A Phase 2, Randomized, Multi-institutional Study of Nivolumab and Ipilimumab Versus Nivolumab, Ipilimumab and Stereotactic Body Radiation Therapy for Metastatic Merkel Cell Carcinoma
Phase: PHASE2
Conditions: Merkel Cell Carcinoma, Skin Cancer
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 
 
 
 
 
A Phase 2, Randomized, Multi-institutional Study of Nivolumab and Ipilimumab 
versus Nivolumab, Ipilimumab and Stereotactic Body Radiation Therapy for 
Metastatic Merkel Cell Carcinoma 
NCT03071406 
 
Version 11 
January 26, 2023 

Clinical Protocol 
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Clinical Protocol 
A Phase 2, Randomized, Multi-institutional Study of Nivolumab and Ipilimumab versus 
Nivolumab, Ipilimumab and Stereotactic Body Radiation Therapy for Metastatic Merkel Cell 
Carcinoma 
 
 
 
 
PI: Sungjune Kim, MD, PhD 
Co-PI: Andrew Brohl, MD 
Co-Investigator: Louis Harrison, MD 
Co-Investigator: Jimmy Caudell, MD, PhD 
Co-Investigator: Nikhil Khushalani, MD 
Co-Investigator: Evan Wuthrick, MD 
Co-Investigator: Zeynep Eroglu, MD 
Co-Investigator: Joseph Markowitz, MD, PhD 
Biostatistician: Dung-Tsa Chen, PhD 
Pathologist: Jane Messina, MD 
Radiologist: Trevor Rose, MD 
OSU Site PI: Dukagjin Blakaj, MD 
 
Collaborating Institutions:  
Ohio State University James Cancer Hospital and Solove Research Institute 
 
 
 
 
 
 
                                                                         

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DOCUMENT HISTORY 
 
 
 
Document 
Date of Issue 
Summary of Change 
Original 
Protocol 
 
 
 
 
 
Not applicable 
 
 

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SYNOPSIS 
Clinical Protocol  
Protocol Title: A Phase 2, Randomized, Multi-institutional Study of Nivolumab and Ipilimumab 
versus Nivolumab, Ipilimumab and Stereotactic Body Radiation Therapy for Metastatic Merkel 
Cell Carcinoma. 
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment 
with Investigational Product(s): 
Stereotactic Body Radiation Therapy 24Gy in 3 fractions.  
Nivolumab 240 mg/dose IV q2 weeks.  
Ipilimumab 1 mg/kg/dose IV q6 weeks.  
Treat subjects until disease progression, unacceptable toxicity or subject withdrawal of consent. 
Study Phase: 2  
Research Hypothesis: Treatment with nivolumab and ipilimumab, or nivolumab and 
ipilimumab in combination with stereotactic body radiation therapy (SBRT) will improve 
objective response rate as compared to nivolumab alone historical control in subjects with 
metastatic Merkel cell carcinoma.   
Objectives: 
Primary: 
• To compare the efficacy, as measured by objective response rate (ORR), provided by 
nivolumab plus ipilimumab with or without SBRT in subjects with metastatic Merkel cell 
carcinoma. 
Secondary: 
• To compare the progression free survival (PFS) of nivolumab and ipilimumab versus SBRT 
plus nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma. 
• To compare the overall survival (OS) of nivolumab and ipilimumab versus SBRT plus 
nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma. 
• To evaluate the local control of irradiated tumor provided by SBRT in combination with 
nivolumab and ipilimumab 
• To assess the overall safety and tolerability of of nivolumab and ipilimumab versus SBRT plus 
nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma. 
• To evaluate whether PD-L1 expression is a predictive biomarker for ORR. 
• To evaluate the Health Related Quality of Life (HRQoL) as assessed by European 
Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. 
 
Exploratory: See Section 1.3.3 of the protocol. 
Study Design:  
This is a Phase 2, randomized, multi-institutional study of nivolumab and ipilimumab alone versus 
in combination with SBRT for subjects (≥18 years) with metastatic Merkel Cell Carcinoma. 
Approximately 50 subjects will be randomized 1:1 and stratified by prior immunotherapy 
exposure. Dose reductions will not be allowed. 

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Treatment Arms: 
Randomized  1:1 [Arm A: Arm B]: Treatment until progression on either arm. 
Arm A: 
Nivolumab 240 mg IV over 30 min q2 weeks and Ipilumumab 1 mg/kg IV over 30 min   
q6 weeks until progression or unacceptable toxicity 
 
Arm B: 
Nivolumab 240 mg IV over 30 min q2 weeks and Ipilumumab 1 mg/kg IV over 30 min   
q6 weeks until progression or unacceptable toxicity 
Radiation to be given at the start of week 2 
 
 
- 8 Gy x3 doses in over ≤ 2 weeks 
SBRT should begin the week following the first dose of nivolumab and ipilimumab. All sites other 
than skin should receive SBRT in consecutive days. Skin lesions can be treated every other day. 
The number of lesions receiving SBRT will be at the treating physician’s discretion based on 
anticipated toxicity. Larger or symptomatic lesions are of higher priority for SBRT. At least one 
target lesion will not receive SBRT, to evaluate ORR. The scatter radiation dose to this target 
lesion should be monitored if located less than 6cm from the irradiated lesions.  
All subjects will be treated until progression of disease, unacceptable toxicity, or subject 
withdrawal of consent. Palliative radiation therapy will not be permitted while being treated under 
the protocol. The need for palliative radiation therapy will be considered progressive disease.   
 
Study Population: Metastatic Merkel cell carcinoma subjects  
Key Inclusion Criteria: 
• At least 18 years of age 
• ECOG PS < 2 
• Active disease measurable by CT or MRI.  
• Prior chemotherapy or immunotherapy will be allowed if new or persistent measurable site(s) 
of disease are present. 
• Prior radiation therapy will be allowed if there is active measurable disease burden. 
• All subjects must be either recurrent, unresectable or Stage IV AJCC (7th edition) and have 
histologically confirmed Merkel cell carcinoma with at least 2 distinct lesions in order to be 
eligible. Please refer to Appendix 1 for description of AJCC 7th editions of TNM and staging. 
 
 
Metastatic/ 
recurrent/ 
unresectable 
Merkel cell 
carcinoma  
 
 
 
Arm A (n = 25) 
Nivolumab 240 mg q2 weeks  
Ipilumumab 1 mg/kg q6 weeks  
 
 
Follow-
up 
Randomize 
1:1
Stratify by 
• Prior immunotherapy 
 
Arm B (n = 25) 
Nivolumab 240 mg q2 weeks 
Ipilumumab 1 mg/kg q6 weeks  
SBRT 24Gy/3fx at the start of week 2 
 

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• All subjects must have at least 2 distinct lesions as documented by a complete physical 
examination or imaging studies within 4 weeks prior to randomization. Imaging studies must 
include a diagnostic CT scan of the involved disease sites and all known sites of resected 
disease and brain magnetic resonance (MRI) or CT (brain CT allowable if MRI is 
contraindicated or if there is no known history of resected brain lesions). 
• Tumor tissue from the core biopsy or resected site of disease must be provided for biomarker 
analyses.  
Key Exclusion Criteria: 
• Subjects with history of Grade 3 toxicity or use of infliximab with prior immunotherapy 
• Patients with active brain metastasis. 
• Subjects with active, known, or suspected autoimmune disease. Subjects with type I diabetes 
mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment are permitted to enroll. 
• Subjects with prior history of non-Merkel cell carcinoma malignancies are excluded except 
adequately treated basal cell, squamous cell skin cancer, chronic lymphocytic leukemia or 
other indolent diseases not requiring therapy; adequately treated, with curative intent, cancer 
from which the patient is currently in complete remission per investigator’s judgment; or 
patients with history of breast cancer and no evidence of disease on hormonal therapy to 
prevent recurrence and patients with prostate cancer on adjuvant hormonal therapy with 
undetectable PSA are eligible. 
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids are permitted in the absence of active autoimmune 
disease. 
Study   Drug: 
Study Drug 
Medication 
Potency 
IP/Non-IP 
Nivolumab Solution 
for Injection 
 
100 mg (10 mg/mL) 
IP 
Ipilimumab Solution 
for Injection 
50 mg (5 mg/mL) 
IP 
 
Study Assessments: Objective response rate is the primary endpoint of the trial. The ORR will 
be calculated as the percentage of patients who had a complete or partial response that was 
confirmed by a subsequent radiologic imaging study or clinical exam according to irRECIST 
criteria among all the patients who received at least one dose of nivolumab and ipilimumab with 
or without SBRT.  
• Screening. 
• Treatment Period: Every 12 weeks ( 7 days) from first dose of study drug through 45 
weeks (relative to the first dose of study drug) 
• Follow-up Period: 
a) Every 12 weeks (  days) through 12 months for subjects who discontinued early from 
treatment (relative to the first dose of study drug) 

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b) Every 12 weeks (  days) if > 12 months through 24 months (relative to the first dose of 
study drug) 
c) Every 6 months (  days) if > 24 months through and up to Year 5 (relative to the 
first dose of study drug). 
Statistical Considerations: 
Sample Size: From historical data, we will consider 17% response rate as not warranting further 
study. We will use 40% response rate as a promising result to pursue further study. In other words, 
we are interested in at least 23% (40% vs. 17%) improvement in treatment efficacy for arms B 
versus A. For each arm, using a Simon Mini-Max two-stage design with 10% type I error rate and 
10% type II error rate, 16 patients will be enrolled in the first stage of the trial. If 2 or fewer 
patients respond, the treatment will be stopped. If 3 or more patients show a response, 8 additional 
patients (a total of 24 patients per group) will be enrolled. If the total number responding is 6 or 
less, we will conclude that the treatment is not effective. If both arms fail at the first or second 
stage, the trial will stop. No winner will be claimed. The sample size will be 32 if both arms fail at 
the first stage and 40 if only one arm fails at the first stage. If only one arm pass the second stage, 
the arm will be the winner. If both arms pass the second stage, we will use the posterior 
probability, Pr(B>A), (probability of the response rate in arm B higher than in arm A) to select the 
winner. A non-informative prior of beta distribution, beta(1,1) in both arms will be used to 
calculate the posterior probability. Arm B will be claimed as the winner if Pr(B>A)>δ= 0.8. 
Endpoints: 
Primary Endpoint: Objective response rate in all randomized subjects  
Secondary Endpoint: Progression free survival and overall survival  
Analyses: Patient demographics and toxicity will be summarized using descriptive statistics. 
Hematologic and non-hematologic toxicity will be analyzed by CTCAE criteria and compared 
between treatment groups using Pearson’s Chi-square test. All tests will be two-sided with an α 
(type I) error ≤0.05 considered to be statistically significant. Continuous variables will be 
described by number of patients, mean, standard deviation, median, minimum and maximum. 
Categorical variables will be tabulated using frequency counts and percentages. The primary 
analysis of ORR in all randomized subjects will be conducted using a two-sided log-rank test. 
The hazard ratio and corresponding two-sided 95% confidence interval (CI) will be estimated 
using a Cox proportional hazards model, with treatment arm as a covariate. PFS medians with 
95% CIs and PFS rates at 6, 12, 24, and 36 months with 95% CIs will be estimated using 
Kaplan-Meier methodology. 
Stopping criteria: A Safety Monitoring Committee will be formed to evaluate the toxicity of 
both arms. Interim analysis will be conducted following accrual of initial cohort of patients in the 
Simon’s two stage design to determine whether SBRT introduces excess unanticipated grade 3 or 
higher toxicities (i.e. radiation pneumonitis, radiation dermatitis, radiation myelitis) prior to 
expansion of the cohorts.  

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TABLE OF CONTENTS 
 
TITLE PAGE ................................................................................................................ 
1 
DOCUMENT HISTORY.............................................................................................. 
2 
SYNOPSIS.................................................................................................................... 
3 
TABLE OF CONTENTS.............................................................................................. 
7 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
11 
1.1 Research Hypothesis.......................................................................................... 
11 
1.2 Study Rationale.................................................................................................. 
11 
1.2.1  Rationale for Nivolumab......................................................................... 
11 
1.2.2  Rationale for Combining SBRT with Nivolumab...................................... 
12 
1.2.3  Rationale for Combining Ipilimumab with SBRT and Nivolumab............. 
13 
1.2.4  Summary………………………………………………………………………………….............. 
13 
1.3 Objectives(s) ..................................................................................................... 
13 
1.3.1  Primary Objectives .................................................................................. 
14 
1.3.2  Secondary Objectives............................................................................... 
14 
1.3.3  Exploratory Objectives ............................................................................ 
14 
1.4 Rationale for Study Design ………….................................................................... 
14 
1.4.1  Rationale for Studying Merkel Cell Carcinoma....................................... 
14 
1.4.2  Immunotherapy for Merkel Cell Carcinoma............................................. 
15 
1.4.3  Rationale for ORR as Primary Endpoint with PFS and OS as a  
Secondary Endpoint................................................................................ 
15 
1.4.4  Rationale for Two Experimental Arm Design..........................................  
15 
1.4.5  Rationale for the Dose and Schedule for Nivolumab...............................  
16 
1.4.6  Rationale for the Dose and Schedule for SBRT.......................................  
16 
1.4.7  Rationale for the Dose and Schedule for Ipilimumab..............................  
17 
1.4.8  Rationale for Treating until Progression, Unacceptable Toxicity, or  
         Withdrawal of Consent…………………………………………...................................  
17 
1.4.9  Rationale for Evaluation of PD-L1 Expression as a Predictive  
Biomarker of Efficacy..............................................................................  
18 
1.4.10 Rationale for Quality of Life Evaluation...................................................  
19   
1.5 Product Development Background....................................................................  
19 
1.5.1  Nivolumab Mechanism of Action...............................................................  
19 
1.5.2  Ipilimumab Mechanism of Action ………………………………………….......................... 
21 
1.5.3  SBRT Background......................................................................................           22 
                1.5.4  Summary of Safety.......................................................................................           22  
1.5.5  Summary of Clinical Activity….................................................................... 
24 
1.5.6  Clinical Pharmacology Summary ............................................................... 
26 
1.6 Overall Risk/Benefit Assessment….................................................................. 
          27 
2 ETHICAL CONSIDERATIONS.................................................................................. 
28 
2.1 Good Clinical Practice ...................................................................................... 
28 
2.2 Institutional Review Board/Independent Ethics Committee............................. 
28 
2.3 Informed Consent.............................................................................................. 
28 
3 STUDY POPULATION…………................................................................................. 
30 
3.1 Inclusion Criteria……. ...................................................................................... 
30 
3.2 Exclusion Criteria……………………………………………............................. 
31 

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3.3 Women of Childbearing Age............................................................................... 
 33 
4 INVESTIGATIONAL PLAN......................................................................................... 
34 
4.1 Study Design and Duration .................................................................................... 
34 
4.2 Concomitant Treatments.......................................................................................... 
35 
4.2.1 Prohibited and/or Restricted Treatments......................................................... 
35 
4.2.2 Permitted Therapy…….................................................................................... 
36 
4.3 Discontinuation of Subjects following any Treatment with Study Drug.......... 
36 
4.4 Post Study Drug Study Follow up .................................................................... 
36 
4.4.1 Withdrawal of Consent ............................................................................ 
37 
4.4.2 Lost to Follow-Up .................................................................................... 
37 
5 STUDY DRUG.......................................................................................................... 
38 
5.1 Investigational Product ..................................................................................... 
38 
5.2 Non-investigational Product ............................................................................. 
38 
5.3 Storage and Dispensing..................................................................................... 
38 
5.4 Method of Assigning Subject Identification ..................................................... 
39 
5.5 SBRT and Drug Dosing Schedule……………… ............................................... 
40 
5.5.1 Dosing Schedule....................................................................................... 
40 
5.5.2 Antiemetic Premedications ...................................................................... 
41 
5.5.3 Dose Modifications ................................................................................... 
41 
5.5.4 Management Algorithms for Immuno-Oncology Agents ………................ 
41 
5.5.5 Dose Delay Criteria …................................................................................ 
41 
5.5.6 Criteria to Resume Treatment.................................................................. 
42 
5.5.7 Discontinuation Criteria.......................................................................... 
43 
5.5.8 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ...... 
44 
5.5.9 Treatment Beyond Progression ………………………………………………..... 
45 
5.6 Treatment Compliance...................................................................................... 
46 
5.7 Destruction of Study Drug ................................................................................ 
46 
6 RADIATION THERAPY........................................................................................... 
47 
6.1 Dose Specification ............................................................................................. 
47 
6.1.1 Dose Fractionation................................................................................... 
47 
6.1.2 Technical Factors…………. ..................................................................... 
 
6.1.2.1 Physical Factors................................................................................ 
47 
6.2 Treatment Target Volume................................................................................... 
51 
6.2.1 Metastasis Location ………………………………………………............................. 
51 
6.3 Dosimetry…………………................................................................................. 
53 
6.3.1 Target Volume Definition based on Metastatic Location............................. 
53 
6.3.2 Planning Techniques……………………………………………….............................. 
54  
6.4 Planning Priorities……….................................................................................... 
56 
6.5 Critical Structures… ............................................................................................. 
57 
6.5.1 Planning SBRT Near Prior Radiotherapy Volume........................................ 
57 
6.5.2 Organs at Risk……..…………. ..................................................................... 
57 
6.5.3 Contouring of Normal Tissue Structures……………….................................. 
58 
6.5.4 Contouring of Target Lesions….................................................................... 
61 
6.5.5 Critical Organ Dose-Volume Limits…………………….................................. 
61 
6.6 Documentation Requirements................................................................................ 
63 
6.7 Compliance Cirteria...................................................... 
63 
6.8 Radiation Therapy Adverse Events………............................................................. 
64 

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6.8.1 Secondary Malignancy………. ..................................................................... 
67 
6.8.2 Second Malignancy………. .......................................................................... 
67 
7 STUDY ASSESSMENTS AND PROCEDURES..................................................... 
68 
7.1 Flow Chart/Time and Events Schedule............................................................. 
68 
7.1.1 Retesting During Screening or Lead-in Period ....................................... 
75 
7.2 Study Materials ................................................................................................. 
75 
7.3 Safety Assessments........................................................................................... 
75 
7.3.1 Imaging Assessment for the Study............................................................ 
76 
7.4 Efficacy Assessments........................................................................................ 
76 
7.4.1 Definitions................................................................................................ 
77 
7.4.2 Methods of measurements........................................................................ 
77 
7.4.3 Date of Progression ................................................................................. 
78 
7.5 Biobanking for Exploratory Correlative Studies 
Assessments...................................................................................... 
78 
7.5.1 Tumor Tissue Specimens.......................................................................... 
79 
7.5.2 Plasma Biomarkers ........................................... 
80 
7.5.3 Peripheral Blood Mononuclear Cells and Myeloid Derived Suppressor 
Cells………………………………………………………….................................... 
80 
7.6 Outcomes Research Assessments ..................................................................... 
80 
8 ADVERSE EVENTS................................................................................................. 
82 
8.1 Serious Adverse Events .................................................................................... 
82 
8.1.1 Serious Adverse Event Collection and Reporting .................................... 
83 
8.2 Nonserious Adverse Events .............................................................................. 
85 
8.2.1 Nonserious Adverse Event Collection and Reporting.............................. 
85 
8.3 Laboratory Test Result Abnormalities.............................................................. 
85 
8.4 Pregnancy.......................................................................................................... 
85 
8.5 Overdose ........................................................................................................... 
86 
8.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
86 
8.7 Other Safety Considerations ............................................................................. 
86 
8.8 Protocol Monitoring Committee…………………………….............................. 
86 
9 STATISTICAL CONSIDERATIONS....................................................................... 
87 
9.1 Statistical Design…………............................................................................... 
87 
9.1.1 Sample Size Calculation............................................................................. 
87 
9.1.2 Populations for Analysis............................................................................ 
87 
9.2 Endpoints .......................................................................................................... 
88 
9.2.1 Primary Endpoint(s) ................................................................................ 
88 
9.2.2 Secondary Endpoint(s)............................................................................. 
88 
9.3 Analyses............................................................................................................ 
90 
9.3.1 Demographics and Baseline Characteristics........................................... 
90 
9.3.2 Efficacy Analyses ..................................................................................... 
90 
9.3.2.1 Primary Endpoint Methods............................................................. 
90 
9.3.2.2 Secondary Endpoint Methods ......................................................... 
90 
9.3.3 Safety Analyses......................................................................................... 
91 
9.3.4 Outcomes Research Analyses .................................................................. 
91 
10 STUDY MANAGEMENT ........................................................................................ 
92 
10.1 Compliance ....................................................................................................... 
92 
10.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
92 

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10.1.2 Required Documentation.......................................................................... 
93 
10.1.3 Registration Procedure………................................................................... 
93 
10.1.4 Adherence to Protocol…………................................................................. 
93 
10.1.5 Emergency Modification……..................................................................... 
93 
10.2 Data Management and Monitoring..................................................................... 
94 
10.2.1 Records Retention………………………………………….. ........................... 
94 
10.2.2 Obligations of Investigators....................................................................... 
94 
10.3 Ethical and Legal Aspects…………................................................................... 
95 
10.2.1 Ethical and Legal Conduct of the Study………………….. ........................... 
95 
10.2.2 Subject Information and Consent............................................................... 
95 
10.4 Publication Policy…………….……................................................................... 
96 
10.5 Confidentiality………………..……................................................................... 
96 
11 GLOSSARY OF TERMS…. ........................................................................................ 
97 
12 LIST OF ABBREVIATIONS........................................................................................ 
98 
13 REFERENCES………………....................................................................................... 
102 
APPENDIX 1 AJCC MERKEL CELL CARCINOMA STAGING............................................  108 
APPENDIX 2 PERFORMANCE STATUS SCALES .....................................................            109 
APPENDIX 3 METHODS OF CONTRACEPTION ........................................................           110 
APPENDIX 4  IMMUNE ADVERSE EVENT MANAGEMENT ALGORITHMS.....................           111 
APPENDIX 5  EORTC QLC-C30 (VER 3) FORM…………………………………..............           118 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1. PD-L1 expression in Merkel cell carcinoma. 91 
patient samples with Merkel cell carcinoma of all stages were 
analyzed for PD-L1 expression by immunohistochemistry. 
Positive PD-L1 status was defined as IHC score > 2+ in more 
than 5% of tumor cells.
1 
INTRODUCTION AND STUDY RATIONALE 
 
1.1 
Research Hypothesis 
Treatment with nivolumab and ipilimumab with or without SBRT will improve objective response rate 
when compared to nivolumab alone in subjects with metastatic Merkel cell carcinoma. 
 
1.2 
Study Rationale 
 
The proposed trial is a Phase 2 randomized, multi-institutional study of nivolumab and ipilimumab 
with or without SBRT in subjects with metastatic Merkel cell carcinoma. Merkel cell carcinoma 
(MCC) is a rare and aggressive cutaneous neuroendocrine malignancy with a propensity for distant 
metastasis with a 5 year survival rate of 25% in metastatic patients1. Currently, there is no standard 
of care or no available treatment for this patient population. Mono- or polychemotherapy can be 
used in metastatic MCC, but responses are generally short-lived with poor outcome2. Therefore, there 
is a significant need for improved therapeutic approach for metastatic MCC patients. Unfortunately, 
studies to define standard care have been limited by the rarity of this cancer.  
 
1.2.1 
Rationale for Nivolumab  
Epidemiology suggests that MCC may be benefit from immunotherapeutic approach. MCC occurs 
more frequently in immunocompromised patients suggesting pathogenesis of MCC involves evasion 
of immune surveillance3.  Furthermore, approximately 80% of MCC are associated with Merkel cell 
polyomavirus4,5, and cancers associated with viral oncogenesis may be more immunogenic. Studies on 
MCC have been limited by the rarity of this cancer, but immunotherapy appears a promising 
therapeutic modality6,7  
There are a series of on-going studies to define the role of immune checkpoint inhibitors in subjects 
with metastatic MCC. Of particular note, PD1 blockade has emerged as a promising therapeutic 
modality for metastatic MCC6,7.  
Nivolumab has been chosen as the standard 
immunotherapeutic agent. This is based on 
prior studies correlating PD-L1 expression to 
therapeutic 
responses 
to 
Nivolumab 
in 
melanoma8 and because in our retrospective 
study of cohort of 91 patients with Merkel cell 
carcinoma, 53.8% of patients demonstrated PD-
L1 expression, and higher stage correlated with 
higher percentage of patients with PD-L1 
expression (Table 1). Similar results have been 
observed by other groups9. Indeed, a recent 
interim report of phase I/II trial of metastatic treatment-naive MCC patients on Pembrilozumab 
reported 14% complete response rate10. Therefore, we anticipate a significant therapeutic efficacy of 
Nivolumab in MCC, which is being evaluated in an on-going multi-institutional clinical trial on 
Nivolumab alone for virus-associated cancers including MCC conducted by BMS.  
 
 

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Figure 1. Synergistic antitumor effects of 
combined radiation therapy and CTLA4 
immunotherapy. (A) B16F10 tumor bearing 
mice were treated with CTLA4 mAb and/or 
15Gy local radiation therapy, and tumor growth 
was assessed at indicated time points. * 
indicates p<0.05 at indicated time points. (B) 
CD3 T cells purified from spleens from mice in 
A were sorted, and re-stimulated ex vivo with 
irradiated B16F10 cells, and proliferation was 
measured by 3[H]-thymidine uptake.  
Figure 2. Adjuvant radiation therapy 
impacts survival in Merkel cell 
carcinoma. Adjuvant radiation therapy 
improved (A) 3-year LRC, (C) DFS, (D) 
OS, which was statistically significant 
on both univariate and multivariate 
analysis. There was also a trend toward 
improved distant metastasis free survival 
(DMFS) (B) with adjuvant XRT. 
1.2.2 
Rationale for Combining SBRT with Nivolumab 
More recently, the capacity of radiation therapy to induce 
systemic 
responses 
via 
immune-activation, 
termed 
abscopal effect, has been an area of active research11-15. 
Preclinical studies from our laboratory and others have 
demonstrated a strong synergy between radiation therapy 
and immunotherapy (Fig 1)11,16,17. , which has now been 
demonstrated in a melanoma clinical trial18.  
While the abscopal effect in MCC is only anecdotal19, our 
preliminary data suggests its presence in MCC. We 
conducted a retrospective study of 300 stage I – II MCC 
patients treated with surgical resection alone vs. surgery and 
adjuvant radiation therapy at Moffitt Cancer Center. 
Adjuvant radiation therapy improved LRC (71.5% vs. 37.8% 
at 3 years, respectively; p<0.001), DFS (57.0% vs. 30.2% at 
3 years, respectively; p<0.001) and OS (73% vs. 66%, 
respectively; p=0.02), on both univariate and multivariate 
analysis (Fig 2)20. More interestingly, there were trends for 
improved distant metastasis free survival (DMFS) with 
adjuvant radiation therapy (67% vs. 59%, respectively; p = 0.07) (Fig 2). The overall survival and 
DMFS benefit from radiation therapy in a disease model prone for distant metastasis suggests the 
abscopal effect as an underlying mechanism.  
Among various immune checkpoint inhibitors, the abscopal effect of SBRT is likely to be most 
strongly synergistic with nivolumab. There is pre-clinical evidence that radiation therapy up-regulates 
PD-L1 in tumor cells (Fig 3) highlighting the role for PD1 axis in tolerogenic tumor 
microenvironment antagonizing systemic immune responses 
during radiation therapy. Consistently, murine studies have 
demonstrated 
that 
targeting 
PD-L1/PD1 
axis 
results 
in 
significantly enhanced anti-tumoral immune responses induced by 
ionizing 
radiation16. 
Furthermore, 
PD-L1 
expression 
was 
associated with the mechanism of resistance to combined radiation 
therapy and ipilimumab in melanoma21.  
The rationale for SBRT to a total dose of 24Gy in 3 fractions as 
opposed to conventional radiation therapy is several fold. 
Preclinical studies have demonstrated that high dose per fraction 
appears to be most immunogenic22,23 leading to immune activation. 
At this higher dose per fraction, a more conformal treatment 
delivered through SBRT is necessary for safety. Moreover, by 
completing radiation therapy in fewer fractions, we can avoid 
repeated irradiation to the tumor infiltrating lymphocytes, which 
will render them ineffective. Also, conformal radiation therapy 
offered by SBRT will spare lymphoid tissues where the immune 
synapse occurs during priming. While definitive and adjuvant 
radiation therapy for MCC has traditionally involved a prolonged 
course of radiation therapy with wider radiation field, a recent study demonstrates that a single fraction 
of 8Gy radiation therapy offers durable palliation in MCC24. Therefore, a more conformal treatment 

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Figure 3. Ionizing radiation upregulates 
PD-L1 in melanoma. B16F10 and SM1 
murine melanoma cells were irradiated to 
15Gy and surface expression of PD-L1 was 
analyzed by flow cytometry.  
delivered through SBRT is more appropriate in the metastatic setting as a modality for systemic 
immune activation while providing local control benefit with minimal acute and long-term toxicities.  
 
1.2.3 
Rationale for Combining Ipilimumab with 
Nivolumab and SBRT 
Although ipilimumab has not been tested directly in MCC 
following withdrawal of the clinical trial prior to accrual 
(NCT01913691), ipilimumab has shown efficacy in melanoma, 
lung cancer, prostate cancer and multiple other immunogenic 
cancers. Therefore, a strong clinical activity in MCC is 
anticipated. 
Furthermore, 
the 
rationale 
for 
combining 
ipilimumab with nivolumab has been well demonstrated by a 
series of Checkmate studies in different disease sites including 
melanoma25-27 and NSCLC28. These studies demonstrated 
significant improvement in objective response rate and progression free survival with the addition of 
ipilimumab. Notably, the abscopal effect of radiation therapy has been most extensively studied in 
combination with ipilimumab. Both radiation therapy and ipilimumab are thought to induce priming 
event for eliciting anti-tumor immune responses. Synergy of these two modalities has been 
demonstrated in multiple preclinical models15,17 as well as in the prospective clinical trial29. For 
instance, 14% CR rate with XRT + Ipilimumab in a phase II metastatic melanoma trial is contrasted 
with 1.5% CR rate in the phase III trial on the Ipilimumab alone arm29,30. Interestingly, PD-L1 
expression has been proposed as the major mechanism of resistance to the combination of radiation 
therapy and ipilimumab. Therefore, there is a strong rationale to test whether ipilimumab will further 
potentiate the efficacy of SBRT and Nivolumab in MCC21.   
 
1.2.4 
Summary 
We have a compelling rationale for combining Ipilimumab and SBRT with Nivolumab for metastatic 
MCC with our preliminary data suggesting a potential abscopal effect of radiation therapy in MCC 
potentiated by Ipilimumab, and expression of PD-L1 in the majority of MCC patients. Poor prognosis 
associated with metastatic MCC requires development of a new and effective therapeutic modality.  
Therefore, we propose to further augment the therapeutic efficacy of PD1 blockade in patients with 
metastatic Merkel cell carcinoma by the abscopal effect of stereotactic body radiation therapy (SBRT) 
and another immune checkpoint inhibitor, ipilimumab to boost immune priming. The optimal 
sequences of immunotherapy to partner with SBRT to maximize the efficacy of combined treatment 
remain elusive, and this study will allow for direct comparison of the clinical benefit, as measured by 
objective response rate, provided by the addition of SBRT to nivolumab and ipilimumab in MCC. 
Finally, the proposed clinical trial is strategically designed to define the standard treatment regimens 
for metastatic Merkel cell carcinoma with acceptable toxicity. The insights on the synergy of SBRT, 
Nivolumab and Ipilimumab drawn from Merkel cell carcinoma will be applicable to other solid 
cancers.   
 
 
1.3 
Objectives(s) 
 
1.3.1 
Primary Objectives 
• To compare the efficacy, as measured by ORR, provided by nivolumab and ipilimumab versus 

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SBRT plus nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma. 
 
1.3.2 
Secondary Objectives 
• To compare the progression free survival (PFS) of nivolumab and ipilimumab versus SBRT plus 
nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma.  
• To compare the overall survival (OS) of nivolumab and ipilimumab versus SBRT plus nivolumab 
and ipilimumab in subjects with metastatic Merkel cell carcinoma. 
• To evaluate the local control of irradiated tumor provided by SBRT in combination with 
nivolumab and ipilimumab 
• To assess the overall safety and tolerability of nivolumab and ipilimumab versus SBRT plus 
nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma. 
• To evaluate whether PD-L1 expression is a predictive biomarker for ORR; 
• To evaluate the Health Related Quality of Life (HRQoL) as assessed by European Organisation for 
Research and Treatment of Cancer (EORTC) QLQ-C30. 
 
1.3.3 
Exploratory Objectives 
• To evaluate associations between Merkel polyomavirus expression status and clinical efficacy 
(ORR, PFS and overall survival (OS)) 
• To explore potential biomarkers associated with clinical efficacy (ORR, PFS, and OS) 
and/or incidence of adverse events by analyzing biomarker measures within the tumor 
microenvironment and periphery (eg, blood, serum, plasma and PBMCs)  in comparison to 
clinical outcomes 
• To assess changes in health status and work and activity impairment in treatment groups 
using the EuroQol EQ-5D and the Work Productivity and Activity Impairment questionnaire 
(WPAI:GH), respectively. 
 
1.4 
Rationale for Study Design 
 
1.4.1 
Rationale for Studying Merkel Cell Carcinoma  
Merkel cell carcinoma is a rare cutaneous malignancy of neuroendocrine origin, which typically 
occurs in elderly patients in areas of the body with frequent sun exposure including the head and 
neck.1, 2 Merkel cell carcinoma also has a higher incidence in the severely immunosuppressed 
population, and has recently been found to be associated with infection by the Merkel cell 
polyomavirus.3, 4 The incidence of MCC is estimated to be approximately 0.3–0.6/100,000 in the US, 
and it appears to have been increasing over the last few decades31.  
Merkel cell carcinoma is perhaps the most aggressive and lethal primary skin cancer, with a high rate 
of locoregional recurrence and the majority of patients die from distant metastasis. Survival rates at 5 
years range from 23-80%.5-9 Despite the poor prognosis, the rarity of this cancer has limited 
conducting prospective, randomized data guiding to guide treatment. Combined with aggressive 
behavior of this cancer refractory to most systemic agents, it has been difficult to define the standard 
of care in MCC.  
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margins with a sentinel lymph node biopsy10-14. Given the high risk of locoregional recurrence 
following surgery alone, adjuvant radiation therapy (RT) is typically recommended.  
Treatment of metastatic MCC has been a clinical challenge and limited options, such that until 
recently, palliative approach to the management of these patients was acceptable. First-line treatment 
typically involved platinum based chemotherapy etoposide, and the second line chemotherapy 
included irinotecan, topotecan and weekly paclitaxel. Surgery and radiation therapy are palliative 
modalities in metastatic MCC. Unfortunately, the response rate to systemic chemotherapy was low 
with poor durability of responses.  
Therefore, alternative approaches for treatment of MCC have been pursued in recent years including 
targeted biotherapy. A phase II trial of imatinib, based on high expression of KIT in MCC, 
demonstrated median progression-free survival at 1 month and 1 year overall survival rate at 17%32. 
Another multi-tyrosine kinase inhibitor, cabozantinib targeting c-met is being tested in a phase II trial. 
However, promising breakthrough for metastatic MCC came through immunotherapy. 
 
1.4.2 
Immunotherapy in Merkel Cell Carcinoma 
The concept of cancer immunotherapy for MCC is based on several key aspects of this particular 
cancer. First, MCC is a viral-associated cancer expressing viral antigens. Because viral proteins 
represent non-self antigens not encountered in thymus, central tolerance mechanisms are not 
anticipated for these antigens. Furthermore, prior studies have shown that patients indeed generate 
adaptive immune response against Merkel viral T antigen, which correlate with tumor load33,34. 
Interestingly, high antibody titers for VP1 appear to have prognostic significance with improved 
progression-free survival33. Improved prognosis was also observed with increased CD8 tumor-
infiltrating lymphocytes35.  
There are several on-going clinical trials to harness immunogenicity of MCC. One effort is a phase I/II 
clinical trial utilizing MCPyV-reactive autologous T cell therapy for metastatic MCC 
(NCT01758458). Other studies also include intratumoral injection of IL-12 (NCT01440816) or TLR-4 
agonist targeting antigen presenting cells to boost anti-tumoral immunity. A phase II cell-based 
immunotherapy utilizing neukoplast (NK-92) (NCT02465957) is also on-going. However, PD-L1/PD1 
axis appears to be the most promising target for cancer immunotherapy in MCC with an excellent 
response rate. 
1.4.3 
Rationale for ORR as Primary Endpoint with PFS and OS as a 
Secondary Endpoint 
The intention of this trial is to ascertain the clinical responses of MCC to different combinations of 
SBRT and immune checkpoint inhibitors, nivolumab and ipilimumab, in metastatic patients. The rate 
of overall response, complete response and partial response of target lesions will be most sensitive in 
detecting the incremental benefit from the addition of SBRT and/or ipilimumab to PD1 blockade 
alone. Larger patient cohorts in each arm will be required to achieve statistical power detect the 
differences in survival outcomes, PFS and OS, which is not feasible in MCC.    
 
1.4.4 
Rationale for Two Experimental Arm Design  
Merkel cell carcinoma is a rare malignancy with the incidence estimated to be approximately 0.3–
0.6/100,000 in the US31. Merkel cell carcinoma is associated with a high rate of locoregional 
recurrence and the majority of patients die from distant metastasis. Survival rates at 5 years range from 
23-80%.5-9 Despite the poor prognosis, the rarity of this cancer has limited conducting prospective, 

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randomized data guiding to guide treatment. Combined with aggressive behavior of this cancer 
refractory to most systemic agents, it has been a clinical challenge to define the standard of care in 
MCC. Most recently, a promising breakthrough for metastatic MCC came through PD1/PDL1 axis 
blockade36,37. Despite excitement elicited by high response rate to PD1 blockade for metastatic MCC, 
further optimization to maximize the benefit of immunotherapy is of pivotal importance in this 
perhaps most aggressive and lethal skin cancer.  
Therefore, we propose a randomized phase II trial in which both arms of the trial are experimental. By 
employing carefully designed two arm Simon’s two stage design, we will compare both experimental 
arms with the historical control as well as each other. Preclinical and clinical evidence extrapolated 
from other solid malignancies including melanoma suggests improved therapeutic efficacy with 
acceptable additional toxicity in both proposed experimental arms. Such clinical trial design is not 
unprecedented. Indeed, even in NRG-HN002 trial, a randomized phase II trial for patients with p16 
positive, non-smoking associated, locoregionally advanced oropharyngeal cancer (NCT02254278), a 
two arm experimental design has been used to expedite optimization of clinical decision making for 
this relatively common disease entity. Given the rarity of this cancer and absence of standard of care 
with acceptable therapeutic efficacy, a two experimental arm design is justified.  
 
1.4.5 
Rationale for the Dose and Schedule for Nivolumab 
Nivolumab was chosen as one of the experimental drugs because of a favorable risk-benefit ratio as 
seen in the large Phase 1 CA20900338. Additionally, other Phase 2 and 3 studies  in  the  nivolumab  
development  program  use  this  dose  and  regimen.  The dose and schedule of nivolumab in this 
study will be 240 mg every two weeks, which is equivalent to 3mg/kg every two weeks, based upon 
the analyses of safety, efficacy, and exposure-response data from the Phase 1 study CA209003. Anti-
tumor activity was observed at dose levels ranging from 1 to 10 mg/kg in melanoma, NSCLC, and 
RCC, as well as at dose levels of 0.1 and 0.3 mg/kg in melanoma. The anti-tumor activity of 
nivolumab in RCC was investigated at dose levels 1 and 10 mg/kg, with the higher activity observed at 
10 mg/kg. The observed anti-tumor activity in melanoma, and NSCLC was highest at 3 mg/kg, 
suggesting that anti-tumor activity approaches a plateau at dose levels of 3 mg/kg and above. 
Consistent with these observations, the results of the exposure-response analyses for these tumor types 
show that the probability of a tumor response tended to approach a plateau for trough concentrations 
produced by 3 and 10 mg/kg every 2 week dosing. 
Nivolumab was adequately tolerated up to 10 mg/kg, the highest dose level tested, and no MTD was 
identified. Although the spectrum, frequency, and severity of nivolumab-related AEs were generally 
similar across the dose levels tested, the 10 mg/kg doses level had numerically higher Grade 3/4 drug-
related SAEs and AEs leading to discontinuation. Therefore, most prior clinical trials employed 
nivolumab dose of 3 mg/kg Q2W. More recently, a flat dose of 240 mg Q2W has been shown to have 
comparable efficacy and toxicity while simplifying dosing strategy. Therefore, based upon the totality 
of the safety, efficacy, and exposure-response data, a flat dose of 240 mg Q2W was selected as the 
dose anticipated to achieve an appropriate balance of efficacy and risk. 
 
1.4.6 
Rationale for the Dose and Schedule for SBRT 
Studies have demonstrated that SBRT for ablative treatment of non-symptomatic, solitary metastases 
is technically feasible. A high rates of in-field cancer control is achieved with acceptable toxicity.  
The rationale for this dose fractionation opposed to conventional radiation therapy or higher radiation 
dose is several fold. Preclinical studies have demonstrated that high dose per fraction appears to be 

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most immunogenic22,23 leading to immune activation. At this higher dose per fraction, a more 
conformal treatment delivered through SBRT is necessary for safety. Moreover, by completing 
radiation therapy in fewer fractions, we can avoid repeated irradiation to the tumor infiltrating 
lymphocytes, which will render them ineffective. Also, conformal radiation therapy offered by SBRT 
will spare lymphoid tissues where the immune synapse occurs during priming. While definitive and 
adjuvant radiation therapy for MCC has traditionally involved a prolonged course of radiation therapy 
with wider radiation field, a recent study demonstrates that a single fraction of 8Gy radiation therapy 
offers durable palliation in MCC24. Therefore, a more conformal treatment delivered through SBRT is 
more appropriate in the metastatic setting as a modality for systemic immune activation while 
providing local control benefit with minimal acute and long-term toxicities. 
Also of note, most disease sites can be treated safely to a dose far exceeding the proposed dose in this clinical 
trial. However, the intent of higher ablative dose of SBRT is maximal local control in placement of 
surgical approach with acceptable toxicity. Contrarily, the primary goal of SBRT in this clinical trial is 
to induce immune activation. Therefore, we will limit our dose to 24Gy in 3 fractions. This dose 
fractionation can be safely delivered in most disease sites with minimal toxicity with anticipated 
durable local responses in Merkel cell carcinoma24. More importantly, preclinical studies have 
demonstrated superior immunogenicity with this fractionation over a higher ablative dose in a single 
fraction secondary to regulatory T cell recruitment associated with higher radiation dose22,23. In the 
absence of clinical evidence that an alternative dose fractionation is equivalent or superior, 24Gy 
delivered in 3 fractions is deemed optimal to exploit the abscopal effect of radiation therapy.  
SBRT will be delivered the week following initiation of nivolumab and ipilimumab. Because immune 
activation by SBRT is by augmenting immune priming by release of tumor antigen and damage-
associated molecular pattern15, SBRT was deliberately scheduled to follow ipilimumab to ensure that 
CTLA-4 blockade is already present at the time of delivery of SBRT. PD1 blockade has been one of 
the major pathways for T cell tolerance or exhaustion. PD-1 and PD-L1 have been shown to be up-
regulated immediately following ionizing radiation in a preclinical murine model suggesting the 
potential role of this tolerance axis in suppressing immunogenicity of SBRT16 (Fig 3). Therefore, 
nivolumab will also be initiated the week prior to SBRT. 
 
1.4.7  
Rationale for the Dose and Schedule for Ipilimumab 
In MDX010-20 (metastatic or unresectable setting), the ipilimumab monotherapy arm was 
administered 3 mg/kg ipilimumab every 3 weeks for four doses with acceptable toxicity. However, in 
combination with nivolumab, 3 mg/kg of ipilimumab elicited significant toxicity in Checkmate-067 
trial for metastatic melanoma despite improved objective response rate with over 50% of patients 
unable to complete the study drugs in the combined arm39. Subsequently, a number of clinical trials 
testing combination of nivolumab and ipilimumab adopted lower dose of ipilimumab with acceptable 
toxicity profiles while retaining improved efficacy28. Of particular note, Checkmate-012 study has 
demonstrated ipilimumab at 1mg/kg Q6W in combination with nivolumab 3mg/kg Q2W is safe with 
significantly improved efficacy in comparison to nivolumab alone40. This combination regimen is also 
being used for Checkmate-358 study, which includes patients with metastatic Merkel cell carcinoma. 
Therefore, we will utilize ipilimumab at 1 mg/kg Q6W in combination with nivolumab in this trial.  
 
1.4.8 
Rationale for Treating until Progression, Unacceptable Toxicity, or 
Withdrawal of Consent 
Throughout the nivolumab and/or ipilimumab development program, most protocols have dosed until 
progression, unacceptable toxicity, or withdrawal of consent in the metastatic setting. In the absence of 

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dose-limiting toxicity, the treatment duration for metastatic cancer in many prior trials was usually not 
restricted. However, these therapeutic agents also come with toxicity. For instance, despite the 
protocol specified treatment duration of 3 years in EORTC 1807141 the median number of doses 
received for subjects in the ipilimumab arm was 7, corresponding to approximately 1 year duration of 
treatment. Additionally, there was a large decline in subjects still receiving dosing at the end of 
induction as compared to those still receiving dosing at the end of 1 year42. Furthermore 48.8% of 
subjects in the ipilimumab arm discontinued treatment due to adverse events related to study drug.  
It should be also noted that the combination of both nivolumab and ipilimumab is associated with 
significantly increased toxicity. In the double-blind, multicenter phase 3 trial (CheckMate 067)25 
testing the safety and efficacy of nivolumab plus ipilimumab versus nivolumab and ipilimumab 
monotherapies, a significant increase in toxicity was seen in the combination group: grades 3–4 
adverse events occurred in 55 % of patients, compared to 16.3 % in patients treated with nivolumab 
alone, and 27.3 % of patients treated with ipilimumab. Treatment-related adverse events leading to 
therapy discontinuation occurred in 36.4, 7.7, and 14.8 % of patients, respectively (most commonly 
diarrhea, fatigue, and pruritus).  
Therefore, in order to minimize toxicity leading to discontinuation of study drug while maintaining 
efficacy of either study drug, ipilimumab is limited to 4 doses while nivolumab will continued until 
progression, unacceptable toxicity or withdrawal of consent.  
 
1.4.9 
Rationale for Evaluation of PD-L1 as a Predictive Biomarker of Efficacy 
PD-L1 is expressed by many tumor types and its expression has been noted to correlate with decreased 
immune system function and worse clinical prognosis. It is hypothesized that PD-L1 expression within 
the tumor microenvironment, either on tumor cells, macrophages or lymphocytes is a means of 
evading immune system detection and destruction. Still others postulate that PD-L1 expression on 
tumor cells is a surrogate for interferon-gamma release from neighboring activated T cells and thus 
portends a good prognosis for immunotherapy agents, and in particular, agents targeting the PD-1/PD-
L1 axis. Preliminary data from two small retrospective analyses supports the latter hypothesis in 
metastatic melanoma. PD-L1 positive status was associated with improved OS, irrespective of 
treatment, relative to PD-L1 negative status in subjects with metastatic melanoma (n = 56)43. 
Similarly, objective responses to nivolumab were limited to subjects defined as PD-L1 positive in a 
subset of subjects from study CA209003  (n  =  42),  which  included  18  melanoma  subjects44. In  
both  of  these  studies,  a prototype IHC assay was used and PD-L1 positive status was defined as 5% 
tumor cell membrane staining or higher within a tumor tissue sample.  
In our retrospective study of cohort of 91 patients with Merkel cell carcinoma, 53.8% of patients 
demonstrated PD-L1 expression, and higher stage correlated with higher percentage of patients with 
PD-L1 expression (Table 1). Similar results have been observed by other groups9. The clinical 
significance of PD-L1 expression as a prognostic and predictive marker for immunotherapy in MCC 
needs to be further defined, but studies from other disease sites, most prominently from melanoma 
suggests that PD-L1 positivity is associated with clinical response to nivolumab.  
Tumor biopsy specimens from melanoma subjects treated with nivolumab or nivolumab in 
combination with ipilimumab across three Phase 1 metastatic melanoma studies (CA209003, 
CA209004 and CA209006) and one Phase I study of completely resected Stage III or Stage IV NED 
melanoma (CA209007) were evaluated for PD-L1 expression. Using a cutoff of 5% tumor cell 
membrane staining, the PD-L1 positivity rate ranged from 27% to 45%45-47 consistent with the rate 
previously reported by Taube et al43 at 45% (24/56 subjects) in metastatic melanoma. Importantly, in 

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the setting of resected Stage III or Stage IV NED in CA209007, a nonsignificant trend for improved 
RFS was observed in PD-L1-positive subjects versus PD-L1-negative subjects at both a 1% and 5% 
tumor cell expression cut-off45. Therefore, PD-L1 expression may be a prognostic marker that may 
also predict for nivolumab clinical activity.  
 
1.4.10 
Rationale for Quality of Life Evaluation 
Available chemotherapy to treat patients with metastatic Merkel cell carcinoma has been been 
associated with substantial toxicities and unclear clinical benefit. Evaluating quality of life (QoL) in 
oncology clinical studies is becoming increasingly important to understand the impact of benefit/risk 
from the patient perspective, and for quality of life adjustments for survival data used in economic 
models supporting access of new drugs. However, QoL data from investigational trials in this 
population are just emerging.  
The EORTC QLQ C-30 will be used to assess changes from baseline of patients’ QoL during and after 
treatment in the different arms of the study. The EQ-5D will be used to assess general health status and 
the data will be used to calculate utilities for use in economic models. The WPAI:GH questionnaire for 
measure of work and activity impairment exhibits strong validity and reliability, plus the ability to 
evaluate the results on impairment in financial terms. Employers are increasingly concerned about the 
burden of illness in their workforce and the associated financial impact. Additionally, some payers of 
healthcare and prescription drugs may want assurance that all cost implications have been considered. 
The costs of lost productivity, in addition to standard direct healthcare costs are increasingly required 
to meet requirements from health authorities for a broader societal perspective. The cost of lost 
productivity as measured by the WPAI:GH will as a result be included as a key cost component of the 
cost-effectiveness model of nivolumab. 
With the emergence of patients that experience long-term survival with immunotherapies, payers, 
physicians and patients are beginning to question not only about the duration of survival (OS) but also 
the quality of survival after treatment discontinuation. Therefore, the EQ-5D-VAS will be utilized to 
assess the quality of survival during the follow-up and survival phase of the trial. 
 
1.5 Product Development Background 
 
1.5.1 
Nivolumab Mechanism of Action 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than as 
self and can be effectively attacked by an activated immune system. An effective immune response in 
this setting is thought to rely on immune surveillance of tumor antigens expressed on cancer cells that 
ultimately results in an adaptive immune response and cancer cell death. This functions by aborting 
the emergence of tumors as they arise and/or causing tumor shrinkage where it is present. Meanwhile, 
tumor progression may depend upon acquisition of traits that allow cancer cells to evade immune 
surveillance  and an effective immune response48. This evasion may occur by exploiting any of the 
checkpoints that control the regulatory immune response, including display of antigens and control of 
co-stimulatory pathways that affect the proliferation of cells involved in immunity. Current 
immunotherapy efforts attempt to break the apparent tolerance of the immune system to tumor cells 
and antigens by either introducing cancer antigens by therapeutic vaccination or by modulating 
regulatory checkpoints of the immune system - either directly by stimulation of immune cells by 
antibodies directed to receptors on T and B cells or indirectly by cytokine manipulation. T-cell 
stimulation is a complex process involving the integration of numerous positive, as well as negative, 

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costimulatory signals in addition to antigen recognition by the T-cell receptor (TCR)49. Collectively, 
these signals govern the balance between T-cell activation and tolerance to antigens48. 
Programmed death  receptor-1  (PD-1,  CD279),  a  55  kD  type  I  transmembrane  protein,  is a 
member of the CD28 family of T-cell costimulary receptors that also includes CD28, CTLA-4, ICOS, 
and BTLA.5 PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine inhibitory 
motif (ITIM) and a membrane distal immunoreceptor tyrosine-based switch motif (ITSM). Two 
ligands specific for PD-1 have been identified: PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273). 
PD-L1 and PD-L2 have been shown to down-regulate T-cell activation upon binding to PD-1 in both 
murine and human systems50,51. PD-1 delivers a negative signal by the recruitment of a protein 
tyrosine phosphatase SHP-2 to the phosphorylated tyrosine residue in the ITSM in its cytoplasmic 
region52,53. PD-1 is primarily expressed on activated T cells, B cells and myeloid cells54.  
Further evidence for a negative regulatory role of PD-1 comes from studies of PD-1-deficient mice. 
PD-1-deficient mice develop various autoimmune phenotypes, including dilated cardiomyopathy, a 
lupus-like syndrome with arthritis and nephritis, and accelerated diabetes mellitus55-57. The emergence 
of these autoimmune phenotypes is dependent upon the genetic background of the mouse strain and 
many of these phenotypes emerge at different times and show variable penetrance. In addition to the 
phenotypes of null mutations, PD-1 inhibition by antibody-mediated blockade in several murine 
models has been found to play a role in the development of autoimmune diseases such as 
encephalomyelitis, graft-versus-host disease, and type I diabetes58,59. Taken together, these results 
suggest that PD-1 blockade has the potential to activate anti-self T-cell responses, but these responses 
are variable and dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is 
not accompanied by a universal loss of tolerance to self antigens. 
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal antibodies 
(mAbs) can enhance the anti-tumor immune response and result in tumor rejection. Antitumor activity 
by PD-1 blockade functions in PD-L1+ tumors as well as in tumors that are negative for  the  
expression  of  PD-L160-65. This  suggests  that  host  mechanisms (ie, expression of PD-L1 in antigen-
presenting cells) limit the antitumor response. Consequently, both PD-L1 positive and negative tumors 
may be targeted using this approach. In humans, constitutive PD-L1 expression is normally limited to 
macrophage-lineage cells, although expression of PD-L1 can be induced on other hematologic cells as 
well, including activated T cells. However, aberrant expression of PD-L1 by tumor cells has been 
reported in a number of human malignancies66-72. PD-L1  expressed  by  tumor  cells  has  been  shown  
to enhance apoptosis of activated tumor-specific T cells in vitro54. Moreover, the expression of PD-L1 
may protect the tumor cells from the induction of apoptosis by effector T cells73. Retrospective 
analyses of several human  tumor  types  suggest  that  tumor  over-expression (as measured by 
immunohistochemistry (IHC)) of PD-L1 may permit immune evasion by tumors. In renal cell 
carcinoma, high surface expression levels of PD-L1 on tumor cells are related to tumor 
aggressiveness69,70. Subjects with high tumor and/or lymphocyte PD-L1 levels are 4.5 times more 
likely to die from their cancer than subjects exhibiting low levels of PD-L1 expression. In addition, in 
multivariate analysis, high expression of PD-L1 is correlated to have a worse overall survival rate 
compared to low expression levels of PD-L174.  
Nivolumab is a fully human, IgG4 (kappa) isotype, mAb that binds PD-1. Blockade of the PD-1 
pathway by nivolumab was studied using the mixed lymphocyte reaction (MLR). PD-1 blockade 
resulted in a reproducible enhancement of both proliferation and IFN- release in the MLR75. The   
effect   of   nivolumab   on   antigen-specific   recall   response   was   investigated   using a 
cytomegalovirus (CMV) -restimulation assay with human peripheral blood mononuclear cells 
(PBMCs), and was evaluated by an enzyme-linked immunosorbent assay (ELISA). These data 

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indicated that nivolumab, versus an isotype-matched control antibody, augmented IFN-g secretion 
from CMV-specific memory T-cells in a dose-dependent manner. PD-1 blockade by nivolumab is 
therefore considered a promising immunotherapeutic option. 
 
1.5.2 
Ipilimumab Mechanism of Action 
Traditional cytotoxic approaches to the treatment of cancer are associated with efficacy and toxicity 
limitations. Thus, there is a clinical need for the development of new therapies for the treatment of 
cancer. Blockade of CTLA-4 (CD152) is a novel approach to the treatment of human malignancies 
that offers an immune-mediated alternative to cancer treatment. CTLA-4 is an activation-induced T-
cell surface molecule. CTLA-4-mediated signals are inhibitory and turn off T-cell dependent immune 
responses. Disrupting CTLA-4 interaction with its ligands B7-1 (CD80) and B7-2 (CD86), which are 
expressed on APCs, augments immune responses. In vivo blockade of CTLA-4, utilizing anti-CTLA-4 
monoclonal antibody (mAb), induced regression of established tumors and enhanced anti-tumor 
immune responses in several murine tumor models. Blockade of CTLA-4-mediated signals is effective 
in inducing rejection of immunogenic cancers in mice. Moreover, when anti-CTLA-4 mAb is used in 
conjunction with granulocyte macrophage colony stimulating factor-secreting tumor vaccines, poorly 
immunogenic cancers in mice are rejected. These findings suggest that CTLA-4 blockade, alone or in 
combination with vaccines, can induce a potent anti-tumor response. 
Advances in understanding the mechanisms regulating T-cell activation have allowed the development 
of better strategies for the immunotherapy of tumors and infectious diseases. Full activation of naïve T 
cells requires not only stimulation of the antigen receptor by peptide/major histocompatability 
complexes, but also co-stimulatory signals mediated by engagement of CD28 by B7 molecules76. T 
cells constitutively express CD28 and expression of B7 molecules is limited to APCs, such as 
dendritic cells, activated macrophages, and activated B cells76. CD28-B7 co-stimulatory signals are 
critical for the induction of T-cell proliferation, cytokine secretion, and effector functions. 
Mechanisms have evolved that regulate and restrict T-cell activation. CTLA-4 (CD152) is an 
activation-induced T-cell surface molecule that also binds CD80 and CD86, but with greater avidity 
than CD28. CTLA-4 ligation down-regulates T-cell responses. Several studies have demonstrated that, 
in vitro, soluble anti-CTLA-4 mAb enhanced T-cell responses, whereas directly crosslinking CTLA-4 
results in blockade of cell cycle progression, diminished cytokine expression, and decreased 
proliferation77-80. Blockade of CTLA-4/B7 interactions prevents induction  of  peripheral  T-cell  
tolerance  upon  vaccination  with  peptides  under  tolerogenic conditions, suggesting that CTLA-4 is 
involved in the induction of anergy81. 
In addition to being expressed on activated effector T cells, CTLA-4 is constitutively expressed on the 
surface of T-regulatory cells. T-regulatory cells suppress immune responses, but the role of CTLA-4 in 
this process is controversial82. The observation that CTLA-4 knockout mice suffer a fatal 
lymphoproliferative disorder supports the idea that CTLA-4 functions as a key negative regulator of T-
cell responses83-85. However, blockade of CTLA-4 function by the antibody does not lead to any 
detectable non-specific T-cell activation or proliferation, although the antibody can augment 
autoimmune responses in mice prone to specific autoimmune disease86. Using anti-CTLA-4 mAbs, 
CTLA-4 blockade enhanced rejection of B7 transfected tumors and induced rejection of unmodified 
tumor cells and immunity to rechallenge in a T-cell-dependent mechanism87. Blockade of CTLA-4 
interaction with its ligands also enhances host responses against bacteria88 and parasites89 and limits 
viral spread in human immunodeficiency virus-infected T cells in vitro90. 
 

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1.5.3 
SBRT Background 
Stereotactic Body Radiotherapy (SBRT) reduces the overall time of radiation treatment and offers a 
greater potential for cell kill compared to standard fractionation schemas of 1.8-3.0 Gy/Day. This 
technique allows for rapid delivery of tumorcidal doses of radiotherapy and provides ablative 
treatment to metastases. The significance of this approach is several fold. First, a highly conformal 
radiation therapy targeting the metastatic tumor burden can be delivered in high dose per fraction 
safely with minimal normal tissue toxicity. Second, by avoiding normal tissue irradiation, we may 
maximize immunogenic cell death from tumor cells while minimizing immune tolerance mechanisms 
evoked by irradiation of normal tissue. Third, SBRT is rapidly deployable and can be delivered to 
metastatic lesions with little or no interruption of systemic therapy allowing a tightly coordinated 
schedule in combination with nivolumab and/or ipilimumab.  
Studies have demonstrated that SBRT for ablative treatment of non-symptomatic, solitary metastases 
is technically feasible, with acceptable toxicity and high rates of in-field cancer control91,92.  SBRT or 
ablative RT approaches have been studied in many clinical trials in different disease sites including 4 
Radiation Therapy Oncology Group (RTOG) clinical trials: RTOG 0236, 0813/0915, 0438 and 0613 
for solitary lesions in lung, liver and spinal metastases respectively in a cooperative group trial setting. 
These trials have provided a framework for successful delivery and quality assurance of complex 
radiotherapy in the cooperative group setting. These trials have demonstrated that ablative doses with 
the Biologically Effective Dose (BED) >100 are needed to achieve high control rates in several disease 
sites for definitive management.  
 
1.5.4 
Summary of Safety 
Nivolumab Monotherapy 
One Phase 1 study (CA209003) has contributed much to the clinical experience with nivolumab 
monotherapy in subjects with melanoma and other solid malignancies38. CA209003 is a Phase 1 open 
label, multiple dose escalation study in 304 subjects with select previously treated advanced solid 
tumors, including melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), 
colorectal cancer, and hormone-refractory prostate cancer. Subjects received nivolumab at doses of 
0.1, 0.3, 1, 3 or 10 mg/kg intravenously every 2 weeks, up to a maximum of 2 years of total therapy. 
As of 03-Jul-2012, a total of 107 melanoma subjects were treated with nivolumab in the dose range of 
0.1 - 10 mg/kg. 
No maximal tolerated dose was identified in CA209003. The incidence, severity and relationship of 
AEs were generally similar across dose levels and tumor types. Nivolumab related AEs of any grade 
occurred in 72.4% of subjects. The most frequent nivolumab related AEs occurring in over 5% of 
subjects included: fatigue (25.7%), rash (13.5%), diarrhea (11.8%), pruritis (10.2%), nausea (7.9%), 
decreased appetite (7.9%), hemoglobin decreased (5.9%) and pyrexia (5.3%). The majority of events 
were low grade, with Grade 3 - 4 drug related AEs observed in 14.8% of subjects. The most common 
Grade 3 - 4 drug-related AEs occurring in over 1% of subjects were: fatigue (1.6%), lymphopenia 
(1.3%), abdominal pain (1%), diarrhea (1%), hypophosphatemia (1%) and pneumonitis (1%). At least 
one SAE was reported for 150 (49.3%) of the 304 subjects at all dose levels. Grade 3 - 4 SAEs were 
reported for 23 subjects (7.6%). Drug-related SAEs occurred in 11.5% of subjects. Grade 3 - 4 drug-
related SAEs reported in at least 2 subjects included: diarrhea (3 subjects, 1.0%), pneumonitis (3 
subjects, 1.0%), pneumonia (2 subjects, 0.7%) and lipase increased (2 subjects, 0.7%). Additional 
select treatment-related AEs have occurred with low frequency (< 5%) but are considered clinically 
meaningful, as they require greater vigilance for early recognition and prompt intervention. These AEs 

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include: ALT increased   (4.3%),   AST   increased   (3.6%),   pneumonitis   (3.3%),   hypothyroidism   
(3.0%), hyperthyroidism (1.3%), renal failure (1.0%), adrenal insufficiency (0.7%) and colitis (0.7%). 
Grade 3 - 4 events of pneumonitis were reported in 3 subjects (1.0%) as described above (1 event was 
Grade 4). Grade 3 events of colitis, ALT increased, and AST increased were reported in 2 subjects 
(0.7%) each. Grade 3 events of adrenal insufficiency, hyperthyroidism, and hypothyroidism were 
reported in 1 subject (0.3%) each. Treatment-related AEs leading to discontinuation were reported in 
18 (5.9%) of the 304 treated subjects on CA209003. Of the treatment-related AEs leading to 
discontinuation, the only events reported in more than 1 subject were pneumonitis (4 subjects; 1.3%) 
and hepatitis (2 subjects; 0.7%). There were 3 (1%) drug related deaths; each occurred after 
development of pneumonitis. Additional details on the safety profile of nivolumab, including results 
from other clinical studies, are also available in the nivolumab IB. 
Ipilimumab Monotherapy 
In MDX010-20 (metastatic or unresectable setting), the ipilimumab monotherapy arm was 
administered 3 mg/kg ipilimumab every 3 weeks for four doses. In this arm, there were 79% drug 
related adverse events, with 21% being Grade 3/4 and 3/131 (2%) being Grade 593. The most frequent 
adverse events of interest were pruritis (33%), diarrhea (33%), rash (30%), colitis (8%), endocrine 
disorders (9%), (aspartate aminotransferase) AST/ (alanine aminotransferase) ALT increased (2%), 
and hepatitis (1%). Any grade immune related adverse events were 60% and the Grade 3/4 immune 
related adverse events for the same cohort was 13% with  the  most  frequent  adverse  events  being  
diarrhea  (5%),  colitis  (5%),  rash  (2%),  and endocrine disorders (3%)30. Additional details on the 
safety profile of ipilimumab, including results from other clinical studies, are also available in the 
ipilimumab IB. 
Nivolumab and Ipilimumab dual therapy 
The safety profile of delivering nivolumab and ipilimumab concurrently was evaluated in a phase I 
trial in melanoma27. Among the 53 patients, grade 3 or 4 adverse events, regardless of attribution, were 
observed in 72% of patients, and grade 3 or 4 treatment-related events were noted in 53%, with the 
most common events being elevated levels of lipase (in 13% of patients), aspartate aminotransferase 
(in 13%), and alanine aminotransferase (in 11%). A total of 6 of 28 patients (21%) had grade 3 or 4 
treatment-related events that were dose-limiting. Nivolumab at a dose of 3 mg per kilogram and 
ipilimumab at a dose of 3 mg per kilogram exceeded the maximum doses that were associated with an 
acceptable level of adverse events (three of six patients had asymptomatic grade 3 or 4 elevated lipase 
levels that persisted for ≥3 weeks). The doses in of nivolumab at 1 mg per kilogram and ipilimumab at 
3 mg per kilogram were identified as the maximum doses that were associated with an acceptable level 
of adverse events (grade 3 uveitis in one patient and grade 3 elevated levels of aspartate 
aminotransferase and alanine aminotransferase in one). Given significant toxicity associated with full 
doses of nivolumab and ipilimumab, dose reduction in ipilimumab was further evaluated in NSCLC 
(Checkmate-032)94. In this study, grade 3 or 4 treatment-related adverse events occurred in ten (19%) 
of 54 patients in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort. The most commonly 
reported grade 3 or 4 treatment-related adverse events were increased lipase and diarrhea. Eight 
patients (15%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort had dose delays due to 
treatment-related adverse events. The most frequent serious adverse events were dyspnea experienced 
by nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort, and diarrhoea, experienced by two (4%) 
patients in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort. 4 (7%) patients discontinued 
treatment because of treatment-related adverse events: one patient each with colitis, pneumonitis, and 
peripheral neuropathy; one patient with dyspnea and pneumonitis. Combination of full dose PD1 
blockade (pembrilozumab) with low dose ipilimumab was further studied in Keynote-029 study95. 

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This phase I/II study of pembrolizumab 2 mg/kg plus low-dose IPI 1 mg/kg every 3 weeks (Q3W) for 
4 doses, followed by pembrolizumab 2 mg/kg Q3W for up to 2 years, demonstrated grade 3 toxicities 
in 6 of 19 evaluable pts (2 of 9 renal cell carcinoma patients, 4 of 10 melanoma patients). Two patients 
experienced 2 grade 3 toxicities each: elevation of pancreatic enzymes and hyperthyroidism in 1 
patient and lipase elevation and pneumonitis in another patient. The remaining grade 3 toxicities were 
ALT/AST elevation (n = 2), colitis (n = 1), and uveitis (n = 1).  
SBRT 
The safety of SBRT technique in various disease sites has been extensively studied. RTOG 023696 was 
a multicenter phase II trial for peripheral T1-T2 N0M0 non-small cell lung cancer. A total of 59 
patients were accrued for the study, and 55 were evaluable. Patients each received three fractions of 18 
Gy (54 Gy total) of SBRT, and treatment lasted between one-and-a-half to two weeks. Treatment-
related grade three and grade four side effects were reported in 15 patients and in two patients, 
respectively. No grade five adverse events were reported. Another phase II clinical trial evaluated the 
role of SBRT in colorectal liver metastases97. Forty-two patients with inoperable colorectal liver 
metastases not amenable to radiofrequency ablation (RFA) were treated with SBRT for a total number 
of 52 lesions. All patients received a total dose of 75 Gy in 3 consecutive fractions. No patients 
experienced radiation-induced liver disease or grade ≥3 toxicity. RTOG 0631 was a multicenter phase 
II/III trial to assess the feasibility and safety of spine radiosurgery (SRS) for localized spine metastases 
in a cooperative group setting. Patients with 1-3 spine metastasis received 16 Gy single fraction SRS. 
Forty-six patients were accrued, and 44 were eligible. There were 4 cervical, 21 thoracic and 19 
lumbar sites. There were no cases of grade 4-5 acute treatment-related toxicity98. A phase II 
prospective trial also evaluated SBRT for unresectable locally recurrent head and neck squamous cell 
carcinoma99. 50 patients with recurrent head and neck cancer within a previously irradiated field that 
received ≥60 Gy were enrolled. Patients received concurrent cetuximab plus SBRT (40-44 Gy in 5 
fractions on alternating days over 1-2 weeks). Acute and late grade 3 toxicity was observed in only 6% 
of patients despite SBRT was given in re-irradiation setting. SBRT was also evaluated for patients 
with locally advanced pancreatic cancer and borderline resectable pancreatic cancer treated at the 
Moffitt Cancer Center. A retrospective review of 72 pancreatic patients treated with a median dose of 
35Gy in 5 fractions demonstrated no acute grade 3 toxicity, and late grade 3 toxicity was minimal 
5.3%100. 
This clinical trial was designed to deliver radiation therapy with minimal additional toxicity to 
nivolumab and ipilimumab. First, this clinical trial utilizes SBRT, which allows conformal radiation 
delivery with minimal radiation spillover to the surrounding normal tissue to prevent toxicity. We will 
only be treating the gross tumor with tight margin with a rapid dose fall off allowing minimal normal 
tissue irradiation. Second, the dose of SBRT in this trial is far lower than the regular SBRT doses in 
various sites. For instance, the typical SBRT dose for a lung lesion or a liver lesion is 20Gy x 3 
fractions. In this trial we are only prescribing to 8Gy x 3 fractions with minimal toxicity anticipated. 
Third, we are also allowing simultaneous integrated boost, or dose-painting. This technique will allow 
8Gy x 3 fractions to the center of the tumor, but at the periphery of the tumor adjacent to the normal 
tissue, we can lower the dose to 5Gy x 3 fractions, further ensuring safety profile.  
 
1.5.5 
Summary of Clinical Activity 
Nivolumab Monotherapy 
Several immune checkpoint inhibitors targeting PD1 or PD-L1 are being tested currently. A recent 
interim report of phase I/II trial of metastatic treatment-naive MCC patients on pembrilozumab 
reported 14% complete response rate10. Therefore, we anticipate a significant therapeutic efficacy of 

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nivolumab in MCC, which is being evaluated in an on-going multi-institutional clinical trial on 
Nivolumab alone for virus-associated cancers including MCC conducted by BMS.  
Otherwise, the clinical activity of nivolumab was demonstrated in multiple tumor types. In 
CA20900338 the clinical activity of nivolumab was demonstrated in melanoma, RCC, and NSCLC. 
Clinical activity was noted across a range of doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 
mg/kg). In CA209003, as of the clinical cut-off date of 03-Jul-2012, a total of 304 subjects with 
melanoma, RCC, and NSCLC have been evaluated for clinical activity. A response of either CR or 
PR, as determined by investigator assessed tumor evaluations based on modified RECIST 1.1, has 
been reported at all dose levels. No responses (CR or PR) have been reported in subjects with 
colorectal carcinoma or castrate-resistant prostate cancer. 
Among 106 subjects with advanced melanoma who received nivolumab and were evaluable for 
response, the preliminary objective response rates were 6/17 (35%), 5/18 (28%), 11/34 (32%), 7/17 
(41%), and 4/20 (20%) for melanoma subjects treated at 0.1, 0.3, 1, 3, and 10 mg/kg, respectively. 
Duration of response range from 3.6 to 11.2, 1.8 to 9.2, 1.9 to 24.9, 9.2 to 22.4, and 17.0 to 25.7 
months in the melanoma subjects treated at 0.1, 0.3, 1, 3, and 10 mg/kg, respectively. Stable disease 
over 24 weeks occurred in an additional 1/18 (6%), 4/34 (12%), 1/17(6%) melanoma subjects at 0.3, 1, 
and 3 mg/kg, respectively. Finally, the PFS-24 week was 41%, 33%, 48%, 55%, and 30% in 
melanoma subjects treated at 0.1, 0.3, 1, 3, and 10 mg/kg, respectively. 
SBRT Monotherapy 
The local control rate of irradiated tumors following SBRT is excellent. For instance, five-year local 
control rate stage I non-small cell lung cancer patients treated with 54 Gy in 3 fractions is in excess of 
80%96. On a particular note, MCC metastases treated with SBRT to 8Gy in a single fraction achieved 
complete responses in 45% of tumors with durable local control in 77% of treated tumors with a 
median follow up of 277 days24.  
The abscopal effect or the capacity of radiation therapy to impact tumors outside the radiation field has 
been recognized for several decades in case reports14. However, its clinical relevance had not been 
fully recognized until recent years. With the advent of immune checkpoint inhibitors, the abscopal 
effect has been more formally tested in clinical trials101. Most recent evidence for the abscopal effect 
of radiation therapy is found with metastatic melanoma. A phase II clinical trial of 20 patients with 
metastatic melanoma treated with combination of radiation therapy and systemic ipilimumab (3 
mg/kg) every three weeks for a total of four treatment cycles demonstrated 55% objective response 
rate including a 9.1% complete response, far exceeding the historical control for ipilimumab alone29. 
Multiple other clinical trials are on-going to evaluate the efficacy of radiation therapy in combination 
with systemic immunotherapy101.  
Ipilimumab Monotherapy  
Ipilimumab has not been directly tested in Merkel cell carcinoma. The anticipated clinical activity in 
MCC is inferred from its efficacy in other solid cancers, most prominently another skin cancer, 
melanoma. In melanoma, a completed Phase 3 study (MDX010-20)93 has demonstrated a clinically 
meaningful and statistically significant survival benefit in pre-treated advanced melanoma. The study 
compared the OS of ipilimumab plus a melanoma-specific vaccine (gp100) to that of gp100 alone. A 
second comparison defined the OS of ipilimumab alone vs gp100 alone. Both comparisons 
demonstrated statistically significant improvements in OS (P = 0.0004 and 0.0026, respectively). The 
1-year survival for the two ipilimumab-containing groups, respectively, was 44% and 46% 
respectively, compared to 25% for the gp100 control group. The 2-year survival was 22%, 24% and 

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14% respectively. The median survival was 10, 10.1, and 6.4 months, for ipilimumab plus gp100, 
ipilimumab monotherapy, and gp100 monotherapy, respectively. 
 
1.5.6 
Clinical Pharmacology Summary 
Ipilimumab Monotherapy 
Ipilimumab has a terminal half-life of approximately 15.4 days. The expected in vivo degradation of 
monoclonal antibodies is to small peptides and amino acids via biochemical pathways that are 
independent of cytochrome P450 enzymes. 
The PPK of ipilimumab was studied with 785 subjects (3200 serum concentrations) with advanced 
melanoma in 4 Phase 2 studies (CA184004, CA184007, CA184008, and CA184022)102, one Phase 3 
study (CA184024) and one Phase 1 study (CA184078). The PPK analysis demonstrated the PK of 
ipilimumab is linear and exposures are dose proportional across the tested dose range of 0.3 mg/kg to 
10 mg/kg, and the model parameters are time-invariant, similar to that determined by 
noncompartmental analyses. 
Upon repeated dosing of ipilimumab, administered q3w, minimal systemic accumulation was observed 
by an accumulation index of 1.5-fold or less and ipilimumab steady-state concentrations were 
achieved by the third dose. The ipilimumab CL of 16.8 mL/h from PPK analysis is consistent with that 
determined by noncompartmental PK analysis. The terminal T-HALF and Vss of ipilimumab 
calculated from the model were 15.4 days and 7.47 L, respectively, which are consistent with that 
determined by noncompartmental analysis. Volume of central compartment (Vc) and peripheral 
compartment were found to be 4.35 L and 3.28 L, respectively, suggesting that ipilimumab first 
distributes into plasma volume and, subsequently, into extracellular fluid space. CL of ipilimumab and 
Vc were found to increase with increase in BW. However, there was no significant increase in 
exposure with increase in BW when dosed on a mg/kg basis, supporting dosing of ipilimumab based 
on a weight normalized regimen. The PK of ipilimumab is not affected by age, gender, race, 
immunogenicity (anti-drug antibody status), concomitant use of chemotherapy, prior therapy, BW, 
performance status, or tumor type. Other covariates had effects that were either not statistically 
significant or were of minimal clinical relevance. Additional details are provided in investigator 
brochure. 
Nivolumab Monotherapy 
Single-dose PK of nivolumab was evaluated in subjects with multiple tumor types in MD1106-
01 whereas multiple dose PK  is  evaluated  in  subjects  in  CA209003.  In  addition, a population 
pharmacokinetic (PPK) model has been developed with data from ± 909 subjects from  
MDX1106-01103, ONO-4538-01104, ONO-4538-02105, CA20900338, and  CA209010106 in subjects 
with progressive advanced/metastatic clear-cell renal cell carcinoma (RCC) who have received 
prior anti-angiogenic therapy, CA209063107 and CA209037108. The body weight normalized dosing 
produces approximately constant trough concentrations over a wide range of body weight, and 
hence is appropriate for future clinical trials of nivolumab. Clearance of nivolumab is similar in all 
tumor types studied and is independent of dose range studied (0.1 to 10 mg/kg). 
Single-dose PK of nivolumab was evaluated in 39 subjects with multiple tumor types in study 
MDX1106-01 in the dose range of 0.3 to 10 mg/kg. The median Tmax across single doses 
ranged from 1.6 to 3 hours with individual values ranging from 0.9 to 7 hours. The PK of 
nivolumab is linear in the range of 0.3 to 10 mg/kg with dose proportional increase in Cmax and 
AUC(INF) with low to moderate  inter-subject  variability  observed  at  each  dose  level (ie, 

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coefficient of variation (CV) ranging from 7 to 45%). Geometric mean clearance (CL) after a single 
intravenous (IV) dose ranged from 0.13 to 0.19 mL/h/kg, while mean volume of distribution (Vz) 
varied between 83 to 113 mL/kg across doses. The mean terminal T-HALF of nivolumab is 17 to 
25 days, which is consistent with half-life of endogenous IgG4, indicating that the elimination 
mechanism of nivolumab may be similar to IgG4. Both elimination and distribution of nivolumab 
appear to be independent of dose in the dose range studied. Additional details are provided in the 
Investigator Brochure. 
1.6 
Overall Risk/Benefit Assessment 
There continues to be a significant unmet need for patients with metastatic Merkel cell carcinoma. 
This is illustrated by poor survival outcome in patients with metastatic MCC and that there is no 
standard of care treatment in metastatic MCC.  
Nivolumab monotherapy has demonstrated clinical activity across several tumor types, including 
advanced prior-treated melanoma, with objective response rates of 20 - 41% in 106 melanoma subjects 
treated at various dose levels in CA209003. The most common AEs of nivolumab monotherapy 
included fatigue, rash, pruritis, diarrhea, and nausea. MCC appears to be also strongly responsive to 
PD1 blockade and there is an on-going study of nivolumab alone in metastatic MCC. 
Ipilimumab has shown to enhance the therapeutic efficacy of nivolumab in several tumor types 
including melanoma and NSCLC. The most common AEs of ipilimumab include rash, pruritis, 
diarrhea, colitis, and endocrine disorders. 
Given the high discontinuation rate due to toxicity with ipilimumab 3 mg/kg in combination with 
nivolumab, a data safety monitoring committee will be involved to periodically evaluate the emerging 
data and trends. 
It is the hypothesis of the trial that there will be improvements in ORR by the addition of SBRT and/or 
ipilimumab to nivolumab in metastatic MCC. The robust clinical activity demonstrated by PD1 
blockade in metastatic MCC, the proven benefit of SBRT and ipilimumab in subjects with various 
solid cancers, the manageable safety profile, and the lack of standard of care for subjects with 
metastatic MCC with poor prognosis supports further development of optimal therapy to define 
standard of care in this population of subjects.  
 
 
 
 
 
 
 
 
 
 
 

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2 
ETHICAL CONSIDERATIONS 
 
2.1 
Good Clinical Practice 
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 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. 
All potential serious breaches must be reported to PI 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. 
Personnel involved in conducting this study will be qualified by education, training, and experience to 
perform their respective tasks. 
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). 
 
2.2 
Institutional Review Board/Independent Ethics Committee 
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 (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. 
 
2.3 
Informed Consent 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate. 
Informed consent form will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have their 
origin in the Declaration of Helsinki. 
Investigators must: 
1. Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 

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2. Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study. 
3. Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, and 
after any revisions are completed for new information. 
5. If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or her 
informed consent during the study, consent must additionally be obtained from the subject. 
6. Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, should 
fully inform the subject or the subject's legally acceptable representative or legal guardian, of all 
pertinent aspects of the study and of any new information relevant to the subject's willingness to 
continue participation in the study. This communication should be documented. 
7. The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, 
in the US, the subjects’ signed HIPAA Authorization. 
8. The consent form must also include a statement that regulatory authorities have direct access to 
subject records.  
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3 
STUDY POPULATION 
For entry into the study, the following criteria MUST be met. 
 
3.1 
Inclusion Criteria 
1. Signed Written Informed Consent 
• 
Subjects must have signed and dated an IRB/IEC approved written informed consent form in 
accordance with regulatory and institutional guidelines. This must be obtained before the 
performance of any protocol related procedures that are not part of normal subject care 
• 
Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, tumor biopsies, and other requirements of the study. 
2. Signed Written Informed Consent 
• 
All subjects must be either recurrent, unresectable or Stage IV AJCC (7th edition) and have 
histologically confirmed Merkel cell carcinoma with confirmed pathology in order to be 
eligible. Please refer to Appendix 1 or description of AJCC 7th editions of TNM and staging. 
• 
At least 18 years of age 
• 
ECOG PS < 2 
• 
Active disease measurable by CT, MRI, or clinical exam  
• 
Prior chemotherapy or immunotherapy will be allowed if new or persistent measurable site(s) 
of disease are present.  
• 
Prior radiation therapy will be allowed if there is active measurable disease burden. 
• 
All subjects must have at least 2 distinct lesions as documented by a complete physical 
examination or imaging studies within 4 weeks prior to randomization. Imaging studies must 
include a CT scan of the involved disease sites and all known sites of resected disease and 
brain magnetic resonance (MRI) or CT (brain CT allowable if MRI is contraindicated or if 
there is no known history of resected brain lesions). 
• 
Tumor tissue from the core biopsy or resected site of disease must be provided for biomarker 
analyses. Prior surgery that required general anesthesia must be completed at least 4 weeks 
before study drug administration. Surgery requiring local/epidural anesthesia must be 
completed at least 72 hours before study drug administration. 
• 
All baseline laboratory requirements will be assessed and should be obtained within 14 days 
of randomization. Screening laboratory values must meet the following criteria. 
 
i) WBCs 
 2000/µL 
ii) Neutrophils 
 1500/µL 
iii) Platelets 
 100 x 10³/µL 
iv) Hemoglobin 
 9.0 g/dL 
v) Creatinine  Serum  creatinine    1.5  x  upper  limit  of  normal  (ULN)  or  creatinine 
clearance > 40 mL/minute (using Cockcroft/Gault formula) 
vi) AST 
 3 x ULN  
vii) ALT 
 3 x ULN 

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viii) 
Total Bilirubin 
 1.5 x ULN (except subjects with Gilbert Syndrome who 
must have total bilirubin < 3.0 mg/dL) 
• 
Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued 
the study as a screen failure (ie, subject has not been randomized / has not been treated). If re-
enrolled, the subject must be re-consented. 
3. Age and Reproductive Status 
• 
Men and women, at least 18 years of age 
• 
Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy 
test (minimum sensitivity  25  IU/L  or  equivalent  units  of  HCG)  within 24 hours prior to 
the start of study drug. 
• 
Women must not be breastfeeding 
• 
WOCBP must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug (s) plus 5 half-lives of study drug plus 30 days (duration of 
ovulatory cycle). The half-life  of  nivolumab  and  ipilimumab  is  up  to  25 days  and 18 
days, respectively. WOCBP should therefore use an adequate method to avoid pregnancy for a 
total of 23 weeks post-treatment completion (Appendix 3). 
• 
Men who are sexually active with WOCBP must agree to follow instructions for method(s) of  
contraception  for  the  duration  of  treatment  with  study  drug  (s)  plus 5 half-lives of the 
study drug (s) plus 90 days (duration of sperm turnover). The half-life of nivolumab and 
ipilimumab is up to 25 days and 18 days, respectively. Men should therefore use an adequate 
method of contraception for a total of 31 weeks post-treatment completion (Appendix 3). 
• 
Azoospermic males and WOCBP who are continuously not heterosexually active are exempt 
from contraceptive requirements. However, they must still undergo pregnancy testing as 
described in this section. 
 
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators 
shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly 
effective methods of contraception. Highly effective methods of contraception have a failure rate of 
< 1% when used consistently and correctly. (Refer to Appendix 3.) 
 
3.2 
Exclusion Criteria 
1. Target Disease Exceptions 
• 
Subjects with active brain metastasis 
2. Medical History and Concurrent Diseases 
• 
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids are permitted in the absence of 
active autoimmune disease. 
• 
Subjects requiring palliative radiation therapy at presentation. 

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• 
Subjects with history of Grade 3 toxicity or use of infliximab with prior immunotherapy. 
• 
Subjects with active, known, or suspected autoimmune disease. Subjects with type I diabetes 
mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment are permitted to enroll. For any cases of uncertainty, it is recommended that the 
Medical Monitor be consulted prior to signing informed consent. 
• 
Subjects with prior history of non-Merkel cell carcinoma malignancies are excluded except 
adequately treated basal cell, squamous cell skin cancer, chronic lymphocytic leukemia or 
other indolent diseases not requiring therapy; adequately treated, with curative intent, cancer 
from which the patient is currently in complete remission per investigator’s judgment; or 
patients with history of breast cancer and no evidence of disease on hormonal therapy to 
prevent recurrence and patients with prostate cancer on adjuvant hormonal therapy with 
undetectable PSA are eligible. 
• 
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids are permitted in the absence of active autoimmune 
disease. 
• 
Any serious or uncontrolled medical disorder or active infection that, in the opinion of the 
investigator, may increase the risk associated with study participation, study drug 
administration, or would impair the ability of the subject to receive protocol therapy. 
3. Physical and Laboratory Test Findings 
• 
Positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic 
acid (HCV RNA) indicating acute or chronic infection. 
• 
Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
4. Allergies and Adverse Drug Reaction 
• 
History of Grade 3 or higher allergy to humanized monoclonal antibodies 
5. Other Exclusion Criteria 
• 
Prisoners or subjects who are involuntarily incarcerated 
• 
Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, 
infectious disease) illness 
• 
Pregnant or nursing women 
• 
Psychological, familial, sociological, or geographical conditions that potentially hamper 
compliance with the study protocol and follow-up schedule; those conditions should be 
discussed with the subject before registration in the trial 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria. 
 
3.3 
Women of Childbearing Potential 

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A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a 
woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause. 
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level. The 
duration of the washout period is a function of the type of HRT used. The duration of the washout 
period below are suggested guidelines and the investigators should use their judgement in checking 
serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during the washout period, 
the woman can be considered postmenopausal: 
• 
1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 
4 week minimum for transdermal products 
• 
8 week minimum for oral products 
Other parenteral products may require washout periods as long as 6 months. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4 
INVESTIGATIONAL PLAN 
 
4.1 
Study Design and Duration 
The study design schematic is presented in Figure 3.1-1. 
 
Figure 4.1-1: 
Study Design Schematic 
 
 
 
The subjects will be treated in both arms until disease progression, unacceptable toxicity, or 
subject withdrawal of consent. 
 
This study will consist of three phases: screening, treatment, and follow-up. For a complete list of 
study required procedures, please refer to Section 5. 
 
Screening Phase: 
• 
Begins by establishing the subject’s initial eligibility and signing of the informed consent form 
(ICF). 
• 
Subject is assessed for complete study eligibility within the required timeframe found in Table 
7.1-1. 
• 
A pregnancy test for WOCBP should be documented within 24 hours prior to the start of the 
first dose of study medication. 
• 
All subjects must have at least 2 distinct lesions as documented by a complete physical 
examination or imaging studies within 4 weeks prior to randomization. Imaging studies must 
include a CT scan of the involved disease sites and all known sites of resected disease and 
brain magnetic resonance (MRI) or CT (brain CT allowable if MRI is contraindicated or if 
there is no known history of resected brain lesions). 
Treatment Phase: 
 
 
 
Metastatic/ 
recurrent/ 
unresectable 
Merkel cell 
carcinoma  
 
 
Arm A (n = 25) 
Nivolumab 240 mg q2 weeks +  
Ipilumumab 1 mg/kg q6 weeks 
Follow-
up 
Randomize 
1:1
Stratify by 
• Prior 
immunotherapy 
 
Arm B (n = 25) 
Nivolumab 240 mg q2 weeks +  
Ipilumumab 1 mg/kg q6 weeks + 
SBRT 24Gy/3fx at the start of week 2 
 
 

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• 
Following confirmation of the subject’s eligibility, the randomization call to the Moffitt 
Cancer Center Biostatistics Core can be made. The subject is randomly assigned to the Arm A 
(nivolumab + ipilimumab) or Arm B (nivolumab + ipilimumab + SBRT). 
• 
Within 2 weeks from randomization the subject must receive the first dose of study 
medication (Day 1 of Week 1) 
• 
On-study laboratory assessments should be drawn within 72 hours prior to dosing 
• 
Adverse event assessments for grade ≥ 2 toxicities should be documented at each clinic visit 
and WOCBP must have a pregnancy test every four weeks +/- 1 week. 
• 
Treated subjects will be evaluated for recurrence every 12 weeks +/- 7 days 
• 
Patient Reported Outcome (PRO) instruments must be completed after randomization, prior to 
the dose of study therapy. 
Follow- up Phase: 
• Begins after 1 year of treatment or when the decision is made to discontinue a subject from 
study therapy. 
• Patient may continue on the study drug under the treatment protocol indefinitely during the 
follow-up phase. 
• After completion of the first two follow -up visits, subjects will be followed every 3 months for 
survival. 
• Subjects who discontinue treatment for reasons other than disease progression will continue to 
have surveillance assessments (until progression) every 12 weeks ± 14 days during the first 
year after randomization, every 12 weeks ± 2 1  days during the second year, every 6 
months ± 4 weeks between Year 3 and Year 5 with the last assessment at Year 5. 
• Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All toxicities (≥ grade 2) will be documented for a 
minimum of 100 days after the last dose of study medication. 
The total duration of the study from start of randomization to final analysis of OS is expected to be 
84 months (36 months of accrual + 48 months of follow-up), assuming an accrual rate of 17 
subjects/year during years 1 – 3.  
Stopping criteria: A Safety Monitoring Committee will be formed to evaluate the toxicity of both 
arms. Interim analysis will be conducted following accrual of initial cohort of patients in the Simon’s 
two stage design to determine whether SBRT introduces excess unanticipated grade 3 or higher 
toxicities (i.e. radiation pneumonitis, radiation dermatitis, radiation myelitis) prior to expansion of 
the cohorts.   
 
4.2 
Concomitant Treatments 
4.2.1 
Prohibited and/or Restricted Treatments 
• 
The following medications are prohibited during the treatment and follow-up phases (before 
recurrence) of the study (unless utilized to treat a drug-related adverse event): 
• 
Immunosuppressive agents 

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• 
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 4.4.2) 
• 
Any concurrent anti-neoplastic therapy (including, but not limited to chemotherapy, hormonal 
therapy, immunotherapy, radiation therapy, or standard or investigational agents for treatment 
of Merkel cell carcinoma other than specified per protocol). 
 
4.2.2 
Permitted Therapy 
Subjects are permitted the use of topical, ocular, intra-articular, intranasal and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted even if > 10 mg daily prednisone (or equivalent). A brief course of 
corticosteroids for prophylaxis (eg, for contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
Intravitreal injections of vascular endothelial growth (VEGF) inhibitors are permitted if used 
according to the approved ocular indication, such as macular degeneration.  
 
4.3 
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the discretion 
of the investigator) for any of the following reasons: 
• 
Subject’s request to stop study treatment 
• 
Progression of the target lesion 
• 
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject 
• 
Termination of the study by Bristol-Myers Squibb (BMS) 
• 
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness 
• 
Additional protocol specified reasons for discontinuation (see Section 4.5.7). 
In the case of pregnancy, the study drug will be permanently discontinued in an appropriate manner 
unless the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study drug. 
All subjects who discontinue study drug should comply with protocol specified follow-up procedures 
as outlined in Section 7. The only exception to this requirement is when a subject withdraws 
consent for all study procedures including post-treatment study follow-up or loses the ability to 
consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric 
or physical illness). 
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the appropriate 
case report form (CRF) page. 
 
4.4 
Post Study Drug Study Follow up 
In this study, ORR, PFS, OS and toxicity are key endpoints. Post study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects who 

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discontinue study drug must continue to be followed for collection of outcome and/or survival follow-
up data as required and in line with Section 7 until death or the conclusion of the study. 
 
4.4.1 
Withdrawal of Consent 
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously authorized 
by subject to provide this information. Subjects should notify the investigator of the decision to 
withdraw consent from future follow-up in writing, whenever possible. The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the withdrawal 
is from further treatment with study drug only or also from study procedures and/or post treatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status (whether the 
subject is alive or dead) is being measured, publicly available information should be used to determine 
vital status only as appropriately directed in accordance with local law. 
 
4.4.2 
Lost to Follow-Up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up is 
defined by the inability to reach the subject after a minimum of three documented phone calls, faxes, 
or emails as well as lack of response by subject to one registered mail letter. All attempts should be 
documented in the subject’s medical records. If it is determined that the subject has died, the site will 
use permissible local methods to obtain the date and cause of death. 
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor- retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and databases, in 
order to obtain updated contact information. If after all attempts, the subject remains lost to follow-up, 
then the last known alive date as determined by the investigator should be reported and documented in 
the subject’s medical records. 
 
 
 
 
 
 
 
 
 
 
 

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5 
STUDY DRUG 
 
This is a non-blinded study which includes investigational products: 
 
Product 
Potency 
Appearance 
Packaging 
Storage Conditions 
Nivolumab 
(Solution for 
Injection) 
10 mg/mL 
Clear to pale 
yellow liquid; 
may contain 
particles 
10 mL/vial 
Store at 2-8’C; 
protect from light or 
freezing 
Ipilimumab 
(Solution for 
Injection) 
5 mg/mL 
Clear to pale 
yellow liquid; 
may contain 
particles 
10 mL/vial 
Store at 2-8’C; 
protect from light or 
freezing 
 
Premedications or medications used to treat infusion-related reactions should be sourced by the local 
site. Solutions used as diluents (0.9% Sodium Chloride or 5% Dextrose) should also be sourced by the 
local site. 
 
5.1 
Investigational Product 
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference in 
a clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) differently than the authorized form, or used for an unauthorized indication, 
or when used to gain further information about the authorized form. 
The investigational product should be stored in a secure area according to local regulations. It is the 
responsibility of the investigator to ensure that investigational product is only dispensed to study 
subjects. The investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
In this protocol, investigational products are: nivolumab and ipilimumab.  
 
5.2 
Non-investigational Product 
Not applicable. 
 
5.3 
Storage and Dispensing 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed and 
contact BMS immediately. 
Study drug not supplied by BMS will be stored in accordance with the package insert. 
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes documentation 
of drug storage, administration and, as applicable, storage temperatures, reconstitution, and use of 
required processes (eg, required diluents, administration sets). 
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection, 5% dextrose 

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injection) will not be supplied by the sponsor and should be purchased locally if permitted by local 
regulations. 
Please refer to the current version of the Investigator Brochure (IB) and/or pharmacy reference sheets 
for complete storage, handling, dispensing, and infusion information for nivolumab and ipilimumab. 
The infusion duration of nivolumab is 30 minutes and for ipilimumab 30 minutes. 
 
5.4 
Method of Assigning Subject Identification 
After a subject’s initial eligibility is established and informed consent obtained, subjects will be 
assigned a study number/ID. Once enrolled and study number assigned, patients will be randomized in 
a 1:1 ratio. The following information is required for subject randomization: 
• 
Subject number 
• 
Date of birth 
• 
AJCC M classification 
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to Arm A (Nivo + Ipi) or 
Arm B (Nivo + Ipi + XRT) stratified by the following factors: 
• 
Prior immunotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.5 
SBRT and Drug Dosing Schedule 
 
5.5.1 
Dosing Schedule 
First dose must be administered within 2 weeks following randomization. Subjects may be dosed up to 
± 2 days before or after the scheduled date if necessary. 
The Dosing schedule is described in Table 5.5-1 and Table 5.5-2. 
 
Table 5.5-1: Dosing Schedule Arm A 
 
Week 1 
Week 2 
Week 3 
Week 5 
Arm A: 
Nivolumab+ 
Ipilimumab 
240 mg 
Nivolumab + 
1 mg/kg 
Ipilumumab 
 
 
 
 
240 mg 
Nivolumab 
 
 
240 mg 
Nivolumab 
 
Week 7 
 
 
 
240 mg 
Nivolumab 
Every 2 weeks + 
1 mg/kg 
Ipilumumab 
Every 6 weeks 
until progression 
or unacceptable 
toxicity 
 
 
  
 
 
Table 5.5-2: Dosing Schedule Arm B 
 
Week 1 
Week 2 
Week 3 
Week 5 
Arm A: 
Nivolumab+ 
Ipilimumab+ 
SBRT 
240 mg 
Nivolumab  
+ 
1 mg/kg 
Ipilumumab 
 
24Gy/3fx 
SBRT (may be 
completed by 
Week 3) 
 
240 mg 
Nivolumab 
 
 
240 mg 
Nivolumab 
 
Week 7 
 
 
 
240 mg 
Nivolumab 
Every 2 weeks + 
1 mg/kg 
Ipilumumab 
Every 6 weeks 
until progression 
or unacceptable 
toxicity  
 
 
 
 
If a subject cannot receive a dose within 2 days of its scheduled administration date, the dose should 
be completely omitted. When the subject is able to re-initiate treatment, dosing should resume at the 
time of the next scheduled dose. Missed doses will not be replaced. 

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5.5.2 
Antiemetic Premedications 
Antiemetic premedications should not be routinely administered prior to dosing of drugs. See 
Section 5.5.8 for premedication recommendations following a nivolumab or ipilimumab related 
infusion reaction. 
 
5.5.3 
Dose Modifications 
There will be no dose modifications permitted. Dose reductions or dose escalations are not permitted. 
 
5.5.4 
Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab and ipilimumab are 
considered immuno-oncology agents in this protocol. Management algorithms have been developed 
to assist investigators in assessing and managing the following groups of adverse events: 
Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, and Neurological. (Appendix 
4)  
Early recognition and intervention are recommended according to the management algorithms; and 
in addition include ophthalmologic evaluations for any visual symptoms in order to evaluate for 
nivolumab or ipilimumab related uveitis. 
The recommendations are to follow the algorithms in the nivolumab investigator brochure for 
immune related events; while the ipilimumab investigator brochure contains similar algorithms, the 
algorithms in the nivolumab brochure have been aligned to accommodate combinations as well as 
nivolumab monotherapy.   
Therefore, the algorithms recommended for utilization are attached for reference. 
For subjects expected who require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an adverse event, consider the following recommendations  
• 
Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic 
infections such as Pneumocystis jiroveci and fungal infections. 
• 
Early consultation with an infectious disease specialist should be considered. Depending on the 
presentation, consultation with a pulmonologist for bronchoscopy or a gastroenterologist for 
endoscopy may also be appropriate. 
• 
In patients who develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the differential diagnosis. 
Additional details on the safety of nivolumab and ipilimumab , including results from clinical 
studies, are available in the IB. 
  
5.5.5 
Dose Delay Criteria 
Because of the potential for clinically meaningful nivolumab-related AEs requiring early recognition 
and prompt intervention, management algorithms have been developed for suspected AEs of selected 

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categories.  
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the event is 
attributed to nivolumab, ipilimumab or both). All study drugs must be delayed until treatment can 
resume.  
Nivolumab and ipilimumab administration should be delayed for the following: 
• Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay 
• Any Grade 3 skin, drug-related adverse event 
• Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase, AST, ALT, or total bilirubin: 
o Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis do not require a dose delay. It is recommended 
to consult with the principle investigator for Grade 3 amylase or lipase abnormalities. 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade ≥  2 toxicity 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥  3 toxicity 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication. 
 
5.5.6 
Criteria to Resume Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 or 
baseline value, with the following exceptions: 
• Subjects may resume treatment in the presence of Grade 2 fatigue  
• Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity  
• Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the 
presence of Grade 2 AST/ALT OR total bilirubin 
• Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section XX) should have treatment permanently discontinued 
• Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed 
• Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment 

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If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
timepoint per protocol. However, if the treatment is delayed past the next scheduled timepoint per 
protocol, the next scheduled timepoint will be delayed until dosing resumes. If the design of the 
study defines that doses may not be omitted [skipped], strongly recommend adding “Doses may not 
be skipped” 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study therapy, 
except as specified in discontinuation section. 
 
5.5.7 
Discontinuation Criteria 
Treatment should be permanently discontinued for the following: 
• Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment  
• Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic adverse event, hypersensitivity reactions, and infusion reactions 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
adverse event, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
o Grade 3 drug-related laboratory 
abnormalities do not 
require treatment 
discontinuation except those noted below 
▪ Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
▪ Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:  
• AST or ALT > 8 x ULN 
 
• Total bilirubin > 5 x ULN 
• Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 
week of onset.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
• Any dosing interruption lasting > 6 weeks with the following exceptions: 

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o Dosing interruptions to allow for prolonged steroid tapers to manage drug-related 
adverse events are allowed. Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 6 weeks, the Investigator must be consulted. Tumor assessments 
should continue as per protocol even if dosing is interrupted 
o Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 6 weeks, the Investigator must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab or 
ipilimumab dosing 
 
5.5.8 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions 
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms.  
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE (Insert version e.g.: 4.0) guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 
and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before additional nivolumab 
administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for  24 
hours). 
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
or bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, then 
restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
Monitor subject closely. If symptoms recur then no further nivolumab or ipilimumab will be 
administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor 

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the subject until resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic premedications are recommended for 
future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional nivolumab or 
ipilimumab administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]). Grade 4: (life threatening; pressor or ventilatory support indicated).  
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV 
(or equivalent), as needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab or ipilimumab will be permanently discontinued. Investigators 
should follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery from symptoms. In the case of late-occurring hypersensitivity 
symptoms (eg, appearance of a localized or generalized pruritis within 1 week after treatment), 
symptomatic treatment may be given (eg, oral antihistamine, or corticosteroids). 
 
5.5.9 
Treatment Beyond Progression 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD.   
Subjects will be permitted to continue treatment beyond initial RECIST 1.1 defined PD as long as 
they meet the following criteria: 
• 
Investigator-assessed clinical benefit and subject is tolerating study drug. 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
Subjects should discontinue study therapy upon further evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions). New lesions are considered measurable at 
the time of initial progression if the longest diameter is at least 10 mm (except for pathological 
lymph nodes, which must have a short axis of at least 15 mm). Any new lesion considered non-
measurable at the time of initial progression may become measurable and therefore included in the 
tumor burden measurement if the longest diameter increases to at least 10 mm (except for 
pathological lymph nodes, which must have an increase in short axis to at least 15 mm). 
However, given the uncertainties around defining progression versus pseudoprogression during 
immunotherapy, treatment will be allowed to be continued beyond protocol-defined progression if, in 
the judgment of the treating physician, further benefit to the patient is possible with continuation of 

Clinical Protocol 
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therapy. For statistical analyses, this will need to be described in patient population information. E.g. 
Subjects who continue treatment beyond initial investigator-assessed, RECIST 1.1-defined 
progression will be considered to have investigator-assessed progressive disease at the time of the 
initial progression event. 
 
5.6 
Treatment Compliance 
Treatment compliance will be monitored by drug accountability as well as the subject’s medical record 
and eCRF. 
 
5.7 
Destruction of Study Drug 
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the responsible 
Study Monitor unless study drug containers must be immediately destroyed as required for safety, or 
to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met: 
• 
On-site disposal practices must not expose humans to risks from the drug. 
• 
On-site  disposal  practices  and  procedures  are  in  agreement  with  applicable  laws  and 
regulations, including any special requirements for controlled or hazardous substances. 
• 
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s standard operating procedures (SOPs) and a copy provided to BMS upon 
request. 
• 
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented. 
• 
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period. 
 
 
 
 
 
 
 
 
 
 
 

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6 
RADIATION THERAPY  
 
Metastatic lesions with the following distribution are eligible to be treated with SBRT on this protocol: 
1 – 4 metastases distinct from the measurable target lesion that will not be irradiated to evaluate 
responses to the abscopal effect and immunotherapy. Larger lesions are given preference for SBRT to 
maximize tumor antigen release. The irradiated lesion will not be included the calculations for 
measurable disease.  
SBRT will be given Week 2 - 3, please see Section 5.5 and 6. SBRT should begin Week 2, and 
therefore, the radiation planning process should begin as the patient is registered for the study prior to 
randomization. SBRT for all metastases should be completed within 2 weeks of the first dose of 
SBRT. Not all metastases need to receive radiation therapy on the same day. 
Most commercially available photon producing treatment units are allowed. As such, conventional 
linear accelerators, specialized linear accelerators with image guidance (e.g., Novalis, Trilogy, 
Synergy, Artiste, TrueBeam) are allowed. These units can be used with conformal dose delivery or 
IMRT. Specialized dose painting accelerators (e.g., Cyberknife, Gammaknife or Tomotherapy) are 
allowed provided they meet the technical specifications of the protocol and are used in a fashion that 
passes the credentialing required by the protocol. Conventional linear accelerators without add- on 
IGRT must have some other IGRT capability like CT-on-rails in the treatment room. 
IGRT is required for this study. Either 3DCRT or IMRT (including VMAT) are all acceptable 
planning techniques. Planning techniques may differ for each lesion to be treated provided that the 
tumor motion is properly accounted for with each technique when the target or targets are in or near 
the thorax region. 
 
6.1 
Dose Specification 
 
6.1.1 
Dose Fractionation 
Patients will receive 24Gy in 3 fractions of radiation in 3 consecutive days for non-skin lesions. Skin 
lesions are allowed to be treated every other day. Simultaneous integrated boost or dose-painting will 
be allowed to meet normal tissue dose constraints. If dose-painting is utilized, we recommend V21Gy 
> 90% of GTV and V24Gy > 1cc. This dose is well below the standard dose fractionation employed 
by SBRT in various disease locations ranging from 30Gy to 45Gy in 3 fractions, which have been 
deemed safe on available evidence and/or expert consensus in each disease site. Therefore we do not 
anticipate treatment related toxicity.  
 
6.1.2 
Technical Factors 
 
6.1.2.1 
Physical Factors 
Only photon (x-ray) beams with photon energies > 6MV will be allowed with the exception of 
radiation therapy to the skin for which electron beams will be allowed. For metastases located within 3 
cm of the lungs, photon energies of 6-10MV are required. For lung central and lung peripheral 
metastases, photon beam energies > 10 MV are allowed only for a limited number (≤50% of all beams 
or all beam angles) of beams that must travel more than a cumulative distance of 10 cm through soft 
tissue (not lung) to reach the isocenter OR a shorter distance if the tumor abuts the chest or abdominal 
wall (i.e., to spare skin dose). 

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FFF photon beams are allowed if the institution has performed SBRT credentialing with FFF beams. 
Minimum Field Aperture (Field Size) Dimension 
Because of uncertainties in beam commissioning resulting from electronic disequilibrium within small 
beam apertures, in general an equivalent square field dimension of 3 cm is recommended for fields used 
for treatment delivery for sites using standard 3-D conformal techniques where nearly all of the PTV is 
encompassed for each beam. It is understood that this may exceed the technical requirements for small 
lesions. In such cases, the prescription dose is still prescribed to the edge of the defined planning 
treatment volume (PTV). For sites using dose painting including IMRT techniques, where by design 
the entire PTV is not encompassed for each beam, smaller beam apertures are allowed.  
All institutions must use heterogeneity correction algorithms approved by IROC Houston independent 
of the treatment planning technique. All doses should be reported in terms of dose-to-water and not in 
terms of dose-to-medium. 
Stereotactic Targeting 
For the purposes of this protocol, the term ‘stereotactic’ implies the targeting, planning, and directing 
of radiation beams along any trajectory in 3-D space toward a target of known 3-D coordinates. The 
coordinate system is defined by reliable ‘fiducials.’ A fiducial may be external or internal to the 
patient’s body. External fiducials may relate to a frame or treatment device. 
Internal fiducials may be implanted markers OR reliably identifiable anatomy that is clearly visible on 
orthogonal kV imaging including the tumor itself. In all cases, the relationship between the fiducial and 
the actual tumor position in real time should be reliably understood for both planning and treatment. 
Isocenter Placement 
When using a gantry mounted linear accelerator for this protocol, the isocenter is defined as the 
common point of gantry, collimator, and couch rotation for the treatment unit. For other types of 
treatment units (e.g., Tomotherapy or CyberKnife), a reference point in space that is typically 
positioned at the center of the target is used instead of a mechanical isocenter. 
When treating multiple lesions, it is best to use multiple isocenters, each centered on a separate lesion. 
Treating different targets on different days is allowed in order to decrease treatment time for a single 
day. For widely spaced lesions (over 10 cm apart), localization is improved when the isocenter is 
placed in the center of each target and image guidance is performed individually for each target. This is 
due to the limitation of most IGRT systems which ignore necessary rotational corrections when table 
shift coordinates are derived. Some platforms, including Cyberknife and Tomotherapy, are inherently 
non-isocentric. These platforms take special account in the setup and treatment process to rigorously 
detect and account for rotations to avoid errors making them exempt from the separate isocenter for 
each lesion requirement. For other platforms, the use of a single isocenter to treat multiple lesions in 
proximity to each other may be allowed if the institution has credentialed successfully for SBRT 
treatment of 2 lesions with a single isocenter setup. 
Composite Dose Calculations 
Composite plans should be generated to incorporate the dose to surrounding normal tissues from each 
metastasis treated. The composite doses to critical normal tissues will be used to evaluate plan 
compliance. Composite planning refers to dose summation from multiple treatment sites on a single 
CT scan that encompasses the relevant anatomy. Composite treatment planning is best accomplished 
by obtaining a planning CT dataset that incorporate all targets and relevant critical structures in the 
imaging study. If this is not possible due to restrictions on the size of the imaging study that can be 

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managed by the treatment planning system, CT datasets should be divided into two parts and treatment 
fields should be adjusted so that dose spillage from the treatment of targets in one dataset to the next is 
minimal such that the dose contributions do not require summation. The two datasets should be 
obtained so that they have some amount of overlap that can be used to fuse the information using a 
rigid registration technique. The use of deformable registration to sum dose is not allowed. In general, 
it is best to perform CT scanning with the patient in the same position. This implies that, for example, 
all lesions planned on a gated CT scan must be treated with gating. If technical limitations are 
encountered in summing dose, contact the PI with questions regarding composite planning. 
Localization, Simulation, and Immobilization 
Patient Positioning (Immobilization) 
Patients will be positioned in a stable position capable of allowing accurate reproducibility of the 
target position throughout treatment. Positions uncomfortable for the patient should be avoided so as 
to prevent uncontrolled movement during treatments. Patient immobilization must be reliable enough 
to ensure that the gross tumor volume (GTV) does not deviate beyond the confines of the planning 
treatment volume (PTV). Positioning patients on flat couches and relying solely on image-guidance 
for reproducible set-up is strongly discouraged. 
Simulation 
All patients will undergo CT-based treatment planning in custom made immobilization devices. CT 
scan range must allow simultaneous view of the patient anatomy and fiducial system for stereotactic 
targeting (if used) and be adequate to ensure contouring of all targeted metastases, as well as necessary 
organs at risk (OAR), defined below. High-resolution CT scans should be obtained with uniform slice 
thickness of ≤ 3mm (ideally 1 – 2 mm) throughout. If a single CT scan cannot be obtained due to a 
large spatial separation between metastases (i.e., cervical and femoral metastases), or planning system 
slice number limitation, multiple CT scans are allowed provided that OAR are entirely encompassed in 
a single CT scan.  CT imaging should be performed so that a composite dose distribution including all 
treated metastases can be created. Ideally all metastases will be treated in one treatment position. 
When treating multiple metastases such as a lung and extremity, varying the treatment position may be 
necessary (i.e. simulation with arms up and arm to the side). Thus, more treatment positions can be 
used at the discretion of the treating oncologist, but every effort should be made to obtain a composite 
distributions. 
The use of IV contrast is required for liver metastases. For other metastases (central & peripheral lung, 
cervical/mediastinal, abdominal-pelvic, and spinal/paraspinal), the use of IV contrast is encouraged 
but will be left to the discretion of the treating physician. The use of other contrast agents is left to the 
discretion of the treating oncologist. Planning datasets without intravenous contrast may be used for 
dose calculation. 
The use of bolus is required for skin primary disease or metastases. The thickness of bolus should 
ensure adequate coverage of the involved skin. 
Respiratory Motion Assessment and Management 
All metastases with potential for respiratory motion should be evaluated by appropriate means 
including 4D CT scan, implanted fiducial marker, or flouroscopy at the time of simulation. Respiratory 
motion management (RMM) including abdominal compression, active breathing control, breath hold, 
end expiratory gating, or fiducial marker tracking, is recommended for any metastasis to be treated 
with motion > 5mm. A recommended approach would be to use an ITV technique for motion < 1cm, 
but for motion > 1cm (typically too large for a free breathing ITV) motion management including but 

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not limited to abdominal compression, active-breathing control (ABC), gating, breath hold, etc. should 
be used. 
If a treatment for multiple metastases (i.e., lung and spine) is designed on a CT scan employing motion 
management (i.e., abdominal compression), all metastases should be treated with the chosen motion 
management technique in order to generate an accurate composite dose calculation. 
Localization Using Daily IGRT 
As an SBRT protocol, this study requires the use of IGRT. NRG Oncology defines IGRT as a 
computer assisted process that uses imaging devices that generate a series of coordinates for shifting 
the patient support system in three orthogonal directions (sometimes including rotational changes) to 
position the treatment beams relative to target regions. The allowed technologies are as follows: cone-
beam CT (CBCT) using either a specially mounted kV imaging head or the MV treatment beam with 
an opposed electronic imaging panel, dual fixed-position in-room kV imaging systems that are 
orthogonal or near orthogonal, an in-room standard diagnostic CT scanner that is geometrically linked 
to the treatment unit, and the Tomotherapy approach. 
Although all of these units are allowed, some might not be appropriate for some disease sites. For 
example, orthogonal imaging techniques result in overlapping structures that are not as easily 
visualized compared to 3D cone-beam approaches. Simple portal imaging approaches that do not use 
computer assistance are not considered to be suitable for this study. 
When the treatment equipment is not equipped with any device that allows direct visualization of 
anatomical structures using the treatment beam, the recommendations of AAPM Task Group Report 
142 for testing the coincidence of the imaging and treatment reference points must be implemented. 
For example, verification of treatment and imaging isocenter coincidence must be performed routinely 
for the CyberKnife, Tomotherapy units as well as any BrainLab equipment that does not include an 
electronic portal imaging device (EPID) that intercepts the treatment beam. 
The minimum IGRT requirement for each metastatic location is listed in Table 6-2. Volumetric 
imaging refers to 3D modalities (e.g., kV cone-beam, MV cone-beam, CT on rails) while orthogonal 
imaging refers to 2D modalities (e.g., kV OBI, ExacTrac). For volumetric imaging, appropriate CT 
window/level thresholds must be employed for registration at each metastatic location as outlined in 
Table 6-3. Additional IGRT may be employed at the discretion of the treating physician (i.e., 
orthogonal kV imaging prior to required volumetric imaging or volumetric imaging even if only 
orthogonal kV imaging is required). Note that when orthogonal kV imaging is employed for sites 
where respiratory motion is expected and not controlled via motion management techniques, care must 
be taken to ensure accurate targeting of the ITV within the treatment. For example, static kV imaging 
at an undetermined breath hold position would not be adequate IGRT for treating a free-breathing lung 
tumor. 
Use of a shortened CT planning scan for registration may be important for IGRT systems that cannot 
handle a large number of CT slices. A subset of the planning CT scan can be uploaded to the IGRT 
system for localization of each metastasis. The CT data should include the metastasis of interest plus at 
least 5cm superiorly and inferiorly. Please note that composite dose must be calculated on a single CT 
scan encompassing all pertinent OAR. 
 
 
 

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Fig 6.2.1-1. Central lung definition. 
Table 6.1-1 
 
Metastatic Location 
Minimum IGRT Requirement 
 
No Fiducials 
With Fiducials** 
Lung--Peripheral+ 
Volumetric (3D) 
Orthogonal kV (2D) 
Lung—Central+ 
Volumetric (3D) 
Orthogonal kV (2D) 
Mediastinal/Cervical LN 
Volumetric (3D) 
N/A 
Liver+ 
Volumetric (3D) 
Orthogonal kV (2D) 
Spinal 
Orthogonal kV (2D) 
Orthogonal kV (2D) 
Osseous* 
Orthogonal kV (2D) 
N/A 
Abdominal-pelvic+ 
Volumetric (3D) 
Orthogonal kV (2D) 
*NOTE: When osseous/rib metastases are classified into another metastatic location, follow the IGRT guidelines for that 
site. 
**NOTE: When a metastasis contains an implanted fiducial that is clearly visible on kV orthogonal or volumetric imaging, 
either method can be used 
+NOTE: Registration using a soft tissue surrogate for the tumor is recommended for lung, liver, and abdominal-pelvic 
metastases for both 3D and 2D IGRT datasets. 
 
6.2 
Treatment Targeting 
Volume 
 
6.2.1 
Metastasis location 
Because of the potentially increased 
risk of pneumonitis from combining 
SBRT with nivolumab, conservative 
SBRT planning is recommended for 
lung lesions. A tight dose constraint 
for lung (V20 < 4% with mean lung 
dose < 4Gy) is required to minimize 
the risk of radiation pneumonitis109 
(Table 6.5.5-1).  
Lung Central: Central lung tumor is 
defined as GTV within 2 cm of 
proximal bronchial tree as described 
in RTOG 0813/0915: Tumor within or touching the zone of the proximal bronchial tree, defined as a 
volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, 
right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus 
right and left lower lobe bronchi). [See Figure 6.2.1-1] Tumors that are immediately adjacent to 

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Fig 6.2.1-2. Diagram of Spine Metastasis and Target Volume 
mediastinal or pericardial pleura (PTV touching the pleura) also are considered central lung tumors. A 
visual representation is shown below in Figure 6-1. 
Lung Peripheral: Metastases within the lung parenchyma with GTV outside of the proximal bronchial 
tree as described above. 
Mediastinal: GTV arising within the anatomic space between the lungs, above the diaphragm, and 
below the thoracic inlet at the level of the top of the sternal notch. Sternal metastases will be assigned 
to the mediastinal location based on potential for normal tissue toxicity. 
Head and Neck: GTV occurring within head and neck parenchyma or cervical lymph node Levels I-VI 
and/or retropharyngeal spaces. 
Liver: GTV arising within the liver. Rib or skin lesions immediately adjacent to the liver will be 
assigned to the liver metastasis location. 
Spinal: Metastases will be assigned to the spinal/paraspinal site if the GTV arises within the vertebral 
bodies expanded by 1 cm. Spinal metastases, shown in Figure 6-2 in black, can involve: 
⚫ The vertebral body only OR 
⚫ The vertebral body and pedicle OR 
⚫ Posterior elements only 
 
For each of these metastases, the PTV delineation will include: 
⚫ the involved vertebral body and both pedicles (solid red line in Figure 6.2.1-2a) OR 
⚫ a more generous delineation of the involved vertebral body and both pedicles (dashed red line 
in Figure 6.2.1-2b) OR 
⚫ the involved vertebral body, both pedicles, and the anterior and posterior elements of the spine 
(solid red line in Figure 6.2.1-2b) OR 
⚫ the spinous process and laminae (solid red line in Figure 6.2.1-2c) 
The target volume may be chosen at the discretion of the treating Radiation Oncologist based on the 
extent of tumor involvement. 
Metastases arising in the ribs within 1 cm of the edge of the vertebral body should be included in the 
spinal metastasis location but osseous metastases planning guidelines are to be used. 
Osseous: GTV arising within an ossesous structure, part of the axial skeleton, not included in the 

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spinal definition. 
⚫ Rib metastases that are within 1 cm of the vertebral bodies will be classified into the spinal 
metastasis location given the similar normal tissues at risk. 
⚫ Rib/scapular metastases within the thorax adjacent to lung parenchyma will be classified into 
the lung metastasis location given the similar normal tissues at risk. 
⚫ Rib/osseous metastases adjacent to mediastinal or cervical structures will be classified into the 
mediastinal/cervical lymph node location given the similar normal tissues at risk. 
⚫ Rib metastases adjacent to the liver will be classified into the liver location given the similar 
normal tissues at risk 
⚫ Rib metastases adjacent to the stomach/abdominal wall will be classified into the intra- 
abdominal location given the similar normal tissues at risk 
⚫ Sternal metastases will be considered part of the mediastinal/cervical lymph nodes location 
given the similar normal tissues at risk. 
Abdominal-pelvic: GTV arising within the anatomic space defined by the diaphragm superiorly, the 
genitourinary diaphragm inferiorly including the peritoneal and retroperitoneal spaces, not including 
liver, osseous, or spinal metastases. 
Skin: GTV arising within the skin or the underlying subcutaneous tissue. If the volume of GTV 
mandates photon beams for treatment, the lesion will be considered part of the neighboring anatomic 
location. 
Extremities: GTV arising within the upper and lower extremities. 
 
6.3 
Dosimetry 
 
6.3.1 
Target Volume Definition Based on Metastatic Location 
Specific SBRT planning parameters depend on the location of the treated metastasis as well as 
mechanism used for motion management/evaluation. In general the GTV is defined as the entirety of 
the primary or metastatic lesions as seen on planning CT scan aided by additional diagnostic imaging 
studies (i.e., PET/CT or MRI). Use of additional diagnostic studies is left to the discretion of the 
treating physician. The CTV=GTV; there is no margin added for microscopic extension. In general, 
either a helical CT or 4DCT will be used for defining the GTV/ITV depending upon the tumor motion 
encountered, although both scans may be acquired at the time of simulation. Typically, the ITV is 
generated using either expiratory/inspiratory phase scans or from reconstructed maximum intensity 
projection (MIP) scans. Maximum/minimum intensity projections (MIP/MinIP) should be used with 
caution because the MIP reconstruction for lung or MinIP reconstruction for liver may erroneously 
define an ITV in cases of significant irregular breathing or when tumors abut soft tissue structures 
(e.g., the diaphragm for MIP) or fat (for the MinIP).  
⚫ A GTV to ITV expansion of greater than 1cm in any one direction is strongly discouraged and 
alternative respiratory management technique is suggested. 
⚫ When osseous/rib or skin metastases are classified into other specific metastatic locations, the 
planning guidelines for that metastatic location should be used. If rib metastases are grouped 
into the spinal metastasis location, then the metastasis should be contoured as defined for 
osseous metastases, but the prescription doses for the spinal region should be used. 

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⚫ Mediastinal lymph nodes should undergo motion assessment and an ITV should be generated 
to account for motion. 
⚫ In general CTV/ITV to PTV expansion will include 5mm circumferential margin and 7mm 
craniocaudal margin, but may be modified at the treating physician’s discretion.  
 
6.3.2 
Planning Techniques 
 
General Considerations: A variety of planning techniques can be used to deliver SBRT for each 
metastasis. General guidelines include the following: 
⚫ Multiple coplanar or non-coplanar beam arrangements are acceptable. 
⚫ Typically 7-13 static radiation beams with equal weighting are used. It is recommended that at 
least 10 beams be used when possible. 
⚫ A minimum field dimension of 3 cm should be observed treating small metastases. 
⚫ Dynamic conformal arcs are acceptable. It is recommended that arcs span at least 340 degrees. 
⚫ For non-IMRT or dose painting techniques, the conformal 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 cm when 
treating small lesions. 
⚫ The prescription isodose line covering 95% the 
PTV will generally be 80-90% but may range 
from 60-90% where the maximum dose is 100%. 
As a result, a “hotspot” will exist within the PTV 
that is equal to the prescription dose divided by 
the prescription isodose line (i.e., 24Gy/0.6 = 
40Gy when 24Gy is prescribed to the 60% 
isodose). 
⚫ Doses higher than the prescription isodose (i.e., 
hotspots) should be manipulated to occur within 
the target. 
 
Dose calculations: All dose distributions shall include corrections for 
tissue heterogeneities. IROC Houston approved algorithms must be used. All doses should be reported 
in terms of dose-to-water and not in terms of dose-to-medium. 
Successful treatment planning will require accomplishment of all of the following criteria: These 
criteria will be assessed on dose calculated independently for each metastasis (i.e., not from composite 
dose calculations) 
⚫ Normalization: The treatment plan should be initially normalized such that 100% corresponds 
to the maximum dose within the PTV (MAXPTV). While this point will typically correspond 
to the PTV center of mass, it can be located elsewhere within the PTV. 
⚫ Prescription Isodose Surface Coverage: The prescription isodose surface will be chosen such 
Fig 6.3.2-1 

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that 95% of the target volume (PTV) is conformally covered by the prescription isodose 
surface. Doses less than 95% of the prescription dose are restricted to the outside edges of the 
PTV as shown in Figure 6-3. The prescription isodose surface selected MUST be ≥ 60% and 
≤90% of the dose maximum within the PTV (MAXPTV). The MAXPTV corresponds to the 
normalization point (100%) of the plan as noted in number 1 above. 
⚫ Target Dose Heterogeneity: Rather than prioritizing target dose homogeneity, SBRT treatment 
planning prioritizes adequate minimum target coverage and rapid dose fall-off gradients 
outside of the target. Hot spots within targets are generally accepted without consequence 
since targets are mostly tumor. The only exception is when the hotspot within the PTV also 
intersects an OAR (see Figure 6.3.2-1). 
⚫ Critical Organ Doses: Respect all critical organ dose-volume limits listed in Section  6.5) 
below 
⚫ High-Dose Spillage: 
◼ Location: Any dose > 105% of the prescription dose should occur within the PTV and not 
within the normal tissues outside the PTV. See Figure 6.2.3-1. 
◼ Volume: Acceptable isodose distributions should be as conformal as possible. To this end 
the ratio of prescription isodose volume to PTV should be as small as possible. 
◆ The ratio of the prescription isodose volume to the PTV volume should be < 1.2. 
Acceptable variations include a ratio of 1.2-1.5. Ratios above 1.5 will be considered 
unacceptable variations. The prescription line for each lesion will be contoured for 
calculation of this ratio. The prescription line will be labelled as V_24. Contours with 
identical doses should be distinguished according to the convention described in 
section 6.5. 
◆ Guidelines for the ratio of the 50% prescription isodose volume to the PTV volume 
(R50%) and for the maximum dose at 2cm (D2cm) from the PTV are given in Table 
6-4. Because it may become more difficult to restrict the 50% isodose volume when 
dose is summed from treatment of multiple metastases, this ratio should be evaluated 
for dose calculated for a single metastasis (i.e., not for composite dose). Additionally, 
the 50% isodose volume may be elongated deliberately in order to avoid OAR thereby 
making it difficult to meet the guidelines in Table 6-4. This is acceptable as long as 
normal tissue constraints are met. 
◆ Given that conformal tumor coverage is often more difficult to achieve in lung than in 
more homogeneous organs, these ratios should serve as a guide for liver, abdominal-
pelvic, mediastinal/cervical metastases as well. 
◆ Elliptically shaped metastases as well as extremity metastases may not meet these 
guidelines. This is acceptable as long as normal tissue constraints are respected. 
◆ These criteria will not be required in treating very small tumors (<2.5 cm axial GTV 
dimension or < 1.5 cm craniocaudal GTV dimension) in which the required minimum 
field size of 3 cm (see  Section 6.2) results in the inability to meet a conformity ratio 
of 1.5. 
 
 

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Table 6.3.2-2 
PTV Volume (cc) 
Ratio of 50% Prescription 
Isodose Volume to PTV 
Volume, R50% 
Maximum Dose at 2cm (D2cm) 
from PTV in any direction as 
% of Prescribed Dose 
1.8 
< 7.5 
<57.0 
3.8 
< 6.5 
<57.0 
7.4 
< 6.0 
<58.0 
13.2 
< 5.8 
<58.0 
22.0 
< 5.5 
<63.0 
34.0 
< 5.3 
<68.0 
50.0 
< 5.0 
<77.0 
70.0 
< 4.8 
<86.0 
95.0 
< 4.4 
<89.0 
126.0 
< 4.0 
<91.0 
163.0 
< 3.7 
<94.0 
NOTE: For values of PTV dimension or volume not specified, linear interpolation between 
table entries is required. 
NOTE: For tumors within 2 cm of the skin, it may be difficult to meet the values for D2cm 
and R50%. In these cases, these criteria will not be used. 
 
6.4 
Planning Priorities 
Every attempt should be made to successfully satisfy all of the planning goals and OAR criteria 
without deviation. In some circumstances, it may not be possible to meet all the ideal criteria leading 
to plans with an acceptable deviation. Thus, suggested priority of planning goals in order of 
importance is: 
⚫ Respect spinal cord, cauda equina, sacral plexus and brachial plexus dose constraints. 
⚫ Meet dose “compactness” constraints including the prescription isodose surface coverage, 
high dose spillage (location and volume), and intermediate dose spillage (D2cm, and R50%) 
as these define the “essence” of SBRT. Dose compactness should be assessed for plans based 
on treatment dose for a single lesion at a time. 
⚫ Meet critical structure constraints other than those listed in 1. The OAR constraints are last in 
priority (except for nervous system tolerance), because they are the least validated. The 
“essence” of a stereotactic plan is captured mostly in the dose compactness criteria, thereby 
justifying their higher priority. As an example in a case where not all goals can be met, it 
would be suggested to meet dose compactness goals without deviation even at the expense of 
a non-spinal cord normal tissue having acceptable deviation. Unacceptable deviations should 
be avoided in all cases. 
⚫ In cases where PTV coverage cannot be achieved while avoiding unacceptable deviations to 
OAR, coverage of a section of PTV including or immediately adjacent to the OAR may be as 
low as 70% of the prescription dose ONLY in this situation (see  Section 6.5.4). 
⚫  

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6.5 
Critical Structures 
 
6.5.1 
Planning SBRT Near Prior Radiotherapy Volumes 
The toxicity of delivering SBRT to multiple metastases in close proximity to prior conventionally 
fractionated EBRT volumes is not known. Therefore, overlap of protocol treatment SBRT isodoses 
with prior fractionated external beam volumes must be avoided. 
 
6.5.2 
Organs at Risk 
For all metastases specific organs at risk (OAR) must be contoured. The specific OAR to be contoured 
will depend on the location of metastases to be treated. In general, OAR within 3cm any single 
metastasis should be contoured. 
 
Lung Central/Lung Peripheral/Mediastinal/Head and Neck metastases: 
• 
Proximal tracheobronchial tree (as defined by Timmerman et al 2006) 
• 
Lungs, left/right/combined 
• 
Heart 
• 
Great vessels 
• 
Esophagus (from cricoid to gastro-esophageal junction) 
• 
Spinal cord 
• 
Chest wall 
• 
Brachial plexus 
• 
Skin 
• 
Liver 
• 
Kidney, left/right 
• 
Larynx 
• 
Stomach 
• 
Brain/brainstem 
• 
Orbits 
• 
Optic nerve/chiasm 
• 
Oral cavity 
• 
Cochlea 
• 
Pharyngeal constrictors 
• 
Parotid gland 
• 
Submandibular gland 
• 
Thyroid 
Abdominal-pelvic metastases (liver, adrenal, lymph nodes): 
• 
Stomach 
• 
Duodenum 
• 
Spinal cord 
• 
Kidney, left/right 
• 
Bowel,large/small 
• 
Rectum 
• 
Bladder 
• 
Skin 
• 
Lungs, left/right/combined 

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• 
Liver 
• 
Chestwall 
• 
Sacral plexus 
• 
Cauda equina 
Spinal Metastases: 
• 
For all spinal metastases, the partial spinal cord volume defined as 5-6 
mm above and below target should be contoured. 
• 
For thoracic and cervical spinal metastases follow guidelines for 
pulmonary/ mediastinal/cervical metastases depending upon nearby 
organs at risk 
• 
For lumbar metastases follow guidelines for Abdominal-pelvic metastases. 
 
Osseous, Skin, Extremity Metastases: 
• 
OAR for osseous, skin and extremity metastases will depend on the location of the 
osseous metastasis 
NOTE: OAR listed above should be contoured if located within 3cm of the osseous metastases. 
 
6.5.3 
Contouring of Normal Tissue Structures 
In order to verify each of these limits, the organs must be contoured such that appropriate volume 
histograms can be generated. Instructions for the contouring of these organs are as follows: 
 
Spinal Cord 
The spinal cord will be contoured based on the bony limits of the spinal canal ending at L2. The spinal 
cord should be contoured starting at least 10 cm above the superior extent of the PTV and continuing 
on every CT slice to at least 10 below the inferior extent of the PTV. This is best defined with fused 
MRI if available. 
Cauda Equina 
Starting at the conus (end of spinal cord, typically around L1 or L2) include the entire spinal canal into 
the sacrum to the filum. This is best defined with fused MRI if available. 
Sacral Plexus 
Include the nerve roots from L5 to S3 on each side from the neuroforamina to the coalescing of the 
nerves at the obturator internus muscle. This is best defined with fused MRI if available. 
Esophagus 
The esophagus will be contoured using mediastinal windowing on CT to correspond to the mucosal, 
submucosa, and all muscular layers out to the fatty adventitia. The esophagus should be contoured 
starting at least 10 cm above the superior extent of the PTV and continuing on every CT slice to at least 
10 cm below the inferior extent of the PTV. 
Brachial Plexus 
The defined ipsilateral brachial plexus originates from the spinal nerves exiting the neuroforamine on 
the involved side from around C5 to T2. However, for the purposes of this protocol, only the major 
trunks of the brachial plexus will be contoured using the subclavian and axillary vessels as a surrogate 

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for identifying the location of the brachial plexus. This neurovascular complex will be contoured 
starting proximally at the bifurcation of the brachiocephalic trunk into the jugular/subclavian veins (or 
carotid/subclavian arteries) and following along the route of the subclavian vein to the axillary vein 
ending after the neurovascular structures cross the second rib. If PTV of all metastases are more than 
10 cm away from the brachial plexus, this structure need not be contoured. This structure is best 
defined with fused MRI if available. 
Heart 
The heart will be contoured along with the pericardial sac. The superior aspect (or base) for purposes 
of contouring will begin at the level of the inferior aspect of the aortic arch (aortopulmonary window) 
and extend inferiorly to the apex of the heart. 
Trachea and Proximal Bronchial Tree 
The trachea and proximal bronchial tree will be contoured as two separate structures using mediastinal 
windows on CT to correspond to the mucosal, submucosa and cartilage rings and airway channels 
associated with these structures. For this purpose, the trachea will be divided into two sections: the 
proximal trachea and the distal 2 cm of trachea. The proximal trachea will be contoured as one 
structure, and the distal 2 cm of trachea will be included in the structure identified as proximal 
bronchial tree. 
Proximal Trachea 
Contouring of the proximal trachea should begin at least 10 cm superior to the extent of the PTV for 
lung metastases or 5 cm superior to the carina (whichever is more superior) and continue inferiorly to 
the superior aspect of the proximal bronchial tree. 
Proximal Bronchial Tree 
The proximal bronchial tree will include the most inferior 2 cm of distal trachea and the proximal 
airways on both sides as indicated in Figure 6.2.1-1. The following airways will be included according 
to standard anatomic relationships: the distal 2 cm of trachea, the carina, the right and left mainstem 
bronchi, the right and left upper lobe bronchi, the intermedius bronchus, the right middle lobe 
bronchus, the lingular bronchus, and the right and left lower lobe bronchi. Contouring of the lobar 
bronchi will end immediately at the site of a segmental bifurcation. If there are parts of the proximal 
bronchial tree that are within GTV, they should be contoured separately, as “proximal bronchial tree 
GTV”, not as part of the “proximal bronchial tree”. 
Whole Lung 
Both the right and left lungs should be contoured as one structure. Contouring should be carried out 
using pulmonary windows. All inflated and collapsed lung should be contoured; however, gross tumor 
(GTV) and trachea/ipsilateral bronchus as defined above should not be included in this structure. 
Proximal Bronchial Tree Plus 2 cm 
As part of determining if lung metastases are central or peripheral, adhering to the eligibility the zone 
of the proximal bronchial tree, the SBRT protocols defined an artificial structure 
2 cm larger in all directions from the proximal bronchial tree. If the GTV falls within this structure, the 
patient is eligible for this protocol. Most treatment planning systems have automatic contouring 
features that will generate this structure without prohibitive effort at the time of treatment planning. 
This structure is not required by the protocol, but its construction is suggested to facilitate 
appropriateness of patient selection. Alternately, participating sites may use ruler tools in the treatment 

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planning software to ensure protocol compliance. 
Skin 
The skin will be defined as the outer 0.5 cm of the body surface. As such it is a rind of uniform 
thickness (0.5 cm) which envelopes the entire body in the axial planes. The cranial and caudal surface 
of the superior and inferior limits of the planning CT should not be contoured as skin unless skin is 
actually present in these locations (e.g., the scalp on the top of the head). 
Great Vessels 
The great vessels (aorta and vena cava, not the pulmonary artery or vein) will be contoured using 
mediastinal windowing on CT to correspond to the vascular wall and all muscular layers out to the 
fatty adventitia. The great vessel should be contoured starting at least 10 cm above the superior extent 
of the PTV and continuing on every CT slice to at least 10 cm below the inferior extent of the PTV. For 
right sided tumors, the vena cava will be contoured, and for left sided tumors, the aorta will be 
contoured. 
Stomach 
The entire stomach and its contents should be contoured as a single structure as a continuation of the 
esophagus and ending at the first part of the duodenum. 
Duodenum 
The wall and contents of the 1st, 2nd, and 3rd parts of the duodenum will be contoured as one structure 
beginning where the stomach ends and finishing as the superior mesenteric artery crosses over the third 
part of the duodenum. 
Bowel (Large/Small) 
From the ileocecal area to include the ascending, transverse, descending and sigmoid colon as one 
structure. 
Rectum 
The entire rectum with contents from the peritoneal reflection of the sigmoid to the anus. 
Bladder 
This organ will be contoured as bladder wall exclusive of urinary contents 
Kidney (renal cortex) 
Both the right and left kidney, excluding renal pelvis/collecting system, should be contoured in their 
entirety (the renal cortex) 
Liver 
The entire liver minus the GTV targets. 
Bile ducts 
May use the portal vein from its juncture with the splenic vein to its right and left birfurcation in the 
liver as a surrogate to identify the bile ducts. 
Femoral Heads 
The ball of the head and socket joint. 
PTV + 2 cm 

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As part of the QA requirements for “low dose spillage” listed above, a maximum dose to any point 2 
cm away in any direction is to be determined (D2cm). To facilitate this QA requirement, an artificial 
structure 2 cm larger in all directions from the PTV is required. Most treatment planning systems have 
automatic contouring features that will generate this structure without prohibitive effort at the time of 
treatment planning. If possible this structure should be constructed as a single contour that is 2 cm 
larger than the PTV. 
Other Structures 
The constraints tables below contain other structures. These are required if the structure is within 10 cm 
of the PTV. 
6.5.4 
Contouring of the Target Lesions 
The primary endpoint of this clinical trial is ORR of a non-irradiated lesion to the combination of 
immunotherapy and radiation therapy outside the field. In order to avoid the direct cytotoxic effect on 
the target lesion by scatter radiation, GTV of the target lesion will need to be contoured if within 10cm 
of the radiation field and ensure mean dose < 2Gy to the volume.   
6.5.5 
Critical Organ Dose-Volume Limits 
Composite dose plans including all treated metastases and organs at risk are recommended to 
minimize toxicity from the field overlap. To facilitate composite planning, dose to all metastases 
should be calculated on a single CT scan simultaneously with in-plane resolution of at least 3 x 3 x 
3mm. If this is not possible, composite plans should be generated incorporating the dose from each 
metastasis treated. The composite doses to critical normal tissues will be used to evaluate plan 
compliance. 
Tables 6.5.5-1 lists maximum dose limits to a point or volume within several critical organs based on 
the 3 fraction SBRT. 
The spinal cord doses are absolute limits, and treatment delivery that exceeds these limits will 
constitute a major protocol violation. However, some OAR (ie, the esophagus, trachea, bronchi and 
heart within the lung) may be situated adjacent to the treated GTV/PTV. As such, there is no specified 
limit as tumors that are immediately adjacent to that organ will not be able to be treated to any of the 
prescription doses without irradiating a small volume of that organ to the prescribed dose. In such a 
case, the planning needs to be done so that there is no hot spot within that organ, even if that organ is 
part of the GTV, PTV, i.e., that no part of any OAR receives more than 105% of the prescribed dose In 
addition, the volume of the OAR in question needs to be minimized, both in length and in the width 
(i.e., circumference), with efforts made to reduce the dose to the contralateral wall of the organ. 
For non-spinal cord organs at risk with known sensitivity to high doses of radiation (including the 
bowel, esophagus, and stomach) included within a PTV or immediately adjacent to PTVs, a 
prescription dose at the lower end of acceptable variation should be used. Additionally, every effort 
should be made to cover the GTV with the prescription dose while ensuring rapid falloff to the organ 
at risk. Coverage of a section of PTV including or immediately adjacent to the OAR may be as low as 
70% of the prescription dose ONLY in this situation. Every effort should be made to cover 100% of 
the GTV by the prescription dose at the lower end of acceptable variation. Since the tumor and normal 
tissue may not allow strict avoidance, the larger volume limits will not be scored as protocol 
Deviations Unacceptable if exceeded. 
For tumors that are not immediately adjacent to any OAR, centers are encouraged to observe prudent 
treatment planning principles in avoiding unnecessary radiation exposure to critical normal structures; 
we expect that the OAR doses will be as low as achievable. 

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Table 6.5.5-1 OAR Dose Limits for 3 fraction SBRT 
Serial Organ 
Volume 
Volume 
Dose (Gy) 
Avoidance Endpoint (Reference) 
Spinal Cord 
<0.03 cc 
18 
Myelitis (Timmerman) 
 
<1.2 cc 
13 
Myelitis (Timmerman) 
Ipsilateral Brachial Plexus 
< 0.03 cc 
26 
Brachial Plexopathy (Timmerman) 
 
<3 cc 
22 
Brachial Plexopathy (Timmerman) 
Cauda Equina 
<0.03 cc 
25.5 
Neuritis (Timmerman) 
 
<5 cc 
21.9 
Neuritis (AAPM TG-101) 
Sacral Plexus 
<0.03 cc 
24 
Neuropathy (AAPM TG-101) 
 
<5 cc 
22.5 
Neuropathy (AAPM TG-101) 
Trachea and Bronchus* 
<0.03 cc 
30 
Stenosis/Fistula (Z4099) 
 
<5cc 
25.8 
Stenosis/Fistula (Timmerman) 
Esophagus* 
<0.03 cc 
27 
Stenosis/Fistula 
(Timmerman/RTOG0618) 
 
<5cc 
17.7 
Stenosis/Fistula (Z4099) 
Heart/Pericardium 
<0.03cc 
30 
Pericarditis (Z4099) 
 
<15 cc 
24 
Pericarditis (Z4099) 
Great vessels* 
<0.03cc 
45 
Aneurysm (Z4099) 
 
<10 cc 
39 
Aneurysm (Z4099) 
Skin 
<0.03cc 
33 
Ulceration (Z4099) 
 
<10cc 
31 
Ulceration (Timmerman) 
Stomach 
<0.03cc 
30 
Ulceration/Fistula (Timmerman) 
 
<10cc 
22.5 
Ulceration/Fistula (Timmerman) 
Duodenum* 
<0.03cc 
24 
Ulceration (Timmerman 2006) 
 
<10cc 
15 
Ulceration (Timmerman 2006) 
Bowel* 
<0.03 cc 
34.5 
Ulceration 
 
<20cc 
24 
Colitis/Fistula (Z4099) 

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Rectum* 
<0.03 cc 
49.5 
Ulceration (Timmerman) 
 
<3.5 cc 
45 
Proctitis/Fistula (Timmerman) 
 
< 20 cc 
27.5 
Proctitis/Fistula (Timmerman) 
Bladder 
0.03cc 
33 
Cystitis/Fistula (Timmerman) 
 
<15 cc 
16.8 
Cystitis/Fistula (AAPM TG-101) 
Penile bulb 
< 3cc 
25 
Impotence (Timmerman) 
Femoral heads 
<10 cc 
24 
Necrosis (Timmerman) 
Bile duct 
< 0.03 cc 
36 
Stenosis (Timmerman) 
Renal hilum/vascular trunk 
<15 cc 
19.5 
Malignant Hypertension (Timmerman) 
Parallel Organ 
Volume 
Volume 
Dose (Gy) 
Avoidance Endpoint (Reference) 
Lung (total) 
< 4% lung 
volume 
20 
Pneumonitis/Lung Function 
 
Mean lung 
dose 
<4 Gy 
Pneumonitis (Timmerman) 
 
1500 cc 
10.5 
Basic Lung Function (Z4099) 
 
1000 cc 
11.4 
Pneumonitis (Z4099) 
Ipsilateral kidney 
<130 cc 
12.3 
Nephritis (Timmerman 2006) 
Total Kidney 
<200cc 
15 
Basic Renal Function 
Liver 
<700 cc 
17.1 
Liver function 
*NOTE: Avoid circumferential irradiation. 
 
6.6 
Documentation Requirements 
Treatment Interruptions 
In general, treatment interruptions should be avoided by preventative medical measures and 
nutritional, psychological, and emotional counseling. Treatment breaks, including indications, must be 
clearly documented on the treatment record. 
 
6.7 
Compliance Criteria 
Treatment Duration 
Per Protocol: Treatment should be completed within 2 week. Acceptable Variation: Treatment 
completing >2 but < 3 weeks Unacceptable Deviation: Treatment completed > 4 weeks 
PTV Dosimetry Compliance 

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A single prescription, 24Gy in 3 fractions, will be used for all tumor lesions receiving SBRT. 
Simultaneous integrated boost planning can be utilized to achieve this dose to a partial tumor volume 
when near a critical organ at risk. Acceptable variation in this clinical scenario is to deliver at least 
7Gy per fraction to the 95% of GTV 
Organ at Risk Dosimetry Compliance 
Respect spinal cord, cauda equina, sacral plexus and brachial plexus dose constraints. Any dose to 
spinal cord, cauda equina, sacral plexus above that listed in Tables 6.5.5-1 will be considered an 
unacceptable deviation. For all other OAR, when OAR dose criteria provided in Section 6.5 cannot be 
accomplished by following planning priorities outlined in Section 6.4, doses to serial OAR of more 
than 105% of the dose prescribed to the PTV will be scored as unacceptable deviations. Doses to 
parallel OAR exceeding 110% of the dose prescribed to the PTV will be scored as unacceptable 
deviations 
 
6.8 
Radiation Therapy Adverse Events 
 
All Radiation Therapy AEs will be scored according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4. Adverse events related to SBRT for the treatment of metastases 
are dependent on the location of the metastases treated as well as from exposure of surrounding 
normal tissues. For all treated metastases, fatigue may occur and should be transient lasting < 8 weeks. 
Other adverse events are likely to be related to the specific metastatic location receiving SBRT: 
 
Lung (Central and Peripheral), Mediastinal, Head and Neck Metastases: 
Cardiac and Pericardial Injury 
Although cardiac and pericardial injury is uncommon in the conventionally fractionated course of RT, 
with large doses per fraction of SBRT a number of possible side-effects can be seen. 
Esophageal/Pharynx/Oral Cavity/Salivary gland Injury 
The radiation effects on the oral cavity, pharynx and esophagus can be acute: esophagitis (i.e., 
dysphagia, causing pain on swallowing, typically relatively soon after RT course is completed, and 
typically resolves on its own within days to a week or longer), mucositis, altered taste, xerostomia or 
chronic, typically manifesting with persistence of acute symptoms, dysphagia due to stenosis, or 
esophageal ulceration, with perforation in the extreme cases. 
Brain/Brainstem/Optic apparatus/Cochlea Injury 
The radiation effects on the CNS includes visual disturbances, auditory disturbances, memory problems, 
and radiation necrosis. While these are rare toxicities, radiation planning should ensure avoidance of the 
critical structures during SBRT.  
Central Airway/Bronchial Injury 
This bronchial injury with subsequent focal collapse of lung may impair overall pulmonary status. It 
also makes further assessment of tumor response more difficult as the collapsed lung approximates the 
treated tumor. Because atelectatic lung and tumor have similar imaging characteristics, radiology 
reports will often describe the overall process as progressive disease while the actual tumor may be 
stable or shrinking. 
The consequences of bronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of pulmonary 

Clinical Protocol 
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function test parameters, pleural effusion or pleuritic pain (associated with collapse), should all be 
graded according to the Common Terminology Criteria for Adverse Events (CTCAE), v. 4; MedDRA, 
v. 12.0. 
Lung Injury 
Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation of the end 
bronchioles and alveoli. Radiation fibrosis is a late manifestation of radiation injury to the irradiated 
lung. Given the small amount of lung that is typically included in the SBRT portals, lung toxicity has 
not been as dose-limiting as in conventionally fractionated large field RT, but it is nevertheless seen, 
can be symptomatic, and may be confused with other causes of respiratory deterioration, including 
infections, and tumor recurrence. 
Given that larger volumes of lung may be irradiated in this protocol compared to SBRT for primary 
tumors, it is very important that a Radiation Oncologist participate in the care of the patient, as the 
clinical picture may be very similar to acute bacterial pneumonia, with fatigue, fever, shortness of 
breath, nonproductive cough, and a pulmonary infiltrate on chest x-ray. The infiltrate on chest x-ray 
should include the area treated to high dose, but may extend outside of these regions. The infiltrates 
may be characteristically “geometric” corresponding to the radiation portal, but may also be ill defined. 
Patients reporting symptoms as above will be promptly evaluated and treated. Mild radiation 
pneumonitis may be treated with nonsteroidal anti-inflammatory agents or steroid inhalers. More 
significant pneumonitis will be treated with systemic steroids, bronchodilators, and pulmonary toilet. 
Supra- and concurrent infections should be treated with antibiotics. Consideration of prophylaxis of 
opportunistic infections should be considered in immunocompromised patients. 
Liver/abdominal-pelvic metastases 
Very likely (80-90%): Fatigue (which generally goes away after the radiation therapy is completed); 
skin irritation, redness, itchiness, discomfort; temporary changes in blood work (decrease in blood 
counts, increase in liver enzymes), without symptoms 
Less likely (30%): Nausea, vomiting (during therapy) – more common if stomach or gastrointestinal 
track irradiated; gastric, esophagus, small bowel or large bowel irritation/ulceration, bleeding, fistula, 
obstruction or changes in motility following therapy (may require medications or surgery) (<10% 
permanent changes); chest wall pain, rib fracture (< 10%) 
Less likely, but serious (<20%): Radiation-induced liver disease (RILD) (<5%). Classic RILD is a 
clinical diagnosis of anicteric ascites, hepatomegaly and elevation of alkaline phosphatase relative to 
other transaminases that may occur 2 weeks to 3 months following radiation to the Liver; non-classic 
RILD includes elevation of liver enzymes and/or any decline in liver function within 12 weeks from 
start of therapy (~20%). RILD can lead to liver failure that could lead to death. There is an increased 
risk of liver toxicity in patients with large tumors and in patients with pre-existing liver disease; 
permanent thrombocytopenia (<1%); this may lead to bleeding; kidney injury (<1%); this may lead to 
changes on imaging and more rarely the need for medication. 
Spinal metastases 
Radiation Myelitis 
Given the proximity and position of spinal cord in relation to the radiosurgery target, every effort 
should be made to minimize the radiation dose to the spinal cord. Radiation myelitis is a subacute or 
chronic clinical syndrome after radiation. The symptoms may include paresthesia,sensory changes, and 
motor weakness including paralysis. There is no active treatment for radiation myelitis; therefore, it is 

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important to prevent any injury to the spinal cord. Corticosteroids are used when clinical symptoms 
develop. 
Radiation Esophagitis 
Patients with thoracic spine treatment will likely develop esophageal mucositis within the first 2 
weeks. These symptoms subside with time; however, adequate symptomatic treatment including 
hydration is advised. There are no long-term adverse events reported with spine radiosurgery. 
However, it is prudent to minimize the radiation spillage in the normal esophagus. The consequences 
of esophageal toxicity, e.g., swallowing difficulty, dysphagia, cough, dehydration, and fistula, should 
be documented. 
Radiation Laryngitis or Pharyngitis 
Patients with cervical spine treatment will likely develop laryngopharyngeal mucositis within the first 2 
weeks. These symptoms subside with time; however, adequate symptomatic treatment including 
hydration is advised. No long-term laryngopharyngeal toxicity has been reported with spine 
radiosurgery. However, it is prudent to minimize the radiation spillage in the normal larynx and 
pharynx. The consequences of toxicity, e.g., swallowing difficulty, dysphagia, cough, dysphonia 
dehydration, and fistula, should be documented. 
Tracheal Injury 
Although no cases of tracheal injury have been reported with spine radiosurgery, it is prudent to 
minimize the radiation spillage in the normal trachea. The consequences of tracheobronchial toxicity, 
e.g., cough, dyspnea, hypoxia, impairment of pulmonary function test parameters, pleural effusion or 
pleuritic pain (associated with collapse), should be documented. 
Radiation Pneumonitis 
There have been no reported cases of symptomatic radiation pneumonitis with spine radiosurgery. 
However, it is prudent to minimize the radiation spillage in the lung tissue. It is strongly recommended 
to use radiation beams directed from posterior to avoid passage of radiation through the lungs. Patients 
with symptoms of pneumonitis will be promptly evaluated and treated. Mild radiation pneumonitis 
may be treated with non-steroidal anti-inflammatory agents or steroid inhalers. More significant 
pneumonitis will be treated with systemic steroids, bronchodilators, and pulmonary toilet. Supra- and 
concurrent infections should be treated with antibiotics. Consideration of prophylaxis of opportunistic 
infections should be considered in immunocompromised patients. 
Compression Fracture of Treated Vertebra 
Radiation doses in excess of 19 Gy for a single fraction are associated with higher rates of vertebral 
body compression (Saghal 2013). In this protocol, doses per fraction this high are not used, so that the 
estimated rate of vertebral body compression fracture following spinal metastases treatment should be 
rare. 
Other Adverse Events 
Short-term or long-term injury to the kidney or upper airway has not been reported. If other severe 
adverse events occur, details should be documented. 
Osseous Metastases 
Erythema, desquamation and alopecia are common side effects from radiation therapy for osseous 
metastases; other effects are determinate on location of metastasis, and may include pain, edema and 

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neuralgia. 
Extremities Metastases: 
Erythema, desquamation and alopecia are common side effects from radiation therapy for extremities. 
Other effects are determinate on location of metastasis, and may include pain, lymphedema. 
Skin Metastases: 
Erythema, desquamation and alopecia are common side effects from radiation therapy for radiation 
therapy to the skin. Other effects are determinate on location of metastasis, and may include pain, 
edema and neuralgia. 
 
6.8.1 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm. 
⚫ Three options are available to describe the event: 
◼ Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
◼ Myelodysplastic syndrome (MDS) 
◼ Treatment-related secondary malignancy 
 
6.8.2 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis 
from the initial malignancy). Second malignancies require ONLY routine reporting via CDUS unless 
otherwise specified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7 
STUDY ASSESSMENTS AND PROCEDURES 
 
7.1 
Flow Chart/Time and Events Schedule 
 
Table 7.1-1: 
Screening Procedural Outline  
 
Procedure 
Screening Visit (Day -
28 till Day -1 prior to 
Randomization) 
Notes 
Eligibility Assessments 
Informed Consent 
x 
Inclusion/Exclusion Criteria 
x 
All inclusion/exclusion criteria should be assessed during 
screening and confirmed prior to randomization. 
Medical History 
x 
Review of pathology report 
x 
 
Tumor Tissue Samples 
x 
Sufficient tumor tissue from the resected site of the disease (a block 
or a minimum of 15 slides) must be available and sent to Moffitt 
Cancer Center for biomarker analysis. If biopsy is performed at the 
treatment sites, fresh tumor will be requested to biomarker studies 
to establish tumor cell lines.  
Safety Assessments 
Physical Examination 
x 
Including height 
Vital Signs 
x 
Including weight, blood pressure (BP), heart rate (HR), temperature 
Oxygen saturation 
x 
              By pulse oximetry 
Performance Status (ECOG) 
x 
Within 14 days prior to randomization 
Assessment of Signs and 
Symptoms 
x 
Within 14 days prior to randomization 
Electrocardiogram (ECG) 
x 
Within 14 days prior to randomization 
Laboratory Tests 
x 
On site/local complete blood count (CBC) w/differential, Chemistry 
panel including: LDH, AST, ALT, ALP, T.Bili, amylase, lipase, 
blood urea nitrogen (BUN) or serum urea level, creatinine, uric acid, 
Ca, Mg, Na, K, Cl, Glucose, endocrine panel (TSH, Free T4, Free 
T3), Hep B/C (HBV sAG, HCV RNA), within 14 days prior to 
randomization. 
Pregnancy Test 
x 
WOCBP only (within 24 hours prior to start). Serum or Urine. 
Efficacy assessment 
Surveillance assessments 
x 
Clinical exam and/or CT scan of the involved disease sites and all 
known sites of resected disease and brain MRI (brain CT allowable if 
MRI is contraindicated or if there is no known history of resected 
brain lesions). 
Other 
Randomization 
x 

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Table 7.1-2: 
On-Treatment Assessments Week 1 - Week 9 
 
Procedure 
Wk1 
Wk2 
Wk3 
Wk5 
Wk7 
Wk9 
Notes 
Safety Assessments 
Targeted Physical Examination 
x 
x 
x 
x 
x 
x 
To be performed within 72 hours of dosing, 
or while undergoing radiation therapy as an 
on treatment visit 
Vital Signs 
x 
x 
x 
x 
x 
x 
Including BP, HR, temperature 
Oxygen saturation 
x 
x 
x 
x 
x 
x 
     By pulse oximetry prior to dosing 
Weight and performance status 
x 
x 
x 
x 
x 
x 
 
Within 72 hours of dosing or while undergoing 
radiation therapy as an on treatment visit 
Adverse Events Assessment 
Continuously 
See Section 6.8. and Section 8 
Review of concomitant medications 
x 
x 
x 
x 
x  
x 
 Pregnancy Test 
x 
 
 
x 
 
x 
 Every 4 weeks  1 week. Serum or Urine. 
Laboratory Tests 
x 
 
   x 
   x 
x   
     x 
Within 72 hrs prior to dosing/SBRT to 
include CBC w/differential, LFT’s, BUN 
or serum urea level, creatinine, Ca, Mg, Na, 
K, Cl, LDH, Glucose, amylase, lipase, TSH 
(with reflexive Free T4/T3) 
Exploratory Biomarker 
Assessments 
Plasma 
x 
x 
x 
x 
Prior to dosing/SBRT 
Peripheral Blood Mononuclear 
Cells (PBMCs) 
x 
x 
x 
x 
Prior to dosing/SBRT 
Efficacy Assessments 
Surveillance Assessments 
Every 12 weeks (± 7 days) from first dose 
of study treatment through 12 months (until 
distant recurrence) 
Clinical exam and/or CT scan of the involved 
disease sites and all known sites of resected 
disease and brain MRI (brain CT allowable if 
MRI is contraindicated or if there is no 
known history of resected brain lesions). Use 
same imaging method as was 
used at screening/baseline. 
Study Drug 
Randomize 
x 
Study Treatment  
x 
RT 
x 
x 
x 
x 
First dose to be administered within 14 days 
of randomization. See Section 5.5. 
Outcome Research  
EORTC-QLQ-C30 
x 
      x 
 
Prior to dosing. D1W1 should be completed 
after randomization but prior to dosing. 
EQ5D (optional) 
x 
      x 
WPAI:GH (optional) 
x 
      x 
Health Care Resource 
Utilization (optional) 
x 
 
 
 
  x 
 

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Table 7.1-3: 
On-Treatment Assessments Week 11 - Week 21  
 
Procedure 
Wk11 
Wk13 
Wk15 
Wk17 
Wk19 
Wk21 
Notes 
Safety Assessments 
Targeted Physical 
Examination 
x 
x 
x 
x 
x 
x 
Vital Signs 
x 
x 
x 
x 
x 
x 
         Including BP, HR, temperature 
Oxygen saturation 
x 
x 
x 
x 
x 
x 
         By pulse oximetry prior to dosing 
Weight and performance 
status 
x 
x 
x 
x 
x 
x 
Within 72 hours of dosing 
Adverse Events Assessment 
Continuously 
          See Section 6.8. and Section 8 
Review of concomitant 
medications 
x 
x 
x 
x 
x 
x 
Laboratory Tests 
     x 
     x 
x    
     x 
x  
     x 
Within 72 hrs prior to dosing to include 
CBC w/differential, LFT’s, BUN or 
serum urea level, creatinine, Ca, Mg, Na, 
K, Cl, LDH, Glucose, amylase, lipase, 
TSH (with reflexive Free T4 and T3) 
Pregnancy Test 
    x 
 
     x 
 
     x 
 Every 4 weeks  1 week. Serum or Urine. 
Exploratory Biomarker  
Plasma 
       x 
 
 
Prior to dosing 
Peripheral Blood 
Mononuclear Cells 
(PBMCs) 
       x 
 
 
Prior to dosing 
Efficacy Assessments 
 
Surveillance Assessments 
Every 12 weeks (± 7 days) from first dose of study 
treatment through 12 months (until distant 
recurrence) 
Clinical exam and/or CT scan of the 
involved disease sites and all known sites 
of resected disease and brain MRI (brain 
CT allowable if MRI is contraindicated or 
if there is no known history of resected 
brain lesions). Use same imaging method 
as was used at screening/baseline. 
Study Drug 
Study Treatment 
x 
x 
x 
x 
x 
x 
See Section 5.5. 
Outcome Research  
 
EORTC-QLQ-C30 
    x 
   x 
 
 
Prior to dosing 
EQ5D (optional) 
    x 
   x 
WPAI:GH (optional) 
    x 
   x 
Health Care Resource 
Utilization (optional) 
 
x 
 
 
x 
 
 
 
 
 
 

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Table 7.1-4: 
On-Treatment Assessments Week 23 - Week 33  
 
Procedure 
Wk23 
Wk25 
Wk27 
Wk29 
Wk31 
Wk33 
Notes 
Safety Assessments 
Targeted Physical 
Examination 
x 
x 
x 
x 
x 
x 
Vital Signs 
x 
x 
x 
x 
x 
x 
         Including BP, HR, temperature 
Oxygen saturation 
x 
x 
x 
x 
x 
x 
         By pulse oximetry prior to dosing 
Weight and performance 
status 
x 
x 
x 
x 
x 
x 
Within 72 hours of dosing 
Adverse Events Assessment 
Continuously 
          See Section 6.8. and Section 8 
Review of concomitant 
medications 
x 
x 
x 
x 
x 
x 
Laboratory Tests 
    x 
     x 
 
 
x 
     x 
 
 
x 
     x 
Within 72 hrs prior to dosing to include 
CBC w/differential, LFT’s, BUN or 
serum urea level, creatinine, Ca, Mg, Na, 
K, Cl, LDH, Glucose, amylase, lipase, 
TSH (with reflexive Free T4 and T3) 
Pregnancy Test 
     x 
 
     x 
 
     x 
 Every 4 weeks  1 week. Serum or Urine. 
Exploratory Biomarker  
Plasma 
   x 
 
Prior to dosing 
Peripheral Blood 
Mononuclear Cells 
(PBMCs) 
   x 
 
Prior to dosing 
Tumor Tissue Sample 
        
       x 
 
Biopsy at 6 months or at the time 
of progression 
Efficacy Assessments 
 
Surveillance Assessments 
Every 12 weeks (± 7 days) from first dose of study 
treatment through 12 months (until distant 
recurrence) 
Clinical exam and/or CT scan of the 
involved disease sites and all known sites 
of resected disease and brain MRI (brain 
CT allowable if MRI is contraindicated or 
if there is no known history of resected 
brain lesions). Use same imaging method 
as was used at screening/baseline. 
Study Drug 
Study Treatment 
x 
x 
x 
x 
x 
x 
See Section 5.5. 
Outcome Research  
 
EORTC-QLQ-C30 
    x 
   x 
 
 
Prior to dosing 
EQ5D (optional) 
    x 
   x 
WPAI:GH (optional) 
    x 
   x 
Health Care Resource 
Utilization (optional) 
 
x 
 
 
x 
 
 
 
Table 7.1-5: 
On-Treatment Assessments Week 35 - Week 45  

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3 
Procedure 
Wk35 
Wk37 
Wk39 
Wk41 
Wk43 
Wk45 
Notes 
Safety Assessments 
Targeted Physical 
Examination 
x 
x 
x 
x 
x 
x 
Vital Signs 
x 
x 
x 
x 
x 
x 
         Including BP, HR, temperature 
Oxygen saturation 
x 
x 
x 
x 
x 
x 
         By pulse oximetry prior to dosing 
Weight and performance 
status 
x 
x 
x 
x 
x 
x 
Within 72 hours of dosing 
Adverse Events Assessment 
Continuously 
          See Section 6.8. and Section 8 
Review of concomitant 
medications 
x 
x 
x 
x 
x 
x 
Laboratory Tests 
    x 
     x 
 
 
x 
     x 
 
 
x 
     x 
Within 72 hrs prior to dosing to include 
CBC w/differential, LFT’s, BUN or 
serum urea level, creatinine, Ca, Mg, Na, 
K, Cl, LDH, Glucose, amylase, lipase, 
TSH (with reflexive Free T4 and T3) 
Pregnancy Test 
     x 
 
     x 
 
     x 
 Every 4 weeks  1 week. Serum or Urine. 
Exploratory Biomarker  
Plasma 
 
 
Prior to dosing 
Peripheral Blood 
Mononuclear Cells 
(PBMCs) 
 
 
Prior to dosing 
Efficacy Assessments 
 
Surveillance Assessments 
Every 12 weeks (± 7 days) from first dose of study 
treatment through 12 months (until distant 
recurrence) 
Clinical exam and/or CT scan of the 
involved disease sites and all known sites 
of resected disease and brain MRI (brain 
CT allowable if MRI is contraindicated or 
if there is no known history of resected 
brain lesions). Use same imaging method 
as was used at screening/baseline. 
Study Drug 
Study Treatment 
x 
x 
x 
x 
x 
x 
See Section 5.5. 
Outcome Research  
 
EORTC-QLQ-C30 
    x 
   x 
 
 
Prior to dosing 
EQ5D (optional) 
    x 
   x 
WPAI:GH (optional) 
    x 
   x 
Health Care Resource 
Utilization (optional) 
 
x 
 
 
x 
 
 
 
 
 
 

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Table 7.1-6: 
On-Treatment Assessments Week 47 - Week 49  
 
Procedure 
Wk47 Wk49  
 
 
 
Notes 
Safety Assessments 
Targeted Physical 
Examination 
x 
x 
 
 
 
 
Vital Signs 
x 
x 
 
 
 
 
Including BP, HR, temperature 
Oxygen saturation 
x 
x 
 
 
 
 
         By pulse oximetry prior to dosing 
Weight and performance 
status 
x 
x 
 
 
 
 
Within 72 hours of dosing 
Adverse Events Assessment 
Continuously 
        See Section 6.8. and Section 8 
Review of concomitant 
medications 
x 
x 
 
 
 
 
Laboratory Tests 
 
 
x 
    x 
 
 
Within 72 hrs prior to dosing to include 
CBC w/differential, LFT’s, BUN or 
serum urea level, creatinine, Ca, Mg, Na, 
K, Cl, LDH, Glucose, amylase, lipase, 
TSH (with reflexive Free T4 and T3) 
Pregnancy Test 
 
    x 
 
 
 Every 4 weeks  1 week. Serum or Urine. 
Exploratory Biomarker  
Plasma 
 
Prior to dosing 
Peripheral Blood 
Mononuclear Cells 
(PBMCs) 
 
Prior to dosing 
Efficacy Assessments 
 
Surveillance Assessments 
Every 12 weeks (± 7 days) from first dose of study 
treatment through 12 months (until distant 
recurrence) 
Clinical exam and/or CT scan of the 
involved disease sites and all known sites 
of resected disease and brain MRI (brain 
CT allowable if MRI is contraindicated or 
if there is no known history of resected 
brain lesions). Use same imaging method 
as was used at screening/baseline. 
Study Drug 
Study Treatment 
x 
x 
 
 
 
 
See Section 5.5. 
Outcome Research  
 
EORTC-QLQ-C30 
   x 
 
 
 
Prior to dosing 
EQ5D (optional) 
   x 
 
WPAI:GH (optional) 
   x 
 
Health Care Resource 
Utilization (optional) 
 
x 
 
 
 
 
 
 
 
 

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Table 7.1-7: 
Follow-Up Procedural Outline  
 
Procedure 
Follow-up Visits 1a and 2 
Survival, Follow up 
Visitsb 
Notes 
Safety Assessments 
 
Targeted Physical 
x 
 
 
Adverse Events 
x 
x 
See Section 6.8. and Section 8 
Laboratory Tests 
x 
 
 
Pregnancy Test 
x 
 
Serum or urine 
Review of Concomitant 
Medication 
x 
 
 
Outcome Research  
 
EORTC-QLQ-C30 
x 
 
 
EQ5D 
x 
x 
 
WPAI:GH 
x 
 
 
Health Care Resource 
x 
 
 
Efficacy Assessments 
 
 
 
 
Surveillance Assessment 
Every 12 weeks (± 7 days) < 12 months 
Every 12  weeks (± 14 days) > 12 months through 24 
months 
Every 6 months (± 4 weeks) > 24 months through and up 
to Year 5 
Until distant recurrence. All time points are relative to the 
first dose of study treatment. 
Clinical exam and/or CT scan of the 
involved disease sites and all known 
sites of resected disease and brain MRI 
(brain CT allowable if MRI is 
contraindicated or if there is no known 
history of resected brain lesions). Use 
same imaging method as was used at 
screening/baseline. 
Survival status 
 
Survival status 
x 
x 
Every 3 months, maybe 
accomplished by visit or phone 
contact, to include subsequent anti- 
cancer therapy 
a Follow-up visit 1 (FU1) = 30 days ( 7 days) from the last dose, Follow-up visit 2 (FU2) = 84 days ( 7 days) from 
follow-up visit 1. 
b First Survival Follow-up visit 30 days ( 7 days) after FU2 
 
 
 
 
 
 
 

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7.1.1         Retesting During Screening or Lead-in Period 
Retesting of laboratory parameters and/or other assessments within any single Screening will be 
permitted (in addition to any parameters that require a confirmatory value). 
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state. 
Laboratory parameters and/or assessments that are included in Section 7. Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultation with 
the Medical Monitor may be needed to identify whether repeat testing of any particular parameter 
is clinically relevant. 
 
7.2 
Study Materials 
• NCI CTCAE version 4.0 
• Nivolumab Investigator Brochure 
• Ipilimumab Investigator Brochure 
• Pharmacy binder 
• Laboratory  manuals  for  collection  and  handling  of  blood  (including  biomarker  and 
immunogenicity) and tissue specimens 
• Site manual for enrollment/randomization worksheets 
• Manual for entry of local laboratory data 
• Pregnancy Surveillance Forms 
• PRO instruments. 
 
7.3 
Safety Assessments 
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, BP, HR, 
temperature and oxygen saturation by pulse oximetry and should be performed as noted in Table 
5.1-1 Notes. Baseline signs and symptoms are those that are assessed within 14 days prior to 
randomization. Concomitant medications will be collected from within 14 days prior to 
randomization through the study treatment  period  and  follow-up visits 1 and 2. During the 
Survival Follow-up visits subsequent only anti-cancer therapy will be collected. 
Baseline local laboratory assessments should be done within 14 days prior to randomization to 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH, Free T4, 
Free T3, and Hep B and C testing (HBV sAg, HCV RNA) (Table 5.1-1). Pregnancy testing for 
WOCBP (done locally) must be performed within 24 hours prior to the initial administration of 
study drug at baseline and then every 4 weeks (+/- 1 week) during the treatment phase. 
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the safety follow-up phase Table 5.1-7, 
toxicity assessments should be done in person. Once subjects reach the survival follow-up phase 
either in person or documented telephone calls to assess the subject’s status are acceptable. 

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Adverse events and laboratory values will be graded according to the NCI CTCAE version 4.0. 
On-study weight and ECOG Performance status and vital signs should be assessed on at each on-
study visit .Vital signs should also be taken as per institutional standard of care prior to, during 
and after dosing. Oxygen saturation by pulse oximetry should be assessed at each on study visit 
prior to dosing. The start and stop time of the infusions should be documented. Physical 
examinations are to be performed as clinically indicated. If there are any new or worsening 
clinically significant changes since the last exam, report changes on the appropriate non-serious or 
serious adverse event page. 
On study local laboratory assessments should be done within 72 hours of dosing to include; CBC 
w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum urea level, 
creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH with reflexive Free T4, Free 
T3. Additional measures including non-study required laboratory tests should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
inducted liver enzyme elevations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline or are deemed irreversible. 
Oxygen saturation by pulse oximetry should be obtained prior to each dosing and at any time a 
subject has any new or worsening respiratory symptoms. Accurate recording and documentation 
of oxygen saturation at two different activity levels is important because drug-related pulmonary 
toxicity can present initially as lower than baseline oxygen saturation. A reading at rest and on 
exertion should be obtained at each time point. The extent of the exertion should be based on the 
judgment of the investigator, but should remain consistent for each individual subject throughout 
the study. If the subject’s status changes, the investigator can alter the extent of exertion based on 
their medical judgment. If a subject shows changes on pulse oximetry or other pulmonary related 
signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, fever) consistent with possible 
pulmonary adverse events, the subject should be immediately evaluated to rule out pulmonary 
toxicity. An algorithm for the management of suspected pulmonary toxicity can be found in the 
nivolumab Investigator’s Brochure. 
Some of the previously referred to assessments may not be captured as data in the eCRF. They are 
intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations. 
 
7.3.1 
Imaging Assessment for the Study 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
 
7.4 
Efficacy Assessments 
Study evaluations will take place in accordance with the flow charts in Section 5. Baseline disease 
assessments should be performed within 28 days prior to the first dose utilizing CT or MRI. In 
addition to neck, chest, abdomen, pelvis, and brain, all known sites of disease should be assessed 
at baseline. Subjects will be evaluated for progression of target lesions or for development of new 
metastases beginning 12 weeks (+/- 7 days) relative to the first dose of study treatment, and will 
continue to have surveillance assessment every 12 weeks (+/- 7 days) for the first 12 months. 
From > 12 months to 24 months after randomization, efficacy assessments should be every 12 

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weeks (+/- 14 days). From > 24 months until Year 5 after first dose of study treatment, efficacy 
assessments should be performed every 6 months (+/- 4 weeks). 
 
7.4.1 
Definitions 
Progression is defined as progressive tumor lesions per immune-related RECIST (irRECIST) 
definition, or appearance of one or more new Merkel cell carcinoma lesions, which can be local or 
distant in location from the irradiated lesions. 
Local Control of Irradiated Lesion: 
Progression of the irradiated tumor lesion is associated with aggressive tumor biologic features 
and resistance to radiation therapy. 
 
Measurable Disease per irRECIST: 
Measurable lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of the measurement to be recorded) with a minimum size of: 
• 10 mm by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm) 
• 10 mm caliper measurement by clinical examination (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 20 mm by chest x-ray. 
Malignant lymph nodes: to be considered pathologically enlarged and measurable per 
RECIST 1.1, a lymph node must be  15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). 
If the measurable disease is restricted to a solitary lesion (visceral or nodal), its neoplastic nature 
must be confirmed either by cytology/histology or by lesion progression certified on the next 
CT/MRI examination. 
Nonmeasurable Disease per irRECIST: 
Nonmeasurable  lesions  include  all  other  lesions,  including  small  lesions  (longest  diameter 
< 10 mm or pathological lymph nodes with  10 and < 15 mm short axis), as well as truly 
nonmeasurable lesions. Lesions considered truly nonmeasurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusions, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 
 
7.4.2 
Methods of measurements 
• CT and MRI are an essential part of the work-up to establish recurrence. Conventional CT 
with IV contrast and MRI gadolinium should be performed with contiguous cuts of 10 mm or 
less slice thickness. Spiral CT should be performed using a 3- or 5-mm contiguous 
reconstruction algorithm; this specification applies to the tumors of the chest, abdomen and 
pelvis while head & neck tumors and those of the extremities usually require specific 
protocols. In each institute the same technique for CT/MRI should be used to characterize 
each new lesion. 
• PET alone will not be considered for the disease assessment. Complementary CT and/or MRI 

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or biopsy must be performed in such cases. 
• Cytology and/or histology are mandatory to confirm progression in doubtful lesions, 
cutaneous, subcutaneous or lymph node lesions. Histological or cytological evidence of 
progression should be attempted in all cases except for brain metastases. 
• Clinically detected new lesions: 
− Superficial cutaneous lesions: the neoplastic nature must be confirmed by 
cytology/histology. 
− Deep subcutaneous lesions and lymph node lesions should be documented by 
ultrasound and histological/cytological evidence should be attempted. In absence of 
pathology report, lesion will be documented with a CT scan/MRI. 
• Tumor markers or auto-antibodies alone cannot be used to assess disease progression. 
 
7.4.3 
Date of Progression 
The first date when p r o g r e s s i o n  was observed is taken into account regardless the 
method of assessment. Therefore progression will be declared for any lesion when: 
• Only imaging was performed and disease progression confirmed 
• Only pathology was done and a new malignancy confirmed (in solitary or in doubtful 
lesions, cutaneous, subcutaneous or lymph node lesions) 
• Both pathology and imaging were done and progression/malignancy confirmed. In this 
case, whatever examination come first its date is considered the date of relapse. 
Note: for documentation, the date of progression is the date that the pathology and/or 
imaging confirms progression--not the date that the information was communicated to the subject.  
 
7.5 
Biobanking for Exploratory Correlative Studies 
A variety of factors that could potentially predict clinical response to nivolumab will be 
investigated in peripheral blood and in tumor specimens taken from all subjects prior to treatment 
and as outlined in Section 7. Data from these investigations will be evaluated for associations with 
RFS, OS and distant metastasis-free survival and/or safety (adverse event) data. In addition, 
analyses of markers between the two treatment arms will provide the necessary data to identify 
and validate biomarkers with predictive vs prognostic value. All samples collected may also be 
used for future exploratory analyses (unless restricted by local requirements) to assess biomarkers 
associated with MCC or immunotherapy treatment. Complete instructions on the collection, 
processing, handling and shipment of all samples described herein will be provided in a separate 
procedure manual. 
Tumor tissue and blood samples are crucial for correlative science studies to determine 
mechanisms by which SBRT and immunotherapy impact the anti-tumoral immune responses. A 
planned sample collection and preparation is necessary in order for these patient tissues can 
preserve integrity for future correlative biomarker studies. The collected samples may be assessed 
for correlative research to dissect underlying mechanisms of immune activation or tolerance in 
MCC or to discover novel therapeutic targets to enhance anti-tumoral immune responses using a 
variety of methodologies inclusive of, but not limited to ex vivo culture, flow cytometry, IHC, 
qRT-PCR, genetic mutation detection and fluorescent in-situ hybridization (FISH). The collected 
tissue will be stored at the MCC Tissue Core with the exception of fresh tumor tissue that will be 

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utilized for Merkel cell line establishment, which will be sent to the PI’s laboratory.  
 
7.5.1 
Tumor Tissue Specimens 
Pre-treatment tumor tissue specimens in the form of a paraffin embedded block or a minimum of 
15 unstained slides will be submitted for PD-L1 IHC assessment. These biopsy samples should be 
from the most recent palliative surgery or biopsy. If surgical resection or biopsy are performed at 
one of the treatment sites, fresh tumor tissue for cell line establishment or fresh frozen tissue for 
tumor cell lysate will also be requested, but not mandated. Tumor specimens not used for clinical 
management will be utilized for research use. Approximately half of tumor tissue from biopsy or 
surgery will be stored as fresh frozen tissue for future IHC or preparation of tumor cell lysate. The 
remaining tumor will be sent directly to the PI’s laboratory in order to establish cell line.  
PD-L1 stained tissue sections will be assessed by a pathologist and membranous PD-L1 
expression scored in tumor and immune cells if a minimum of a hundred (100) evaluable tumor 
cells are present. Subjects with positive, negative or indeterminate (membrane staining is obscured 
by high cytoplasmic staining or melanin content) IHC already has been well established at MCC 
tissue core for PD-L1. The cut-off for positive PD-L1 status was defined as IHC score > 2+ in 
more than 5% of tumor cells. 
In addition, this pre-treatment tumor sample may be used to assess other putative predictive 
biomarkers of SBRT, nivolumab or ipilimumab efficacy and/or to better characterize the tumor-
immune microenviroment post-resection. Of note, prior studies have suggest the expression of 
Merkel polyomavirus in tumor correlates with better responses to PD1 blockade37. Therefore, 
Merkel polyomavirus large T antigen will be evaluated by IHC or viral load evaluated by qRT-
PCR. Various other molecular markers with potential predictive value for the treatment of MCC 
with nivolumab, ipilimumab and other immunotherapies are currently under investigation and may 
be assessed in this study. These tumor tissue biomarkers include, but are not limited to PD-1, PD-
L2, TILs or subpopulations of TILs and a Th1 immune mRNA expression signature. In addition, 
other methods of measuring tumor PD-L1 expression may also be assessed. Characterization of 
the tumor-immune microenvironment post-resection may involve assessment of other T cell 
checkpoint receptors and ligands (eg, Lag-3, Tim-3) and intratumoral immune cell subsets, 
including but not limited to NK cell, B-cell and T-cell lymphocytes. 
Tumor tissue samples may also be collected during treatment, upon disease progression or 
completion of treatment. This second surgical resection or biopsy will be strongly recommended 
for correlative biomarker studies, but also not mandated. For lesions from active disease, fresh 
tumor may be used for cell line establishment. Otherwise, this sample may be used for preparation 
of tumor cell lysate for ex vivo recall responses, or for the assessment of markers implicated in 
resistance to immunotherapeutic agents, including but not limited to other T cell checkpoint 
receptors and ligands (eg, Lag-3, Tim-3) and intratumoral immune cell subsets, including but not 
limited to, T regulatory cells and myeloid derived suppressor cells. These samples may also be 
used to investigate the effect of nivolumab or ipilimumab the expression of potentially relevant 
predictive and/or prognostic MCC biomarkers, including, but not limited to BRAF mutation and 
PD-L1. Both the pre-treatment tumor sample and the sample collected upon recurrence may be 
retrospectively assessed for BRAF mutation status, as well as for the expression of other immune 
or MCC related genes, RNAs and/or proteins, or for the presence of immune cell populations 
using a variety of methodologies inclusive of, but not limited to IHC, qRT-PCR, genetic mutation 
detection and fluorescent in-situ hybridization (FISH).  
 

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7.5.2 
Plasma Biomarkers 
Blood samples for exploratory serum and plasma biomarker analyses will be drawn at the time 
points indicated in Section 7.1. Separate blood samples will be collected and processed for serum 
and plasma and then put in frozen storage. Serum and plasma samples may be assessed by ELISA, 
seromics, microRNA profiling, circulating tumor DNA measurements, metabolomics and/or other 
relevant multiplex-based protein assay methods for immune or Merkel cell carcinoma-related 
factors that will predict for SBRT, nivolumab or ipilimumab benefit or correlate with SBRT, 
nivolumab or ipilimumab-related adverse events. Numerous potential serum/plasma-based 
biomarkers are currently under investigation for their potential to predict or correlate with safety 
or efficacy to radiation therapy, nivolumab, ipilimumab or other immunotherapies, including but 
not limited to levels of soluble PD-L1, anti-tumor antibodies, cytokines, chemokines, 
inflammatory factors, NKG2D ligands (e.g., soluble MICA) and microRNAs (such as, but not 
limited to, miR-513 and miR19b. Plasma will be prepared along with PBMC. 
 
7.5.3 
Peripheral Blood Mononuclear Cells  
Myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are immune cell 
populations capable of suppressing T cell activation and proliferation. Low pre-treatment MDSC 
in peripheral blood may be associated with better overall survival in Merkel cell carcinoma 
patients treated with the immunotherapeutic agents. Peripheral blood samples will be taken prior 
to initiation of study therapy and at designated timepoints on-treatment (see Section 7.1 for 
additional details on the blood sample collection schedule) for PBMC and MDSC preparation. 
PBMC and MDSC samples may be retrospectively assessed for correlative research to dissect 
underlying mechanisms of immune activation or tolerance in MCC or to discover novel 
therapeutic targets to enhance anti-tumoral immune responses using a variety of methodologies 
inclusive of, but not limited to ex vivo culture, flow cytometry, IHC, qRT-PCR, genetic mutation 
detection and fluorescent in-situ hybridization (FISH). 15cc of whole blood will be collected at 
week 1, 2, 3, 7, 13 and 25. PBMC from blood will be prepared with Ficoll gradient prior to 
freezing for future flow cytometry and ex vivo culture studies. Plasma will be stored for plasma 
biomarker studies (Section 7.5.2). Additional 5cc of whole blood will be collected in Cytochex for 
flow cytometric analysis.  
 
7.6 
Outcomes Research Assessments 
HRQoL will be assessed using the EORTC QLQ-C30. The EORTC QLQ-C30 is the most 
commonly used QoL instrument in skin cancer clinical studies. It is a 30-item instrument that has 
gained wide  acceptance  in  oncology  clinical  studies.  The  EORTC  QLQ-C30  comprises 6 
functional scales (physical functioning, cognitive functioning, emotional functioning, social 
functioning and global quality of life) as well as nine symptom scales (fatigue, pain, 
nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). Except for the overall health status and global quality of life items, responses for all 
items are 4 point categorical scales ranging from 0 (Not at all) to 4 (Very much). The overall 
health status/quality of life responses are 7-point Likert scales. 
General health status will be measured using the EQ-5D. The EQ-5D is a standardized instrument 
for  use  as  a  measure  of  self-reported  health  status.  The  EQ-5D  comprises 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort and anxiety) and a visual analog rating scale 
(VAS). The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale 
where the endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health 

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state’. This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents. The utility data generated from the EQ-5D is recommended for and 
commonly used in cost effectiveness analysis. 
Work Productivity and Activity Impairment: General Health (WPAI:GH) is a 6-item questionnaire 
yielding four different types of scores. The WPAI:GH was created as a patient-reported 
quantitative assessment of the amount of absenteeism (work time missed), presenteeism 
(impairment at work), work productivity (overall work impairment/absenteeism plus 
presenteeism) and daily activity impairment attributable to general health. WPAI:GH outcomes 
are  expressed as impairment percentages, with higher numbers indicating  greater impairment and 
less productivity, ie, worse outcomes. The recall period in all WPAI:GH validation studies is 7 
days. The general literature on recall burden suggests that a longer recall period would not be 
suitable for the type of information being elicited in the WPAI:GH. In theory, a shorter recall 
period would improve accuracy of WPAI:GH responses, but this has not been tested. Assessment 
of work productivity will be conducted at each site (or remotely) with the appropriately translated 
and validated version of the WPAI:GH. All PRO instruments will be administered during on-
study, and follow-up phases as outlined in Tables of Section 5.1, respectively, to all randomized 
subjects. Healthcare resource utilization data (eg, hospitalizations, non-protocol specified medical 
visits, diagnostics, etc) will be collected for all randomized subjects. The resource utilization 
capture is specific to hospital admission utilization data and non-protocol specified visits related to 
study therapy. Resource utilization questions will be asked as outlined in Table of Section 5.1 
during screening, on-study, and follow-up phases, respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
ADVERSE EVENTS 

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An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug. 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
Not  related:  There  is  not  a  reasonable  causal  relationship  between  study  drug administration 
and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
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.) 
 
8.1 
Serious Adverse Events 
A Serious Adverse Event (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 
⚫ 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.) Potential drug induced liver injury (DILI) is also 
considered an important medical event. (See Section 6.6 for the definition of potential 
DILI.) Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) 
via the study drug is an SAE. 
Deaths due to disease progression will not be reported as an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs.  
Any component of a study endpoint that is considered related to study therapy (eg, death is an 

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endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE. 
NOTE: 
The following hospitalizations are not considered SAEs: 
⚫ a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event) 
⚫ elective surgery, planned prior to 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 other than to remedy ill health and planned prior to entry into 
the study. 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 reason). 
⚫ Admission for administration of anticancer therapy in the absence of any other SAEs  
 
8.1.1 
Serious Adverse Event Collection and Reporting 
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s or the legal representative’s written consent to participate in the study, all 
SAEs, whether related or not related to study drug, must be collected, including those thought to 
be associated with protocol-specified procedures. All SAEs must be collected that occur during 
the screening period and within 100 days of discontinuation of dosing. If applicable, SAEs must 
be collected that relate to any later protocol-specified procedure (eg. a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, 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 Report Form. 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the eCRF. The paper SAE/pregnancy surveillance forms are only 
intended as a back-up option when the eCRF system is not functioning. In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to: 
SAE Email Address: Worldwide.Safety@BMS.com  
SAE Facsimile Number: 609-818-3804 
 

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For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site. 
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.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes  available,  a  follow-up  SAE  report  should  be  sent  within  24  hours  to  the  BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization. 
Any event that is both serious and unexpected must be reported to the Food and Drug 
Administration (FDA) as soon as possible and no later than 7 days (for a death or life-threatening 
event) or 15 days (for all other SAEs) after the investigator’s or institution’s initial receipt of the 
information. BMS will be provided with a simultaneous copy of all adverse events filed with the 
FDA.  
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
• 
An SAE report should be completed for any event where doubt exists regarding its 
seriousness.  
• 
For studies with long-term follow-up periods in which safety data are being reported, 
include the timing of SAE collection in the protocol. 
• 
If the investigator believes that an SAE is not related to study drug, 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 Report Form. 
• 
If only limited information is initially available, follow-up reports are required. (Note: 

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Follow-up SAE reports should include the same investigator term(s) initially reported.) 
• 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to BMS 
using the same procedure used for transmitting the initial SAE report. All SAEs should be 
followed to resolution or stabilization.  All SAEs should be followed to resolution or stabilization. 
 
8.2 
Nonserious Adverse Events 
A nonserious adverse event is an AE not classified as serious. 
 
8.2.1 
Nonserious Adverse Event Collection and Reporting 
The collection of new nonserious AE information should begin at initiation of study drug and 
continue until 100 days from the last dose of study drug. 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 withholding or discontinuation of study drug and for those present 
at the end of study treatment as appropriate. All identified nonserious AEs must be recorded and 
described on the nonserious AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study. 
 
8.3 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate: 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
Any laboratory test result abnormality that required the subject to have study drug omitted 
or discontinued 
• 
Any laboratory test result abnormality that required the subject to receive specific 
corrective therapy. 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value). 
 
8.4 
Pregnancy 
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half 
lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours and in accordance with SAE reporting procedures. 
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). 
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject 
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subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. 
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
8.5 
Overdose 
All occurrences of overdose must be reported as SAEs. 
 
8.6 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
Potential drug induced liver injury is defined as: 
AT (ALT or AST) elevation > 3 times ULN (5 x ULN in patients with liver metastasis) AND 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, including, 
but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration 
of other drug(s) known to be hepatotoxic. 
 
8.7 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
 
8.8 
Protocol Monitoring Committee 
A Protocol Monitoring Committee (PMC) will be established to provide oversight of safety and 
efficacy considerations in the protocol. The PMC meets monthly and reviews accrual, patterns and 
frequencies of all adverse events, protocol violations and when applicable, internal audit results.  
 
 
 
 
 

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9 
STATISTICAL CONSIDERATIONS 
 
9.1 
Statistical Design 
The result of Nivolumab alone clinical trial for virus-associated cancers including MCC is 
pending, but the estimated objective response rate with Nivolimab alone is estimated around 17% 
based on Avelumab and Pembrilozumab trial for patients without prior immunotherapy exposure 
or previously failed prior immunotherapy (refractory). Therefore, we will consider a 17% response 
rate as not warranting further study. We will use a 40% response rate as a promising result to 
pursue further study. In other words, we are interested in at least 23% improvement in treatment 
efficacy for either one of the two arms: Nivolimab + SBRT + Ipilimumab (Arm B) or Nivolimab + 
Ipilimumab (Arm A). Since both treatments are experimental therapy in this targeted population, 
Simon two-stage design is used to evaluate the treatment efficacy. To determine the best treatment 
arm, we utilize a Bayesian posterior probability with Simon two-stage design in a two-arm 
randomized trial in order to have objective comparison between the two arms110. This design has 
several unique features: (1) Randomization reduces selection bias and allows a greater degree of 
comparability, (2) The Simon two-stage design will allow for termination of an ineffective drug 
earlier when compared to historical control data, and (3) The Bayesian posterior probability 
provides additional power to detect a definitive differential treatment effect. This design has been 
employed in various lung cancer trials at Moffitt Cancer Center.   
 
9.1.1 
Sample Size Calculation 
From historical data, we will consider 17% response rate as not warranting further study. We will 
use 40% response rate as a promising result to pursue further study. In other words, we are 
interested in at least 23% (40% vs. 17%) improvement in treatment efficacy for arms B versus A. 
For each arm, using a Simon Mini-Max two-stage design with 10% type I error rate and 10% type II 
error rate, 16 patients will be enrolled in the first stage of the trial. If 2 or fewer patients respond, 
the treatment will be stopped. If 3 or more patients show a response, 8 additional patients (a total of 
24 patients per group) will be enrolled. If the total number responding is 6 or less, we will conclude 
that the treatment is not effective. If both arms fail at the first or second stage, the trial will stop. No 
winner will be claimed. The sample size will be 32 if both arms fail at the first stage and 40 if only 
one arm fails at the first stage. If only one arm pass the second stage, the arm will be the winner. If 
both arms pass the second stage, we will use the posterior probability, 𝑃𝑟(𝐵> 𝐴), (probability of 
the response rate in arm B higher than in arm A) to select the winner. A non-informative prior of 
beta distribution, beta(1,1) in both arms will be used to calculate the posterior probability. Arm B 
will be claimed as the winner if 𝑃𝑟(𝐵> 𝐴) > 𝛿= 0.8. 
Operating Characteristics 
The operating characteristics of the design is evaluated by simulation (10000 times) using R 
software (www.r-project.org) with "clinfun" package. In particular, we are interested in the 
probability of (correctly) selecting an arm as superior to the other arm if it is truly superior, and 
conversely, the probability of (incorrectly) selecting an arm that is no better than the other arm. 
Power Analysis 
Power: Assuming that the true probabilities of response in arms B and A are 40% and 17%, 
respectively (scenario 1: 23% difference of response rate), the overall probability (power) of 
correctly choosing arm B as superior is 85% on the basis of superiority shown at the end of the trial. 

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The probability of stopping arm A early and declaring arm B superior at the end of the trial is 81%. 
There are 9% of both arms passing the second stage with 4% claiming arm B as the winner by the 
Bayesian posterior probability. In a 18% difference of response rate, the overall power is 74% and 
77% for the comparison of arms B and A with 35% versus 17% (scenario 2) and 40% versus 22% 
(scenario 3), respectively. Proportion of both arms passing the 2nd stage is 8% in scenario 2 
(scenario 3: 23%), with 2% (scenario 3: 10%) claiming arm B as the winner by the Bayesian 
posterior probability. 
Type I error 
Type I error: In the null hypothesis of a 17% response rate in both arms, there are 9% 
misclassifying arm B as winner (i.e., 9% type I error). Among them, only 1% has both arms passing 
the 2nd stage, and less than 0.01% misclassify arm B as winner. 
Summary 
Summary: With 𝛿=0.8, the design has a 85% power to detect a 23% difference of response rate. The 
power decreases to a range of 74-77% to differentiate a 18% difference of response rate. The type I 
error is controlled at 9% when both arms have a 17% response rate. 
Tables of Power Analysis 
 
Scenario 1: Arm B=0.4 versus Arm A=0.17 (Overall power of Arm B= 85%) 
 
B.fail.stage1 B.fail.stage2 B.pass 
A.fail.stage1 0.01 
0.04 
0.42 
A.fail.stage2 0.01 
0.03 
0.39 
A.pass 
0 
0.01 
0.09 
Both arms passing the 2nd stage: 9%. Among them, Arm B claims 4.31% as winner 
Overall power of Arm B= 85% 
 
Scenario 2: Arm B=0.35 versus Arm A=0.17 (Overall power of Arm B= 74%) 
 
B.fail.stage1 B.fail.stage2 B.pass 
A.fail.stage1 0.02 
0.08 
0.38 
A.fail.stage2 0.02 
0.07 
0.33 
A.pass 
0 
0.02 
0.08 
Both arms passing the 2nd stage: 8%. Among them, Arm B claims 2.33% as winner 
Overall power of Arm B= 74% 
 
Scenario 3: Arm B=0.4 versus Arm A=0.22 (Overall power of Arm B= 77%) 
 
B.fail.stage1 B.fail.stage2 B.pass 
A.fail.stage1 0.01 
0.03 
0.25 

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A.fail.stage2 0.01 
0.03 
0.41 
A.pass 
0.01 
0.02 
0.23 
Both arms passing the 2nd stage: 23%. Among them, Arm B claims 9.89% as winner 
Overall power of Arm B= 77% 
 
Scenario 4: Arm B=0.17 versus Arm A=0.17 (Type I error= 8.89%) 
 
B.fail.stage1 B.fail.stage2 B.pass 
A.fail.stage1 0.22 
0.2 
0.04 
A.fail.stage2 0.2 
0.19 
0.04 
A.pass 
0.05 
0.04 
0.01 
Both arms passing the 2nd stage: 1%. Among them, Arm B claims 0.01% as winner 
Type I error= 8.89% 
 
 
9.1.2 
Populations for Analyses 
• All enrolled subjects: All subjects who signed an informed consent form and were 
registered. 
• All randomized subjects: All subjects who were randomized to any treatment arm in the 
study. 
• All treated subjects: All subjects who received any study drug nivolumab, ipilimumab or 
SBRT. 
• Biomarker  subjects:  All  randomized  subjects  with  available  biomarker  data  (PD-L1 
expression status, Merkel cell polyomavirus expression, and other assays). 
 
9.2 
Endpoints 
 
9.2.1 
Primary Endpoint(s) 
The primary endpoint is ORR. The primary endpoint of ORR will be the sum of the rate of 
complete response, partial response and stable disease of non-irradiated target lesions.  
 
9.2.2 
Secondary Endpoint(s) 
The first secondary endpoint is PFS. PFS will be programmatically determined based on the 
disease progression date provided by the investigator and is defined as the time between the date 
of randomization and the date of first progression (local, regional or distant metastasis) or death 
(whatever the cause), whichever occurs first. (Note: a subject who dies without reported 
progression will be considered to have progressed on the date of death.) For subjects who remain 
alive and whose disease has not progressed, PFS will be censored on the date of last evaluable 
disease assessment. 
The second secondary endpoint (OS) is defined as the time between the date of randomization and 
the date of death. For subjects without documentation of death, OS will be censored on the last 

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date the subject was known to be alive. OS will be followed continuously while subjects are on the 
study drug and every 3 months via in-person or phone contact after subjects discontinue the study 
drug. 
To third secondary endpoint to compare the local control of irradiated tumor provided by SBRT in 
combination with nivolumab versus nivolumab and ipilimumab will be assessed by the local 
control rate of the irradiated lesion. 
The fourth secondary endpoint (to assess the safety and tolerability of nivolumab, SBRT and 
ipilimumab) will be measured by the incidence of adverse events, serious adverse events, deaths, 
and laboratory abnormalities. 
The fifth secondary endpoint (to evaluate PD-L1 expression as a predictive biomarker) will be 
measured by the endpoint RFS based on PD-L1 expression level. 
The sixth secondary objective (to evaluate HRQoL) will be measured by mean changes from 
baseline in the EORTC-QLQ-C30 global health status/QoL composite scale and by mean changes 
from baseline in the remaining EORTC QLQ-C30 scales in all randomized subjects. 
 
9.3 
Analyses 
 
9.3.1 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment arm as randomized 
using descriptive statistics for all randomized subjects. 
 
9.3.2 
Efficacy Analyses 
 
9.3.2.1 
Primary Endpoint Methods 
Objective-response rate (ORR) including Complete Response (CR) rate, Partial Response (PR) 
rate, and Stable Disease (SD) rate will be calculated through exact binomial distribution with a 2-
sided 95% confidence interval among patients who obtain a least one dose of study drug.  
 
9.3.2.2 
Secondary Endpoint Methods 
The PFS analyses will be conducted using a two-sided log-rank test stratified by prior 
immunotherapy exposure in randomized subjects. The hazard ratio and corresponding two-sided 
95% CI will be estimated using a Cox proportional hazards model, with treatment group as a 
single covariate, stratified by the above factors. PFS curves, PFS medians with 95% CIs, and PFS 
rates at 6, 12, 24 and 36 months with 95% CIs will be estimated using Kaplan-Meier 
methodology. 
The OS analysis will be conducted using a two-sided log-rank test stratified by prior 
immunotherapy exposure at screening in randomized subjects. The hazard ratio and corresponding 
two-sided (1-adjusted α)% CI will be estimated using a Cox proportional hazards model, with 
treatment arm as a single covariate, stratified by the above factors. OS curves, OS medians with 
95% CIs and OS rates at 12 and 24 months with 95% CIs will be estimated using Kaplan-Meier 
methodology. 
The local control (LC) of irradiated lesions will be conducted using a two-sided log-rank test 
stratified by prior immunotherapy exposure at screening in randomized subjects. The hazard ratio 
and corresponding two-sided (1-adjusted α)% CI will be estimated using a Cox proportional 
hazards model, with treatment arm as a single covariate, stratified by the above factors. LC curves, 

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LC medians with 95% CIs and LC rates at 12 and 24 months with 95% CIs will be estimated using 
Kaplan-Meier methodology. 
To evaluate PD-L1 expression as a predictive biomarker, a Cox proportional hazards model will 
be used to test the interaction between PD-L1 expression (positive vs negative) and treatment arm 
for the primary and secondary endpoint. Additionally, ORR will be analyzed within each PD-L1 
expression subgroup (positive and negative) including log-rank tests and hazard ratios with 
corresponding confidence intervals. PFS curves and medians will be estimated using Kaplan-
Meier methodology. These analyses will be descriptive and not adjusted for multiplicity.  
 
9.3.3 
Safety Analyses 
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.0 by treatment group. All on-study AEs, treatment-related 
AEs, SAEs, and treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v 
4.0 criteria by system organ class and preferred term. On-study lab parameters including 
hematology, chemistry, liver function, and renal function will be summarized using worst grade 
NCI CTCAE v 4.0 criteria. 
 
9.3.4 
Outcomes Research Analyses 
EORTC QLQ C-30 
The analysis of EORTC QLQ C-30 will be performed in all randomized who have an assessment 
at baseline and at least one follow-up assessment.  
All scales and single items are scored on a categorical scales and linearly transformed to 0-to-100 
scales with higher scores for a functional scale representing higher levels of functioning, 
higher scores for the global health status/quality of life representing higher levels of global health 
status/quality of life and higher scores for a symptom scale representing higher level of 
symptoms. 
EORTC QLQ C-30 global health status/QoL composite scale data and the remaining EORTC 
QLQ C-30 scale data will be summarized by timepoint using descriptive statistics for each 
treatment arm. Exploratory analyses may be performed to examine differences between the 2 
arms.  
 
 
 
 
 
 
 
 
 
 
 

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10 
STUDY MANAGEMENT 
 
10.1 
Compliance 
 
10.1.1 
Compliance with the Protocol and Protocol Revisions 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations.  Once this essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB-approved consent form. 
 
10.1.2 
Required Documentation 
Before the study can be initiated at any site, the site will be required to provide regulatory 
documentation to the Moffitt Clinical Research Network (MCRN) at Moffitt Cancer Center. Sites 
must provide a copy of their informed consent to the MCRN Coordinating Center for review and 
approval prior to submission of any documents to the site’s IRB. Any changes re- quested by the 
site’s IRB must be provided to the MCRN staff for review and approval prior to resubmission to 
the IRB. 
The MCRN Coordinating Center must receive the following trial specific documents either by 
hardcopy, fax, or email before a site can be activated for any trial: 
1. 
IRB Approval Letter that includes the protocol version and date 
2. 
FDA Related Forms 1572/1571/310 as appropriate 
3. 
Signed Protocol Title Page 
4. 
IRB Approved Consent Form 
5. 
Site Delegation of Responsibility Log 
6. 
Signed  Financial Interest Disclosure Forms (principal and sub investigators) 
7. 
Updated  Investigator/Personnel  documents  (CVs,  licenses,  Conflict  of  Interest 
statements, etc.) as needed 
8. 
Updated Laboratory Documents (certifications, normal ranges, etc.) as needed  
9. 
Signed protocol specific Task Order 
A study initiation visit (or teleconference) will be held prior to the start of any study related 
activity at the site. Attendance is required for:  

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• 
The site PI and appropriate research staff 
• 
Moffitt PI and MCRN research coordinator 
 
The requirements of the protocol and all associated procedures and processes will be reviewed and 
agreed upon prior to the activation of the study. The MCRN utilizes the EDC system, OnCore. 
OnCore training will be scheduled if indicated with the appropriate staff from the site.  
 
10.1.3 
Registration Procedure 
All subjects must be registered with the MCRN Coordinating Center to be able to participate in a 
trial. The participating site must fax or email the completed study specific eligibility checklist and 
registration forms, supporting documents and signed informed consent to the Coordinating Center. 
Unsigned or incomplete forms will be returned to the site. Once documents are received, the 
MCRN Research Coordinator will review them to confirm eligibility and to complete the 
registration process. If eligibility cannot be confirmed, the research coordinator will query the site 
for clarification or additional documents as needed. Subjects failing to meet all study eligibility 
requirements will not be registered and will be unable to participate in the trial. 
Upon completion of registration, the MCRN Research Coordinator will provide the participating 
site with the study sequence number.  Within 24-48 hours after registration, it is the site’s 
responsibility to: 
• 
Enter the demographic and on-study patient information into the OnCore database. 
• 
Order investigational agent(s) if indicated per protocol. 
 
It is the responsibility of the participating Investigator or designee to inform the subject of 
the research treatment plan and to conduct the study in compliance with the protocol as agreed 
upon with Moffitt Cancer Center and approved by the site’s IRB. 
To register a patient send the completed signed eligibility checklist along with supporting 
documentation to the MCRN via email at affiliate.research@moffitt.org or via fax at 813-745-
5666, Monday through Friday between 8:00AM and 5:00PM(EST). 
 
10.1.4 
Adherence to Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol. 
 
10.1.5 
Emergency Modifications 
Moffitt Cancer Center and Affiliate investigators may implement a deviation from, or a change of, 
the protocol to eliminate an immediate hazard(s) to trial subjects without prior H. Lee Moffitt 
Cancer Center or their respective institution’s approval/favorable opinion.  
For Institutions Relying on Moffitt’s IRB: 
For any such emergency modification implemented, a Moffitt IRB modification form must be 
completed by Moffitt Research Personnel within five (5) business days of making the change. 
For Institutions Relying on Their Own IRB: 

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For Affiliate investigators relying on their own instution’s IRB, as soon as possible after the 
modification has been made, the implemented deviation or change and the reasons for it should be 
submitted to Moffitt Principal Investigator for agreement and the Affiliate institution’s IRB for 
review and approval. (Once IRB’s response is received, this should be forwarded to the MCRN.)  
 
10.2 
Data Management and Monitoring 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies.  Monitoring will be performed regularly to verify data is accurate, complete, and 
verifiable from source documents; and the conduct of the trial is in compliance with the currently 
approved protocol/ amendments, Good Clinical Practice (GCP), and applicable regulatory 
requirements. 
To obtain access to OnCore, the site research staff must complete an OnCore Access Request 
Form and a Moffitt Information Systems Confidentiality Agreement (provided in the MCRN 
Handbook at the site initiation visit) and submit both to the Coordinating Center. Once the 
completed forms are received, the site coordinator will receive VPN access, logon/password, and 
information on how to access OnCore using the VPN. The MCRN Coordinating Center will 
provide OnCore training to the site once initial access is granted and on an ongoing basis, as 
needed.  
 
10.2.1 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator. In the case of a study with 
a drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
 
10.2.2 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered into the eCRFs. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all eCRFs will be reviewed by 

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the Principal Investigator and will require his/her final signature to verify the accuracy of the data. 
 
 
10.3 
Ethical and Legal Aspects 
 
10.3.1 
Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the investigator abide by Good Clinical Practice (GCP) 
guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The study will 
also be carried out in keeping with applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating centers 
before start of the study, according to GCP, local laws, regulations and organizations.  When 
necessary, an extension, amendment or renewal of the EC/IRB approval must be obtained and also 
forwarded to Bristol-Myers-Squibb. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol.   
Modifications to the study protocol will not be implemented by the investigator without discussion 
and agreement by Bristol-Myers-Squibb.  However, the investigator may implement a deviation 
from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects without 
prior IEC/IRB/Bristol-Myers-Squibb approval/favorable opinion.  As soon as possible, the 
implemented deviation or change, the reasons for it and, if appropriate, the proposed protocol 
amendment should be submitted to the IEC/IRB/head of medical institution.  Any deviations from 
the protocol must be explained and documented by the investigator. 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and properly documented. 
 
10.3.2 
Subject Information and Consent 
Each subject/legal representative or proxy consenter will have ample time and opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the informed 
consent form and has done so, may he/she enter the study.  Additionally, the investigator and other 
information provider (if any) will personally sign and date the form.  The subject/legal 
representative or proxy consenter will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 

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In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed consent 
was obtained prior to these procedures. 
1. 
If the patient is not capable of providing a signature, a verbal statement of consent can also 
be given in the presence of an impartial witness (independent of Bristol-Myers-Squibb and the 
investigator).  This is to be documented by a signature from the informing physician as well as by 
a signature from the witness. 
2. 
For minors or adults under legal protection, consent shall be given by the legal guardian(s).  
The consent of a minor or adult under legal protection shall also be requested where such a person 
is able to express his/her own will.  His/her refusal or the withdrawal of his/her consent may not 
be disregarded. 
3. 
In emergency situations, when prior consent of the patient is not possible, the consent of the 
patient’s legal representative(s) or proxy consenter, if present, should be requested.  The patient 
should be informed about the study as soon as possible and his/her consent to continue the study 
should be requested. 
The informed consent form and any other written information provided to subjects/legal 
representatives or proxy consenters will be revised whenever important new information becomes 
available that may be relevant to the subject’s consent, or there is an amendment to the protocol 
that necessitates a change to the content of the subject information and/or the written informed 
consent form.  The investigator will inform the subject/legal representative or proxy consenter of 
changes in a timely manner and will ask the subject to confirm his/her participation in the study by 
signing the revised informed consent form.  Any revised written informed consent form and 
written information must receive the IEC/IRB`s approval/favorable opinion in advance of use. 
 
10.4 
Publication Policy 
Bristol-Myers-Squibb recognizes the right of the investigator to publish results upon completion 
of the study.  However, the investigator must send a draft manuscript of the publication or abstract 
to Bristol-Myers-Squibb at least thirty days in advance of submission in order to obtain approval 
prior to submission of the final version for publication or congress presentation.  This will be 
reviewed promptly and approval will not be withheld unreasonably.  In case of a difference of 
opinion between Bristol-Myers-Squibb and the investigator(s), the contents of the publication will 
be discussed in order to find a solution which satisfies both parties. All relevant aspects regarding 
data reporting and publication will be part of the contract between Bristol-Myers-Squibb and the 
investigator/institution. 
The Principal Investigator should ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov. 
 
10.5 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 
 

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11 
GLOSSARY OF TERMS 
 
Term 
Definition 
Complete Abstinence 
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests.  Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence. 
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence. 
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence 

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12 
LIST OF ABBREVIATIONS 
 
Term 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AT 
aminotransaminases 
AUC(INF) 
area under the concentration-time curve from time zero extrapolated to 
infinite time 
HCG 
human chorionic gonadotrophin 
BMS 
Bristol-Myers Squibb 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI 
confidence interval 
CL 
clearance 
cm 
centimeter 
Cmax 
maximum observed concentration 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
Complete response 
CRF 
Case Report Form, paper or electronic 
CT 
computed tomography 
CTA 
Clinical trial agreement 
CTCAE 
common terminology criteria for adverse events 
CTLA-4 
cytotoxic T lymphocyte associated antigen-4 
CTV 
Clinical Target Volume 
DILI 
drug-induced liver injury 
dL 
deciliter 
DLT 
dose limiting toxicity 
DMC 
data monitoring committee 

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DMFS 
distant metastases-free survival 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EFS 
Event-free survival 
ELISA 
enzyme-linked immunosorbent assay 
EOI 
end of infusion 
EORTC 
European Organization for Research and Treatment of Cancer 
EDC 
Electronic Data Capture 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GTV 
Gross Tumor Volume 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
Human Immunodeficiency Virus 
HR 
heart rate or hazard ratio 
HRQoL 
Health Related Quality of Life 
HRT 
hormone replacement therapy 
IB 
Investigator Brochure 
irAE 
immune-related adverse event 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IP 
Investigational product 
IRB 
Institutional Review Board 
ITSM 
immunoreceptor tyrosine-based switch motif 
ITV 
Internal Target Volume 
IU 
International Unit 
IV 
intravenous 
IVRS 
Interactive Voice Response System 
kg 
kilogram 

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L 
liter 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
MDSC 
Myeloid derived suppressor cells 
mg 
milligram 
mL 
milliliter 
MLR 
mixed lymphocyte reaction 
MRI 
Magnetic resonance imaging 
MTD 
maximum tolerated dose 
MU 
million units 
g 
microgram 
N 
number of subjects or observations 
N/A 
not applicable 
NSCLC 
non-small cell lung cancer 
NED 
no evidence of disease 
ng 
nanogram 
NIMP 
non-investigational medicinal products 
OAR 
Organs at Risk 
Obs. 
Observation 
ORR 
Objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD-1 
programmed death receptor-1 
PFS 
Progression free survival 
PK 
pharmacokinetics 
PPK 
Population pharmacokinetic 
PR 
Partial response 
PRO 
Patient Reported Outcome 
PTV 
Planning Target Volume 
QoL 
Quality of Life 
QLQ-C30 
Quality of Life Questionnaire-Core 
RCC 
renal cell carcinoma 

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RT 
radiation therapy 
TCR 
T-cell receptor 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBRT 
Stereotactic Body Radiation Therapy 
SNP 
single nucleotide polymorphism 
T-HALF 
Half life 
Tmax 
time of maximum observed concentration 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog rating scale 
Vz 
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline) 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
WPAI:GH 
Work Productivity and Activity Impairment : General Health 

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13 
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APPENDIX 1 
AJCC MERKEL CELL CARCINOMA STAGING 
 
 
 
 
Source: Lemos, B. D. et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel 
cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. Journal 
of the American Academy of Dermatology 63, 751-761 (2010)  
 
 
 
 
 
 
 
 
 

 
 
 
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APPENDIX 2 
PERFORMANCE STATUS SCALES 
 
STATUS 
SCALES 
STATUS 
KARNOFSKY 
ZUBROD- 
ECOG-
O
Normal, no complaints 
100 
0 
Normal activity 
Able to carry on normal 
activities Minor signs or 
f di
90 
0 
Symptoms, but fully 
ambulatory 
Normal activity with effort 
80 
1 
Cares for self. Unable 
to carry on normal 
i i
d
70 
1 
Symptomatic, but in 
bed < 50% of the day. 
Requires occasional 
assistance, but able to care 
f
f hi
d
60 
2 
Requires considerable 
assistance and frequent 
medical care 
50 
2 
Needs to be in bed 
> 50% of the day, but 
not bedridden 
Disabled. Requires special 
d
i
40 
3 
Severely disabled. 
Hospitalization indicated 
h
h d
h
30 
3 
Very sick. 
Hospitalization 
A i
20 
4 
Unable to get out of 
bed 
Moribund 
10 
4 
Dead 
0 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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APPENDIX 3 
METHODS OF CONTRACEPTION 
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as 
listed below: 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
• Male condoms with spermicide1,2 
• Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP 
subject or male subject’s WOCBP partner. Female partners of male subjects participating in 
the study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug 
• Nonhormonal IUDs, such as ParaGard 
• Tubal ligation 
• Vasectomy. 
• Complete Abstinence* 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. Subjects who choose 
complete abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable alternate methods of 
highly effective contraception must be discussed in the event that the subject chooses to 
forego complete abstinence. 
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal sponge 
• Male Condom without spermicide 
• Progestin only pills by WOCBP subject or male subject’s WOCBP partner 
• Female Condom*. 
* A male and female condom must not be used together 
 
 
 
 
 
 
1 Kestelman P. et. al., Efficacy of the Simultaneous Use of Condoms and Spermicides Family Planning 
Perspectives.Vol 23 (5); October 1991. 
2 Gabbay MB, Thomas J, Gibbs A, Hold P. A Randomized Crossover Trial of The Impact of Additional Spermicide 
on Condom Failure Rates. Sex Transm Dis 2008; 35: 862-8.Date: 22-Feb-2016  

 
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Management 
• Continue  I-O therapy per 
protocol 
• Symptomatic treatment 
• Delay I-O therapy per protocol 
• Symptomatic treatment 
• Discontinue I-O therapy per 
protocol 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone  IV or  IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider lower endoscopy 
Follow-up 
• Close monitoring for worsening symptoms. 
• Educate patient to report worsening immediately 
If worsens: 
• Treat as Grade 2 or 3/4 
If improves to grade 1: 
•  Resume I-O therapy per protocol 
If persists > 5-7 days or recur: 
•  0.5-1.0 mg/kg/day methylprednisolone or oral equivalent 
•  When symptoms improve to grade 1, taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol. 
If worsens or persists > 3-5 days with oral steroids: 
•  Treat as grade 3/4 
If improves: 
• Continue steroids until grade 1, then taper over at 
least 1 month 
If persists > 3-5 days, or recurs after improvement: 
• Add infliximab 5 mg/kg (if no contraindication). 
Note: Infliximab should not be used in cases of 
perforation or sepsis 
APPENDIX 4 
IMMUNE ADVERSE EVENT MANAGEMENT ALGORITHMS 
 
GI Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. Opiates/narcotics 
may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis. 
 
Grade of Diarrhea/ 
Colitis 
(NCI CTCAE v4) 
Grade 1 
Diarrhea:< 4 stools/day over baseline; 
Colitis: asymptomatic 
Grade 2 
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 hrs; 
not interfering with ADL 
Colitis: abdominal pain; blood in stool 
Grade 3-4 
Diarrhea (G3): ≥7 stools per day over 
baseline; incontinence; IV fluids ≥24 
hrs; interfering with ADL 
Colitis (G3):  severe abdominal pain, 
medical intervention indicated, 
peritoneal signs 
G4: life-threatening, perforation 
 
Patients on IV steroids may be switched to an equivalent dose of oralcorticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids

 
Clinical Protocol  
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Renal Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy 
 
Grade of Creatinine 
Elevation 
(NCI CTCAE v4) 
 
Management                                                        Follow-up
Grade 1 
Creatinine > ULN and  > 
than baseline but  ≤ 1.5x 
baseline 
 
• Continue I-O therapy per protocol 
• Monitor creatinine weekly 
If returns to baseline: 
•Resume routine creatinine monitoring per protocol 
If worsens: 
•Treat as Grade 2 or 3/4
 
 
 
Grade 2-3 
Creatinine > 1.5x baseline 
to ≤ 6x ULN 
 
• Delay I-O therapy per protocol 
• Monitor creatinine every 2-3 days 
• 0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or oral 
equivalent 
• Consider renal biopsy 
If returns to Grade 1: 
•Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume I-O therapy 
and routine creatinine monitoring per protocol 
 
If elevations persist > 7   days or worsen: 
•Treat as Grade 4
 
 
 
 
Grade 4 
Creatinine > 6x ULN 
• Discontinue I-O therapy per 
protocol 
• Monitor creatinine daily 
• 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Consult nephrologist 
• Consider renal biopsy 
 
 
If returns to Grade 1  : Taper steroids over at least 1 month and 
add prophylactic antibiotics for opportunistic infections
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral 
corticosteroids 
 

 
Clinical Protocol  
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Pulmonary Adverse Event Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging 
and pulmonary consultation. 
 
Grade of
Pneumonitis 
(NCI CTCAE v4) 
Management                                                      Follow-up
 
Grade 1 
Radiographic changes only 
• Consider delay of I-O therapy 
• Monitor for symptoms every 2-3 
days 
• Consider Pulmonary and ID 
consults 
 
• Re-image at least every 3 weeks 
If worsens: 
• Treat as Grade 2 or 3-4
 
 
 
Grade 2 
Mild to moderate  new 
symptoms 
 
 
 
 
 
 
Grade 3-4 
Severe new symptoms; 
New/worsening hypoxia; 
Life-threatening 
• Delay I-O therapy per protocol 
• Pulmonary and ID consults 
• Monitor symptoms daily, consider 
hospitalization 
• 1.0 mg/kg/day methyl- 
prednisolone IV or oral equivalent 
• Consider  bronchoscopy , lung 
biopsy 
 
 
 
• Discontinue  I-O therapy per 
protocol 
• Hospitalize 
• Pulmonary and ID consults 
• 2-4  mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider bronchoscopy, lung 
biopsy 
• Re-image every 1-3 days 
If improves: 
• When symptoms return to near baseline, taper steroids over 
at least 1 month and then resume I-O therapy per protocol 
and consider prophylactic antibiotics 
If not improving after 2 weeks  or worsening: 
• Treat as Grade 3-4 
 
 
 
 
 
 
If improves to baseline: 
• Taper steroids over at least 6 weeks 
If not improving after 48 hours or worsening: 
• Add additional immunosuppression (e.g. infliximab, 
cyclophosphamide, IVIG, or mycophenolate mofetil)
 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral 
corticosteroids.

 
Clinical Protocol  
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114 
 
 
 
 
 
Hepatic Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for 
obstruction. 
 
Grade of Liver 
Test  Elevation 
(NCI CTCAE v4) 
 
Management                                                        Follow-up
Grade 1 
AST or ALT > ULN  to 3.0 x 
ULN and/or T. bili > ULN 
- 1.5 x ULN 
 
 
• Continue I-O therapy per protocol 
 
• Continue LFT monitoring per protocol 
If worsens: 
• Treat as Grade 2 or 3-4
 
 
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN and/or T. bili > 1.5 
to ≤ 3 x ULN 
 
 
• Delay I-O therapy per protocol 
• Increase frequency of monitoring 
to every 3 days 
If returns to baseline: 
•Resume routine monitoring, resume I-O therapy per protocol 
 
If elevations persist > 5-7  days or worsen : 
• 0.5-1 mg/kg/day methylprednisolone or oral equivalent and 
when LFT returns to grade 1 or baseline, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per protocol
 
 
 
 
Grade 3-4 
AST or ALT > 5 x ULN 
and /or T.bili >3 x ULN 
 
 
• Discontinue  I-O therapy* 
• Increase frequency of monitoring 
to every 1-2 days 
•  1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent** 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consult gastroenterologist 
 
If returns to grade 2: 
• Taper steroids over at least 1 month 
 
 
If does not improve in >3-5 days, worsens or rebounds: 
• Add mycophenolate mofetil 1 g BID 
• If no response within an additional 3-5 days, consider other 
immunosuppressants per local guidelines
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*I-O therapy may be delayed rather than discontinued  if AST/ALT  ≤ 8 x ULN and T.bili ≤ 5 x ULN. 
**The recommended  starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.

 
Clinical Protocol  
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115 
 
 
Endocrinopathy Management Algorithm 
 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field testing, 
endocrinology consultation, and imaging. 
 
Asymptomatic 
TSH elevation 
• Continue I-O therapy per protocol 
• If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 subsequent measurements: include fT4 at 
subsequent cycles as clinically indicated; consider endocrinology consult
 
 
 
 
 
Symptomatic 
endocrinopathy 
 
• Evaluate endocrine function 
• Consider pituitary scan 
 
Symptomatic with abnormal lab/pituitary scan: 
• Delay I-O therapy per protocol 
•  1-2 mg/kg/day methylprednisolone IV or  PO equivalent 
• Initiate appropriate hormone therapy 
 
No abnormal lab/pituitary MRI scan but symptoms persist: 
• Repeat labs in 1-3 weeks / MRI in 1 month 
If improves  (with or without 
hormone replacement): 
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections 
• Resume I-O therapy per protocol 
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component
 
 
 
 
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock 
out of proportion to 
current illness 
• Delay or discontinue I-O therapy per protocol 
• Rule out sepsis 
• Stress dose of IV steroids with mineralocorticoid activity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out,  then treat as above for symptomatic 
endocrinopathy
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, 
once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.

 
Clinical Protocol  
CA209-737 
 
116 
 
Follow-up 
If persists > 1-2 weeks or recurs: 
• Consider skin biopsy 
• Delay I-O therapy per protocol 
• Consider 0.5-1.0 mg/kg/day methylprednisolone IV or 
oral  equivalent. Once improving , taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol 
If worsens: 
• Treat as Grade 3-4 
If improves to Grade 1: 
• Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections 
• Resume I-O therapy per protocol 
 
 
 
 
 
 
Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
Grade of 
Rash 
(NCI CTCAE v4) 
 
Management
 
 
 
Grade 1-2 
Covering  ≤ 30% 
BSA* 
 
• Symptomatic therapy (e.g. antihistamines, 
topical steroids) 
• Continue I-O therapy per protocol
 
 
 
 
 
Grade 3-4 
Covering >30% BSA; 
Life threatening 
consequences* 
• Delay or discontinue I-O therapy per 
protocol 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0 mg/kg/day IV methylprednisolone 
IV or IV equivalent
 
 
 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*Refer to NCI CTCAE v4 for term-specific  grading criteria.

 
Clinical Protocol  
CA209-737 
 
117 
 
 
 
 
Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
Grade of 
Neurological 
Toxicity 
(NCI CTCAE v4) 
 
 
Management                                                           Follow-up
 
Grade 1 
Asymptomatic or 
mild symptoms; 
Intervention not 
indicated 
 
 
• Continue I-O therapy per protocol 
 
Continue to monitor the patient. 
If worsens: 
• Treat as Grade 2 or 3-4
 
Grade 2 
Moderate symptoms; 
Limiting instrumental 
ADL 
• Delay I-O therapy per protocol 
• Treat symptoms per local guidelines 
• Consider  0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or  PO 
equivalent 
 
If improves to baseline: 
•Resume I-O therapy per protocol when improved to baseline 
If worsens: 
• Treat as Grade 3-4
 
 
Grade 3-4 
Severe symptoms; 
Limiting self-care 
ADL; 
Life-threatening 
 
 
• Discontinue I-O therapy per protocol 
• Obtain neurology consult 
• Treat symptoms per local guidelines 
•  1.0-2.0 mg/kg/day IV 
methylprednisolone  IV or IV equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
 
If improves to Grade 2: 
• Taper steroids over at least 1 month 
 
If worsens or atypical presentation: 
• Consider IVIG or other immunosuppressive therapies per 
local guideline
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of 
tapering or earlier, once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids 
should be taken into account when switching to the equivalent dose of oral corticosteroids. 

Clinical Protocol  
CA209-737 
 
118 
 
 
APPENDIX 5 EORTC QLQ-C30 (VER 3) FORM 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential. 
Please 
fill 
in 
your 
initials:                                    
 
Your      birthdate      (Day,      Month,      Year):                     
 
Today's date (Day, Month, Year):                 31    
 
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 

Clinical Protocol  
CA209-737 
 
119 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
For  the  following  questions  please  circle  the  number  between  1  and  7  
that best applies to you 
 
29. How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent