cause fetal harm. The use of ipilimumab 
during human pregnancy has not been formally studied in clinical trials. There have been 
7 known pregnancies during ipilimumab treatment: in 3 female subjects and in the 
partners of 4 male study subjects. Two (2) of the 3 female pregnancies ended with elected 
terminations. The third female subject had a history of seizures and delivered the baby at 
36 weeks gestation. The baby had respiratory complications that resolved by birth week 
16. Three (3) of the 4 partners of male study subjects had full term, normal babies. The 
fourth baby had small ureters, which are expected to grow as the baby matures. Although 

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these outcomes do not indicate that stillbirths or other severe abnormalities will occur, 
pregnancy should be avoided during treatment with ipilimumab. 
Immune-mediated Adverse Reactions with Ipilimumab.  
 
Ipilimumab can result in severe and fatal immune-mediated reactions due to T-cell 
activation and proliferation. 
Immune-related Gastrointestinal Events 
 
The clinical presentation of GI immune-related AEs included diarrhea, increase in the 
frequency of bowel movements, abdominal pain, or hematochezia, with or without fever. 
Fatalities due to GI perforation have been reported in clinical trials of ipilimumab. Patients 
should be carefully monitored for GI symptoms that may be indicative of immune-related 
colitis, diarrhea, or GI perforation. Diarrhea or colitis occurring after initiation of ipilimumab 
therapy should be evaluated to exclude infectious or alternate etiologies. In clinical trials, 
immune-related colitis was associated with evidence of mucosal inflammation, with or 
without ulcerations, and lymphocytic infiltration. 
Immune-related Hepatotoxicity 
 
Hepatic immune-related AEs were mostly clinically silent and manifested as 
transaminase or bilirubin laboratory abnormalities. Fatal hepatic failure has been reported 
in clinical trials of ipilimumab. Serum transaminase and bilirubin levels must be evaluated 
before each dose of ipilimumab as early laboratory changes may be indicative of 
emerging immune-related hepatitis. Elevations in liver function tests (LFTs) may develop 
in the absence of clinical symptoms. Increase in LFT or total bilirubin should be evaluated 
to exclude other causes of hepatic injury, including infections, disease progression, or 
medications, and monitored until resolution. Liver biopsies from patients who had 
immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils, 
lymphocytes, and macrophages). 
Immune-related Skin Toxicity 
 
Skin immune-related AEs presented mostly as a rash and/or pruritus. Some subjects 
reported vitiligo associated with ipilimumab administration. Fatal toxic epidermal 
necrolysis has been reported in clinical trials of ipilimumab.  
Immune-related Endocrinopathy 
 
Ipilimumab can cause inflammation of the endocrine system organs, specifically 
hypophysitis, hypopituitarism, and adrenal insufficiency and patients may present with 
nonspecific symptoms, which may resemble other causes such as brain metastasis or 
underlying disease. The most common clinical presentation includes headache and 
fatigue. Symptoms may also include visual field defects, behavioral changes, electrolyte 
disturbances, and hypotension. Adrenal crisis as a cause of the patient’s symptoms 

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should be excluded. Based on the available data with known outcome, most of the 
subjects symptomatically improved with hormone replacement therapy. It is possible that 
long-term hormone replacement therapy will be required for subjects developing 
hypophysitis/hypopituitarism after treatment with ipilimumab. 
Immune-related Neurological Events 
 
Neurological manifestations included muscle weakness and sensory neuropathy. 
Fatal Guillain-Barré syndrome has been reported in clinical trials of ipilimumab. Patients 
may present with muscle weakness. Sensory neuropathy may also occur. Unexplained 
motor neuropathy, muscle weakness, or sensory neuropathy lasting more than 4 days 
should be evaluated and non-inflammatory causes such as disease progression, 
infections, metabolic syndromes, and medications should be excluded. 
Other Immune-related AEs 
 
Ocular inflammation, manifested as Grade 2 or Grade 3 episcleritis or uveitis, was 
associated with concomitant diarrhea in a few subjects (< 1%) and occasionally occurred 
in the absence of clinically apparent GI symptoms. Other presumed immune-related AEs 
reported include, but were not limited to, arthritis/arthralgias, pneumonitis, pancreatitis, 
autoimmune (aseptic) meningitis, autoimmune nephritis, pure red cell aplasia, 
noninfective myocarditis, polymyositis, and myasthenia gravis, of which were individually 
reported for < 1% of subjects.  
 
Overall, immune-related AEs commonly started within 3 to 10 weeks from first dose, 
were successfully managed in most instances by omitting doses, discontinuing dosing, 
and/or through administering symptomatic or immunosuppressive therapy, including 
corticosteroids, as mentioned above and detailed in Section 7. Immune-related AEs 
generally resolved within days to weeks in the majority of subjects.  
1.5.3 Clinical Efficacy of Ipilimumab in Melanoma 
 
The clinical efficacy of ipilimumab as a single agent at a dose of 3 mg/kg administered 
every 3 weeks for 4 doses has been established in MDX010-20 (a randomized, controlled 
study in previously-treated, locally advanced/metastatic melanoma), which led to 
approval of ipilimumab by the FDA for the treatment of unresectable or metastatic 
melanoma. In study CA184024, the addition of 10 mg/kg ipilimumab to dacarbazine led 

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to a prolongation of overall survival in patients with previously untreated melanoma and 
was feasible with an acceptable safety profile. 
 
Overall survival and other efficacy endpoints were assessed in ipilimumab studies. 
Overall Survival: Prolongs survival in patients with metastatic melanoma who have failed 
prior treatment. 
Best Objective Response Rate (BORR): By the conventional mWHO & irRC criteria 
confirmed objective responses have been observed in subjects receiving ipilimumab. 
These responses tend to be durable with the majority of subjects who achieve objective 
responses progression-free at the end of long observation periods. 
Disease Control Rate (DCR): Disease stabilization in subjects receiving ipilimumab is a 
key characteristic of anti-tumor activity. Stable disease, sometimes of long duration, or 
slow steady decline of tumor lesion size over long periods of time, has been observed. 
Consequently, SD as well as objective responses (both captured in DCR) are important 
for completely characterizing anti-tumor activity of ipilimumab 
Progression-Free Survival (PFS): Some subjects demonstrate initial tumor volume 
increase before response, possibly due to T-cell infiltration as shown by biopsies. 
Consequently, PFS incompletely captures all patterns of activity and may underestimate 
the clinical activity of ipilimumab. 
 
Rationale for Using Immune-Related Tumor Assessment Criteria (irRC) 
 
Ipilimumab is an immuno-stimulating antibody with evidence of anti-cancer activity 
(durable objective response and stable disease) in subjects with advanced melanoma, 
including subjects with established brain disease. Observations of clinical activity defined 
by tumor response endpoints defined by conventional criteria (eg, mWHO) may be 
inadequate to realize the kinetics and magnitude of clinical benefit achieved with 
ipilimumab. 
 
Histopathologic evidence has demonstrated ipilimumab can produce an influx or 
expansion of tumor infiltrating lymphocytes. Therefore, early increases in lesion size 
detected radiologically or upon gross examination could be misinterpreted as progressive 
tumor growth and precede objective tumor shrinkage. In addition the appearance of new 
lesions may have categorized a subject to have progressive disease using conventional 
tumor assessment criteria despite the concurrent observation of objective tumor 
responses in pre-existing lesions and a net reduction in global tumor burden that includes 
the new lesions. 
 
Hence the appearance of new lesions in and of themselves may not necessarily 
constitute progressive disease. The immune-related response criteria (irRC) were 

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developed as a tool to gauge tumor response using the changes in global tumor burden. 
In addition, the irRC may be useful to inform a physician’s decision to continue dosing in 
subjects who may receive benefit from additional ipilimumab therapy. The ir-response 
assessment is based solely on objective measurements (SPD) of index and new lesions. 
Non-index lesions are not considered. 
MDX010-20 (Phase 3, 3 mg/kg, previously treated melanoma) 
The design and results of the MDX010-20 trial are discussed in Section 1.2.1. 
CA184024 (Phase 3, previously untreated melanoma, 10 mg/kg) 
 
CA184024 evaluated the addition of 10 mg/kg ipilimumab to dacarbazine in patients 
with previously untreated, metastatic melanoma. A total of 502 patients were randomized 

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to receive up to 8 cycles of dacarbazine 850 mg/m2 q3w, with either ipilimumab 10 mg/kg 
or placebo cycles 1-4, and as maintenance after completion of chemotherapy.  
 
The two arms were well balanced regarding most baseline characteristics, as shown 
in Table 6. 
 
 

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Table 6: 
CA184024 Baseline Characteristics 
 
Ipilimumab + DTIC 
n = 250 
Placebo 
+ 
DTIC 
n = 252 
Age (years) 
 
 
 
Mean 
57.5 
56.4 
Gender (%) 
 
 
 
Male 
60.8 
59.1 
 
Female 
39.2 
40.9 
M Stage (%) 
 
 
 
M0 
2.4 
3.2 
 
M1a 
14.8 
17.1 
 
M1b 
25.6 
24.6 
 
M1c 
57.2 
55.2 
ECOG PS (%) 
 
 
 
0 
70.8 
71.0 
 
1 
29.2 
29.0 
LDH (%) 
 
 
 
≤ ULN  
62.8 
55.6 
 
> ULN  
37.2 
43.7 
 
≤ 2x ULN 
86.4 
85.3 
 
> 2x ULN 
13.6 
13.9 

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Table 6: 
CA184024 Baseline Characteristics 
 
Ipilimumab + DTIC 
n = 250 
Placebo 
+ 
DTIC 
n = 252 
Prior adjuvant therapy (%) 
26.4 
26.6 
Prior therapy for advanced 
disease (%) 
0 
0 
 
 
Patients on the ipilimumab arm received a median of 3 ipilimumab induction doses, 
versus 4 placebo induction doses on the placebo arm. A total of 17.4% and 21.1% of 
patients continued to receive maintenance ipilimumab or placebo, for a median of 4 and 

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2 doses, respectively. The number of patients who received all 8 dacarbazine doses was 
12.2% in the ipilimumab arm, and 21.5% in the placebo arm. 
 
The study met its primary end-point of prolonging overall survival in patients treated 
with ipilimumab (HR 0.72 (95% CI, 0.59 – 0.87), median OS 11.2 vs 9.1 months, 
p = 0.0009). The OS Kaplan-Meier curve is presented in Figure 3. 
Figure 3: 
CA184024 Kaplan-Meier Plot of Overall Survival - All Randomized 
Subjects 
 
 
 
One, two and three year survival rates were 47.3%, 28.5% and 20.8% in the 
ipilimumab arm, and 36.3%, 17.9% and 12.2% in the placebo arm. 
 
PFS, a secondary end-point, was also prolonged by the addition ipilimumab, HR 
0.76 (95% CI, 0.63 - 0.93). The median PFS was 2.8 months in the ipilimumab and vs 
2.6 months in the placebo arm, p = 0.006. 
 
BORR was increased from 10.3% in the placebo arm to 15.2% in the ipilimumab arm 
(Table 7). More importantly, duration of response was more than twice as long in the 
ipilimumab arm (19.3 months) than in the placebo arm (8.1 months). 

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Table 7: 
CA184024 Tumor Response 
 
Ipilimumab 
+ 
DTIC 
n = 250 
Placebo 
+ 
DTIC 
n = 252 
Disease Control Rate, n 
(%) 
83 (33.2) 
76 (30.2) 
BORR (CR + PR), n (%) 
38 (15.2) 
26 (10.3) 
 
Complete response 
4 (1.6) 
2 (0.8) 
 
Partial response 
34 (13.6) 
24 (9.5) 
 
Stable disease 
45 (18.0) 
50 (19.8) 
 
Progressive disease 
111 (44.4) 
131 (52.0) 
Duration of response, 
months 
19.3 
8.1 
 
1.6 Overall Risk/Benefit Assessment 
 
Ipilimumab is the first drug to demonstrate prolonged survival in subjects with pre-
treated advanced melanoma, based on a large, multinational, double-blind, pivotal, 
Phase 3 study supported by a comprehensive Phase 2 program.  
 
The unique immune-based mechanism of action is reflected in the clinical patterns of 
anti-cancer activity in some patients. Ipilimumab impacts tumor cells indirectly, and 
measurable clinical effects emerge after the immunological effects. Tumor infiltration with 
lymphocytes and the associated inflammation (documented by biopsy in some subjects) 
is likely the cornerstone of the effect of ipilimumab and can manifest in various patterns 
of clinical activity leading to tumor control. In some cases, inflammation may not be noted 
by radiological examination and objective response is observed with the first tumor 
assessment in a manner seen in patients receiving other types of anti-cancer treatments. 
In other cases, response may be preceded by an apparent increase in initial tumor volume 
and/or the appearance of new lesions, which may be mistaken for tumor progression on 
radiological evaluations. Therefore, in subjects who are not experiencing rapid clinical 
deterioration, confirmation of progression is recommended, at the investigator’s 
discretion, to better understand the prognosis as well as to avoid unnecessarily initiating 
potentially toxic alternative therapies in subjects who might be benefitting from treatment. 

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Immune-related response criteria were developed based on these observations to 
systematically categorize novel patterns of clinical activity and are currently being 
prospectively evaluated in clinical studies. 
 
In metastatic diseases, stabilization is more common than response, and in some 
instances is associated with slow, steady decline in tumor burden over many months, 
sometimes improving to partial and/or complete responses. Thus, the immune-based 
mechanism of action of ipilimumab results in durable disease control, sometimes with 
novel patterns of response, which contribute to its improvement in OS. 
 
The immune-based mechanism of action is also reflected in the safety profile. The 
most common drug-related AEs are immune-mediated, consistent with the mechanism of 
action of the drug and generally medically-manageable with topical and/or systemic 
immunosuppressants. As previously discussed, the immune-mediated adverse reactions 
primarily involve the GI tract, skin, liver, endocrine glands, and nervous system. 
 
The early diagnosis of immune-mediated adverse reactions is important to initiate 
therapy and minimize complications. Immune-mediated adverse reactions are generally 
manageable using symptomatic or immunosuppressive therapy as recommended 
through detailed diagnosis and management guidelines, as described fully in the current 
IB. The management guidelines for general immune-mediated adverse reactions and 
ipilimumab-related GI toxicities, hepatotoxicity, endocrinopathy, and neuropathy are 
provided in the appendices of the current IB.  
 
In summary, ipilimumab offers clinically meaningful and statistically significant 
survival benefit to patients with pre-treated advanced melanoma and evidence of clinical 
activity in randomized studies in other tumor types. These findings, together with evidence 
of a safety profile that is manageable with careful monitoring and appropriate intervention 
for treatment of immune-mediated toxicities, suggest an acceptable benefit to risk ratio. 
 
Hypo-fractionated radiation therapy is currently used for many indications including 
treating solitary, oligometastatic, or oligo-progressive disease in a number of cancers.  
Indeed, hypo-fractionated radiation therapy delivered with stereotactic precision and on-
board image guidance allows ablative doses of radiation therapy to be delivered to 
masses in the brain, lung, liver, spine, and selected abdominal sites.  One of the main 
obstacles to the success of immunotherapy is the fact that the immune system is tolerant 
to antigens on growing tumors. There is evidence that CTLA-4 blockade was effective 
when used in combination with radiation to produce granulocyte/macrophage colony-
stimulation factor 41-42. Combining CTLA-4 antibody with radiation treatment showed to 
be superior to radiation treatment alone in a preclinical tumor model 41. In this study, we 
will use the standard doses for SBRT.  We hypothesize that hypo-fractionated radiation 
therapy causes aberrant cell death processes which may result in additional antigen 
presentation.  When combined with ipilimumab the additional antigen presentation may 
incite a more robust immune response.  Therefore, the overall risk-benefit ratio for 

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patients entering this protocol is therefore at least comparable to and possibly better than 
alternative options. 
2.0 STUDY OBJECTIVES 
2.1 Primary Objective 
 
The primary objective of this study is: 
 
-  
To determine the progression-free survival of patients with oligometastatic 
melanoma treated with the combination of stereotactic ablative radiation therapy 
(SABR) and ipilimumab in patients with oligometastatic melanoma using mWHO 
criteria 
 
2.2 Secondary Objectives 
 
The secondary objectives of this study are as follows: 
 
-  To evaluate the 6-month progression-free survival of the combination of SABR and 
3 mg/kg ipilimumab in patients with oligometastatic melanoma using irRC criteria 
 
- 
To evaluate the tolerability and safety of the combination 
- 
To evaluate the response rate based on mWHO & irRC criteria2 
- 
To evaluate the local control rate 
- 
To evaluate the overall survival rate 
 
2.3 Exploratory/Correlative Objectives: 
 
The exploratory objectives of this study are as follows: 
 
- 
Evaluate changes in blood and serum markers:  absolute lymphocyte count, T-
cell activation markers, T-cell suppression markers, T-helper cells and related 
cytokines, T-reg markers, co-stimulatory molecules, and serum cytokines when 
SABR is added to the ipilimumab regimen 
 
- 
Evaluate genomic DNA mutations in key melanoma genes and their correlation 
with response, progression-free survival, and overall survival 
 

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3.0 STUDY DESIGN 
3.1 General Design 
Phase II, single-arm, open label, non-randomized study with ipilimumab and SABR 
as outlined in the treatment plan.  Patients with oligometastatic melanoma who are 
treatment naïve or previously treated with a non-ipilimumab regimen will be treated with 
ipilimumab 3 mg/kg.  Each ipilimumab cycle is 3 weeks (21 days) with treatment 
administered on day 1.  SABR to 1-3 metastatic sites will be delivered in-between the 
second and third ipilimumab doses.  All patients are expected to complete four cycles of 
ipilimumab.  Response will be assessed with contrasted CT imaging prior to ipilimumab 
therapy and after the 4th ipilimumab treatment using mWHO & irRC criteria2. Correlative 
studies will focus on identifying changes in blood and serum T-cell activation and 
expression markers when SABR is added to the ipilimumab regimen and to evaluate the 
effect of key melanoma genomic DNA mutations on outcomes like response, progression-
free survival and overall survival with this regimen. 
 
The study will consist of the following schedule:   
 
3.1.1 Screening 
- 
Assessment of the subject’s eligibility to participate as determined by the 
inclusion/exclusion criteria. 
 
3.1.2 Treatment 
-        The recommended dose of ipilimumab as a single agent is 3 mg/kg administered 
intravenously over a 90-minute period every 3 weeks for a total of four doses, as 
tolerated. 
 
-        Laboratory evaluations should be performed and the results examined before 
administration of each ipilimumab dose. 
 
-         As durable disease stabilization and/or objective tumor response can be seen 
after early progression before Week 12, it is recommended that, in the absence of 
dose-limiting toxicities (eg, serious immune-mediated adverse reactions), all four doses 
of ipilimumab be administered over the initial 12 weeks even in the setting of apparent 
clinical progression, providing the subject’s performance status remains stable. 
 
-        All subjects who are treated with ipilimumab including those who may have 
discontinued treatment for drug-related AEs and/or who have evidence of clinical 
progression during the treatment period, should obtain a 12-week tumor assessment. 
 
- 
Based on clinical experience in the ongoing and completed melanoma studies, 
the following recommendations apply for subject management in light of the Week 12 or 
later tumor assessments: 

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The appearance of new lesions in subjects with other stable or shrinking baseline 
tumor burden may be experiencing clinical benefit and should continue in follow-up 
and/or maintenance therapy before alternative anti-cancer agents are considered. 
These subjects can be seen to have continued tumor shrinkage in follow-up scans. 
As long as overall tumor burden is stable or decreasing, subjects should remain in 
follow-up and/or maintenance, even in the presence of new lesions. 
Clinical progression warranting alternative anti-cancer treatment should be 
considered only in subjects whose overall tumor burden appears to be substantially 
increased and/or in subjects whose performance status is decreased. 
 
In our study we propose to evaluate a combination of ipilimumab and SABR in 
patients with oligometastatic melanoma in a phase II trial. 
 
The study will consist of the following schedule: ipilimumab will be administered 
on week 1 at a dose of 3 mg/kg.  
 
Subsequent cycles of ipilimumab will be given every three weeks (week 4, 7, & 
10). 
 
SABR will be delivered between the second and third doses of ipilimumab 
(usually week 5-6 if no delays for ipilimumab toxicity) using the following suggested 
schedules:  18 Gy x 3 to peripheral lung, 10 Gy x 5 to central lung, 10 Gy x 5 to liver, 6 
Gy x 5 to nodal stations, 12 Gy x 3 to adrenal, 24 Gy x 1 brain < 2 cm, 18 Gy x 1 brain 
2-3 cm, and 15 Gy x 1 brain > 3 cm, 16-18 Gy x 1 to vertebral sites. 
 
Duration of therapy: Patients will receive at least 12 weeks of therapy and will be 
observed for toxicity for 90 days after the last ipilimumab infusion.  Patients will remain 
on study until evidence of progression by both mWHO and irRC or death. Patients in 
whom new lesions develp or baseline lesions grow will receive additional ipilimumab 
treatments to complete induction therapy. 
 
3.1.3 Reinduction 
 
-    Patients with stable disease for 3 months’ duration after completion of ipilimumab 
therapy (usually week 12) will be offered re-induction ipilimumab at 3 mg/kg at the treating 
physicians discretion1. 
 
-    Patients with a confirmed partial or complete response after completion of ipilimumab 
therapy (usually week 12) will be offered re-induction ipilimumab at 3 mg/kg at the treating 
physicians discretion1. 
 
 
 
3.1.4 Follow-up  
 

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− Subjects who are no longer receiving ipilimumab because of unacceptable 
toxicity (refractory Grade > 3 immune-mediated adverse reactions) or due to 
investigator judgment are managed in follow-up. Efficacy assessments for these 
subjects during follow-up are as per the standard of care. Date of death is 
recorded. 
 
− Subjects who discontinue ipilimumab treatments should be followed until death or 
the closure of the study (whichever is first). 
 
− Subjects who are no longer receiving ipilimumab because of clinical progression 
and who have switched to alternative treatment are not followed formally except 
to record the date of death. 
3.2 Primary Study Endpoints 
- Rate of progression-free survival of ipilimumab and SABR in patients with 
oligometastatic melanoma as measured from the time of study enrollment until the first 
documented date of disease progression by mWHO criteria 
3.3 Secondary Study Endpoints 
- Rate of progression-free survival of ipilimumab and SABR in patients with 
oligometastatic melanoma as measured from the time of study enrollment until the first 
documented date of disease progression by irRC criteria 
- Frequency of grade 3 and grade 4 toxicities according to CTCAE (Common Toxicity 
Criteria for Adverse Events) version 4 
 
- Frequency of objective response rate, defined as complete response + partial response, 
measured by CT using modified World Health Organization (mWHO) criteria 
 
- Frequency of objective response rate, defined using irRC 
 
-  Rate of local failure, as measured from the time of study enrollment until the first 
documented date of failure within the irradiated field  
 
-  Rate of overall survival, as measured from the time of study enrollment until the time of 
death 
 
3.4  Correlative/Exploratory Study Endpoints 
Blood and tissue samples will be collected for research purposes. Planned studies 
include exploration of certain gene mutations and serum markers as predictors of 
response to ipilimumab treatment. Proteomics expression patterns will be used to 

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determine if they are a prognostic/predictive marker for treatment response. Research 
lab studies will also evaluate if primary tumor cells and melanoma stem like cells can 
be isolated from the tissues using our in-house laboratory techniques. These cells 
may be transitioned to long-term cell lines for further research.  
Sample collection scheme  
Blood and serum samples for correlative analysis will be collected pre-treatment, 
prior to ipilimumab infusions and after completion of the treatment portion of the trial. 
The various time points for blood draw are shown in red circles with timelines. 
Tissue samples will also be collected in the event that re-biopsy or surgical resection 
is clinically indicated. 
 
 
The Week 6-7 blood draw illustrated above will take place prior to the 3rd ipilimumab 
infusion and is hereafter referred to as the “Week 7” blood draw. 
Blood and serum markers: We propose to determine the expression levels of various 
seromic proteins and cell surface markers. The marker proposed includes: 
Blood markers: 
- 
Change in Absolute Lymphocyte count (ALC) and LDH. 
T cell markers: 
- 
Change in Immune regulation after Ipilumimab infusion by measuring CD152 (CTLA-
4) and CD28 (Co-stimulatory signal) by FACS. 
- 
Change in T cell activation markers CD3, CD4, CD8, HLA-DR, ICOS, C11b, CD69, 
CD137, CD154, CXCL16 by FACS. 
- 
Change in T cell suppressor – Myeloid derived suppressor cells CD14 and HLA-DR. 

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-  Change in T helper 17 (Th17) cells and related cytokines IL-17 and IL-22 by intracellular 
cytokine staining and FACS- Change in Regulatory T cells ‘Tregs’ CD4, CD25/LAP, 
and CD127 by FACS and  IDO by mass spectrometer 
- 
Change in B-7 family costimulatory molecules: CD80(B7-1), CD86(B7-2) by FACS. 
 
Cytokine Markers: 
-   Change in cytokine milieu as assessed by the Bioplex Assays using serum samples: 
Human 8-plex assay; IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFN-γ, TNF-α and Human 
Th17 cytokine panel; IL-1β, IL-4, lL-6, IL-10, IL-17A , IL-17F, IL-21, IL-22 , IL-23 , IL-
25, IL-31, IL-33, IFN-γ, sCD40L, TNF-α, IL-17A/F by ELISA or FACS. 
 
Tissue sections: Genomic DNA from the tissue sections will be isolated along with 
matched blood samples and will be used for the following analysis; 
-  
Ratio of effector and regulatory T cells “Teff/Treg” by correlating with the levels of 
FoxP3 and IDO by IHC and RT-QPCR respectively in tissues when available. 
- 
Rate of mutation and correlation to outcomes of key melanoma genes BRAF, 
NRAS, KIT, CDKN2A, PIK3CA, PTEN, TP53, MEK, EGFR, Akt, using castPCR 
technique. 
- 
The tissue microarray (TMAs) obtained after Dermatopathologist selected/ 
reviewed area will be used for fluorescence based Immunohistochemistry and the 
expression intensity of images will be scored using an automated system. 
- 
Change in tumor antigens over time such as Melan-A, NY-ESO-1, MAGE, MART-
1, gp-100, and tyrosinase. The co-localization and subcellular localization / 
abundance will also be determined. We will also include ELISA based assay to 
estimate the antibody required for neutralizing melanoma antigens in serum. 

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4.0 SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
For entry into the study, the following criteria MUST be met. Any exceptions from the 
protocol-specific selection criteria must be approved by the Principal Investigator and/or 
the Institutional Review Board (IRB) before enrollment. 
Patients must have baseline evaluations performed prior to the first dose of study 
drug and must meet all inclusion and exclusion criteria. Results of all baseline evaluations 
will be reviewed by the Principal Investigator prior to enrollment, to verify that all inclusion 
and exclusion criteria have been satisfied. In addition, the patient must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written informed 
consent must be obtained from the patient prior to screening procedures being performed. 
The following criteria apply to all patients enrolled onto the study unless otherwise 
specified. 
4.1 Inclusion criteria 
1) 
Willing and able to give written informed consent. 
2) 
> 18 years of age 
3)  
ECOG Performance Status 0-2 (see Appendix I) 
4)  
Histologic diagnosis of melanoma with metastatic disease to a visceral organ (lung, 
liver, brain, adrenal, nodal station outside the regional lymph drainage of the primary, 
vertebral bodies)   
5)  
1-3 sites of metastatic disease able to be targeted by SABR 
6)  
Required values for initial laboratory tests:  
 

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• WBC 
≥ 2000/uL 
• ANC 
≥ 1000/uL 
• Platelets ≥ 75 x 103/uL 
• Hemoglobin 
≥ 9 g/dL (≥ 80 g/L; may be transfused) 
• Creatinine ≤ 2.0 x ULN 
• AST/ALT ≤ 2.5 x ULN for patients without liver metastasis, 
                                   ≤ 5 times for liver metastases 
• Bilirubin 
≤ 2.0 x ULN, (except patients with Gilbert’s Syndrome, who  must 
have a total bilirubin less than 3.0 mg/dL) 
• No active or chronic infection with HIV, Hepatitis B, or Hepatitis C. 
• Negative Pregnancy test at screening 
• WOCBP must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 3 days before the start of 
ipilimumab. 
 

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7.) Women of childbearing potential (WOCBP)  and male subjects of fathering potential 
must be using an adequate method of contraception to avoid pregnancy throughout the 
study and for up to 3 months  after the last dose of investigational product, in such a 
manner that the risk of pregnancy is minimized.  
WOCBP include any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as: 
• Amenorrhea ≥ 12 consecutive months without another cause, or 
• For women with irregular menstrual periods and taking hormone replacement 
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level 
≥ 35 mIU/mL. 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal 
products, skin patches, or implanted or injectable products), or mechanical products such 
as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to 
prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, 
vasectomy) should be considered to be of childbearing potential. 
Men of fathering potential must be using an adequate method of contraception to 
avoid conception throughout the study [and for up to 3 months after the last dose of 
investigational product] in such a manner that the risk of pregnancy is minimized. 
 
 
4.2 Exclusion Criteria 
 
Subjects meeting any of the following criteria must not be enrolled in the study: 
 
1) Any other malignancy from which the patient has been disease-free for less than 
3 years, with the exception of adequately treated and cured basal or squamous 
cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix. 
 
2) Autoimmune disease: Patients with a history of inflammatory bowel disease, 
including ulcerative colitis and Crohn’s Disease, are excluded from this study, as 
are patients with a history of symptomatic disease (eg, rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune vasculitis [eg, Wegener’s Granulomatosis]); motor neuropathy 
considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia 
Gravis). 
 
3) Any underlying medical or psychiatric condition, which in the opinion of the 

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investigator will make the administration of ipilimumab hazardous or obscure the 
interpretation of AEs, such as a condition associated with frequent diarrhea. 
. 
4) Any non-oncology vaccine therapy used for prevention of infectious diseases (for 
up to 1 month before or after any dose of ipilimumab). 
 
 
 
5) Concomitant therapy with any of the following: IL-2, interferon, other non-study 
immunotherapy regimens, cytotoxic chemotherapy, other investigation therapies 
 
6) Concomitant therapy with immune-suppressants or chronic use of systemic 
corticosteroids. 
 
7) Must be off prior systemic therapies for 2 weeks prior to enrollment. Patients that 
have been previously treated with systemic therapy adjuvantly or for metastatic 
disease remain eligible as long as they continue to meet all other eligibility criteria 
(oligometastatic, no visceral metastasis > 5 cm, eligible for SABR) 
 
8)  Prior radiation therapy that at the treating physician’s discretion makes SABR 
unsafe 
 
9)  No clinically significant evidence of pleural effusion or ascites 
 
10) Congestive heart failure > class II NYHA or unstable angina 
 
11) Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy 
 
12) Major surgery, open biopsy or significant traumatic injury within 2 weeks of first 
dose of study drug 
 
13) A visceral metastasis greater than 8 cm  
 
14) A visceral metastasis that due to its location cannot be safely treated with SABR 
 
15) Women of childbearing potential (WOCBP), defined above in Section 4.1, who: 
a. are unwilling or unable to use an acceptable method of contraception to 
avoid pregnancy for their entire study period and for at least 3 months  after 
cessation of study drug, or 
b. have a positive pregnancy test at baseline, or 
c. are pregnant or breastfeeding. 
 
 
16) Male subjects of reproductive potential who are unwilling or unable to use an 
acceptable method of contraception with their female partners for their entire study 

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period and for at least 3 months after cessation of study drug. 
 
17) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) 
for treatment of either a psychiatric or physical (eg, infectious) illness. 
 
18) Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to study drug, or excipients or to dimethyl sulfoxide 
(DMSO) 
 
 
Sexually active WOCBP must use an effective method of birth control during the 
course of the study, in a manner such that risk of failure is minimized. Before study 
enrollment, WOCBP must be advised of the importance of avoiding pregnancy during 
study participation and the potential risk factors for an unintentional pregnancy. All 
WOCBP MUST have a negative pregnancy test before first receiving ipilimumab. If the 
pregnancy test is positive, the patient must not receive ipilimumab and must not be 
enrolled in the study. 
 
4.3 Gender/Minority/Pediatric Inclusion for Research 
This study includes both genders and minority patients. Pediatric patients are 
excluded. 
4.4 Subject Recruitment and Screening 
Patients who are 18 year of age or older with oligometastatic melanoma are eligible 
for this study.  Patients can be recruited from PI or co-investigators’ clinical practices. 
Potential study subject should be notified to PI and study designated research 
nurse/research associate. Appropriate laboratory or diagnostic testing necessary to meet 
any noted inclusion or exclusion criteria will be ordered through the recruiting physician. 
PI of the study will screen and determine the final eligibility of the subject for enrollment.  
 
4.5 Early Withdrawal of Subjects 
4.5.1 When and How to Withdraw Subjects 
Patients will be informed that they have the right to withdraw from the study at any 
time for any reason, without prejudice to their medical care.  The investigator also has the 
right to withdraw patients from the study for any of the following reasons: 
1. Intercurrent illness 
2. Occurrence of an unacceptable adverse event 
3. Patient request 
4. Protocol violations  
5. Non-compliance 
6. Administrative reasons 
7. Failure to return for follow-up 

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8. General or specific changes in the patient’s condition unacceptable for further 
treatment in the judgment of the investigator 
 
At the time of withdrawal, all study procedures outlined for the End of Study visit 
should be completed.  The primary reason for a patient’s withdrawal from the study is to 
be recorded in the source documents. 
 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
According to FDA regulations, when a subject withdraws from the study, the data 
collected on the subject to the point of withdrawal remains part of the study database and 
may not be removed. 
 
A subject who is withdrawing needs to state whether he/she wishes to provide 
continued follow-up and further data collection subsequent to withdrawal from the 
interventional portion of the study.  
 
If a subject withdraws from the interventional portion of the study, but agrees to 
continued follow-up of associated clinical outcome information as described in the 
previous bullet, the subject will continue follow up visit and evaluation per the protocol. 
 
If a subject withdraws from the interventional portion of a study and does not consent 
to continued follow-up of associated clinical outcome information, study data related to 
the subject collected prior to the subject’s withdrawal from the study will be included in 
the study analysis.  

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5.0 STUDY DRUG  
Ipilimumab 
5.1 Dose Calculations 
Each patient will receive ipilimumab 3 mg/kg infusions over 90 minutes (not bolus 
or IV push) on weeks 1, 4, 7, & 10. 
Calculate Total Dose as follows: 
            Patient body weight in kg x (3) mg = total dose in mg 
Calculate Total Infusion Volume as follows: 
            Total dose in mg ÷ 5 mg/mL = infusion volume in mL 
Calculate Rate of Infusion as follows: 
            Infusion volume in mL ÷ 90 minutes = rate of infusion in mL/min. 
For example, a patient weighing 114 kg (250 lb) would be administered 342 mg of 
ipilimumab (114 kg x 3 mg/kg = 342 mg) with an infusion volume of 342 mL (342 
mg ÷ 1 mg/mL = 342 mL) at a rate of approximately 2.5 mL/min (342 mL ÷ 2.5 
mL/min) in 137 minutes. 
The total dose must be calculated using the most recent subject weight (obtained 
within 3 days of the dosing visit, and prior to the infusion). The maximum dose of 
ipilimumab is 400 mg. Therefore, patients ≥ 133 kg should not receive a dose > 
400 mg.  
5.2 Storage, Preparation, and Administration 
Ipilimumab injection must not be administered as an IV push or bolus injection. 
Care must be taken to assure sterility of the prepared solutions, since the drug 
product does not contain any antimicrobial preservatives or bacteriostatic agents. 
Do not shake product. 
Inspect parenteral drug products visually for particulate matter and discoloration 
prior to administration. Discard vial if solution is cloudy, there is pronounced 

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discoloration (solution may have pale yellow color), or there is foreign particulate 
matter other than translucent-to-white, amorphous particles. 
 
Preparation of Solution 
Allow the vials to stand at room temperature for approximately 5 minutes prior to 
preparation of infusion. 
Withdraw the required volume of ipilimumab and transfer into an intravenous bag. 
Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to 
prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 
mg/mL. Mix diluted solution by gentle inversion. 
Store the diluted solution for no more than 24 hours under refrigeration (2°C to 
8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). 
Discard partially used vials or empty vials of ipilimumab. 
 
Administration Instructions 
Do not mix ipilimumab with, or administer as an infusion with, other medicinal 
products. 
Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP after each dose. 
Administer diluted solution over 90 minutes through an intravenous line containing 
a sterile, non-pyrogenic, low-protein-binding in-line filter. 
See the current Investigator Brochure for additional information on allowable filter 
types.  The infusion must be completed in 90 minutes with a 10 ml normal saline 
flush at the end. 
Ipilimumab should be administered under the supervision of a physician 
experienced in the use of intravenous (IV) agents. Ipilimumab is administered as 
an IV infusion only. 
5.3 Dose Modification 
Ipilimumab Dose Skipping Rule 

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Decisions to skip an ipilimumab dose must be made on specified safety criteria. 
Treatment with ipilimumab will be skipped or discontinued if the subject 
experiences at least one adverse event, specified below, considered by the 
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treatment. The investigator should contact BMS for any adverse event that will 
prompt a skipped dose or discontinuation of ipilimumab. 
The following criteria will be used to determine dose skipping, restarting doses, or 
discontinuing ipilimumab. 
It may be necessary to skip study drug dosing for the following related 
adverse event(s): 
Any ≥ Grade 2 non-skin related adverse event (including immune-mediated 
adverse reactions), except for laboratory abnormalities 
Any ≥ Grade 3 laboratory abnormality 
Any adverse event, laboratory abnormality or intercurrent illness that, in the 
judgment of the investigator, presents a substantial clinical risk to the subject with 
continued dosing. 
 
It is necessary to skip study drug dosing for the following adverse events: 
Any ≥ Grade 3 skin related adverse event regardless of causality. 
 
Restart ipilimumab dosing if/when the adverse event(s) resolve(s) to 
≤ Grade 1 severity or returns to baseline within 2 weeks of planned dose 
administration: 
If the adverse event has resolved, restart ipilimumab dosing at the next scheduled 
time point per protocol.  
If the adverse event has not resolved in the protocol-specified dosing window (3 
weeks [±3 days]), the next scheduled dose will be skipped and dosing will be 
resumed at the subsequently scheduled dose. 
If > 1 dose is expected to be skipped, the dosing schedule modifications must be 
discussed with the principal investigator prior to implementation.  
5.4 Discontinuation of Study Therapy 
Subjects MUST be discontinued from study therapy AND withdrawn from the study 
for the following reasons: 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 

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Any clinical adverse event, laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued treatment with study 
therapy is not in the best interest of the subject 
Pregnancy 
− 
All WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g., missed or late menstrual period) at 
any time during study participation. Institutional policy and local regulations 
should determine the frequency of on study pregnancy tests for WOCBP enrolled 
in the study. 
− 
The investigator must immediately notify BMS in the event of a confirmed 
pregnancy in a patient participating in the study. 
Termination of the study by Bristol-Myers Squibb (BMS). 
Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness. 
 
Permanent Discontinuation of Ipilimumab 
Permanent Discontinuation for Related Adverse Events  
Permanently discontinue ipilimumab for any of the following: 
 Persistent moderate adverse reactions or inability to reduce corticosteroid dose 
to 7.5 mg prednisone or equivalent per day. 
 Severe or life-threatening adverse reactions, including any of the following: 
− 
Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in 
stool frequency (7 or more over baseline), stool incontinence, need for 

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intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, and 
gastrointestinal perforation 
− 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 
times the upper limit of normal or total bilirubin >3 times the upper limit of normal 
− 
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash 
complicated by full thickness dermal ulceration, or necrotic, bullous, or 
hemorrhagic manifestations 
− 
Severe motor or sensory neuropathy, Guillain-Barré syndrome, or 
myasthenia gravis 
− 
Severe immune-mediated reactions involving any organ system (eg, 
nephritis, pneumonitis, pancreatitis, non-infectious myocarditis, hypophysitis) 
− 
Immune-mediated ocular disease that is unresponsive to topical 
immunosuppressive therapy 
− 
Any adverse event, laboratory abnormality or intercurrent illness which, in 
the judgment of the investigator, presents a substantial clinical risk to the patient 
with continued dosing.  
− 
The development of progression as defined in the irRC2 as at least a 25% 
increase in tumor burden compared with nadir (at any single time point) in 2 
consecutive observations at least 4 weeks apart and/or clinical deterioration of 

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subject’s condition such that further benefit from ipilimumab dosing is unlikely or 
requires a change of therapy at the treating physician’s discretion. 
Please refer to the IB for specific treatment algorithms. 
The following neurological adverse event requires permanent 
discontinuation of ipilimumab and defines unacceptable neurotoxicity: 
− 
Any motor neurologic toxicity >/= Grade 3 regardless of causality 
− 
Any >/= Grade 3 treatment related sensory neurologic toxicity 
 
Please refer to the IB for specific treatment algorithms. 
 
Exceptions to Permanent Discontinuation 
Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor 
reaction and a potential therapeutic response. This includes inflammatory 
reactions at sites of tumor resections or in draining lymph nodes, or at sites 
suspicious for, but not diagnostic of metastasis. 
Hospitalization for ≤ Grade 2 adverse events where the primary reason for 
hospitalization is to expedite the clinical work-up. 
Patients with the following conditions where in the investigator’s opinion continuing 
study drug administration is justified: 
− 
Ocular toxicity that has responded to topical therapy. 
− 
Endocrinopathies where clinical symptoms are controlled with appropriate 
hormone replacement therapy. Note: Ipilimumab may not be restarted while the 
patient is being treated with systemic corticosteroids except for patients on stable 
doses of hormone replacement therapy such as hydrocortisone. 
 
5.5 Immune-Related Adverse Events (irAEs) Reactions and Immune-mediated 
Adverse Reactions: Definition, Monitoring, and Treatment 
Blocking CTLA-4 function may permit the emergence of auto-reactive T cells and 
resultant clinical autoimmunity. Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, 
hepatitis, and hypopituitarism were drug-related, presumptive autoimmune events, 

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now termed immune-mediated adverse reactions, noted in previous ipilimumab 
studies. 
For the purposes of this study, an immune-related adverse reaction is defined as 
an adverse reaction of unknown etiology associated with drug exposure and 
consistent with an immune phenomenon. Efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an 
event an immune-related adverse reactions. Serologic, immunologic, and 
histologic (biopsy) data should be used to support the diagnosis of an immune-
related toxicity. Suspected immune-related adverse reactions must be 
documented on an AE or SAE form. Another term for an irAE is an immune-
mediate adverse reaction, as it is termed in the Ipilimumab US Prescribing 
Information. Both terms may be used in this protocol document.  
Patients should be informed of and carefully monitored for evidence of clinically 
significant systemic immune-mediated adverse reactions (e.g., systemic lupus 
erythematosus-like diseases) or organ-specific immune-mediated adverse reaction 
(e.g., rash, colitis, uveitis, hepatitis or thyroid disease). If an immune-mediated 
adverse reaction is noted, appropriate work-up (including biopsy if possible) 
should be performed, and steroid therapy may be considered if clinically 
necessary.   
It is unknown if systemic corticosteroid therapy has an attenuating effect on 
ipilimumab activity. However, clinical anti-tumor responses have been maintained 
in patients treated with corticosteroids and discontinued from ipilimumab. If 
utilized, corticosteroid therapy should be individualized for each patient. Prior 
experience suggests that colitis manifested as ≥ Grade 3 diarrhea requires 
corticosteroid treatment. 
Specific treatment algorithms for immune-mediated adverse reactions adverse 
events are included as appendices in the IB. 
Other Guidance 
Treatment of Infusion Reactions Associated with Ipilimumab 
Since ipilimumab contains only human protein sequences, it is less likely that any 
allergic reaction will be seen in patients. However, it is possible that infusion of 
ipilimumab will induce a cytokine release syndrome that could be evidenced by 
fever, chills, rigors, rash, pruritus, hypotension, hypertension, bronchospasm, or 
other symptoms. No prophylactic pre-medication will be given unless indicated by 

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previous experience in an individual patient. Reactions should be treated based 
upon the following recommendations. 
-For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, 
flushing, rash): 
− 
Decrease the rate of infusion until recovery from symptoms, remain at 
bedside and monitor patient. 
− 
Complete the ipilimumab infusion at the initial planned rate. 
− 
Diphenhydramine 50 mg IV may be administered at the discretion of the 
treating physician and patients may receive additional doses with close 
monitoring. 
− 
Premedication with diphenhydramine may be given at the discretion of the 
investigator for subsequent doses of ipilimumab. 
-For moderate symptoms (any symptom not listed above [mild symptoms] or below 
[severe symptoms] such as generalized pruritus, flushing, rash, dyspnea, 
hypotension with systolic BP >80 mmHg):  
− 
Interrupt ipilimumab. 
− 
Administer diphenhydramine 50 mg IV. 
− 
Monitor patient closely until resolution of symptoms. 
− 
Corticosteroids may abrogate any beneficial immunologic effect, but may 
be administered at the discretion of the treating physician. 
− 
Resume ipilimumab infusion after recovery of symptoms. 
− 
At the discretion of the treating physician, ipilimumab infusion may be 
resumed at one half the initial infusion rate, then increased incrementally to the 
initial infusion rate. 
− 
If symptoms develop after resumption of the infusion, the infusion should 
be discontinued and no additional ipilimumab should be administered that day. 
− 
The next dose of ipilimumab will be administered at its next scheduled 
time and may be given with pre-medication (diphenhydramine and 

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acetaminophen) and careful monitoring, following the same treatment guidelines 
outlined above. 
− 
At the discretion of the treating physician additional oral or IV 
antihistamine may be administered prior to dosing with ipilimumab. 
-For severe symptoms (e.g., any reaction such as bronchospasm, generalized 
urticaria, systolic blood pressure <80 mm Hg, or angioedema): 
− 
Immediately discontinue infusion of ipilimumab, and disconnect infusion 
tubing from the subject. 
− 
Consider bronchodilators, epinephrine 1 mg IV or subcutaneously, and/or 
diphenhydramine 50 mg IV, with solumedrol 100 mg IV, as needed. 
− 
Patients should be monitored until the investigator is comfortable that the 
symptoms will not recur. 
− 
No further ipilimumab will be administered. 
In case of late-occurring hypersensitivity symptoms (e.g., appearance within one 
week after treatment of a localized or generalized pruritus), symptomatic treatment 
may be given (e.g., oral antihistamine, or corticosteroids). 
Treatment of Ipilimumab-Related Isolated Drug Fever 
 In the event of isolated drug fever, the investigator must use clinical judgment to 
determine if the fever is related to the ipilimumab or to an infectious etiology. If a 
patient experiences isolated drug fever, for the next dose, pre-treatment with 
acetaminophen or non-steroidal anti-inflammatory agent (investigator discretion) 
should be instituted and a repeated antipyretic dose at 6 and 12 hours after 
ipilimumab infusion, should be administered. The infusion rate will remain 
unchanged for future doses. If a patient experiences recurrent isolated drug fever 
following premedication and post dosing with an appropriate antipyretic, the 
infusion rate for subsequent dosing should be decreased to 50% of the previous 
rate. If fever recurs following infusion rate change, the investigator should assess 
the patient’s level of discomfort with the event and use clinical judgment to 
determine if the patient should receive further ipilimumab. 
Monitoring and Management of Immune-mediated Adverse Reactions 
Immune-mediated Enterocolitis 
 Patients will be monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, 

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rule out infectious etiologies and consider endoscopic evaluation for persistent or 
severe symptoms. 
 Permanently discontinue ipilimumab in patients with severe enterocolitis and 
initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or 
equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and 
continue to taper over at least one month. In clinical trials, rapid corticosteroid 
tapering resulted in recurrence or worsening symptoms of enterocolitis in some 
patients.  For steroid-refractory colitis infliximab 5 mg/kg IV or cyclosporine 2 
mg/kg IV for 7 days are recommended43. 
 Withhold ipilimumab dosing for moderate enterocolitis; administer anti-diarrheal 
treatment and, if persistent for more than one week, initiate systemic 
corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. 
Immune-mediated Hepatitis 
 Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess 
patients for signs and symptoms of hepatotoxicity before each dose of ipilimumab. 
In patients with hepatotoxicity, rule out infectious or malignant causes and 
increase frequency of liver function test monitoring until resolution. 
Permanently discontinue ipilimumab in patients with Grade 3–5 hepatotoxicity and 
administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or 
equivalent. When liver function tests show sustained improvement or return to 
baseline, initiate corticosteroid tapering and continue to taper over 1 month. 
Across the clinical development program for ipilimumab, mycophenolate treatment 
has been administered in patients who have persistent severe hepatitis despite 
high-dose corticosteroids. Withhold ipilimumab in patients with Grade 2 
hepatotoxicity. 
Immune-mediated Dermatitis 
 Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. 
Unless an alternate etiology has been identified, signs or symptoms of dermatitis 
should be considered immune-mediated.   
 Permanently discontinue ipilimumab in patients with Stevens-Johnson syndrome, 
toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, 
or necrotic, bullous, or hemorrhagic manifestations. Administer systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When 
dermatitis is controlled, corticosteroid tapering should occur over a period of at 

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least 1 month. Withhold ipilimumab dosing in patients with moderate to severe 
signs and symptoms.  
 For mild to moderate dermatitis, such as localized rash and pruritus, treat 
symptomatically. Administer topical or systemic corticosteroids if there is no 
improvement of symptoms within 1 week. 
Immune-mediated Neuropathies 
 Monitor for symptoms of motor or sensory neuropathy such as unilateral or 
bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue 
ipilimumab in patients with severe neuropathy (interfering with daily activities) such 
as Guillain-Barré-like syndromes.  Institute medical intervention as appropriate for 
management of severe neuropathy. Consider initiation of systemic corticosteroids 
at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. 
Withhold ipilimumab dosing in patients with moderate neuropathy (not interfering 
with daily activities). 
Immune-mediated Endocrinopathies 
 Monitor patients for clinical signs and symptoms of hypophysitis, adrenal 
insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may 
present with fatigue, headache, mental status changes, abdominal pain, unusual 
bowel habits, and hypotension, or nonspecific symptoms which may resemble 
other causes such as brain metastasis or underlying disease. Unless an alternate 
etiology has been identified, signs or symptoms of endocrinopathies should be 
considered immune-mediated. 
 Monitor thyroid function tests and clinical chemistries at the start of treatment, 
before each dose, and as clinically indicated based on symptoms. In a limited 
number of patients, hypophysitis was diagnosed by imaging studies through 
enlargement of the pituitary gland. Withhold ipilimumab dosing in symptomatic 
patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of 
prednisone or equivalent, and initiate appropriate hormone replacement therapy. 
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations 
 The following clinically significant immune-mediated adverse reactions were seen 
in less than 1% of ipilimumab-treated patients in previous studies:   nephritis, 
pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. 
 Across the clinical development program for ipilimumab, the following likely 
immune-mediated adverse reactions were also reported with less than 1% 
incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia 
rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic 

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vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune 
thyroiditis. 
 Permanently discontinue ipilimumab for clinically significant or severe immune-
mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone or equivalent for severe immune-mediated adverse 
reactions. 
 Administer corticosteroid eye drops to patients who develop uveitis, iritis, or 
episcleritis. Permanently discontinue ipilimumab for immune-mediated ocular 
disease that is unresponsive to local immunosuppressive therapy. 
Liver Function Test (LFT) Assessments Required Before Administration of 
Ipilimumab 
 Liver function tests (AST, ALT, T. bilirubin) will be evaluated for every subject 
prior to administration of ipilimumab. Blood samples must be collected and 
analyzed at local or central labs within 3 days prior to dosing. LFT results must be 
reviewed by the principal investigator (or designee) to meet dosing criteria 
specifications: ≤ 2.5 x ULN for AST, ALT and ≤ 1.5 x ULN for T. bilirubin unless 
liver metastases are present in which case LFT ≤ 5 x ULN for AST, ALT and T. 
bilirubin ≤ 3.0 x ULN) prior to dosing.  
 If during the course of treatment abnormal LFT values are detected, the subject 
must be managed using the hepatotoxicity algorithm section of the ipilimumab 
Investigators. 
5.6 Prohibited and Restricted Therapies During the Study 
Prohibited Therapies 
 Patients in this study may not use vaccines for the treatment of cancer or 
prevention of disease unless indicated as a component of the protocol regimen 
(including those for common medical conditions) for up to one month pre- and 
post-dosing with ipilimumab. Concomitant systemic or local anti-cancer 

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medications or treatments are prohibited in this study while receiving ipilimumab 
treatments.   
 
Patients may not use any of the following therapies during the study: 
- Any non-study anti-cancer agent (investigational or non-investigational) 
- Any other investigational agents 
- Any other CTLA-4 inhibitors or agonists 
- Anti PD-1 or anti PD-L1 antibodies 
- CD137 agonists 
- Immunosuppressive agents 
- Chronic systemic corticosteroids 
- Any non-oncology vaccine therapies used for the prevention of infectious diseases 
(for up to 30 days prior to or after any dose of study drug). 
Precautions 
Caution is advised when considering treatment with high-dose IL-2 in patients who 
have previously been administered ipilimumab, particularly in patients who 
experienced ipilimumab-related diarrhea/colitis. Colonoscopy or sigmoidoscopy 
with biopsy may be advisable prior to IL-2 administration once the patient is no 
longer receiving ipilimumab. 
5.7 Method for Assigning Subjects to Treatment Groups 
 
This is an open label phase 2 study. There is no randomization. Patients will all 
receive ipilimumab 3 mg/kg for 4 doses 3 weeks apart.  Between the second and third 
dose SABR will be used to oligometastatic sites. 
5.8 Subject Compliance Monitoring 
 
Records of study medication used, dosages administered, and intervals between 
visits will be recorded during the study. The radiation treatment record will be reviewed 
and recorded.  
 
5.9 Prior and Concomitant Therapy 
No other concomitant chemotherapy or systemic anti-melanoma therapy is allowed 
for the study.  

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6.0 STUDY PROCEDURES 
6.1 Treatment overview 
 
We will evaluate the combination of ipilimumab and SABR in patients with 
oligometastatic melanoma in this phase II trial. 
 
The study will consist of the following schedule: ipilimumab will be administered on 
week 1 at a dose of 3 mg/kg.  
 
Subsequent cycles of ipilimumab will be given every three weeks (week 4, 7, & 10). 
 
SABR will be delivered between the second and third doses of ipilimumab (week 5-6) 
using the following suggested schedules:  18 Gy x 3 to lung, 10 Gy x 5 to liver, 6 Gy x 6 
to nodal stations, 12 Gy x 3 to adrenal, 18 Gy x 1 to bone, and 24 Gy x 1, 18 Gy x 1, 15 
Gy x 1 to < 2.0 cm, 2.0-3.0 cm, and >3 cm brain metastases, respectively. 
 
 
Duration of therapy: Patients will receive at least 12 weeks of therapy and will be 
observed for toxicity for 90 days after the last ipilimumab infusion.  Patients will remain 
on study until evidence of progression or death.  Patients who meet criteria for 
reinduction therapy remain on study and re-induction is recommended if the criteria in 
Section 3.1.3 are met. 
                             
 
 
 
 
6.2  Screening 
 
Within four weeks of starting treatment, patients will have baseline hematologic 
studies including complete blood count plus differential, blood chemistry studies including 
chemistries, hepatic and renal function tests, thyroid and ACTH levels and a pregnancy 
test.  Women of childbearing potential will have a pregnancy test within 3 days of starting 
treatment. 
 
Within four weeks of starting treatment, patients will have CT of the chest, 
abdomen, and pelvis and/or PET/CT scan. 
 
6.3.  Stereotactic Ablative Radiation Therapy 
 
6.3.1 Radiation Therapy 
 
SABR has now been formally defined and described in a published guideline 
from the American College of Radiology and American Society for Therapeutic 

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Radiology and Oncology.  This protocol will respect that guideline. The term stereotactic 
for the purposes of this protocol implies the targeting, planning, and directing of therapy 
using beams of radiation along any trajectory in 3-D space toward a target of known 3-D 
coordinates. The coordinate system is defined by reliable “fiducial” markers. This differs 
from conventional radiation therapy, in which therapy is directed toward less-than-
reliable skin marks or bony landmarks that are indirectly referenced to the tumor 
(surrogates). This protocol will require treatments to be conducted with the use of a 
fixed 3-D coordinate system defined by fiducials. The coordinate system defined by the 
fiducials should be directly related to the radiation-producing device (e.g., couch and 
gantry) in a reproducible and secure fashion. Capability should exist to define the 
position of targets within the patient according to this same 3-D coordinate system.  As 
such, the patient is set up for each treatment with the intention of directing the radiation 
toward an isocenter or target according to the known 3-D coordinates as determined in 
the process of treatment planning. The nature of the fiducials themselves may include 
radiopaque markers or rods placed at known locations in a frame or fixed structure 
adjacent to the patient as well as use of the tumor itself as a fiducial (e.g., acquiring 
tomographic views of the tumor simultaneously with the treatment). Metallic “seeds” 
placed within the tumor will be allowed to constitute a fiducial so long as the methods 
are validated and a plan is in place to identify seed migration (e.g., redundant seeds 
placed). 
 
6.3.2 Fractionation, Total Dose and Radiation Therapy Planning 
 
Megavoltage external beam photon radiation therapy will be used delivered by a 
linear accelerator generating 6 MV photons or in the case of SRS to the brain a Gamma 
Knife.  A CT simulation or MR simulation will be used for radiation therapy planning.  
During simulation where appropriate a 4-D CT should be used to determine the motion of 
targeted metastases with respiration.  Efforts to limit respiratory motion such as gated 
treatment, Active Breath Control systems, or abdominal compression should be used in 
order to minimize necessary GTV to ITV expansions. 
 
6.3.3 Field Definition 
 
Gross tumor volume (GTV) is defined as the full extent of the imaging abnormality.  
ITV is defined as the GTV plus margin needed to account for physiologic motion 
as determined by the data acquired at the time of 4-D CT. 
Clinical target volume (CTV) equals ITV in SABR.  
The planning target volume (PTV1) includes the CTV plus a 0.5 cm margin for set-
up error and/or patient motion. Exact margins will be left to the discretion of the treating 
radiation oncologist. 
 
 
6.3.4 Dose Considerations 
 

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Lung SABR recommended doses:  18 Gy x 3 to peripheral lung masses, 10 Gy x 
5 to central lung masses given 2 fractions per week 
 
Liver SABR recommended doses: 10 Gy x 5 given 2-3 fractions per week 
 
Nodal station SABR recommended doses:  6 Gy x 6 given 3 fractions per week 
 
Adrenal SABR recommended doses:  12 Gy x 3,  
 
Vertebral body SABR recommended doses:  16-18 Gy x 1 respecting normal 
tissue spinal cord constraints particularly no more than 10 Gy to 10% of cord volume 
 
Brain parenchymal SABR recommended doses:  24 Gy x 1, 18 Gy x 1, 15 Gy x 1 
to < 2.0 cm, 2.0-3.0 cm, and >3 cm brain metastases, respectively dosed to the 50-70% 
isodose line if using Gamma Knife SRS. 
 
Fractionation: Treatment shall be given 2-3 days per week at the treating 
radiation oncologist’s discretion.  
 
Dose Homogeneity: The dose throughout the treatment volume will be within 
10% of the prescribed dose. Wedges, compensation, and other methods  
of generating a uniform dose distribution are encouraged.  IMRT can be used to shape 
dose around critical normal structures. 
 
Isodose Plans:  The isodose distribution for the composite plan shall be 
calculated. The prescription point and the outline or the tumor volume shall be shown. 
 
Image guidance:  Pre-treatment kilovoltage on board CT imaging will be done for 
localization, and shifts will be made as appropriate per the treating radiation oncologist. 
 
Treatment Modification: Uninterrupted treatment is planned, and SABR fractions 
should occur during the period between the 2nd and 3rd doses of ipilimumab (generally 
weeks 5-6).  SABR can be delayed at the physician’s discretion if there is concern for 
overlapping toxicities with ipilimumab, but SABR should always be delivered between 
infusion 2 and infusion 3 of ipilimumab.  The entire course of SABR should be delivered 
within the 3 week period between ipilimumab infusions, except in the case of a grade 3+ 
toxicity in the middle of the course of SABR.  If a grade 3+ toxicity occurs during SABR 
which interrupts the delivery of SABR, then the final SABR fractions will be delivered 
after the toxicity returns to grade or lower with appropriate supportive care measures. 
 
On Treatment Management:  The patient will be examined at least once a week 
during the course of radiation therapy. 
 
6.3.5 Dosimetry 
 

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3D Conformal Planning 
 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom 
designed for each case to deliver highly conformal prescription dose distributions. Non-
opposing, non-coplanar beams are preferable. Typically, ≥ 10 beams of radiation will be 
used with roughly equal weighting. Generally, more beams are used for larger lesion 
sizes. When static beams are used, a minimum of seven non-opposing beams should 
be used. For arc rotation techniques, a minimum of 340 degrees (cumulative for all 
beams) should be utilized. 
For this protocol, the isocenter is defined as the common point of gantry and couch 
rotation for the treatment unit. Field aperture size and shape should correspond nearly 
identically to the projection of the PTV along a beam’s eye view (i.e., no additional 
“margin” for dose buildup at the edges of the blocks or MLC jaws beyond the PTV). The 
only exception will be when observing the minimum field dimension of 3.5 cm when 
treating small lesions (see 
above). As such, prescription lines covering the PTV will typically be the 60-90% line 
(rather than 95-100%); however, higher isodoses (hotspots) must be manipulated to 
occur within the target and not in adjacent normal tissue. The isocenter in stereotactic 
coordinates will be determined from system fiducials (or directly from the tumor in the 
case of volumetric imaging) and translated to the treatment record.  The treatment dose 
plan will be made up of multiple static beams or arcs as described above. The plan 
should be normalized to a defined point corresponding closely to the center of mass of 
the PTV (COMPTV). Typically, this point will be the isocenter of the beam rotation; 
however, it is not a protocol requirement for this point to be the isocenter.  Regardless, 
the point identified as COMPTV must have defined stereotactic coordinates and 
receive 100% of the normalized dose.  Because the beam apertures coincide nearly 
directly with the edge of the PTV (little or no added margin), the external border of the 
PTV will be covered by a lower isodose surface than usually used in conventional 
radiotherapy planning, typically around 80% but ranging from 60-90%. The prescription 
dose will be delivered to the margin of the PTV and fulfill the requirements below.  As 
such, a “hotspot” will exist within the PTV centrally at the COMPTV with a magnitude of 
prescribed dose times the reciprocal of the chosen prescription isodose line (i.e., 60-
90%). 
 
Intensity Modulated Radiation Therapy (IMRT) 
 
IMRT is allowed in this study. The NCI Guidelines for the Use of IMRT can be 
found on the RTOG homepage, http://www.rtog.org/.  The use of IMRT in this study is at 
the discretion of the treating radiation oncologist.  IMRT should be considered only 
when target coverage, OAR dose limits, or dose spillage 
are not achievable with 3D conformal planning. In addition, IMRT plans should follow 
the same planning principles as discussed above for 3D conformal planning. The 
number of segments (control points) and the area of each segment should be optimized 
to ensure deliverability and avoid complex beam fluences. Ideally, the number of 
segments should be minimized (2-3 segments per beam should be adequate), and the 

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area of each segment should be maximized (the aperture of one segment from each 
beam should correspond to the projection of the PTV along a beam’s eye view). 
 
6.4  Interruption and discontinuation 
Treatment delays are occasionally encountered during radiation therapy due to 
logistic problems (e.g. machine break downs, patient transportation issues) or public 
holidays.  If this occurs radiation therapy shall be completed as soon as possible.  
6.5 Visit Schedule 
 
6.5.1 Pre-Study Clinical Laboratory Tests and Procedures 
Prior to study treatment each patient will have the following assessments. 
 
Within 4 weeks of starting study treatment: 
 
• Radiologic studies for baseline tumor measurements with CT or MRI scanning 
(PET/CT is optional) 
• History and physical exam 
• CBC 
• CMP 
• Thyroid function and ACTH 
• Urinalysis 
• Serum pregnancy test 
• Blood collection for correlative endpoints 
 
Within 3 days prior to first ipilimumab infusion 
• Urine or Serum pregnancy test for WOCBP 
 
6.5.2 On-Study Clinical Laboratory Tests and Procedures 
Before ipilimumab infusion: 
 
• Evaluation for adverse events 
• CBC and CMP 
• Blood collection for correlative endpoints (before 2nd and 3rd ipilimumab infusion, 
before initiation of SABR) 
 
6.5.3 Follow-up Clinical Laboratory Tests and Procedures  
 
Thirty days after 4th ipilimumab infusion (+/- 20 days) with the goal of 30 days for 
the first visit 
 
• History and physical examination 
• Evaluation for adverse events 
• CBC and CMP 

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• Blood collection for correlative endpoints:Week 12, 16, 20, 24, 35, and 50  (+/-20 
days 
 
6.6 Study Procedures By Visit and Treatment Cycle 
Note that results of all safety laboratory tests (that is, all chemistry and all hematology 
results) must be obtained and reviewed before ipilimumab administration, as applicable. 
All laboratory results must be within the established range before ipilimumab is 
administered. All induction period laboratory samples must be collected within a window 
of up to 4 weeks before administration of ipilimumab. Laboratory evaluations using a local 
laboratory must be performed and the result examined by the investigator before 
administration of each dose of ipilimumab. 
6.6.1 Study Completion or Early Discontinuation Visit 
At the time of study early withdrawal, the reason for early withdrawal and any new 
or continuing adverse events should be documented. 
6.6.2  Study Drug Discontinuation 
If study drug administration is discontinued, the reason for discontinuation will be 
recorded. 
6.7  Study Materials 
Bristol-Myers Squibb (BMS) will provide ipilimumab at no cost for this study. 
6.8  Safety Assessments 
All patients who receive at least one dose of ipilimumab will be considered evaluable for 
safety parameters. Additionally, any occurrence of non-SAE or SAE from time of 
consent forward, up to and including follow-up visits, will be reported. See Section 8: 
Adverse Event Reporting. 
Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 
(http://ctep.cancer.gov). Safety assessments will be based on medical review of 
adverse event reports and the results of vital sign measurements, physical 
examinations, and clinical laboratory tests. 
6.9 Adverse events 
The types of expected adverse events of SABR are directly related to the 
anatomical site being treated with SABR: 

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Lung SABR:   
 
Expected acute toxicities- cough, dyspnea, fatigue 
Possible sub-acute toxicities- radiation pneumonitis, rib fracture, chest wall 
pain 
Liver SABR: 
Expected acute toxicities- fatigue, diarrhea, increase in LFT’s, nausea, 
vomiting 
Possible sub-acute toxicities- chronic LFT elevation, gastric ulcer, duodenal 
ulcer, liver dysfunction 
Spine SABR: 
 
Expected acute toxicities- fatigue, nausea, vomiting, diarrhea 
 
Possible sub-acute toxicities- radiation myelitis, vertebral fracture 
Adrenal SABR: 
 
Expected acute toxicities- fatigue, nausea, vomiting, diarrhea 
Possible sub-acute toxicities- small bowel ulceration, small bowel 
obstruction 
Nodal SABR: 
Expected acute toxicities- fatigue, skin erythema, nausea, vomiting, 
diarrhea 
Possible sub-acute toxicities- skin fibrosis, small bowel ulceration, small 
bowel obstruction 
Brain stereotactic radiosurgery 
 
Expected acute toxicities- headache, fatigue 
 
Possible sub-acute toxicities- seizure, cerebral radionecrosis 
Information about all adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical examination, 
laboratory test or other means, will be collected and recorded and followed as 
appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, 
symptom, or medical condition occurring after starting the study drug even if the event is 
not considered to be related to study drug.  Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen after starting study 
drug. Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms, are considered clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of 
the patient at each visit during the study. Adverse events also may be detected when they 

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are volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 
 
1. the severity grade (mild, moderate, severe) or CTCAE v4.0 criteria (grade 1-4) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication taken; non-drug therapy given; hospitalization/prolonged hospitalization) 
5. whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include 
changes in study drug treatment including possible interruption or discontinuation, starting 
or stopping concomitant treatments, changes in the frequency or nature of assessments, 
hospitalization, or any other medically required intervention. Once an adverse event is 
detected, it should be followed until its resolution, and assessment should be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study drug, the interventions required to treat it, and the outcome. 
 
6.10 Definition of Efficacy Assessments 
 
• Rate of progression-free survival of ipilimumab and SABR in patients with 
oligometastatic melanoma as measured from the time of study enrollment until the 
first documented date of disease progression by both mWHO and irRC criteria. 
 
• Frequency of grade 3 and grade 4 toxicities according to CTCAE (Common 
Toxicity Criteria for Adverse Events) version 4 
 
• Frequency of objective response rate, defined as complete response + partial 
response, measured by mWHO criteria based on radiographic response rate will 
be determined based on re-staging CT of the chest, abdomen and pelvis 
 
• Frequency of objective response rate, defined using the immune related response 
criteria (irRC) based on radiographic response rate will be determined based on 
re-staging CT of the chest, abdomen and pelvis 
 
• Rate of local failure, as measured from the time of study enrollment until the first 
documented date of failure within the irradiated field  
 
• Rate of overall survival, as measured from the time of study enrollment until the 
time of death 
 

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Biopsy, clinical evidence and radiographic evidence are all acceptable and will be used 
to document progression. 
 
Overall survival:  will be calculated as the time from entry on the study until the time of 
death. 
 
Re-staging imaging with contrast-enhanced CT or MRI of the chest, abdomen, and pelvis 
will be performed before treatment, prior to 3rd ipilimumab infusion, 4 weeks after the final 
ipilimumab infusion (week 14 if there are no interruptions), and every 3 months for the 
first 2 years, then every 6 months during years 2-5. 
 
The first re-staging scans after the week 14 imaging will be done at the 6 months from 
enrollment time point so that the endpoint of 6 month progression-free survival can be 
assessed. 
 
All patients that have been treated on protocol with SABR and ipilimumab will have re-
staging imaging even if they were taken off of protocol for adverse events after the SABR.  
Patients who do not have SABR due to adverse events from the first 2 infusions of 
ipilimumab are not required to complete re-staging imaging. 
 
Patients who meet the criteria for Complete Response or Partial Response will have a re-
imaging 4-weeks later to confirm the response. 
 
6.10.1 Definition of Measurable/Non-Measurable and Index/Non-Index Lesions 
 
Definitions of lesions are based on mWHO criteria or immune-related response 
criteria (irRC) in this study. 
 
Definition of Measurable and Non-Measurable Lesions 
 
Measurable Lesions are lesions that can be accurately measured in two 
perpendicular diameters, with at least one diameter ≥ 20 mm and the other dimension ≥ 
10 mm (10 mm x 10 mm for spiral CT). The area will be defined as the product of the 
largest diameter with its perpendicular. Skin lesions can be considered measurable. 
 
Non-Measurable 
(evaluable) 
Lesions 
are 
all 
other 
lesions, 
including 
unidimensionally measurable disease and small lesions (lesions without at least one 
diameter ≥ 20 mm), and any of the following: 
− Lesions occurring in a previously irradiated area (unless they are documented as 
new lesions since the completion of radiation therapy), bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitis 
cutis/pulmonis, abdominal masses that are not pathologically/cytologically 
confirmed and followed by imaging techniques and cystic lesions. 
− All measurable and non-measurable lesions should be measured at screening and 
at the defined tumor assessment timepoints (see Section 5, Table 2). Extra 

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assessments may be performed, as clinically indicated, if there is a suspicion of 
progression. 
 
Definition of Index/Non-Index Lesions 
All measurable lesions, up to a maximum of five lesions per organ and ten lesions in 
total, should be identified as index lesions to be measured and recorded on the medical 
record at Screening. The index lesions should be representative of all involved organs. In 
addition, index lesions should be selected based on their size (lesions with the longest 
diameters), their suitability for accurate repeat assessment by imaging techniques, and 
how representative they are of the patient’s tumor burden. At Screening, a sum of the 
products of diameters (SPD) for all index lesions will be calculated and considered the 
baseline sum of the products of diameters. Response criteria to be followed are listed 
below. The baseline sum will be used as the reference point to determine the objective 
tumor response of the index lesions at tumor assessment (TA). 
Measurable lesions, other than index lesions, and all sites of non-measurable disease, 
will be identified as non-index lesions. Non-index lesions will be recorded on the medical 
record and should be evaluated at the same assessment time points as the index lesions. 
In subsequent assessments, non-index lesions will be recorded as “stable or decreased 
disease,” “absent,” or “progression.” 
 
6.10.2 Modified World Health Organization criteria for response 
 
The mWHO criteria were developed as a hybrid tumor response classification 
system using elements of both the WHO and RECIST criteria in an attempt to more 
accurately measure tumor lesions and estimate tumor responses. 
 
Definition of Index Lesion Response Using mWHO Criteria 
 
Complete Response: Complete disappearance of all index lesions. 
 
Partial Response: Decrease, relative to baseline, of 50% or greater in the sum of the 
products of the two largest perpendicular diameters of all index lesions. 
 
Stable Disease: Does not meet criteria for complete or partial response, in the absence 
of progressive disease. Subject with PR or CR that is not confirmed after at least 4 weeks 
are scored as SD unless they have new primary lesions. 
 
Progressive Disease: At least 25% increase in the sum of the products of all index 
lesions (taking as reference the smallest sum recorded at or following baseline) and/or 
the appearance of any new lesion(s). 
 
Definition of Non-Index Lesion Response Using mWHO 
 
Complete Response: Complete disappearance of all non-index lesions. 
 

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Stable Disease: A decrease or tumor stabilization of one or more non-index lesions. 
Subject with PR or CR that is not confirmed after at least 4 weeks are scored as SD 
unless they have new primary lesions. 
 
Progressive Disease: Progression of non-index lesion(s) (e.g., an increase in pleural 
effusions, or other fluid collections defined as an approximate doubling of the volume 
which was present at baseline or nadir, unless there is radiographic evidence of a benign 
cause for the fluid collection or the effusion is cytologically negative for malignant cells). 
 
Determination of Overall Response Using mWHO 
Overall Response (OR) is determined as the combination of assessments of index and 
non-index lesions using the following criteria: 
Index 
Lesion 
Assessment 
Non-Index Lesion 
Assessment 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
CR or SD 
No 
PR 
SD 
CR or SD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Best OR is the best confirmed response designation over the study as a whole, 
recorded between the date of first dose until the last tumor assessment for the individual 
patient in the study. The assessment of response at 12 weeks has particular emphasis 
due to the mechanism of action of ipilimumab inducing immune responses as basis for 
clinical responses. For the assessment of best OR, all available assessments per patient 
are considered. CR or PR determinations included in the best OR assessment must be 
confirmed by a second (confirmatory) evaluation meeting the criteria for response and 
performed no less than 4 weeks after the criteria for response are first met.  
 
Patients will be assessed for efficacy by CT of chest, abdomen, and pelvis at 
baseline and every 6 weeks while on study and every 3 months thereafter, regardless of 
the location of known metastases. Similar methods of tumor assessment and similar 
techniques must be used to characterize each identified and reported lesion at screening 
and during subsequent tumor assessments. Imaging-based evaluation is preferred to 
clinical examination. 
 
MRI of the brain will be used if brain metastases are being treated on study or if 
neurologic symptoms suggest concern for new or progressive disease within the brain. 
. 
If progressive disease is assessed based only on a new lesion(s) found on bone 
scans, additional imaging studies of the lesion(s) should be performed to confirm the 
malignant nature of the new findings on the bone scan. Increased intensity of uptake in 
previously abnormal areas on bone scans is not considered progressive disease, unless 

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the lesions seen on the correlative imaging studies performed of this area meet the criteria 
for progression. New areas of abnormal uptake on a bone scan represent progressive 
disease.  
 
 
 
6.10.3 Definition of Tumor Response Using irRC 
 
The sum of the products of diameters at tumor assessment using the irRC for 
progressive disease incorporates the contribution of new measurable lesions. Each net 
Percentage Change in Tumor Burden per assessment using irRC criteria accounts for the 
size and growth kinetics of both old and new lesions as they appear. 
 
Definition of Index Lesions Response Using irRC 
 
irComplete Response (irCR): Complete disappearance of all index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 
irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum 
of the products of the two largest perpendicular diameters of all index and all new 
measurable lesions (ie., Percentage Change in Total Tumor Burden). Note: the 
appearance of new measurable lesions is factored into the overall tumor burden, but does 
not automatically qualify as progressive disease until the SPD increases by ≥25% when 
compared to SPD at nadir. 
 
irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of 
progressive disease. 
 
irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor 
Burden (i.e., taking sum of the products of all index lesions and any new lesions) when 
compared to SPD at nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
 
irComplete Response (irCR): Complete disappearance of all non-index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 
irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not 
considered in the definition of PR, these terms do not apply. 
 
irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does 
not constitute progressive disease unless/until the Percentage Change in Tumor Burden 
increases by 25% (i.e., the SPD at nadir of the index lesions increases by the required 
amount). 
 
Impact of New Lesions on irRC 

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New lesions in and by themselves do not qualify as progressive disease. However their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 
criteria for tumor response. Therefore, new non-measurable lesions will not discontinue 
any subject from the study. 
 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: The sum of the products of 
the two largest perpendicular diameters of all index lesions is measured and captured as 
the SPD baseline. At each subsequent tumor assessment, the sum of the products of the 
two largest perpendicular diameters of all index lesions and of new measurable lesions 
are added together to provide the Immune Response Sum of Product Diameters (irSPD). 
 
Immune-Related Complete Response (irCR): Complete disappearance of all tumor 
lesions (index and nonindex together with no new measurable/unmeasurable lesions) for 
at least 4 weeks from the date of documentation of complete response.  
 
Immune-Related Partial Response (irPR): A decrease, relative to baseline of the irSPD 
compared to the previous SPD baseline, of 50% or greater is considered an immune 
Partial Response (irPR).  
 
Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria 
for immune complete response or immune partial response, in the absence of progressive 
disease.  
 
Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to 
confirm PD by serial imaging. Any of the following will constitute progressive disease: 
− At least 25% increase in the sum of the products of all index lesions over baseline 
SPD calculated for the index lesions. 
− At least a 25% increase in the sum of the products of all index lesions and new 
measurable lesions (irSPD) over the baseline SPD calculated for the index lesions. 
 
Table 11: 
Immune-Related Response Criteria Definitions 
Index 
Lesion 
Definition 
Non-
Index 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
Percent 
change 
in 
tumor burden 
(including 
measurable 
new 
lesions 
when 
present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
> -50% 
irPR 
<-50% 
to 
<+25% 
irSD 

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Index 
Lesion 
Definition 
Non-
Index 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
Percent 
change 
in 
tumor burden 
(including 
measurable 
new 
lesions 
when 
present) 
Overall 
irRC 
Response 
>+25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
<-50% 
to 
<+25% 
irSD 
>+25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
>+25% 
irPD 
 
Immune-Related Best Overall Response Using irRC (irBOR)  
 
irBOR is the best confirmed irRC overall response over the study as a whole, 
recorded between the date of first dose until the last tumor assessment before 
subsequent therapy (except for local palliative radiotherapy for painful bone lesions) for 
the individual subject in the study. For the assessment of irBOR, all available 
assessments per subject are considered. 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a 
second (confirmatory) evaluation meeting the criteria for response and performed no less 
than 4 weeks after the criteria for response are first met. 
 
Response Endpoints 
 
Ipilimumab is expected to trigger immune-mediated responses, which require 
activation of the immune system prior to the observation of clinical responses. Such 
immune activation may take weeks to months to be evident. Some patients may have 
objective volume increase of tumor lesions or other disease parameters (based on study 
indication, ie, hematologic malignancies) within 12 weeks following the start of ipilimumab 
dosing. Such patients may not have had sufficient time to develop the required immune 
activation or, in some patients, tumor volume or other disease parameter increases may 
represent infiltration of lymphocytes into the original tumor or blood. In conventional 
studies, such tumor volume or relevant laboratory parameter increases during the first 12 
weeks of the study would constitute PD and lead to discontinuation of imaging to detect 
response, thus disregarding the potential for subsequent immune-mediated clinical 
response.  
Therefore, patients with tumor volume increase detected or lack of laboratory 
parameter response documentation prior to week 12 but without rapid clinical 
deterioration should continue to be treated with ipilimumab and clinically observed with a 
stringent imaging schedule to allow detection of a subsequent tumor response. This will 
improve the overall assessment of the clinical activity or ipilimumab and more likely 

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capture its true potential to induce clinical responses. Tumor assessments will be made 
using modified WHO criteria. 
 
7.0 STATISTICAL PLAN 
7.1 Sample Size Determination 
Overall, this study will require 32 evaluable patients. We estimate that we will 
accrue 1-2 patients per month; therefore, thus, the minimum study duration will be 16 
months (2 accruals per month) and the maximum is 32 months (1 accrual per month for 
32 patients).  
Current literature and experience with ipilimumab in metastatic melanoma in this 
patient population shows that we can expect ipilimumab + SABR will not be considered 
promising in this patient population if at most 15% of patients are progression-free and 
alive at 6 months, because that is the expected 6 month PFS for ipilimumab alone1. For 
this agent to be considered promising in this patient population, we would expect an 
improvement in the 6-month PFS rate to at least 35% with this regimen in this patient 
population. Constraining the Type I and II error rates to 10% each, the study design will 
require 32 evaluable patients to test these hypotheses regarding the 6-month PFS rate 
with ipilimumab when given in combination with the stereotactic ablative radiation therapy 
in this patient population. If we see at least 8 patients who have are alive and progression-
free at 6 months after initiation of treatment out of the 32 evaluable patients, we will 
consider this sufficient evidence that this regimen has promising activity in this patient 
population. Otherwise, if 7 or fewer patients have are alive and progression-free at 6 
months, we will consider this regimen to not be sufficiently active in this population of 
oligometastatic melanoma patients.   
 
7.2 Statistical methods 
 
All evaluable patients will be included in calculating the 6-month PFS rate for the 
study along with corresponding 95% binomial confidence intervals (assuming the number 
of patients who are progression-free and alive at 6 months is binomially distributed).  The 
numerator will be the number of patients at 6-months from enrollment who have either a 
complete response, a partial response, or stable disease (i.e. have not progressed) on 
re-staging imaging and who are alive.  The denominator will be the number of patients on 
trial who received ipilimumab and SABR. 
 
In addition, several secondary endpoints will be evaluated in these subjects: 
• Toxicity and Tolerability. Frequency and severity of adverse events and 
tolerability of the regimen in each of the patient groups will be collected and 
summarized by descriptive statistics.  As per NCI CTCAE v4.0, the term toxicity is 
defined as adverse events that are classified as either possibly, probably, or 
definitely related to study treatment. The maximum grade for each type of toxicity 
will be recorded for each patient, and frequency tables will be reviewed to 
determine toxicity patterns. In addition, we will review all adverse event data that 

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is graded as 3, 4, or 5 and classified as either “unrelated” or “unlikely to be related” 
to study treatment in the event of an actual relationship developing. The incidence 
of severe (grade 3+) adverse events or toxicities will be described. We will also 
assess tolerability of the regimens through assessing the number of patients who 
required dose modifications and/or dose delays. In addition, we will also capture 
the proportion of patients who go off treatment due to adverse reactions or even 
those who refuse further treatment for lesser toxicities that inhibit their willingness 
to continue participation on the trial. These tolerability measures will be assessed 
within each of the treatment arms and we will explore differences in these 
measures between the arms. All patients who have received at least one dose of 
any of the therapeutic agents in a treatment arm will be evaluable for toxicity and 
tolerability. 
• Overall response. All evaluable patients (i.e. eligible patients who have received 
at least two doses of ipilimumab and SABR) will be assessed in terms of their best 
response to therapy by both mWHO and irRC. Those who achieve a partial 
response (PR) or complete response (CR) will be considered responses and the 
overall response rate will be calculated as the number of PRs and CRs divided by 
the total number of evaluable patients. Best overall response rate will be reported 
taking into account all post-treatment imaging. 
• Overall survival and progression-free survival as continuous time-to-event 
outcomes. All evaluable patients will be used for this analysis.  Kaplan-Meier 
curves will be used to estimate overall and progression-free survival.  Each of 
these variables is measured from the date of study registration to the date of event 
(i.e., death or disease progression).  In the case of the overall survival endpoint 
the date of last follow-up is to be used if no event has occurred at their last 
evaluation.  In the case of the progression-free survival endpoint the date of last 
tumor assessment is to be used if no event has occurred at their last evaluation. 
• Correlative markers: Several correlative markers will be explored in this trial in 
relation to clinical outcomes of interest, and in particular in relation to the primary 
endpoint of 6-month PFS rate. Given the limited overall sample size as well as the 
relatively limited expected proportion of patients who are progression-free and 
alive at 6 months, these analyses will be largely exploratory and hypothesis-
generating in nature. Markers will be summarized univariately in a quantitative 
manner and also summarized by clinical outcome group (e.g. prog-free and alive 
at 6 months vs. not). Graphical analyses will be largely used to assess potential 
patterns and relationships; e.g. side-by-side boxplots to assess differences in 
continuous marker levels between those with vs. without the clinical improvement. 
We may also explore changes in these markers in relation to baseline, with clinical 
outcome incorporated through use of different plotting characters. Overall, 
hypothesis testing will largely be avoided given the sample size limitations but we 
will still obtain important preliminary data that can inform future studies and help 
better understand the mechanisms of this treatment regimen in this patient 
population.  
 
 

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Statistical and Data Analysis: 
Assistance in statistical analysis will be provided by the Center for Biostatistics for 
The Ohio State University Comprehensive Cancer Center.  
7.3 Subject Population(s) for Analysis 
All subjects enrolled in the study received at least two doses of ipilimumab and 
SABR will be used for analysis of the primary endpoint. 
 
7.4 Interim Analysis- Safety 
 
 
Prior use of 3mg/kg ipilimumab alone has resulted in a 10-15% grade 3+ 
autoimmune related toxicity rate.  If the addition of SABR to ipilimumab doubles the risk 
of grade 3+ autoimmune related toxicity, that would be unacceptable.  Therefore, our 
null hypothesis will be that 70% or more of the patients will be severe immune related 
toxicity-free.  We will conduct an interim analysis after the treatment of 18 patients to 
assess the null hypothesis versus the alternative hypothesis of 90% or more of the 
patients will be severe immune related toxicity-free.  If at the interim analysis 14 or more 
patients are severe immune related toxicity-free then we will continue to enroll to the 
planned enrollment of 32 patients.  If 5 or more patients have severe immune related 
toxicities we will consider this combination too toxic for further investigation. 
 
8.0 STUDY CALENDAR 
 
 
See appendix II. 
9.0 INVESTIGATIONAL PRODUCT: IPILIMUMAB 
The investigational product is defined as a pharmaceutical form of an active 
ingredient being tested as a reference in the study, whether blinded or unblinded. In this 
study, the investigational product is ipilimumab and is unblinded. 
Other medications used in the study as support or escape medication for 
preventative, diagnostic, or therapeutic reasons, as components of the standard of care 
for a given diagnosis, are considered noninvestigational products. In this protocol, 
noninvestigational product(s) is/are: SABR. 
The investigational combination is the use of ipilimumab with SABR.  Individually 
ipilimumab is approved for use in metastatic melanoma and SABR is a commonly used 
palliative treatment for oligometastatic or oligoprogressive cancers of many types. 
9.1 Identification 
Ipilimumab is available in concentrations of 5 mg/mL (50 mg/10 mL and 
200 mg/40 mL). The sterile solution in the vial is clear and colorless. Ipilimumab is 
administered via intravenous infusion only. 

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9.2  Packaging and Labeling 
BMS will provide ipilimumab at no cost for this study. Ipilimumab will be provided in 
open-label containers. The labels will contain the protocol prefix, batch number, content, 
storage conditions, and dispensing instructions along with the Investigational New Drug 
(IND) caution statement. 
9.3  Storage, Handling, and Dispensing 
9.3.1 Storage 
Ipilimumab must be stored in a secure area according to local regulations. The 
investigator must ensure that it is stored at a temperature ≥ 2°C and ≤ 8°C. 
9.3.2 Handling and Disposal 
As with all injectable drugs, care should be taken when handling and preparing 
ipilimumab. Whenever possible, ipilimumab should be prepared in a laminar flow hood or 
safety cabinet using standard precautions for the safe handling of intravenous agents 
applying aseptic technique. Latex gloves are required. If ipilimumab concentrate or 
solution comes in contact with skin or mucosa, immediately and thoroughly wash with 
soap and water. After final drug reconciliation, unused ipilimumab solution should be 
disposed at the site following procedures for the disposal of anticancer drugs. 
9.3.3 Dispensing 
It is the responsibility of the investigator to ensure that ipilimumab is only dispensed 
to study subjects. The ipilimumab must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
9.4 Drug Ordering and Accountability 
9.4.1 Initial Orders 
Following submission and approval of the required regulatory documents, a supply of 
ipilimumab may be ordered from BMS. Investigators must complete a Drug Request Form 
and email it to: distribution.allentown@thermofisher.com. 
If for any reason the e-mail drug request form is not successfully transmitted, contact 
Emily Kahora at Fisher Clinical Services: 
Phone: +1 484.538.2121 
Fax: +1 610.871.9382 
Email: emily.kahora@thermofisher.com or www.fisherclinicalservices.com. 

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It is recommended you send a test message to the Fisher Clinical Service e-mail 
address upon receipt of the Drug Request Form. Please include in the subject line: “BMS 
IST Drug Order -- Test.” This will ensure your site is recognized by Fisher and your future 
orders will be received without incident. 
Ipilimumab vials (40 mL) are shipped in quantities of five. The initial order should 
be limited to 25 vials (5 cartons of 5 vials each). Allow 5 business days for shipment of 
drug from BMS receipt of the Drug Request Form. Drug is protocol specific, but not patient 
specific. All product will be shipped via Federal Express in a temperature-controlled 
container. Shipments will be made from Fisher Clinical Services on Monday through 
Thursday for delivery onsite Tuesday through Friday. There will be no weekend or holiday 
delivery of drugs. 
It is possible that sites may have more than one ipilimumab clinical study ongoing at 
the same time. It is imperative that only product designated for this protocol number 
be used for this study. To help segregate product for this study from other 
investigational or marketed product, stickers bearing the BMS protocol number will be 
provided and should be affixed to the front of the outer carton just above the company 
name so as not to obscure any marking. 
9.4.2 Re-Supply 
Reorders 
should 
be 
emailed 
directly 
to 
Fisher 
Clinical 
Services 
(distribution.allentown@thermofisher.com) for shipment within 5 business days. When 
assessing need for resupply, institutions should keep in mind the number of vials used 
per treatment dose, and that shipments may take 5 business days from BMS receipt of 
request. Drug is not patient specific. Be sure to check with your pharmacy regarding 
existing investigational stock to assure optimal use of drug on hand. 
9.5 Ipilimumab Accountability 
It is the responsibility of the investigator to ensure that a current record of ipilimumab 
disposition is maintained at each study site where ipilimumab is inventoried and disposed. 
Records or logs must comply with applicable regulations and guidelines, and should 
include: 
• Amount received and placed in storage area. 
• Amount currently in storage area. 
• Label ID number or batch number and use date or expiry date. 
• Dates and initials of person responsible for each ipilimumab inventory 
entry/movement. 

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• Amount dispensed to and returned by each subject, including unique subject 
identifiers. 
• Amount transferred to another area/site for dispensing or storage. 
• Non-study disposition (e.g., lost, wasted, broken). 
• Amount destroyed at study site. 
9.6 Ipilimumab Destruction 
If ipilimumab is to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal and that procedures for proper disposal 
have been established according to applicable regulations, guidelines, and institutional 
procedures. Appropriate records of the disposal must be maintained. 
10 ADVERSE EVENT REPORTING 
10.1 Collection of Safety Information 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational combination, whether or not 
considered related to the investigational combination. 
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, 
subjects should not be questioned regarding the specific occurrence of one or more AEs.) 
10.1.1 Serious Adverse Events 
A serious AE (SAE) is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)      
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect  

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• is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are not 
limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)   
• Suspected transmission of an infectious agent (eg, any organism, virus or infectious 
particle, pathogenic or non-pathogenic) via the study drug is an SAE. 
Although pregnancy, overdose, cancer are not always serious by regulatory definition, 
these events must be handled as SAEs.  (See Section 8.4 for reporting pregnancies.) 
 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department lasting less than 24 hours 
that does not result in admission (unless considered an “important medical event” or 
a life-threatening event) 
• elective surgery planned before signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these cases. 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative). 
 
10.1.2 Nonserious Adverse Events 
A nonserious adverse event is an AE not classified as serious. 
10.2 Assignment of Adverse Event Intensity and Relationship to Investigational 
Product 
The following categories and definitions of causal relationship to investigational product 
as determined by a physician should be used: 
• Related: There is a reasonable causal relationship to investigational product 
administration and the adverse event. 
• Not Related: There is not a reasonable causal relationship to investigational product 
administration and the adverse event. 

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The expression “reasonable causal relationship” is meant to convey in general that there 
are facts (eg, evidence such as de-challenge/re-challenge) or other arguments to suggest 
a positive causal relationship. 
10.3 Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, 
subjects should not be questioned regarding the specific occurrence of one or more AEs.) 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather 
than its individual symptoms. The following information should be captured for all AEs: 
onset, duration, intensity, seriousness, relationship to investigational product, action 
taken, and treatment required. If treatment for the AE was administered, it should be 
recorded in the medical record. 
The investigator shall supply the sponsor and Ethics Committee with any additional 
requested information, notably for reported deaths of subjects. 
10.3.1 Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol-specified procedures. All 
SAEs must be collected that occur within 70 days of discontinuation of dosing of the 
investigational product. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). The investigator should notify 
BMS of any SAE occurring after this time period that is believed to be related to the 
investigational product or protocol-specified procedure. 
All SAEs whether related or unrelated to the ipilimumab, must be immediately reported 
to BMS (by the investigator or designee) within 24 hours of becoming aware of the event. 
If only limited information is initially available, follow-up reports are required. The original 
SAE form must be kept on file at the study site. 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
AND reported to the Ohio State University IRB via the electronic Buck-IRB 
website reporting system: http://orrp.osu.edu/irb/buck-irb/ per OSU IRB 
policy. 

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Ohio State University  Cancer IRB 
Office of Responsible Research Practices 
1960 Kenny Road 
Columbus, Ohio 43210 
Phone: 614 292-5958 
Serious adverse events, whether related or unrelated to investigational product, 
must be recorded on the SAE page and reported expeditiously to BMS (or designee) to 
comply with regulatory requirements. An SAE report should be completed for any event 
where doubt exists regarding its status of seriousness.  
All SAEs must be immediately reported by confirmed facsimile transmission (fax) 
and mailing of the completed SAE page. In some instances where a facsimile machine is 
not available, overnight express mail may be used. If only limited information is initially 
available, follow-up reports are required. (Note: Follow-up SAE reports should include the 
same investigator term(s) initially reported.) In selected circumstances, the protocol may 
specify conditions that require additional telephone reporting.  
If the investigator believes that an SAE is not related to the investigational product, 
but is potentially related to the conditions of the study (such as withdrawal of previous 
therapy, or a complication of a study procedure), the relationship should be specified in 
the narrative section of the SAE page. 
If an ongoing SAE changes in its intensity or relationship to the investigational product, 
a follow-up SAE report should be sent immediately to the sponsor. As follow-up 
information becomes available it should be sent immediately using the same procedure 
used for transmitting the initial SAE report. All SAEs should be followed to resolution or 
stabilization. 
10.3.2 Handling of Expedited Safety Reports 
In accordance with local regulations, BMS will notify investigators of all SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously 
described in the Investigator Brochure). In the European Union (EU), an event meeting 
these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
investigator notification of these events will be in the form of an expedited safety report 
(ESR).  
Other important findings which may be reported by the sponsor as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of 

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efficacy that poses significant hazard to study subjects, clinically significant safety finding 
from a nonclinical (eg, animal) study, important safety recommendations from a study 
data monitoring committee, or sponsor decision to end or temporarily halt a clinical study 
for safety reasons. 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the Investigator Brochure. Where required by local regulations or when there is a 
central IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. 
The investigator and IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information.  
In addition, suspected serious adverse reactions (whether expected or unexpected) 
shall be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate reports). 
10.3.3 Nonserious Adverse Events 
The collection of nonserious AE information should begin at initiation of investigational 
product. Nonserious AE information should also be collected from the start of a placebo 
lead-in period or other observational period intended to establish a baseline status for the 
subjects.  
If an ongoing nonserious AE worsens in its intensity, or if its relationship to the 
investigational product changes, a new nonserious AE entry for the event should be 
completed. Nonserious AEs should be followed to resolution or stabilization, or reported 
as SAEs if they become serious. Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of investigational product, or those that are present at the 
end of study participation. Subjects with nonserious AEs at study completion should 
receive post-treatment follow-up as appropriate. 
All identified nonserious AEs must be recorded and described in the medical record. 
10.3.4 Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the 
course of the study, in a manner such that risk of failure is minimized. Before enrolling 
WOCBP in this clinical study, the investigator must review the guideline about study 
participation for WOCBP which can be found in the GCP Manual for Investigators. The 
topics include the following: 
• General Information 

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• Informed Consent Form 
• Pregnancy Prevention Information Sheet 
• Drug Interactions with Hormonal Contraceptives 
• Contraceptives in Current Use 
• Guidelines for the Follow-up of a Reported Pregnancy. 
Before study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this discussion. 
All WOCBP MUST have a negative pregnancy test within 3 days before receiving 
ipilimumab. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent 
units of HCG. If the pregnancy test is positive, the subject must not receive ipilimumab 
and must not be enrolled in the study. 
In addition, all WOCBP should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
If, following initiation of the investigational product, it is subsequently discovered 
that a study subject is pregnant or may have been pregnant at the time of investigational 
product exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety). The investigator must immediately notify 
BMS of this event and record the pregnancy on the Pregnancy Surveillance Form (not an 
SAE form). Initial information on a pregnancy must be reported immediately to BMS, and 
the outcome information provided once the outcome is known. Completed Pregnancy 
Surveillance Forms must be forwarded to BMS according to SAE reporting procedures. 
Any pregnancy that occurs in a female partner of a male study participant should 
be reported to the sponsor. Information on this pregnancy will be collected on the 
Pregnancy Surveillance Form. 
Protocol-required procedures for study discontinuation and follow-up must be 
performed on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other 
appropriate pregnancy follow-up procedures should be considered if indicated. In 
addition, the investigator must report to BMS, and follow-up on information regarding the 
course of the pregnancy, including perinatal and neonatal outcome. Infants should be 
followed for a minimum of 8 weeks. 

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10.3.5 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded in the medical 
record. 
 
 
All SAEs must be sent to BMS as stated above (Section 10.3.1, paragraph 1). 
 
 
 
 
 
10.4 Data and Safety Monitoring Committee 
 
 
 
The data and safety monitoring plan will involve the continuous evaluation of 
safety, data quality and data timeliness. Investigators will conduct continuous review 
of data and patient safety at their regular Disease Group meetings (at least monthly) 
and the discussion will be documented in the minutes. The PI of the trial will review 
toxicities and responses of the trial where applicable at these disease center 
meetings and determine if the risk/benefit ratio of the trial changes. Frequency and 
severity of adverse events will be reviewed by the PI and compared to what is 
known about the agent/device from other sources; including published literature, 
scientific meetings and discussions with BMS, to determine if the trial should be 
terminated before completion. Serious adverse events and responses will also be 
reviewed by the OSUCCC Data and Safety Monitoring Committee (DSMC). The PI 
will also submit a progress report (biannually for Phase II and quarterly for Phase I) 
that will be reviewed by the committee per the DSMC plan. All reportable Serious 
Adverse Events (SAE) will also be reported to the IRB of record as per the policies 
of the IRB. 
11.0 DATA HANDLING AND RECORD KEEPING 
11.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 

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• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 
 
11.2 Informed Consent 
 
Investigators must ensure that subjects, or, in those situations where consent 
cannot be given by subjects, their legally acceptable representative, are clearly and fully 
informed about the purpose, potential risks, and other critical issues regarding clinical 
studies in which they volunteer to participate. Freely given written informed consent must 
be obtained from every subject or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative, prior to clinical study participation, 
including informed consent for any screening procedures conducted to establish subject 
eligibility for the study. 
 
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society. 
 
11.3 Source Documents 
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents   Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments involved in the clinical trial. 
11.4 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All sections of each CRF must 
be completed and each page identified with the patient’s assigned registration number 
and initials.   All missing data must be explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the 
item is not applicable to the individual case, write “N/A”.  All entries should be printed 
legibly in ink.  Only the Principal Investigator or authorised Co-investigator can sign the 
CRFs for assurance of exactitude and completeness of each page. 
If any entry error has been made, to correct such an error, draw a single straight 
line through the incorrect entry and enter the correct data above it.  All such changes 
must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 

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clarification of illegible or uncertain entries, print the clarification above the item, then 
initial and date it.  
11.5 Monitoring and Audit 
 
This study will be monitored by Ohio State University Comprehensive Cancer 
Center per their institutional guidelines.  
 
In addition, an agent of BMS, the FDA or another national regulatory authority 
may audit the study centre in depth for study quality assurance. This audit may include 
review of all source documents, treatment records, original clinic case notes, etc. 
Patient confidentiality will be maintained at all times and consent for this review will 
be obtained before entry of the patient into the study by the patient’s signature on the 
consent form. 
11.6 Records Retention 
The investigator must arrange for the retention of the patient identification codes 
(i.e. hospital/unit code, trial identification code and trial number) for as long as the BMS 
requests after completion or discontinuation of the clinical trial. Other source 
documents, such as patient files and clinic case notes, must be retained for the 
maximum period of time permitted by the hospital, institution or private practice, and if 
this is less than BMS requires after the completion or discontinuation of the clinical trial, 
then BMS must be notified to arrange record retention. 
The investigator will also be required to retain his/her copies of the CRFs and other 
study documentation for as long as BMS requests this.  If the principal investigator 
relocates or retires, or otherwise withdraws his/her responsibility for maintaining the 
study documentation, BMS must be notified (in writing) so that adequate provision can 
be made with regard to the patient identification codes, their copies of the study 
documentation (e.g. copies of the CRFs) and other source data (if available). This 
responsibility may be transferred to Glaxo SmithKline who will make arrangements to 
store the data.. 
12.0 ETHICAL AND REGULATORY CONSIDERATIONS 
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH) and in accordance with 
the ethical principles underlying European Union Directive 2001/20/EC and the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to 
initiation of the study. 

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All potential serious breaches must be reported to BMS immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study 
or the protocol, which is likely to affect, to a significant degree, the safety or physical or 
mental integrity of the subjects of the study or the scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective task(s). This study will not use the 
services of study personnel where sanctions have been invoked or where there has been 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
Systems with procedures that ensure the quality of every aspect of the study will be 
implemented. 
12.1 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
Before 
study 
initiation, 
the 
investigator 
must 
have 
written 
and 
dated 
approval/favorable opinion from the IRB/IEC for the protocol, consent form, subject 
recruitment materials/process (eg, advertisements), and any other written information to 
be provided to subjects. The investigator should also provide the IRB/IEC with a copy of 
the Investigator Brochure or product labeling, information to be provided to subjects and 
any updates.  
The investigator should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures 
In addition, the investigator must provide the following documentation: 
• The IRB annual re-approval of the protocol. 
• The IRB approval of any revisions to the informed consent document or 
amendments to the protocol. 
 
Details of the IRB’s composition including names of their members, their 
qualifications and what function they perform on the committee (e.g.: chairman, 
specialist, lay-member) will be made available to conform to regulations governing the 
conduct of clinical trials. If available, the constitution of the IRB must also be supplied. 
13.0 TISSUE/SPECIMEN COLLECTION AND CORRELATIVE ANALYSIS 
 
13.1  Background 
 
 
The purpose of this correlative study is to evaluate if highly conformal, high dose 
per fraction radiation therapy like SABR, given concurrently with ipilimumab will improve 

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progression-free survival for patients with oligometastatic melanoma (3 or fewer sites of 
metastatic disease). 
 
13.2  Screening for Eligibility 
 
All patients enrolled on the study will be eligible for the correlative studies. 
 
13.3  Planned Correlative Analyses  
 
Blood and tissue samples will be collected for research purposes.  Planned studies 
include exploration of certain gene mutations and serum markers as predictors of 
response to ipilimumab and SABR combination treatment.  Proteomics expression 
patterns will be used to determine if they are a prognostic or predictive marker for 
treatment response.  We plan to also evaluate if primary tumor cells and melanoma stem-
like cells can be isolated from the tissues using stem-like cell isolation techniques.  These 
cells may be transitioned to long-term cell lines for further research. 
 
There are currently no standard prognostic or predictive markers to evaluate or 
anticipate outcome of ipilimumab and SABR combination therapy.  This study provides 
the opportunity for exploratory analysis of several hypotheses that may predict outcome.  
Hence, we propose to collect pilot data comparing pre-treatment with post-treatment 
proteomic and genetic features in this cohort of melanoma patients.  Furthermore, we will 
conduct investigations of genomic and proteomic levels to more completely understand 
melanoma biology and further elucidate its response in the setting of current ipilimumab 
and high dose per fraction radiation therapy. 
 
Immune tolerance and immunoediting are the two principle mechanisms by which 
solid tumors evade detection and destruction by the immune system.  Immune tolerance 
is a process by which tumor cells become resistant to activated immune effector cells.  In 
contrast, immunoediting occurs when tumors manipulate their microenvironment by 
creating complex local and regional immunosuppressive networks that consist of various 
tumor-derived cytokines and other soluble factors.  Consequently, we will include relevant 
cytokine and protein biomarkers that modulate immunoediting and immunosuppression. 
 
13.4  Specimen Collection   
 
 
Optional blood and serum samples for correlative analysis will be collected pre-
treatment (Week 1), prior to 2nd ipilimumab infusion (Week 4), before initiation of SABR 
(week 5), prior to 3rd ipilimumab infusion (Week 7), prior to 4th ipilimumab infusion (Week 
10), 2 weeks after ipilimumab (Week 12), and at weeks 16, 20, 24, 35, and 50.  (Please 
see section 3.4 Figure). 
 
Whole blood will be collected at each time point for whole blood marker and serum 
marker assessments.  For whole blood markers, 30 mL blood will be collected in 3 x 10-
mL heparin containing tubes.  For serum markers, 10 mL blood will be collected in a 10 

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mL red top tube. 
  
Tissue sections: Genomic DNA from the tissue sections of patients biopsy or resection 
material will be isolated and paired with matched blood samples and will be used for the 
following analysis: 
1. We propose to sequence them to identify the key gene mutational status and 
whether the mutation is germline or somatic. 
2. Determination of the wild type v mutant type ratio of key melanoma genes such as 
BRAF, NRAS, KIT, CDKN2A, PIK3CA, PTEN, TP53, MEK, EGFR, Akt, etc. using 
castPCR technique. 
3. The tissue microarray (TMAs) obtained after Dermatopathologist selected/ 
reviewed area will be used for fluorescence based Immunohistochemistry and the 
expression intensity of images will be scored using an automated system. 
4. The co-localization and subcellular localization and intensity of histologic staining 
will also be determined. 
5. Tumor antigens such as Melan-A, NY-ESO-1, MAGE, MART-1, gp-100, 
tyrosinase, PSA, PAP, and PSMA. 
 
Additional post-treatment biopsy or resection tissues will also be analyzed if they become 
available.  Planned post-treatment biopsy is not part of this study. 
Blood and Serum Markers: We propose to determine the expression levels of various 
seromic proteins and cell surface markers. The marker proposed includes: 
1. Absolute lymphocyte count (ALC), CD152 (CTLA-4) by flow cytometry, CD28 by 
flow cytometry, LDH. 
2. T cell activation markers CD3, CD4, CD8, HLA-DR, ICOS, C11b, CD69, CD137, 
CD154, CXCL16, CTLA-4, and PD-1. 
3. T cell suppressor – Myeloid derived suppressor cells CD14 and HLA-DR. 
4. T helper 17 (Th17) cells and related cytokines IL-17 and IL-22. 
5. Regulatory T cells ‘Tregs’ CD4, CD25/LAP and FoxP3, CD127, IDO. 
6. Ratio of effector and regulatory T cells “Teff/Treg”. 

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7. B-7 family costimulatory molecules: CD80(B7-1), CD86(B7-2). 
8. Bioplex Assays using serum samples: Human 8-plex assay; IL-2, IL-4, IL-6, IL-8, 
IL-10, GM-CSF, IFN-γ, TNF-α, CXCL9 and Human Th17 cytokine panel; IL-1β, IL-
4, lL-6, IL-10, IL-17A , IL-17F , IL-21 , IL-22 , IL-23 , IL-25, IL-31, IL-33, IFN-γ, 
sCD40L, TNF-α, IL-17A/F. 
 
Blood specimens will be picked up by personnel from the laboratory of Dr. Palanichamy 
for subsequent processing and analysis. 
 
Kamalakannan Palanichamy, Ph.D. 
Department of Radiation Oncology 
Arthur G. James Cancer Hospital & 
Richard J. Solove Research Institute 
400 W. 12th Avenue, Ste 385E 
Columbus, OH  43210 
Office (614)-685-4245 
Fax (614) 293-4044 
Email:  Kamalakannan.palanichamy@osumc.edu  
 
 
13.5 Correlative Strategy 
1. Serum and blood sample volume: From patient to patient relative abundance of 
proposed markers may vary widely due their immune response and individual 
variability. Hence there may be some markers which would require higher volume 
of samples because of their low abundance / antigen presentation which would be 
a bottle neck for the proposed analysis. We propose to overcome the sample 
volume limitations by two approaches i) by multiplexing the assays and ii) by 
positive selection of that particular antigen using antibody coated bead technology. 
 
2. Fluorescence based IHC: Historically conventional IHC was used for scoring by 
dermatopathologists and introducing this new approach to predict the outcome 
may not be a head to head comparison. We propose to stain TMA both by 
conventional IHC and Fluorescence based IHC. A Dermatopathlogist will score the 

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conventional TMAs and the scores will be compared to the scores generated by 
automated system to avoid discrepancy.   
 
The expected outcome of this study is to identify the endpoints that correlate with, or 
predict the following events; 
1. Clinical benefit 
2. Progression-free survival 
3. Overall Survival 
4. Immune related adverse events 
5. Antitumor immune response in real-time 
6. Characterizing the steps involved in abscopal effect with radiotherapy 
7. Identifying the subset which will derive more clinical benefit from the genetic and 
proteomic profiles. 
8. Developing biomarkers to predict the response to treatment, PFS, and OS at early 
stage of treatment and also duration of response.  
 
13.6  Confidentiality/Storage 
 
• The patient’s name and/or other identifying information should be removed from 
the pathology report, blocks, or slides.  However, the surgical pathology numbers 
and de-identified information must NOT be removed. 
• De-identified samples will be stored securely for an indefinite period of time in the 
laboratory of Dr. Palanichamy  
14.0 STUDY FINANCES 
14.1 Funding Source 
The study is funded through a grant from BMS. 
14.2 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 OSUMC prior to participation in this study.   

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14.3 Subject Stipends or Payments 
There is no subject stipend/payment. 
15.0 PUBLICATION PLAN 
Any formal presentation or publication of data from this trial may be published after 
review and comment by BMS (Grantor) prior to any outside submission.  BMS must 
receive copies of any intended communication in advance of publication (at least fifteen 
working days for presentational materials and abstracts and thirty working days for 
manuscripts).   These requirements acknowledge BMS’s responsibility to provide peer 
input regarding the scientific content and conclusions of such publications or 
presentations.  Principal Investigation/Institution shall have the final authority to determine 
the scope and content of its publications, provided such authority shall be exercised with 
reasonable regard for the interests of BMS and, in accord with the trial contract and shall 
not permit disclosure of BMS confidential or proprietary information. 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the Grantor for the purposes of performing 
the study, will be published or passed on to any third party without the consent of the 
Grantor.   
 
 
 
 
 

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16.0 REFERENCES 
References 
 
1. 
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with 
metastatic melanoma. N Engl J Med 2010;363:711-723. 
2. 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-7420. 
3. 
Melero I, Hervas-Stubbs S, Glennie M, et al. Immunostimulatory monoclonal antibodies for 
cancer therapy. Nat Rev Cancer 2007;7:95-106. 
4. 
O'Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel 
strategy for the treatment of melanoma and other malignancies. Cancer 2007;110:2614-2627. 
5. 
Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class 
of immunomodulatory antibodies for cancer treatment. J Clin Oncol 2008;26:5275-5283. 
6. 
Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II 
study comparing the tolerability and efficacy of ipilimumab administered with or without 
prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 
2009;15:5591-5598. 
7. 
Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated 
advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. 
Lancet Oncol 2010;11:155-164. 
8. 
O'Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in 
patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann 
Oncol 2010;21:1712-1717. 
9. 
Nagorsen D, Scheibenbogen C, Marincola FM, et al. Natural T cell immunity against cancer. Clin 
Cancer Res 2003;9:4296-4303. 
10. 
Clemente CG, Mihm MC, Jr., Bufalino R, et al. Prognostic value of tumor infiltrating lymphocytes 
in the vertical growth phase of primary cutaneous melanoma. Cancer 1996;77:1303-1310. 
11. 
Hakansson A, Gustafsson B, Krysander L, et al. Tumour-infiltrating lymphocytes in metastatic 
malignant melanoma and response to interferon alpha treatment. Br J Cancer 1996;74:670-676. 
12. 
Mihm MC, Jr., Clemente CG, Cascinelli N. Tumor infiltrating lymphocytes in lymph node 
melanoma metastases: a histopathologic prognostic indicator and an expression of local 
immune response. Lab Invest 1996;74:43-47. 
13. 
Peggs KS, Quezada SA, Korman AJ, et al. Principles and use of anti-CTLA4 antibody in human 
cancer immunotherapy. Curr Opin Immunol 2006;18:206-213. 
14. 
Tarhini AA, Iqbal F. CTLA-4 blockade: therapeutic potential in cancer treatments. Onco Targets 
Ther 2010;3:15-25. 
15. 
Robert C, Ghiringhelli F. What is the role of cytotoxic T lymphocyte-associated antigen 4 
blockade in patients with metastatic melanoma? Oncologist 2009;14:848-861. 
16. 
Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential 
role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp 
Med 2000;192:295-302. 

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17. 
Kaehler KC, Piel S, Livingstone E, et al. Update on immunologic therapy with anti-CTLA-4 
antibodies in melanoma: identification of clinical and biological response patterns, immune-
related adverse events, and their management. Semin Oncol 2010;37:485-498. 
18. 
Morse MA. Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb. Curr Opin Mol 
Ther 2005;7:588-597. 
19. 
Weber JS, O'Day S, Urba W, et al. Phase I/II study of ipilimumab for patients with metastatic 
melanoma. J Clin Oncol 2008;26:5950-5956. 
20. 
Delaney G, Jacob S, Barton M. Estimation of an optimal radiotherapy utilization rate for 
gynecologic carcinoma: part II--carcinoma of the endometrium. Cancer 2004;101:682-692. 
21. 
Burnette BC, Liang H, Lee Y, et al. The efficacy of radiotherapy relies upon induction of type i 
interferon-dependent innate and adaptive immunity. Cancer Res 2011;71:2488-2496. 
22. 
Hallahan DE, Spriggs DR, Beckett MA, et al. Increased tumor necrosis factor alpha mRNA after 
cellular exposure to ionizing radiation. Proc Natl Acad Sci U S A 1989;86:10104-10107. 
23. 
Zhang JS, Nakatsugawa S, Niwa O, et al. Ionizing radiation-induced IL-1 alpha, IL-6 and GM-CSF 
production by human lung cancer cells. Chin Med J (Engl) 1994;107:653-657. 
24. 
Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early 
stage lung cancer. JAMA 2010;303:1070-1076. 
25. 
Timmerman RD. Surgery versus stereotactic body radiation therapy for early-stage lung cancer: 
who's down for the count? J Clin Oncol 2010;28:907-909. 
26. 
Brown PD, Brown CA, Pollock BE, et al. Stereotactic radiosurgery for patients with 
"radioresistant" brain metastases. Neurosurgery 2002;51:656-665; discussion 665-657. 
27. 
Chang EL, Selek U, Hassenbusch SJ, 3rd, et al. Outcome variation among "radioresistant" brain 
metastases treated with stereotactic radiosurgery. Neurosurgery 2005;56:936-945; discussion 
936-945. 
28. 
Clarke JW, Register S, McGregor JM, et al. Stereotactic radiosurgery with or without whole brain 
radiotherapy for patients with a single radioresistant brain metastasis. Am J Clin Oncol 
2010;33:70-74. 
29. 
Hara W, Tran P, Li G, et al. Cyberknife for brain metastases of malignant melanoma and renal 
cell carcinoma. Neurosurgery 2009;64:A26-32. 
30. 
Stinauer MA, Kavanagh BD, Schefter TE, et al. Stereotactic body radiation therapy for melanoma 
and renal cell carcinoma: impact of single fraction equivalent dose on local control. Radiat Oncol 
2011;6:34. 
31. 
Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection for stage IV melanoma: 
Results of Southwest Oncology Group Clinical Trial S9430. Cancer 2011. 
32. 
Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a 
patient with melanoma. N Engl J Med 2012;366:925-931. 
33. 
Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require 
CD8+ T cells: changing strategies for cancer treatment. Blood 2009;114:589-595. 
34. 
Ludgate CM. Optimizing Cancer treatments to induce an acute immune response; radiation 
abscopal effects, PAMPS and DAMPS. Clin Cancer Res 2012. 
35. 
Kroemer G, Zitvogel L. Abscopal but desirable: The contribution of immune responses to the 
efficacy of radiotherapy. Oncoimmunology 2012;1:407-408. 
36. 
Hiniker SM, Chen DS, Knox SJ. Abscopal effect in a patient with melanoma. N Engl J Med 
2012;366:2035; author reply 2035-2036. 
37. 
Stamell EF, Wolchok JD, Gnjatic S, et al. The Abscopal Effect Associated With a Systemic Anti-
melanoma Immune Response. Int J Radiat Oncol Biol Phys 2012. 

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38. 
Frey B, Rubner Y, Wunderlich R, et al. Induction of abscopal anti-tumor immunity and 
immunogenic tumor cell death by ionizing irradiation - implications for cancer therapies. Curr 
Med Chem 2012;19:1751-1764. 
39. 
Ishiyama H, Teh BS, Ren H, et al. Spontaneous Regression of Thoracic Metastases While 
Progression of Brain Metastases After Stereotactic Radiosurgery and Stereotactic Body 
Radiotherapy for Metastatic Renal Cell Carcinoma: Abscopal Effect Prevented by the Blood-Brain 
Barrier? Clin Genitourin Cancer 2012. 
40. 
Hodge JW, Sharp HJ, Gameiro SR. Abscopal regression of antigen disparate tumors by antigen 
cascade after systemic tumor vaccination in combination with local tumor radiation. Cancer 
Biother Radiopharm 2012;27:12-22. 
41. 
Pilones KA, Kawashima N, Yang AM, et al. Invariant natural killer T cells regulate breast cancer 
response to radiation and CTLA-4 blockade. Clin Cancer Res 2009;15:597-606. 
42. 
van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-
stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and 
metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 1999;190:355-366. 
43. 
Van Assche G, Vermeire S, Rutgeerts P. Treatment of severe steroid refractory ulcerative colitis. 
World J Gastroenterol 2008;14:5508-5511. 
 
 
 
 

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Appendix I: ECOG Performance Status Scale 
 
 
Grade Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self- care. Totally confined 
to bed or chair. 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix II: Study Schedule 

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Pre-Treatment 
During Treatment 
Follow-Up visits start within 30 
days of last dose (+/- 20 days), 
with the goal of 30 days for the 
first follow-up visit.  
 
<  4 
Week 
prior 
to 
first 
treat
ment 
<3 days 
Prior 
 To 
 first 
treatme
nt 
Day 1 
Prior 
to 
Week 
4 
Week 
5 
Before 
SABR 
Prior 
to 
Week 
7 
Prior 
to 
Week 
10 
Week 
14 
Q3 
months 
for first 
2 years 
Q6 
months 
for year 
2- 5 
Annu
-ally 
for 5 
years 
At 
Pro
gres
sion 
History and 
physical exam 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Consent 
Obtained 
X 
 
 
 
 
 
 
 
 
 
 
 
Record Prev. 
Therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood 
Specimen 
Banking 
 
 
X 
X 
X 
X 
X 
^ 
$ 
 
 
 
Vital signs 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic 
biopsy 
* 
 
 
 
 
 
 
 
 
 
 
* 
Contrast-
enhanced CT 
or MRI of the 
abdomen and 
pelvis 
X 
 
 
 
 
X@ 
 
X@ 
* 
* 
* 
 
CT chest 
X 
 
 
 
 
X 
 
X 
* 
* 
* 
 
Whole-body 
PET-CT scan of 
body 
(optional) 
X 
 
 
 
 
 
 
 
* 
* 
* 
 
CBC w/diff & 
ANC, platelets 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
CMP including 
LFTs 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Thyroid Fxn 
and ACTH 
level 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
CrCl 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue to 
next page 
 
 
 
 
 
 
 
 
 
 
 
 
 

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*preferred/at the discretion of the treating physicians 
xmandatory 
^ Post-treatment blood draw will occur at week 12 (two weeks after 4th ipilimumab 
infusion) 
$  During the follow-up period blood collections will occur at week 16, week 20, week 24, 
week 35 and week 50 per Section 3.4. 
 
@ Will delayed if ipilimumab dosing is delayed:  CT will be prior to infusion 3, and 4 weeks 
after infusion 4. 
xx SAEs are to be reported to sponsor and IRB up to 70 days after last treatment with 
ipilimumab per protocol 
 
Appendix III:  Comparison between WHO criteria and the irRC2 
 
 
 
 
< 4 
weeks 
prior 
to 
first 
treat
ment 
<3 days 
Prior 
 To 
 first 
treatme
nt 
Day 1 
Prior 
to 
Week 
4 
 
Prior 
to 
Week 
7 
Prior 
to 
Week 
10 
Week 
14 
Q3 
months 
for first 
2 years 
Q6 
months 
for year 
2- 5 
Annu
al-ly 
for 5 
years 
At 
Pro
gres
sion 
Serum 
pregnancy test 
X 
Xx 
 
 
 
 
 
 
 
 
 
 
HIV, Hep B 
and C test 
X 
 
 
 
 
 
 
 
 
 
 
 
Ipilimumab  
 
 
X 
X 
 
X 
X 
 
 
 
 
 
SABR  
 
 
 
 
 
X 
 
 
 
 
 
 
Adverse event 
evaluation 
 
 
X 
X 
 
X 
X 
X 
At 90xx 
days 
post-
treatm
ent 
 
 
 
Tumor 
banking 
* 
 
 
 
 
 
 
 
 
 
 
* 

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