Dual Immune Checkpoint Blockade and Hypofractionated Radiation in Patients With Salivary Gland Cancers
Phase: PHASE1
Conditions: Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Neoplasm in the Lung, Salivary Gland Carcinoma, Stage IV Major Salivary Gland Cancer AJCC v8, Stage IVA Major Salivary Gland Cancer AJCC v8, Stage IVB Major Salivary Gland Cancer AJCC v8, Stage IVC Major Salivary Gland Cancer AJCC v8
Sponsor: University of Washington

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
Dual Immune Checkpoint Blockade and Hypofractionated Radiation in Patients with Salivary Gland 
Cancers 
 
 
Protocol number:  CA209-8G3 
 
 
Principal Investigators 
Cristina P. Rodriguez, MD 
Associate Professor 
University of Washington 
Ph: 206 288 2048 
Fax: 206 288 7543 
Email: rodrigcr@uw.edu 
 
Upendra Parvathaneni, MD 
Associate Professor 
University of Washington 
       Email: Upendra@uw.edu 
Subinvestigators: 
Renato Martins, MD, MPH 
Keith Eaton, MD, PhD 
Laura Chow, MD 
Christina Baik, MD, MPH 
Bernardo Goulart, MD 
Rafael Santana-Davila, MD 
Sylvia Lee, MD 
 
 
TRIAL REGISTRATION NUMBER: NCT03749460
IRO REC'D OCT 20  2021
FHCRC IRB Approval  
NOV 18 2021 
Document Released Date

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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STUDY SYNOPSIS 
Background 
No therapeutic treatment standard exists for recurrent or metastatic salivary gland 
cancers. There is preliminary data that a minority of patients may respond to single agent 
pembrolizumab (Cohen, 2016). The dual inhibition of PDL-1 and CTLA-4 is an approach 
that has garnered significant enthusiasm, due to robust preclinical data showing 
synergistic antitumor efficacy.  
 
This data is supported by prospectively collected clinical data, in immunotherapy naive 
melanoma patients, wherein improved objective response rates and progression free 
response rates were observed with the combination of nivolumab and ipilimumab 
compared to either agent (Larkin, 2015). Multiple ongoing studies in other tumor types 
are examining the activity of this combination. 
 
The role of radiation therapy in transforming the tumor microenvironment to increase the 
activity of immune checkpoint inhibition is an area of significant scientific interest. There 
is preclinical data supporting that the exposure to immune checkpoint inhibitors prior to 
therapeutic radiation is associated with increased antitumor activity. The clinical 
observation of the abscopal effect further supports the potential clinical utility of 
radiation therapy in inducing responses to immune check point inhibition. 
 
Hypothesis 
Dual immune checkpoint blockade with nivolumab and ipilimumab combined with 
hypofractionated palliative radiation therapy is safe and well tolerated in patients with 
advanced salivary gland carcinomas. 
 
Objectives: 
Primary Objective: 
Demonstrate that nivolumab, ipilimumab and hypofractionated palliative radiation therapy 
is safe and well tolerated in patients with advanced salivary gland carcinomas. 
 
Secondary Objective(s): 
1. Evaluate the objective response rate 
2. Determine overall and progression free survival 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Exploratory Objective(s): 
Collect tumor and blood for correlative studies 
 
Study Design 
This is a single arm, open label, prospective study evaluating the safety and clinical efficacy 
of the combination of nivolumab, ipilimumab and hypofractionated palliative radiation 
therapy (SBRT) in patients with advanced salivary gland cancer. 
Patients enrolled will receive the following treatment (see Section 5.1.1): 
1. 
Nivolumab 3mg/kg IV Q 2 weeks x 12 doses followed by Nivolumab 480 mg IV 
Q4 weeks x 8 doses 
2. 
Ipilimumab 1 mg/kg IV Q6 weeks x 4 doses 
3. 
Hypofractionated radiation therapy (SBRT) given to a total dose of 24Gy given in 
3 fractions every other day over 1 week and initiated 2 weeks after the first dose 
of nivolumab and ipilimumab. The target lesion will be a local/regional or 
metastatic disease site that per the multidisciplinary head and neck team, requires 
local control for palliation and/or prevention of impending symptoms. 
Both nivolumab and ipilimumab have well established toxicity profiles as a single agent and 
in combination. However, since the combination of nivolumab, ipilimumab and palliative 
radiation has not previously been described or studied, the first 6 patients who will be 
enrolled in this study will represent the initial safety run-in phase. Patients will receive full 
dose nivolumab and ipilumumab. Enrollment will be halted until these first 6 patients 
complete the first 12 weeks of treatment and acute toxicities will be reviewed. If more than 
2 DLTs (to be defined in Section 5.1.2) are noted in this 6 patient cohort, a dose 
modification will be implemented (Section 5.1.1) for the remaining 14 patients who will be 
enrolled in the expansion cohort. Enrollment period is 24 months and duration of the trial 48 
months.  
 
 
Study Population 
 
The study aims to enroll patients with salivary gland carcinomas (WHO, 2005), who are not 
candidates for curative intent therapy and who have a target lesion (either local/regional or 
distant metastatic site involving the lung and/or bone), that requires local control for 
palliation, as determined by a multidisciplinary team. 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Inclusion Criteria: 
1. 
Histologically proven salivary gland carcinoma (WHO, 2005) arising from a 
previous head and neck primary site, and located within the head and neck region, 
lung or bone, and who are not candidates for curative intent therapy. 
 
2. 
≥18 years old at the time of signing informed consent. 
 
3. 
Demonstrated disease progression during, or after discontinuation, of the most 
recent line of systemic therapy. For patients who have received no prior systemic 
therapy, demonstrated progression in the 3 months prior to trial participation 
assessed by the treating physician. 
 
4. 
Have received any number lines of prior systemic therapy (including systemic 
therapy in the curative intent setting). 
 
5.        Have a lesion/s deemed suitable by the treating physicians for SBRT with the 
intent of palliation or prevention of symptoms. This lesion must be:  
 
a)  1-3 non-overlapping sites in the head and neck region OR 
b) metastatic lesions outside the H&N region in the lung or bone (a 
minimum of 1 and a maximum 5 lesions will be irradiated), provided 
there is no significant overlap between the lesions.   
 
Patients should have RECIST 1.1 criteria measurable disease in addition 
to the lesion/s treated with SBRT. If the site/s of SBRT were previously 
radiated to high dose RT (>50Gy), there should be >6 month time interval 
between the last dose of radiation and the start of SBRT.  
 
6. 
Have the ability to tolerate required SBRT-related procedures (e.g.: lie flat and 
hold position for treatment) as determined by the treating physician 
 
7. 
Be willing and able to provide written informed consent for the trial and comply 
with the study visit requirements 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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8. 
Have measurable disease based on RECIST 1.1. (in addition to the lesion/s that 
will be treated with stereotactic radiation therapy)   
 
9. 
 Have provided tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. Tissue requirement will be waived if deemed 
contraindicated or not clinically available/accessible for resection per the treating 
physician (PI approval required). 
 
10. 
Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
11. 
Demonstrate adequate organ function as defined in below, based on screening 
labs should be performed within 28 days of treatment initiation.  
− 
Hemoglobin ≥ 9.0 g/dL 
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
− 
Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
− 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will not 
apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis 
or hepatic pathology), who will be allowed only in consultation with their 
physician. 
− 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤ 5x ULN 
− 
Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and 
Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance. 
12. 
Evidence of post-menopausal status OR negative urinary or serum pregnancy test 
for female pre-menopausal patients. Women will be considered post-menopausal 
if they have been amenorrheic for 12 months without an alternative medical 
cause. The following age-specific requirements apply:  
− 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy, or hysterectomy).  
− 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 year 
ago, had chemotherapy-induced menopause with last menses >1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
13. 
Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. 
   
14. 
Female subjects of childbearing potential should be willing to use 1 method of 
highly effective birth control or be surgically sterile, or abstain from heterosexual 
activity for the course of the study through 180 days after the last dose of study 
medication (Reference Section 8.1).  Subjects of childbearing potential are those 
who have not been surgically sterilized or have not been free from menses for > 1 
year.  
 
15. 
Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 180 days after the last dose of study 
therapy. 
 
16. 
Patient is ≥ 5 years free of another primary malignancy, except: a) if the other 
malignancy is basal cell carcinoma or cervical carcinoma in situ or b) if the other 
primary malignancy is not considered clinically significant and is requiring no 
active intervention 
 
Exclusion Criteria: 
The subject must be excluded from participating in the trial if the subject: 
 
1. 
Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks of the first dose of treatment. 
 
2. 
Has a target lesion/s for SBRT that demonstrate any of the following: 
a. located within 2 cm of the proximal bronchial tree 
b. > 5 cm (> 50 cc) in greatest dimension 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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3. 
Has a target lesion/s in a region that previously received high dose RT (>50 Gy) 
demonstrating any of the following:  
a. 
carotid artery encasement (> 180 degrees)  
b. 
unprotected carotid artery (i.e. skin is directly over the carotid without 
intervening soft tissue, especially after prior neck dissection without a 
vascularized free flap) (a&b due to risk of carotid blow out) 
c. 
skin infiltration by tumor (due to risk of fistula) 
d. 
located in the larynx/hypopharynx primaries (due airway threat) 
e. 
treated with high dose radiation therapy (>50 Gy) within 6 months or less 
of trial enrollment 
 
4. 
Prior receipt of an anti-PD-1, anti-PDL1 or anti-CTLA4 immune checkpoint 
inhibitor. 
 
5. 
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of nivolumab or ipilimumab. The following are exceptions to this 
criterion: 
-         Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection) 
- 
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent 
- 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
6.        Has received a prior monoclonal antibody within 4 weeks prior to study Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier.  
 
7.        Has received prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from adverse events due to a previously administered 
agent. 
            -Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
            -Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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8. 
Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or in situ cervical cancer that has undergone potentially 
curative therapy.  
 
9.        Has known brain metastases or spinal cord compression unless the patient is 
stable (asymptomatic; no evidence of new or emerging brain metastases; and 
stable and off steroids for at least 14 days prior to start of study treatment). 
Following radiotherapy and/or surgery of the brain metastases patients must wait 
4 weeks following the intervention and before initiating study treatment with 
imaging to confirm stability.   
 
10. 
Has an active autoimmune disease requiring systemic treatment within the past 2 
years or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects 
with vitiligo or resolved childhood asthma/atopy would be an exception to this 
rule.  Subjects that require intermittent use of bronchodilators or local steroid 
injections would not be excluded from the study.  Subjects with hypothyroidism 
stable on hormone replacement will not be excluded from the study. 
 
11. 
Has a history of or evidence of active interstitial lung disease or non-infectious 
pneumonitis. 
 
12.      Has an active infection requiring systemic therapy. 
 
13.      Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best interest 
of the subject to participate, in the opinion of the treating investigator. 
 
14.   Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
15.      Is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the pre-screening or screening 
visit through 180 days after the last dose of trial treatment. 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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16.      Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
 
17.      Has evidence of acute or chronic hepatitis B, or hepatitis C 
 
18. 
Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
 
19. 
Has a history of primary immunodeficiency or an allogeneic organ transplant  
 
20. 
Known history of previous clinical diagnosis of tuberculosis 
 
21. 
Uncontrolled intercurrent illness including, but not limited to symptomatic 
congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, seizures 
Statistical Plan 
 
There are multiple ongoing studies in various tumor types exploring the activity of 
nivolumab and ipilimumab. In a published report of the combination in patients with 
advanced NSCLC treated on a phase I study (Checkmate 012), treatment related serious 
adverse events were observed in 28% of patients (Hellmann Lancet Oncol, 2017). This 
study plans to accrue 20 patients, a sample size that would allow us to estimate grade 3 
or higher acute drug related toxicity rate of 30% with a confidence interval of 20% (95% 
confidence level) or an upper bound of 50%. This would allow us to reasonably exclude 
a clinically significant increase in toxicity with the addition of radiation therapy to the 
nivolumab and ipilimumab combination as defined by the upper bound of the confidence 
interval. 
 
Toxicities will be summarized as the number and percentage of patients with each type 
of toxicity. Responses will be summarized as frequencies and percentages. The Kaplan 
Meier method will be used to estimate overall survival and progression free survival. 
Outcomes will be calculated from the date of study entry to the date of the 
corresponding event. We will use multivariate statistics to test the hypotheses that 
pretreatment intratumoral immune cell phenotype and PD-L1expression predict response 
response to therapy, and that therapy alters systemic immunophenotype. 
 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Study Schema 
 
 
 
 
 
 
 
 
 
 
Note: refer to Dosing and Administration (Section 5.1.1) for further details on treatment scenarios.  
 
Number of Centers: 1 
Number of Subjects: A maximum of 20 subjects will be enrolled. 
Screening 
and 
enrollment 
Weeks 1-6 
Day 1 Week 1 
 
Nivolumab 3mg/kg IV 
over 30 mins Q2 weeks x 
3 doses  
and 
Ipilimumab 1mg/kg  IV 
over 60 mins x 1 Q 6 
weeks x 1 dose 
 
Week 3 
 
SBRT every other day to a 
total dose of 24Gy  
Weeks 6-24 
 
Nivolumab 3 mg/kg IV 
over 30 mins Q2 weeks x 
9 doses 
 
and 
 
Ipilimumab 1mg/kg IV 
over 60 mins Q 6 weeks 
x 3 doses 
Weeks 25 to 52 
 
 
Nivolumab 480mg IV over 
30 mins Q4 weeks x 8 
doses 
 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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TABLE OF CONTENTS 
 
STUDY SYNOPSIS ...................................................................................................................................................... 1 
TABLE OF CONTENTS ............................................................................................................................................ 11 
ABBREVIATIONS AND DEFINITION OF TERMS ................................................................................................ 13 
1. 
INTRODUCTION ............................................................................................................................................... 19 
2. 
STUDY OBJECTIVES ....................................................................................................................................... 20 
3. 
ETHICAL CONSIDERATIONS ......................................................................................................................... 21 
4. 
INVESTIGATIONAL PLAN/STUDY DESIGN ................................................................................................ 22 
4.2 
Study Schema ............................................................................................................................................. 22 
4.3 
Efficacy Measurements .............................................................................................................................. 24 
4.4 
Inclusion Criteria: ...................................................................................................................................... 25 
4.5 
Exclusion Criteria: ..................................................................................................................................... 27 
5. 
TREATMENT ..................................................................................................................................................... 30 
5.1 
Systemic Therapy ....................................................................................................................................... 30 
5.1.1 
Dosage and Administration ................................................................................................................... 30 
5.1.2 
Definition of DLT .................................................................................................................................. 31 
5.1.3 
Dose Delays/Modifications .................................................................................................................... 33 
5.2 
Radiation Therapy ...................................................................................................................................... 36 
5.2.1 
Stereotactic Targeting and Treatment .................................................................................................... 37 
5.2.2 
Target Contouring .................................................................................................................................. 37 
5.2.3 
Treatment planning, dose fractionation and specification ..................................................................... 38 
6. 
STUDY DRUGS ................................................................................................................................................. 42 
6.1 
Storage of Study Drug ................................................................................................................................ 42 
6.2 
Concomitant medications ........................................................................................................................... 43 
Permitted concomitant medications ..................................................................................................................... 43 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Excluded Concomitant Medications .................................................................................................................... 43 
7. 
SCHEDULE OF ASSESSMENTS ...................................................................................................................... 46 
7.1 
Trial Procedures ......................................................................................................................................... 49 
7.1.1 
Administrative ....................................................................................................................................... 49 
7.1.2 
Clinical Procedures/Assessments ........................................................................................................... 50 
Withdrawal of informed consent for donated biological samples ....................................................................... 57 
7.1.3 
Other Procedures ................................................................................................................................... 59 
7.1.4 
Visit Requirements ................................................................................................................................ 59 
8. 
SAFETY AND REPORTING ............................................................................................................................. 61 
8.1 
DEFINITIONS FOR SERIOUS ADVERSE EVENTS ............................................................................. 62 
8.2 
ADVERSE EVENTS ................................................................................................................................. 64 
8.3 
NONSERIOUS ADVERSE EVENT ......................................................................................................... 64 
9. 
STATISTICAL CONSIDERATIONS ................................................................................................................ 67 
Sample size determination ....................................................................................................................................... 67 
10. 
STUDY MANAGEMENT ............................................................................................................................. 67 
Monitoring of the study ........................................................................................................................................... 68 
11. 
REFERENCES ............................................................................................................................................... 69 
 
 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation 
or 
special term 
Explanation 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
ANOVA 
Analysis of Variance 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
B-HCG 
Beta-Human Chorionic Gonadotropin 
BMS 
Bristol-Myer Squibb 
BrdU 
Bromodeoxyuridine 
C 
Cycle 
CBCT 
Cone Beam Computed Tomography 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance 
CR 
Complete response 
CRF 
Case Report Form 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Abbreviation 
or 
special term 
Explanation 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
DILI 
Drug-Induced Liver Injury 
DLT 
Dose Limiting Toxicity 
DMSO 
Dimethyl Sulfoxide 
DNA 
Deoxyribonucleic Acid 
DSMC 
Data and Safety Monitoring Committee 
EC 
Ethics Committee, synonymous to Institutional Review Board and 
Independent Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Ethylenediaminetetraacetic 
ERC 
Ethics Review Committee 
ESR 
Expediated Safety Report 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FNA 
Fine Needle Aspiration 
GI 
Gastrointestinal 
GTV 
Gross Target Volume 
Gy 
Gray 
hCG 
Human chorionic gonadotropin 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Abbreviation 
or 
special term 
Explanation 
HA 
Health Administration 
H&E 
Hematoxylin & Eosin 
HIV 
Human immunodeficiency virus 
H&N 
Head and Neck 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ID 
Investigational Drug 
IDL 
Intermediate Density Lipoprotein 
 
 
IDO 
Indoleamine-pyrrole 2,3-dioxygenase 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IGTV 
Internal Gross Tumor Volume 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IGRT 
Image guided RT 
IGTV 
Internal Gross Tumor Volume 
IHC 
Immunohistochemistry 
ILS 
Interstitial lung disease 
IMRT 
Intensity-Modulated Radiation Therapy 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Abbreviation 
or 
special term 
Explanation 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IP 
Investigational product  
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IV 
Intravenous 
mAB 
Monoclonal Antibody 
MLC 
Mixed Lymphocyte Culture 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NBF 
Neutral Buffered Formalin 
NSCLC 
Non–small-cell lung cancer 
OAR 
Organ at Risk  
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PET 
Positron Emission Tomography 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Abbreviation 
or 
special term 
Explanation 
PFS 
Progression-free survival 
PRV 
Planning organ at Risk Volume  
PT 
Prothrombin Time 
PTV 
Planning Target Volume 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RT 
Radiation Therapy 
SAE 
Serious adverse event 
SBRT 
Stereotactic Body Radiation Therapy 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SRC 
Scientific Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T4 
Thyroxine 
TSC 
Tumor Slice Culture 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
VEGF 
Vascular Endothelial Growth Factor 
VMAT 
Volumetric Modulated Arch Radiotherapy 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Abbreviation 
or 
special term 
Explanation 
XRT 
Radiotherapy 
 
 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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1. 
INTRODUCTION 
 
Salivary gland carcinomas represent <5% of all head and neck malignancies and are characterized by marked morphologic and 
biologic diversity.  These arise from the secretory acini and associated myoepithelial cells in the three paired major salivary glands, 
and minor salivary glands located throughout the upper aerodigestive epithelium.  The current WHO histological classification 
identifies 24 subtypes, with the most common being adenoid cystic carcinoma, mucoepidermoid carcinoma, salivary duct carcinomas 
and adenocarcinomas (Barnes, 2005).  The current standard of care for early or locally advanced disease is curative intent resection 
followed by adjuvant radiation for tumors at high risk for recurrence (Schroeder, 2008). 
 
Currently, there is no standard of care for the treatment of incurable (unresectable and metastatic) salivary gland malignancies.  
Clinical trials that have examined the activity of systemic therapy have been difficult to interpret due to small numbers, heterogeneous 
patient populations, and the frequent observation of prolonged stable disease, a likely reflection of the indolent biology of certain 
salivary gland tumors, such as adenoid cystic carcinomas. Historical regimens tested more than 20 years ago have employed cisplatin 
and cisplatin-based combinations (response rates of 20% or lower) (Laurie, 2006).  Two of the largest contemporary studies conducted 
in North America have examined single agent paclitaxel (response rate 26% in non-adenoid cystic carcinoma subtypes, 0 in adenoid 
cystic carcinomas), and a gemcitabine carboplatin combination (response rate 24%) (Gilbert, 2006; Laurie, 2010). In these two studies 
median progression free survival was 5-6 months and median overall survival was 12-14 months, (KM estimates of 1year overall 
survival 50%, 3year overall survival 25%).  Even lower response rates have been demonstrated with prospective evaluation of the 
activity of various molecular targeted agents such as trastuzumab, gefitinib, imatinib and lapatinib, with essentially no objective 
response rates noted (Haddad, 2003; Jakob, 2014; Pfeffer, 2007; Agulnik 2007). 
 
The experience with immune checkpoint inhibitors in this rare disease is limited. Preliminary reports on the anti-PD1 monoclonal 
antibody pembrolizumab, demonstrated an objective response in approximately 10% of patients with salivary gland cancers, among a 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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population enriched for >1% PDL1 tumor expression (Cohen, 2016). There is increasing interest in exploring the efficacy of immune 
checkpoint inhibition in this population. 
 
The dual inhibition of PDL-1 and CTLA-4 is an approach that has garnered significant enthusiasm, due to robust preclinical data 
showing synergistic antitumor efficacy. This data is supported by prospectively collected clinical data, in immunotherapy naive 
melanoma patients, wherein improved objective response rates and progression free response rates were observed with the 
combination of nivolumab and ipilimumab compared to either agent alone (Larkin, 2015).  Multiple ongoing studies in other tumor 
types are examining the activity of this combination. 
 
The role of radiation therapy in transforming the tumor microenvironment to increase the activity of immune checkpoint inhibition is 
an area of significant scientific interest. There is preclinical data supporting that the exposure to immune checkpoint inhibitors prior to 
therapeutic radiation is associated with increased antitumor activity (Twyman-Saint Victor, 2015).  The clinical observation of the 
abscopal effect further supports the potential clinical utility of radiation therapy in inducing responses to immune check point 
inhibition (Postow, 2012). 
Therefore this clinical trial aims to examine the safety and efficacy of dual immune checkpoint blockade and palliative hypofractionated 
radiation therapy in salivary gland carcinomas. Our institution has had prior experience with implementation and completion of clinical 
trials in this rare disease. 
2. 
STUDY OBJECTIVES 
 

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Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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2. 1 Primary Objective: 
To demonstrate that nivolumab, ipilimumab and hypofractionated palliative radiation therapy is safe and well tolerated in patients 
with advances salivary gland carcinomas. 
 
2.2 Secondary Objective(s): 
1. Evaluate the objective response rate according to RECIST 1.1 
2. Determine overall and progression free survival 
 
2.3 Exploratory Objective(s): 
Collect tumor and blood for correlative studies 
 
3. 
ETHICAL CONSIDERATIONS 
The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are 
consistent with ICH/Good Clinical Practice, and applicable regulatory requirements.  
The protocol will be approved and reviewed by the Cancer Consortium Scientific Review Committee (SRC) and the 
Institutional Review Board (IRB). Once activated, the protocol will be reviewed at least annually by both institutional entities. 
The protocol, the proposed informed consent and all forms of participant information related to the study (e.g., advertisements 
used to recruit participants) will be reviewed and approved by the Cancer Consortium IRB and SRC.  Any changes made to the 
protocol will be submitted as a modification and will be approved by the IRB prior to implementation.   
Trial oversight will be carried out by the Protocol Director, Dr. Cristina Rodriguez, and her research staff, who will be 
qualified by education, training and experience to perform their respective tasks, (services of personnel for whom sanctions 
have been invoked for scientific misconduct or fraud will not be used). They will meet weekly to review recently acquired data 
and adverse events. The data recorded within the research charts and protocol database is compared with the actual data that is 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
22 
 
available from the medical record and/or clinical histories. Data detailed in the research case report forms includes the nature 
and severity of all toxicities, which are also reported as described above.  
4. 
INVESTIGATIONAL PLAN/STUDY DESIGN 
4.1     Study Design Overview 
This study will be carried out as a single institution, single arm phase I/II unblinded trial.  A maximum of 20 patients will be enrolled.  
Each patient will be treated with nivolumab, ipilimumab and stereotactic body radiation therapy. Nivolumab will be continued for a 
total of 12 cycles, unless evidence of unacceptable toxicity, disease progression or withdrawal of patient consent were to occur.   
4.2 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: refer to Dosing and Administration (Section 5.1.1) for further details on treatment scenarios.  
Screening 
and 
enrollment 
Weeks 1-6 
 
Day 1 Week 1 
 
Nivolumab 3mg/kg mg 
IV over 30 mins Q2 
weeks x 3 doses  
and 
Ipilimumab 1mg/kg  IV 
over 60 mins x 1 Q 6 
weeks x 1 dose 
 
Week 3 
 
SBRT every other day to a 
total dose of 24Gy  
Weeks 6-24 
 
Nivolumab 3 mg/kg IV 
over 30 mins Q2 weeks x 
9 doses 
 
and 
 
Ipilimumab 1mg/kg IV 
over 60 mins Q 6 weeks 
x 3 doses 
            Weeks 25 to 52 
 
 
Nivolumab 480mg IV over 
30 mins Q4 weeks x 8 
doses 
 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
23 
 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
24 
 
 
 
Both ipilimumab and nivolumab are FDA approved, and the safety profile of both agents 
have been extensively studied. However, because the combination with radiation has not 
been previously studied, the first 6 patients of this study will represent the initial run-in 
phase of the triplet combination of nivolumab, ipilimumab and palliative radiation.  The 
initial doses of ipilimumab and nivolumab will be administered on day 1 of therapy.  
Stereotactic radiation will be initiated on Week 3 of treatment.  SBRT will be delivered to 
a total dose of 24 Gy, given in 3 fractions of 8Gy every other day.  Treatment will be 
continued according to the study schema unless patient withdraws consent, has confirmed 
disease progression, and/or develops toxicity that results in treatment discontinuation.   
 
Enrollment will be halted until these first 6 patients complete the first 12 weeks of 
treatment and acute toxicities will be reviewed. If more than 2 DLTs (to be defined in 
Section 5.1.2) are noted in this six patient cohort, a dose modification will be 
implemented (Section 5.1.1) for the remaining 14 patients who will be enrolled in the 
expansion cohort. 
 
Serum correlative studies will be collected at the following timepoints: at baseline, prior to 
week 8, and prior to week 16 of treatment. Archived formalin fixed paraffin embedded 
tissue (obtained in the 12 months prior to trial enrollment) will be collected from patients 
enrolled. If the patient does not have archived tissue available, a fresh biopsy will be 
obtained. Tissue requirement will be waived if deemed contraindicated or not clinically 
available/accessible for resection per the treating physician (PI approval required). 
 
4.3 
Efficacy Measurements 
 
Adverse events will be monitored throughout the trial and graded in severity according to 
the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 
 
Patients will be evaluated every 8 weeks (± 7 days) with radiographic imaging to assess 
response to treatment. CT or MRI will be used, per PI discretion, to scan areas of known 
disease. All imaging will be assessed using Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 for determination of overall response rate (ORR) and progression-free 
survival (PFS).  
 
 
  

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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4.4 
Inclusion Criteria: 
 
1. Histologically proven salivary gland carcinoma (WHO, 2005) arising from a previous 
head and neck primary site, and located within the head and neck region, lung or 
bone, and who are not candidates for curative intent therapy. 
 
2. ≥18 years old at the time of signing informed consent. 
 
3. Demonstrated disease progression during, or after discontinuation, of the most recent 
line of systemic therapy. 
 
4. Have received any number lines of prior systemic therapy (including systemic 
therapy in the curative intent setting). 
 
5. Have a target lesion/s deemed suitable by the treating physicians for SBRT with the 
intent of palliation or prevention of symptoms. This lesion must be:  
a) 1-3 non-overlapping sites in the head and neck region OR   
b) metastatic lesions outside the H&N region in the lung or bone (a minimum of 1 
and a maximum 5 lesions will be irradiated), provided there is no significant 
overlap between the lesions.   
 
Patients should have RECIST 1.1 criteria measurable disease in addition to the 
lesion/s treated with SBRT. If the site/s of SBRT were previously radiated to high 
dose RT (>50Gy), there should be >6 month time interval between the last dose of 
radiation and the start of SBRT.  
 
6. Have the ability to tolerate required SBRT-related procedures (e.g.: lie flat and hold 
position for treatment) as determined by the treating physician 
 
7. Be willing and able to provide written informed consent for the trial and comply with 
the study visit requirements 
 
8. Have measurable disease based on RECIST 1.1. (in addition to the lesion/s that will 
be treated with stereotactic radiation therapy)   
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
26 
 
9. Have provided tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. Tissue requirement will be waived if deemed 
contraindicated or not clinically available/accessible for resection per the treating 
physician (PI approval required). 
 
10.  Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
11.  Demonstrate adequate organ function as defined in below, based on screening labs 
should be performed within 10 days of treatment initiation.  
− Hemoglobin ≥ 9.0 g/dL 
− Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
− Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
− Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will 
not apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of 
hemolysis or hepatic pathology), who will be allowed only in consultation with 
their physician. 
− AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless 
liver metastases are present, in which case it must be ≤ 5x ULN 
− Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft 
and Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance. 
12.  Evidence of post-menopausal status OR negative urinary or serum pregnancy test for 
female pre-menopausal patients. Women will be considered post-menopausal if they 
have been amenorrheic for 12 months without an alternative medical cause. The 
following age-specific requirements apply:  
− Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy, or hysterectomy).  
− Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
27 
 
hormonal treatments, had radiation-induced menopause with last menses >1 
year ago, had chemotherapy-induced menopause with last menses >1 year 
ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
 
13.  Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required. 
 
14.  Female subjects of childbearing potential should be willing to use 1 method of highly 
effective birth control or be surgically sterile, or abstain from heterosexual activity for 
the course of the study through 180 days after the last dose of study medication 
(Reference Section 8.1).  Subjects of childbearing potential are those who have not 
been surgically sterilized or have not been free from menses for > 1 year.  
 
15. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 180 days after the last dose of study therapy. 
 
16. Patient is ≥ 5 years free of another primary malignancy, except: a) if the other 
malignancy is basal cell carcinoma or cervical carcinoma in situ or b) if the other 
primary malignancy is not considered clinically significant and is requiring no active 
intervention 
 
4.5 
Exclusion Criteria: 
The subject must be excluded from participating in the trial if the subject: 
 
1. 
Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks of the first dose of treatment. 
 
2. 
Has a target lesion/s for SBRT that demonstrate any of the following: 
a. located within 2 cm of the proximal bronchial tree 
b. > 5 cm (> 50 cc) in greatest dimension 
 
3. 
Has a target lesion/s in a region that previously received high dose RT (>50 Gy) 
demonstrating any of the following:  
a. 
carotid artery encasement (> 180 degrees)  

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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b. 
unprotected carotid artery (i.e. skin is directly over the carotid without 
intervening soft tissue, especially after prior neck dissection without a 
vascularized free flap) (a&b due to risk of carotid blow out) 
c. 
skin infiltration by tumor (due to risk of fistula) 
d. 
located in the larynx/hypopharynx primaries (due airway threat) 
e. 
treated with high dose radiation therapy (>50 Gy) within 6 months or less 
of trial enrollment 
 
4. 
Prior receipt of an anti-PD-1, anti-PDL1 or anti-CTLA4 immune checkpoint 
inhibitor. 
 
5. 
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of nivolumab or ipilimumab. The following are exceptions to this 
criterion: 
-          Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection) 
- 
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent 
- 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
6.        Has received a prior monoclonal antibody within 4 weeks prior to study Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier.  
 
7.        Has received prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from adverse events due to a previously administered 
agent. 
            -Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
            -Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
 
8. 
Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
29 
 
carcinoma of the skin, or in situ cervical cancer that has undergone potentially 
curative therapy.  
 
9.        Has known brain metastases or spinal cord compression unless the patient is 
stable (asymptomatic; no evidence of new or emerging brain metastases; and 
stable and off steroids for at least 14 days prior to start of study treatment). 
Following radiotherapy and/or surgery of the brain metastases patients must wait 
4 weeks following the intervention and before initiating study treatment with 
imaging to confirm stability.   
 
10. 
Has an active autoimmune disease requiring systemic treatment within the past 2 
years or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects 
with vitiligo or resolved childhood asthma/atopy would be an exception to this 
rule.  Subjects that require intermittent use of bronchodilators or local steroid 
injections would not be excluded from the study.  Subjects with hypothyroidism 
stable on hormone replacement will not be excluded from the study. 
 
11. 
Has a history of or evidence of active interstitial lung disease or non-infectious 
pneumonitis. 
 
12.      Has an active infection requiring systemic therapy. 
 
13.      Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best interest 
of the subject to participate, in the opinion of the treating investigator. 
 
14.   Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
15.      Is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the pre-screening or screening 
visit through 180 days after the last dose of trial treatment. 
 
16.      Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
30 
 
17.      Has evidence of acute or chronic hepatitis B, or hepatitis C 
 
18. 
Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
 
19. 
Has a history of primary immunodeficiency or an allogeneic organ transplant  
 
20. 
Known history of previous clinical diagnosis of tuberculosis 
 
21. 
Uncontrolled intercurrent illness including, but not limited to symptomatic congestive 
heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic 
ulcer disease or gastritis, seizures 
 
5. 
TREATMENT 
 
5.1 
 Systemic Therapy 
 
5.1.1 
Dosage and Administration 
The treatment to be used in the run-in phase (initial 6 patients) of this trial is outlined in the table 
below. If ≤ 1 DLT is observed in the run-in phase, then the remaining 14 patients will be provided 
treatment per the following: 
 
Drugs 
Dose/Potency Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Weeks 1-24 
1. Nivolumab 
 
 
3 mg/kg 
 
Q2 weeks  
 
IV infusion 
Maximum of 12 
doses 
 
2. Ipilimumab 
1mg/kg 
Q6 weeks 
IV infusion 
Maximum of  4 
doses 
Weeks 25-52 
1. Nivolumab 
480mg IV flat 
dose 
Q4 weeks 
IV infusion 
Maximum of 8 doses 
 
 

Clinical Study Protocol RG1718030 
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IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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If 2 or more DLTs (defined in Section 5.1.2) are observed in the run-in phase, the following 
treatment will be used for the remaining 14 patients to be treated on the clinical trial protocol: 
Drugs 
Dose/Potency Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Weeks 1-24 
1. Nivolumab 
 
 
3 mg/kg 
 
Q4 weeks  
 
IV infusion 
Maximum of 6 doses 
 
2. Ipilimumab 
1mg/kg 
Q8 weeks 
IV infusion 
Maximum of  3 
doses 
Weeks 25-52 
1. Nivolumab 
480mg IV flat 
dose 
Q6 weeks 
IV infusion 
Maximum of 4 doses 
 
Patients who experience a DLT in the run-in phase, will have dose interruptions/reductions as 
outlined in Section 5.1.3. 
 
 
5.1.2 
Definition of DLT 
Dose-limiting toxicities (DLTs) will be evaluated during the run-in phase consisting of 
the first 6 patients enrolled in this trial.  The period for evaluating DLTs will be from the 
time of first administration of nivolumab and ipilumumab until 12 weeks.  Adverse event 
monitoring will continue for these subjects throughout the course of their treatment as 
outlined in the Schedule of Study Assessments, these adverse events will include 
potential XRT related toxicities.  Subjects who do not remain on the study up to this time 
for reasons other than DLT will be replaced with another subject. Grading of DLTs will 
follow the guidelines provided in the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0.   
 
A DLT will be defined as any Grade 3 or higher toxicity that occurs during the DLT 
evaluation period. Toxicity that is clearly and directly related to the primary disease or to 
another etiology is excluded from this definition. The following will be DLTs: 
• 
Any Grade 4 irAE 
• 
Any ≥ Grade 3 colitis 
• 
Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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• 
Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days 
of the initiation of maximal supportive care 
• 
Any Grade 3 irAE, excluding colitis or pneumonitis, that does not 
downgrade to Grade 2 within 3 days after onset of the event despite optimal medical 
management including systemic corticosteroids or does not downgrade to ≤ Grade 1 or 
baseline within 14 days 
• 
Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN 
• 
Any ≥ Grade 3 non-irAE, except for the exclusions listed below 
− Grade 3 fatigue lasting ≤ 7 days 
− Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) 
that is managed with or without systemic corticosteroid therapy and/or 
hormone replacement therapy and the subject is asymptomatic 
− Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.) 
− Concurrent vitiligo or alopecia of any AE grade 
− Grade 3 infusion-related reaction (first occurrence and in the absence of 
steroid prophylaxis) that resolves within 6 hours with appropriate clinical 
management 
− Grade 3 or 4 neutropenia that is not associated with fever or systemic 
infection that improves by at least 1 grade within 3 days. Grade 3 or Grade 
4 febrile neutropenia will be a DLT regardless of duration or reversibility 
− Grade 3 or 4 lymphopenia 
− Grade 3 thrombocytopenia that is not associated with clinically significant 
bleeding that requires medical intervention, and improves by at least 1 grade 
within 3 days 
− Isolated Grade 3 electrolyte abnormalities that are not associated with 
clinical signs or symptoms and are reversed with appropriate maximal 
medical intervention within 3 days 
 
 
• 
Grade 4 hematologic toxicity, not described in exclusions above 
• 
Prolonged delay (>2 weeks) in initiating second dose of nivolumab or 
ipilimumab due to treatment-related toxicity 
• 
Grade 5 toxicity, i.e., death 
 
Dose modification/delays according to Section 5.1.3 will apply to the patients who 
experience DLTs in the run-in phase. 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Immune-related AEs are defined as AEs of an immune nature (i.e., inflammatory) in the 
absence of a clear alternative etiology. In the absence of a clinically significant 
abnormality, repeat laboratory testing will be conducted to confirm significant laboratory 
findings prior to designation as a DLT.  
During this DLT period, patients who received <90% of the nivolumab OR ipilimumab 
infusion on day 1 (e.g., because the infusion of either drug had to be discontinued due to 
an infusion reaction) and did not experience a DLT will not be taken into account in the 
assessment of the overall DLT rate for the phase I run-in cohort and will be replaced. 
 
5.1.3 
Dose Delays/Modifications 
Toxicity will be graded using Common Terminology Criteria for Adverse Events 
(CTCAE version 5.0). The protocol will change to CTCAE version 6.0 if is published 
within the course of the trial.   
 
Because the toxicities of both nivolumab and ipilimumab overlap, a patient meeting dose 
delay criteria within weeks 1- 24 will have both nivolumab and ipilimumab held until 
improvement of the adverse event to Grade 1 or baseline and retreatment criteria are 
met. 
 
Nivolumab may be delayed until the next planned ipilimumab if the next ipilimumab 
dose is scheduled within the next 12 days. This will permit periodic ipilimumab or 
ipilimumab-placebo dosing to be synchronized with nivolumab dosing. 
 
Ipilimumab should be dosed at the specified interval regardless of any delays in 
intervening nivolumab doses. However, in order to maintain periodic synchronized 
dosing of ipilimumab and nivolumab, the dosing days of nivolumab and ipilimumab may 
be adjusted within the permitted -2/+3 day window, as long as consecutive nivolumab 
doses are given at least 12 days apart. Ipilimumab may be delayed beyond the -2/+3 
day window if needed to synchronize with the next nivolumab dose 
  
 
 
5.1.3.1 
Dose Delay Criteria 
Doses of both nivolumab and ipilimumab (during study weeks 1-24) or nivolumab alone 
(during study weeks 25-52) should be held if any of the following are observed: 
 
• Any Grade ≥3 non-skin, drug-related adverse event, except for fatigue and laboratory 
abnormalities 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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• Any Grade ≥3 drug-related laboratory abnormality with the following exceptions for 
lymphopenia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), or 
total bilirubin or asymptomatic amylase or lipase: 
− Grade 3 lymphopenia does not require a dose delay 
− If a subject has a baseline AST, ALT, or total bilirubin that is within 
normal limits, delay dosing for drug-related Grade 2 toxicity 
− 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 Grade ≥3 drug-related amylase or lipase abnormality that is not 
associated with symptoms or clinical manifestations of pancreatitis does 
not require dose delay. 
 
• Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
 
5.1.3.2 
Criteria for Resuming Treatment 
 
Subjects may resume treatment with nivolumab and ipilimumab (weeks 1-24) or 
nivolumab (weeks 2-52) when drug-related AE(s) resolve(s) 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. 
• Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to 
baseline before treatment is resumed. 
• Subjects who received systemic corticosteroids for management of any drug-
related toxicity must be off corticosteroids or have tapered down to an equivalent 
dose of prednisone ≤10 mg/day. 
• Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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During weeks 1-24, ipilimumab may not be resumed sooner than 6 weeks (-2/+3  days) 
after the prior dose. In general, it should be feasible to synchronize dosing of both 
nivolumab and ipilimumab drugs when resuming treatment. In order to facilitate this, the 
dosing days of nivolumab and ipilimumab may be adjusted within the permitted -2/+3day 
window, as long as consecutive nivolumab doses are given at least 12 days apart. 
If an ipilimumab dose is delayed beyond 6 weeks from the prior ipilimumab dose, then 
subsequent ipilimumab doses should be rescheduled to maintain the 6 week interval 
between consecutive ipilimumab. 
 
5.1.3.3 
Criteria for permanent discontinuation of nivolumab and ipilimumab 
 
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question: 
 
• 
The subject or legal representative (such as a parent or legal guardian) 
withdraws consent. 
• 
Confirmation of PD and investigator determination that the subject is no 
longer benefiting from treatment with nivolumab and ipilimumab 
• 
Dosing delays lasting 12 weeks or more  
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing 
• 
Adverse event that, in the opinion of the investigator or the sponsor, 
contraindicates further dosing 
• 
Subject noncompliance that, in the opinion of the investigator or sponsor, 
warrants withdrawal; e.g., refusal to adhere to scheduled visits 
• 
Subject is determined to have met one or more of the exclusion criteria for 
study participation at study entry and continuing investigational therapy 
might constitute a safety risk 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
36 
 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
The subject is lost to follow-up 
• 
Completed all doses of study drug 
• 
Grade ≥ 3 infusion reaction 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.   
Subjects who are permanently discontinued from receiving investigational product will 
be followed for safety, including the collection of any protocol-specified blood 
specimens, unless consent is withdrawn or the subject is lost to follow-up or enrolled in 
another clinical study.  All subjects will be followed for survival.  Subjects who decline 
to return to the site for evaluations will be offered follow-up by phone every 3 months as 
an alternative. 
 
5.2 
Radiation Therapy 
All subjects will be immobilized in a custom designed device in the appropriate position to 
isolate the index lesion. Radiotherapy treatment planning CT scans (with contrast, unless 
contraindicated) will be required to define the gross target volume (GTV) and planning target 
volume (PTV). PET-CT and/or MRI imaging are preferred to delineate volumes as accurately as 
possible. The treatment planning CT scan should be acquired with the subject in the same 
position and immobilization device, as for the treatment. Treatment planning will be done using 
a 3D based CT treatment planning system. All tissues to be irradiated must be included in the CT 
scan. Planning CT scan will be done at 1.25 mm intervals from encompassing the region of 
interest with sufficient margin for treatment planning. 
 
 

Clinical Study Protocol RG1718030 
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IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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5.2.1 
Stereotactic Targeting and Treatment 
 
SBRT has now been formally defined and described in a published guideline from the American 
College of Radiology and American Society for Therapeutic Radiology and Oncology (Potters, 
2004). This protocol will respect that guideline. The term stereotactic, for the purposes of this 
protocol, implies the targeting, planning, and directing of therapy using beams of radiation along 
any trajectory in 3-D space toward a target of known 3-D coordinates. The coordinate system is 
defined by reliable “fiducial” markers. This differs from conventional radiation therapy, in which 
therapy is directed toward less-than-reliable skin marks or bony landmarks that are indirectly 
referenced to the tumor (surrogates). This protocol will require treatments to be conducted with 
the use of a fixed 3-D coordinate system defined by fiducials. The coordinate system defined by 
the fiducials should be directly related to the radiation-producing device in a reproducible and 
secure fashion. Capability should exist to define the position of targets within the patient 
according to this same 3-D coordinate system. As such, the patient is set up for each treatment 
with the intention of directing the radiation toward a target according to the known 3-D 
coordinates as determined in the process of treatment planning. The nature of the fiducials 
themselves may include radiopaque markers or rods placed at known locations in a frame or 
fixed structure adjacent to the patient as well as use of the tumor itself as a fiducial (e.g., 
acquiring tomographic views of the tumor simultaneously with the treatment). Metallic “seeds” 
placed within the tumor will be allowed to constitute a fiducial so long as the methods are 
validated and a plan is in place to identify seed migration (e.g., redundant seeds placed). 
 
5.2.2 
Target Contouring 
Gross Tumor Volume (GTV) is defined as all known gross disease encompassing the selected 
index lesion. The GTV will consist of the index lesion as visualized on CT +/- PET/CT, and/or 
MRI. Image fusion is encouraged when using multiple modalities to define the GTV. 
 
Clinical Target Volume (CTV) will be the same as GTV for most cases. In case of uncertainty, 
GTV could be expanded to CTV by 2-3mm per clinician discretion.  
 
Internal Gross Tumor Volume (IGTV) is defined for mobile index lesions at the discretion of the 
treating physician. For mobile index lesions, a 4-D CT scan will be acquired in order to account 
for the motion of the lesion during treatment. The IGTV will be defined as the union of the 
visualized index lesion on all gated CT data sets. 
 
Planning Target Volume (PTV) will be defined as per convention for photon beam radiotherapy. 
A 3-dimensional margin of 3-5mm will be created on the CTV or IGTV (if available) to allow 
for daily set-up variance. For Proton beam radiotherapy, an additional range uncertainty is added 
during planning. 
 
Organ at Risk volume (OAR) is contoured as visualized on the planning CT or MR scan. 

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Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Planning organ at Risk Volume (PRV) is the OAR expanded for setup uncertainty or organ 
motion. The physician will contour the OAR. The dosimetrist will create the PRV by expanding 
the OAR by 1-3 mm, depending on the situation.  
 
Pertinent Organs at Risk (OARs) in the index region are contoured as applicable: 
 
 
Spinal cord, Brain stem, Brachial plexus (roots & trunks) 
 
 
Optic pathways – optic nerves, optic chiasm, Retina, Cornea 
 
 
Carotid artery (Internal & common),  
 
 
Cochlea & vestibular apparatus  
 
 
Skin (3-5 mm of body outline) 
Larynx (infrahyoid supraglottis to bottom of cricoid. Only include the endolarynx 
within the cartilaginous framework 
 
 
Other uninvolved mucosal structures e.g.: oral cavity & pharynx 
 
 
Facial Bones: Mandible, Maxilla, temporal bone that pertain to index region 
                        Esophagus 
                        Heart and Pericardium 
                        Lungs 
                        Ribs 
                        Trachea and Large/Central Bronchi 
                        Bronchii – smaller airways 
 
  
5.2.3 
Treatment planning, dose fractionation and specification 
Computer based planning & QA will be performed using our standard institutional SBRT 
guidelines, including corrections for tissue heterogeneity, and robustness analysis (for Proton 
therapy). Treatment planning may be done with IMRT, VMAT, Proton beam RT (Pencil beam 
RT or Uniform scanning). 
The dose prescription will be as follows: 24 Gy given in 3 fractions to PTV (80-95% IDL) 
delivered at 8 Gy per fraction every other day. 
Dose rate: For the purpose of this study, dose rate utilized will be that which is commissioned by 
the manufacturer and the medical physics group for external beam radiotherapy delivery by the 
treating institution. There will be no special dose rate modifications required for this study. 
The following PRV dose constraints will be used: (adopted from Timmerman RD. An overview 
of  hypofractionation. Seminars of Radiation Oncology 2008 Oct;18(4):215-222). 
 
Spinal cord  max 21Gy, 18Gy (< 0.35cc), 12 Gy (<1cc) 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
39 
 
 
Brain stem max 23 Gy, 18 Gy (< 0.5cc) 
 
Optic chiasm max 15 Gy, 12 Gy (< 0.2cc) (for bilateral blindness risk) 
 
Ipsilateral Optic nerve max 18 Gy, 15 Gy (< 0.2cc) 
 
Contralateral optic nerve max 12 Gy, 10 Gy (< 0.5cc)  
 
Carotid artery max 15 Gy, (V12 Gy to < 30% of carotid volume) 
 
Brachial plexus max 24 Gy, 20 Gy (< 3cc)   
 
Esophagus* max 24 Gy, 17 Gy (< 5cc) 
            Heart/Pericardium max 24 Gy, 20 Gy (< 15cc) 
            Trachea*  max 24 Gy, 15 Gy (< 4cc) 
            Bronchus max 23 Gy, 18 Gy (< 1cc) 
            Ribs max 24 Gy, 20 Gy (< 5cc) 
            Skin 24 Gy (< 10cc), 20 Gy (<10cc) 
            Lung (Right & Left) – Volume to spare > 1000cc to </= 12 Gy and  
                                              > 1500 cc to </= 11.5 Gy, V15 Gy < 35% 
           Liver – spare >700cc to </=19 Gy 
Stomach – max 22 Gy, 16 Gy to < 10cc 
 Rest of OARS = ALARA 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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* avoid circumferential radiation 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed for 
each case to deliver highly conformal prescription dose distributions. Non-opposing, 
noncoplanar beams are preferable. Typically, ≥ 10 beams of radiation will be used with roughly 
equal weighting for photon planning. Generally, more beams are used for larger lesion sizes. 
When static beams are used, a minimum of 7 non-opposing beams should be used. For arc 
rotation techniques, a minimum of 340 degrees (cumulative for all beams) should be utilized. For 
arc rotation techniques, a minimum of 340 degrees (cumulative for all beams) should be utilized.  
Proton beam planning is performed with 2-4 beams.  In order to obtain acceptable coverage, 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 should be when observing the minimum field 
dimension of 3.5 cm when treating small lesions (see above). As such, prescription lines 
covering the PTV will typically be the 60-90% line (where the maximum dose is 100%); 
however, higher isodoses (hotspots) must be manipulated to occur within the target and not in 
adjacent normal tissue. The treatment isocenter or setup point in stereotactic coordinates will be 
determined from system fiducials (and can be adjusted pretreatment depending on the results 
from localization imaging studies) and translated to the treatment record. 
Dose specifications 
Successful treatment planning will require accomplishment of all of the following criteria: 
 
1. Maximum dose: The treatment plan should be created such that 100% corresponds to 
the maximum dose delivered to the patient. This point must exist within the PTV. 
2.   Prescription isodose: The prescription isodose surface must be ≥ 60% and < 90% of 
the maximum dose. 
3.   Prescription Isodose Surface Coverage: The prescription isodose surface will be 
chosen such that 95% of the target volume (PTV) is conformally covered by the 
prescription isodose surface (PTV V95%RX = 100%) and 99% of the target volume 
(PTV) receives a minimum of 90% of the prescription dose (PTV V90%RX > 99%). 
4.  High Dose Spillage: The cumulative volume of all tissue outside the PTV receiving a 
dose > 105% of prescription dose should be no more than 15% of the PTV volume. 
Conformality of PTV coverage will be judged such that the ratio of the volume of the 
prescription isodose meeting criteria 1 through 4 to the volume of the PTV is ideally < 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
41 
 
1.2 (see table below). These criteria will not be required to be met 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 3.5 cm results in the inability 
to meet a conformality ratio of 1.2. The “None” and “Minor” entries in this table 
define the Per Protocol, Variation Acceptable and Deviation Unacceptable 
Compliance Criteria. 
5.  Intermediate Dose Spillage: The falloff gradient beyond the PTV extending into 
normal tissue structures must be rapid in all directions and meet the following criteria: 
a.  Location: The maximum total dose over all fractions in Gray (Gy) to any point 2 cm 
or greater away from the   PTV in any direction must be no greater than D2CM where 
D2CM is given by the table below. 
b.  Volume: The ratio of the volume of the 34 or 12 Gy isodose volume to the volume of 
the PTV must be no greater than R50% where R50% is given by the table below 
(adapted from RTOG 0915). This table is used for all prescription requirements 
irrespective of calculation algorithm and total treatment dose. 
  
 
 
 
 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
42 
 
 
 
Image guided RT (IGRT) is required with physician review per institutional QA requirements 
before each treatment is delivered. Cone beam CT will be matched to target volume to be treated 
and bony anatomy or other defined fixed fiducials. If CBCT is unavailable, orthogonal pair KV 
imaging matched to bony anatomy closest to PTV is acceptable. 
 
 
6. 
STUDY DRUGS 
 
The following investigational drugs will be provided. Premedications or medications used to 
treat infusion-related reactions should be sourced by the investigative sites if available and 
permitted by local regulations. 
 
Product 
Description 
Potency 
Packaging/Appearance 
Storage Conditions 
(per label) 
(Nivolumab) 
Solution 
for Injection 
100 mg 
(10 mg/mL) 
10 mL/vial (5 or 
10 vials/carton) 
Store at 
2° - 8°C. 
Protect from 
light and 
freezing. 
Ipilimumab Solution 
for Injection 
200 mg 
(5 mg/mL) 
40 mL/vial 
(4 vials/carton) 
Store at 2°- 8°C. 
Protect from 
light and 
freezing. 
 
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 the official study site by 
authorized personnel according to local regulations. 
 
6.1 
Storage of Study Drug 
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 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
43 
 
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 (e.g., required diluents, administration sets). 
Infusion-related supplies (e.g., IV bags, in-line filters, 0.9% sodium chloride injection, 5% 
dextrose 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. 
 
6.2 
Concomitant medications 
 
Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except 
for those medications identified as “excluded” as listed under Excluded Concomitant 
Medications. 
 
Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapies. 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment.  Concurrent use of 
hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy) is acceptable.   
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled and intranasal corticosteroids is permitted. A temporary period of 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
44 
 
steroids will be allowed for different indications, at the discretion of the principal 
investigator (e.g., chronic obstructive pulmonary disease, radiation, nausea, etc.). 
4. Live attenuated vaccines within 30 days of nivolumab and ipilimumab dosing (i.e., 30 
days prior to the first dose, during treatment with nivolumab and ipilimumab for 30 days 
post discontinuation of nivolumab and ipilimumab).  Inactivated vaccines, such as the 
injectable influenza vaccine, are permitted. 
   
Table 2. Prohibited and Rescue Medications 
Prohibited medication/class of drug: 
Usage: 
Additional investigational anticancer therapy 
concurrent with those under investigation in this 
study 
Should not be given whilst the patient is on IP 
treatment   
mAbs against CTLA-4, PD-1, or PD-L1 
Should not be given whilst the patient is on IP 
treatment through 90 days after the last dose of IP 
Any concurrent chemotherapy, local therapy 
(except palliative radiotherapy for non-target 
lesions, 
e.g., 
radiotherapy, 
surgery, 
radiofrequency ablation), biologic therapy, or 
hormonal therapy for cancer treatment 
Should not be given whilst the patient is on IP 
treatment. 
(Concurrent 
use 
of 
hormones 
for 
non-cancer-related 
conditions 
[e.g., insulin 
for 
diabetes and hormone replacement therapy] is 
acceptable.) 
Immunosuppressive medications, including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or its 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor α blockers   
Should not be given whilst the patient is on IP 
treatment. (Use of immunosuppressive medications for 
the management of IP-related AEs or in patients with 
contrast allergies is acceptable.  In addition, use of 
inhaled, topical, and intranasal corticosteroids is 
permitted. 
Live attenuated vaccines 
Should not be given through 30 days after the last dose 
of IP during the study 
VEGF inhibitors such as sunitinib, sorafenib 
and bevacizumab 
Should not be given 90 days prior to first dose of 
investigational drug and with 30 days after last dose of 
investigational drug 
 

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IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Rescue/supportive medication/class of drug: 
Usage: 
Concomitant 
medications 
or 
treatments 
(e.g,, acetaminophen 
or 
diphenhydramine) 
deemed necessary by the Investigator to provide 
adequate prophylactic or supportive care, 
except for those medications identified as 
“prohibited” as listed above 
To be administered as prescribed by the Investigator 
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc.]) 
Should be used when necessary for all patients 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
46 
 
 
7. 
SCHEDULE OF ASSESSMENTS 
 
Assessments to be 
performed at the times 
stipulated in the table and 
as clinically required in 
the management of the 
subject 
Screening 
all assessments to be performed pre-infusion unless stated 
otherwise 
 
 
 
Weeks 1-6  
Weeks 
7-24    
Weeks 
25-52   
End of 
treatment 
 
Safety 
Follow-
Upn 
 
 
Long-
Term 
Follow-
Upo 
 
Survival 
Follow-
Upp 
Day 
- 28 to - 1 
Day 1 of the Week (-2/+3) 
-2/+3 
-2/+3 
-30  
±14 
±14 
Week 
-4 to -1 
Week1 
Week3 
Week5 
 
 
Q8 wks Q12 wks  
Written informed consent 
X 
  
  
  
 
  
  
 
 
 
Demography and history of 
tobacco and alcohol use 
X 
  
  
 
  
  
 
 
 
Previous treatments for 
head and neck cancer 
X 
  
  
  
  
 
  
  
 
 
 
Tumor tissue sample  
X 
 
 
 
 
 
Formal verification of 
eligibility criteria 
X 
  
  
  
  
 
  
  
 
 
 
Medical and surgical 
history 
X 
  
  
  
  
 
  
  
 
 
 
Urine hCG or serum βhCGa 
X 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signsc  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weightc 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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Assessments to be 
performed at the times 
stipulated in the table and 
as clinically required in 
the management of the 
subject 
Screening 
all assessments to be performed pre-infusion unless stated 
otherwise 
 
 
 
Weeks 1-6  
Weeks 
7-24  
Weeks 
25-52    
End of 
treatment 
 
 
Safety 
Follo
w-Upn 
 
 
 
Long-
Term 
Follow-
Upo 
 
 
Survival 
Follow-
Upp 
Day 
- 28 to - 1 
Day 1 of the Week (-2/+3) 
-2/+3 
-2/+3 
-30 
±14 
±14 
Week 
-4 to -1 
Week1 
Week3 
Week5  
 
 
Q8 wks 
Q12 wks 
Nivolumab administration   
 
Xd 
 Xd 
Xd 
Xd  
Xe 
  
 
 
 
Ipilimumab administration 
 
  
X  
  
 
Xf  
  
 
 
 
 
Adverse event/serious 
adverse event assessment 
and concomitant 
medications c 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Radiation therapy 
evaluation and  radiation 
planning/simulation 
X 
   
  
 
 
 
 
 
 
 
Palliative hyporfractionated 
Radiation therapy 
Xg 
 
 
 
 
 
 
 
ECOG performance statusc 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
TSH with reflexive free T4h 
X 
Repeat every 12 weeks 
 
 
 
 
Complete blood counti 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum chemistryi 
X 
X 
 X 
X  
X  
X 
 
 
 
 
Urinalysisj 
X 
Additional testing as clinically indicated 
 
 
 
 
Coagulation parametersk 
X 
Additional testing as clinically indicated 
 
 
 
 
Correlative blood samplesl 
X 
 
 
 
X 
 
 
 
 
 
Tumor assessmentsm  
X 
  
  
 
  X  
X 
 
 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
X 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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a  Pre-menopausal female subjects of childbearing potential only 
b Full physical examination at screening and baseline; targeted physical examination prior to each administration of investigational drug, 
discontinuation of treatment and safety follow-up 
c To be done on each visit prior to administration of investigational drug. Concomitant medication collected up to the Safety Follow (-
30 days post last dose of study treatment) or initiation of new anti-cancer treatment. AEs will be collected up to 100 days post last dose 
of study treatment or initiation of new anti-cancer treatment.   
d On weeks 1-24, see Section 5.1.1 for Nivolumab administration (-2/+3days), nivolumab doses are given at least 12 days apart 
e On weeks 25-52, see Section 5.1.1 for Nivolumab administration(-2/+3days) at a flat dose of 480mg, nivolumab doses are given at 
least 12 days apart  
f On weeks 1-24, see Section 5.1.1 for Ipilimumab administration(-2/+3 days) for 3 doses 
g XRT to begin 2 weeks after the first dose of Nivolumab and Ipilimumab and to be completed in 2 weeks 
h Add free T4 if TSH is abnormal. Repeat at least every 12 weeks. 
i If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 1. Results for 
safety blood test must be available and reviewed before commencing an infusion.  During weeks 7-24: CBC and serum chemistries will 
be done every 2 weeks prior to the nivolumab or nivolumab/ipilimumab infusions. During weeks 25-52: CBC and serum chemistries 
will be performed every 4 weeks prior to each nivolumab infusion. 
j Urinalysis performed at Screening and then as clinically indicated. 
k Coagulation tests: prothrombin time, aPTT and INR – only performed at Screening and then as clinically indicated. 
l Correlative blood samples will be collected on 3 occasions, prior to week 1, prior to week 8 and prior to week 16. 
m Timing of CT scans for tumor assessments will be every 8 weeks (+/- 7 days). 
n If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30 day Safety Follow-up visit 
must occur before the first dose of the new therapy. Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up. 
o Follow-up phase for patients that discontinue treatment for reasons other than disease progression (see Section 7.1.4.5). 
p Patients that have documented disease progression or starts treatment on new anti-cancer therapy will move into the survival follow-
up phase.  

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IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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7.1 
Trial Procedures 
7.1.1 
Administrative  
 
The Schedule of Assessments chart- Section 7 summarizes the trial procedures to be performed 
at each visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator and/or Sponsor. 
 
7.1.1.1 
Informed Consent 
The approved informed consent form will adhere to the ethical principles that have their origin in 
the Declaration of Helsinki.  Investigator obtaining consent must ensure that subjects--or, in 
those situations where consent cannot be given by subjects, their legally acceptable 
representatives--are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which they volunteer to participate.  Consent must be 
documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion.  
 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.  The initial informed consent form, any subsequent revised written informed consent 
form and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.   
 
The subject or his/her legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial.  The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that captures 
the subject’s dated signature or by the subject’s legally acceptable representative’s dated 
signature. 
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial.  
 
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   

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7.1.1.4 Prior and Concomitant Medications Review 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication.  
 
7.1.1.5 Disease Detail, Treatments and Subsequent Anti-Cancer Therapy 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first 
dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move 
into survival follow-up.  
 
7.1.2 
Clinical Procedures/Assessments 
7.1.2.1 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Schedule of Assessments (Section 7) and more frequently if 
clinically indicated.  Adverse experiences will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE Version 5.0 (see Sections: 5.1.2, 8.2, 8.3). 
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, and 
action taken with regard to trial treatment. AE collection will start once the subject signs consent 
and up to 100 days after the last dose of study treatment.  
 
7.1.2.2 Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening/baseline period. Clinically significant abnormal findings should be recorded as medical 
history. For cycles that do not require a full physical exam per the Schedule of Assessments 
(Section 7), the investigator or qualified designee will perform a targeted physical exam as 
clinically indicated prior to trial treatment administration, treatment discontinuation and during the 
safety follow-up.   
 
7.1.2.3 
Vital Signs  
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment, at treatment discontinuation and during the safety 
follow-up as specified in the Schedule of Assessments (Section 7).  Vital signs should include 
temperature, pulse, respiratory rate, weight and blood pressure. 
 

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IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
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7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment, discontinuation of trial treatment, and during the 
safety and long-term follow-up visits as specified in the Schedule of Assessments (Section 7).   
 
7.1.2.5 Tumor Imaging and Assessment of Disease 
See Section 4.3 for efficacy assessments.  
 
7.1.2.6 Correlative Blood Collection 
Blood will be collected for research purposes on three occasions: prior to week 1, prior to week 8 
and prior to week 16. Blood will be separated into cellular and serum components for 
preservation and batch analysis.  Flow cytometric evaluation of CD3, CD4, CD8, CD14, PD-1, 
PD-L1, PD-L2 on peripheral blood mononuclear cells. 
Specimen Requirements: Submission for flow cytometry 
• 
A 5-10 mL specimen of peripheral blood in a lavender- (EDTA) or green- (sodium 
heparin) tube is acceptable for each draw. 
• 
Storage/Transport Temperature: Specimens can be transported with a cold pack or wet 
ice, but do not fix or freeze specimens. 
• 
Unacceptable Conditions: Frozen specimens, specimens greater than 48 hours old, 
specimens fixed in formalin for flow cytometry 
 
Address for shipping specimens:  
Attn: Jenny Mao Zhengwei, Hematopathology  
Seattle Cancer Care Alliance 
Hematopathology Laboratory G7800 
825 Eastlake Ave E. 
Seattle, WA  98109 
 
 
7.1.2.7 Tumor Tissue Collection 
All patients will be required, unless waived by treating physician, to submit archival tissue as part 
of study participation.  In patients who do not have archival tissue, a pretreatment tumor biopsy 
will be performed, unless deemed contraindicated by the treating physician. These samples will be 
submitted centrally for immunohistochemical expression studies involving proteins in the PD-1 
family as well as CD3, CD69 and FOXP3.  Acceptable archival tissue for correlative studies 
include formalin fixed paraffin embedded tissue collected within 12 months of study enrollment. 
Patients who do not have acceptable FFPE tissue will be required to undergo a study related biopsy 
to obtain fresh tissue. In cases where biopsies yield insufficient tissue for both tumor slice culture 
(TSC) and PDL1 testing, TSC testing will take priority. Any tissue not used for tumor slice culture 
will be submitted for PDL1 testing. 
 
 

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52 
 
PD-L1 Testing 
To ensure comparability of data across all studies of nivolumab and ipilimumab and to gain real 
world experience on the performance of this assay, it is strongly encouraged that all studies that 
include PD-L1 testing utilize the Ventana SP263 assay.  Testing should be restricted to the Ventana 
SP263 assay and should be performed in accordance with the package insert on the Ventana 
Benchmark platform (Ultra or XT).   
 
The Ventana SP263 assay is fully analytically validated test characterized through to the 
completion of reader precision studies in the non-small cell lung cancer (NSCLC) and squamous 
cell carcinoma of the head & neck (SCCHN).  For these tumors, the Ventana SP263 assay has a 
fully reproducibility data package supporting cut-off and scoring algorithm. Following completion 
of ATLANTIC and HAWK clinical trials, the assay will be associated with clinical utility.  In 
other cancer types (bladder, pancreatic, gastric, hepatocellular, triple negative breast, ovarian, 
esophageal, nasopharyngeal, glioblastoma, soft tissue sarcoma, cholangiocarcinoma, small cell 
lung, melanoma and cervical HPV+ cancers), the Ventana SP263 assay has only limited clinical 
performance data.   
 
Sample collection for PD-L1 testing 
• 
The preferred tumor sample for the determination of a patient’s PD-L1 status is the one 
taken following the completion of the most recent prior line of therapy.  Samples taken at 
this time reflect the current PD-L1 status of the tumor and considered clinically most 
relevant.   
• 
Samples should be collected via a core needle of 18 gauge or larger or be collected by an 
incisional or excisional tumor biopsy.  Where institutional practice uses a smaller gauge 
needle, samples should be evaluated for tumor cell quantity (i.e., >100 tumor cells) to allow 
for adequate PD-L1 immunohistochemistry analyses.   
• 
When the collection of a new sample is not clinically appropriate, archival samples may be 
utilized provided the specimen it is not older than12 months.  When archival samples are 
used to assess PD-L1 status, the age of the sample / date of collection should be captured.   
• 
Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin.  
Samples from fine needle aspirates (FNA) or decalcified bone are not appropriate for PD-
L1 analysis.   
Sample data collection for PD-L1 testing 
The following fields of data should be collected from the site/institution collecting and if, indicated 
shipping of the samples:   
• Patient identifier (ecode or unique identifier) 
• Specimen identifier (written on the specimen) 
• Site identifier 
• Specimen collection date 
• Type of specimen submitted 

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• Quantity of specimen 
• Date of sectioning 
• Archival of fresh tumor 
• Tumor type 
• Primary tumor location 
• Metastatic tumor location (if applicable) 
• Fixative 
The following fields of data should be collected from PD-L1 testing laboratory: 
• Are the negative and positive controls stained correctly 
• Is the H&E material acceptable 
• Is morphology acceptable 
• Total percent positivity of PD-L1 in tumor cells 
• PD-L1 status (positive, negative or NA) in tumor cells  
• Total percent positivity of PD-L1 in infiltrating immune cells 
The Ventana SP263 assay to measure PD-L1 in tumors is experimental.  As with all tests, there is 
a chance of false positive (the test shows high PD-L1 when it is not there) or false negative (the 
test does not show PD-L1 when it is there) results may occur.   
 
Sample processing and if indicated submission process for PD-L1 testing 
Preparing Stored samples for testing 
• 
Where samples already exist, they should be retrieved from the Bio-Bank storage location.  
These blocks should undergo quality review, prior to evaluation or shipment.  Where it is 
not possible or indicated to ship the block to a testing laboratory, unstained slides should 
be prepared from the paraffin-embedded tumor sample block (described below) prior to 
evaluation or shipment.   
Preparing newly acquired samples for PD-L1 testing 
• 
If patients are undergoing a biopsy procedure that provides the option to submit newly 
acquired samples, this sample should be used to determine PD-L1 status. Where clinically 
acceptable, a minimum of 2 core biopsies should be collected and processed to FFPE in a 
single block.  The provision of 2 cores is advised in order to provide sufficient tissue for 
PD-L1 assessment.  
• 
It is recommended that core needle tumor biopsies are collected using an 18 gauge or larger 
needle and the process should be image-guided.  Excisional or incisional samples are also 
adequate.  If this is not per the institutions normal practice and a smaller gauge needle is 
used then the number of cores collected should be increased to allow sufficient material for 
successful PD-L1 testing (>100 tumor cells) and embedded in the same block.  If available, 
a single excisional biopsy of at least 4 mm in diameter may substitute for all core biopsies.  
Fixation of biopsy samples for PD-L1 testing 
• 
Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing.  To 
fix newly acquired tissue, place immediately (within 30 min of excision) into an adequate 

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Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
54 
 
volume of 10% v/v neutral buffered formalin (NBF).  Samples should remain in fixative 
for 24 – 48 hours at room temperature.   
• 
It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10 
volume excess) and that large specimens (if any) are incised prior to fixation to promote 
efficient tissue preservation.   
Embedding in paraffin for PD-L1 testing 
• 
An overnight processing schedule into paraffin wax is recommended  
• 
Below is the suggested routine overnight processing schedule: 
Storage of tumor blocks for PD-L1 testing 
• 
FFPE blocks should be stored at ambient temperature and protected from light until 
shipment by courier at ambient temperature. FFPE blocks are stable under these conditions 
for an indefinite period. 
Quality control of samples to be used for PD-L1 testing 
• 
Tissue should be assessed by the site pathologist prior to PD-L1 testing.   
• 
Each sample should be reviewed for: 
• Adequate fixation 
• Good preservation of morphology 
• Presence of tumor tissue 
• Histopathology consistent with indication 
 
• Greater than 100 tumor cells are required to determine PD-L1 status – tumor cell 
content must be reviewed prior to testing in order for PD-L1 obtain a valid result.   
If indicated, shipping samples to a PD-L1 testing laboratory 
• When submitting sample to for PD-L1 testing the recommendation is to ship the block in 
order for sectioning to occur at the laboratory.  Blocks should be shipped  - containing 
enough  material to  be provided to allow a minimum of 5, and preferably 10, sections to 
be cut (each 4  micron thick) to be used for PD-L1 testing.    
Sectioning instructions 
• Where it is not possible or indicated to ship the block to laboratory for PD-L1 testing, 
unstained slides should be prepared from the paraffin-embedded tumor sample block as 
described below:   
• A minimum of 5-10 x 4 micron (μm) thick, unstained sections should be provided 
for PD-L1 testing 
• A new disposable microtome blade must be used for each block to prevent 
contamination between Slides are stable under these conditions for 6 months. 
• patient samples 
• Apply one section per slide to positively-charged Superfrost glass slides  

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
55 
 
• The sections should be dried overnight between room temperature and 37°C. Do 
not dry sections at temperatures above 37°C. 
Sections should be stored at ambient temperature and protected from light until use or shipment to 
testing lab by courier at ambient temperature.  It is recommended that slides are cut freshly prior 
to PD-L1 testing and they are used within 90 days of being cut to obtain PD-L1 status 
 
Fresh tumor biopsies for tumor slice culture 
Patients who do not have suitable archival tissue will be consented for fresh tissue biopsies.  Dr. 
Venu Pillarisetty’s lab will oversee the collection of fresh tissue during this biopsy. Tissue will 
be collected for tumor slice culture (TSC) preparation as described below. In cases where 
biopsies yield insufficient tissue for both TSC and PDL1 testing, TSC testing will take priority. 
Any tissue not used for tumor slice culture will be submitted for PDL1 testing. 
 
TSC Preparation 
Fresh treatment biopsy tissue in excess of that required for central IHC will be mounted and 
sliced (250 µm) using a Leica vibrating microtome. This tissue will be placed in 24-well plates in 
an air-liquid interface culture system using media optimized by our group for TSC. 
Experiment #1 – Immune cell populations 
TSC will be cultured for 1 to 6 days with control antibody, DMSO control, nivolumab (dose to 
be determined) alone, ipilimumab (1 µM) alone, or a combination of both drugs.  
 
IHC for CD4, CD8, FOXP3, CD68  
When adequate tissue is available for replicates, we will perform flow cytometry on enzyme-
digested, disaggregated slices to measure: 
Macrophage phenotype (CD68, HLA-DR, CD163, CD115, CD206) 
T cell phenotype (general): CD3, CD4, CD8, CD25 
T cell memory phenotype (CD45RO, CD127, CD28, CD27, CD62L, CCR7) 
T cell inhibitor phenotype (PD-1, CTLA-4, LAG3, TIM3) 
Tumor immune related markers (PD-L1, class I MHC, HLA-DR) 
 
Experiment #2 – Induction of CD8+ T cell function 
Upon completion of each culture period after drug treatment, slices will be treated with SR-
FLICA caspase 3/7 assay reagent (Immunochemistry Technologies) for 1 hr, fixed, and then 
stained with DAPI prior to imaging by confocal microscopy to measure apoptosis. Fixed tumor 
slices will then be paraffin embedded and sectioned. IHC will be performed for CD8 and Ki67 
(to measure proliferation) or granzyme B (to measure cytotoxic activity) or cleaved caspase 3 (to 
measure apoptosis). Number of positive cells for each marker will be determined. 
 
Experiment #3 – Correlation of induction of cytotoxic T cell function with PD-L1 
expression 

Clinical Study Protocol RG1718030 
Drug Substance: Nivolumab and Ipilimumab 
IND Number:140818 
Protocol version 3.0 April 17, 2019 
 
56 
 
We hope to have access to the centrally determined PD-L1 expression so that we will be able to 
correlate our CD8+ T cell functional data with induction of CD8+ T cell function. 
 
Experiment #4 – Correlation of induction of cytotoxic T cell function with clinical response 
We will use multivariate statistics to test the hypothesis that the degree of immune checkpoint 
inhibition-triggered CD8+ T cell activation and carcinoma cell death in TSC predicts response in 
our ongoing clinical trial. 
  
Experiment #5 – Rescue of drug-refractory CD8+ T cell activation   
Biopsies from patients with lack of clinical response will be placed in TSC and treated with 
combinations of nivolumab and ipilimumab and monoclonal antibodies designed to block 
additional immune checkpoints (GITR, LAG-3, TIM-3, CTLA-4), as this strategy may overcome 
T cell exhaustion.(Lu et al., 2014)  
 
Experiment #6 – Correlation between T cell infiltrate and immunosuppressive signals 
IHC of tumor tissue for cellular subtypes (CD3, CD4, CD8, FOXP3, CD68) and 
immunosuppressive molecules (PD-1, PD-L1, TIM-3, LAG-3, CTLA-4, IL-10, TGF-beta1, IDO, 
FASL). We will use multivariate statistics to correlate T cell infiltrate density and level of 
immunosuppressive signaling. Furthermore, we will be able to confirm whether the tumors fall 
into their expected category of level of T cell infiltration, as we believe that the 
immunophenotype is more important than traditional histology in determining response to 
immune checkpoint inhibition. 
 
Experiment #7 – CD8+ T cell suppression 
The proliferation of CD8+ TIL from TSC (cultured with or without exogenous IL-2 +/- 
CD3/CD28 beads) will be measured in two ways: directly by Ki67 staining, and indirectly by 
treating the TSC with BrdU and then subsequently staining for it. In both cases TSC will be 
fixed, embedded and double stained after 1 to 6 days in culture to determine what percentage of 
CD8+ T cells are cycling. Duplicate slices will be digested with collagenase-DNAse-
hyaluronidase cocktail in rotating flasks to obtain a single-cell suspension. CD8+ T cell 
proliferation and activation state, as well as macrophage polarization, will be tested using a 
multi-color flow cytometry panel. We will correlate these data with those from Experiment #1 to 
determine if high-level expression of multiple immunosuppressive signals has functional 
consequences in the TSC. 
 
Experiment #8 – Combination immune checkpoint inhibition 
TSC will be cultured for 1 to 6 days with control antibody or nivolumab and ipilimumab  (dose 
to be determined). 
Upon completion of each culture period, slices will be treated with SR-FLICA caspase 3/7 assay 
reagent (Immunochemistry Technologies) for 1 hr, fixed, and then stained with DAPI prior to 

Cli nical St u d y Pr ot oc ol R G 1 7 1 8 0 3 0  
Dr u g S u bsta nce : Ni v ol u ma b a n d I pili m u ma b  
I N D N u m b er: 1 4 0 8 1 8 
Pr ot o c ol v ersi o n 3. 0  A pril  1 7, 2 0 1 9 
 
5 7  
 
i ma gi n g b y c o nf ocal micr osc o p y t o meas ure a p o pt osis. Fi xe d t u m or slices will t he n be paraffi n 
e m be d de d a n d s ecti o ne d. I H C will be perf or me d f or C D 8 a n d Ki 6 7 (t o meas ure pr oliferati o n) or 
gra nz y me B (t o meas ure c yt ot o xic acti vit y) or clea ve d cas pase 3 (t o meas ure a p o pt osis). 
 
T o deter mi ne w h et her i m m u ne c hec k p oi nts i n fact i n hi bit t he pr oliferati o n of T cells i n t he T S C, 
eac h of t h e k n o w n c h ec k p oi nt m olec ules will be i n hi bite d, eit her b y a nti b o d y ( P D- 1, TI M- 3, 
L A G -3, C T L A -4, I L -1 0, T G F - b eta 1, F A S L) or usi n g a s mall m olec ule (I D O) i n t he or ga n ot y pic 
c ult ures. If t he c hec k p oi nt is s u p pressi n g c yt ot o xic T cell pr oliferati o n, we w o ul d e x pect t o see 
i ncreas e d Ki- 6 7 stai ni n g, a n d i ncrease d Br d U u pta ke b y C D 8 + T cells i n t he T S C.  I n t u m ors t hat 
e x press m ulti ple c hec k p oi nt m olec ules, i n hi biti o n of se veral pat h wa ys ma y be re q uire d t o 
o verc o me T ce ll f u ncti o n al e x ha usti o n; i n t hese cases, t he effects of c o m bi nati o n of c hec k p oi nt 
i n hi bit ors o n T cell pr oliferati o n will be i n vesti gate d.  Assess me nt of T-cell e x ha usti o n a n d 
resc ue will be base d o n t he sti m ulate d e x pressi o n of I F N. Si n gle-cell s us pe nsi o ns fr o m t u m or 
slices will be treate d wit h G ol gi pl u g a n d sti m ulate d wit h C D 3/ C D 2 8 bea ds (f or T C R a n d 
c osti m ulati o n) or P M A/i o n o m yci n ( b y passi n g T C R si g nali n g) pri or t o perf or mi n g i ntracell ular 
c yt o ki ne stai ni n g f or fl o w c yt o metr y.  T he pr o p orti o n of I F N -e x pressi n g C D 8 + T cells i n t he 
T S C will be c o m pare d bet wee n treat me nt a n d c o ntr ol sa m ples.  F or all i m m u n o hist ol o gical a n d 
fl o w c yt o metric a n al yses, a mi ni m u m of 1 0 0 cells of i nterest will be sc ore d f or eac h e n d p oi nt.  
Res ults bet wee n treate d a n d c o ntr ol gr o u ps will be a nal yze d b y t- t est a n d A N O V A. D ata will be 
a nal yze d acr oss t u m ors wit h relati o n t o le vel of T cell i nfiltrati o n a n d i m m u n os u p pressi ve si g nal 
e x pressi o n. 
 
Wit h dr a w al of i nf or m e d c o nse nt f or d o n ate d bi ol o gic al s a m ples 
If a s u bject wit h dr a ws c o nse nt t o t he use of d o nate d sa m ples, t he sa m ples will be dis p ose d 
of/ destr o ye d, a n d t he acti o n d oc u me nte d.  As c ollecti o n of t he bi ol o gical sa m ples is a n i nte gral 
part of t he st u d y, t he n t he s u bject is wit h dra w n fr o m f urt her st u d y partici pati o n. 
T he Pri nci p al I n vesti gat or:  
•  
E ns ures  t hat  bi ol o gical  sa m ples  fr o m  t hat  s u bject,  if  st ore d  at  t he  st u d y  site,  are  
i m me diatel y i de ntifie d, dis p ose d of / destr o ye d, a n d t he acti o n d oc u me nte d 
•  
E ns ures  t he  la b orat or y(ies)  h ol di n g  t he  sa m ples  is/are  i nf or me d  a b o ut  t he  wit h dra w n  
c o nse nt i m me diatel y a n d t hat sa m ples are dis p ose d/ destr o ye d, t he acti o n d oc u me nte d a n d 
t he si g ne d d oc u me nt ret ur ne d t o t he st u d y site 
•  
E ns ures t hat t he s u bject is i nf or me d a b o ut t he sa m ple dis p osal.  
  
 
7. 1. 2. 8  L a b or at or y S afet y E v al u ati o ns ( He m at ol o g y, C he mistr y a n d Uri n al ysis) 
At baseli ne a n d d uri n g tr eat me nt l ocal la b orat or y c ollecti o n a n d assess me nts are t o i ncl u de: 
he mat ol o g y, c he mistr y, uri nal ysis, he patic pa nel, pre g na nc y t est (f or W O C B P) a n d c orrel ati ve 
bl o o d c ollecti o n (see Secti o n 7 a n d Ta ble 3 .)  
 
 

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Protocol version 3.0 April 17, 2019 
 
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Table 3. Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Collect T4 if TSH abnormal (repeat ≤ every 
12 weeks) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Thyroid stimulating hormone (TSH) (repeat 
≤ every 12 weeks) 
 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Blood for correlative studies 
 
 
 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 

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Protocol version 3.0 April 17, 2019 
 
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7.1.3 
Other Procedures 
7.1.3.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8. 
 
7.1.4 
Visit Requirements 
Visit requirements are outlined in Section 7 –Schedule of Assessments.   Specific procedure-
related details are provided above in Section 7.1.1-7.1.2 - Trial Procedures. 
 
7.1.4.1 
Screening Period 
The following assessments will be performed up to 28 days prior to initiation of study treatment: 
• Written informed consent 
• Verification of eligibility 
• Full Physical Examination 
• Vital Signs and weight 
• ECOG performance status 
• Demographic and history of tobacco and alcohol use 
• Medical and previous treatment history 
• Pregnancy test or Serum B-HCG in females of childbearing age (within 72 hours of 
starting therapy) 
• Tumor tissue sample collection  
• Correlative blood collection 
• Hematology panel  (within 3 days of starting therapy repeat on C1D1 not required) 
• PT/INR and aPTT (at screening and when clinically indicated) 
• Serum Chemistry panel (within 3 days of starting therapy repeat on C1D1 not required) 
• Urinalysis (at screening and when clinically indicated) 
• TSH and T4 if TSH abnormal (repeat ≤ every 12 weeks) 
• Tumor imaging of known sites of disease  
• Radiation therapy planning/simulation 
• Adverse event/serious adverse event review 
• Concomitant medication review 
 
7.1.4.2 Treatment Period  
The following assessments will be performed on day 1 of each cycle and must be performed no 
more than 24 hours prior to treatment unless otherwise specified: 
• Targeted physical examination 
• Vital Signs and weight 
• ECOG performance status 
• Hematology panel 
• PT/INR and aPTT (as clinically indicated) 

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Protocol version 3.0 April 17, 2019 
 
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• Serum chemistry panel 
• Urinalysis (as clinically indicated) 
• TSH and T4 if TSH abnormal (repeat ≤ every 12 weeks) 
• Correlative blood collection as indicated in Section 7 
• Radiation therapy as outlined in Sections 5.1.1. and 7 
• Nivolumab and Ipilimumab therapy as outlined in Section 5.1.1 (-2/+3 days), nivolumab 
doses are given at least 12 days apart 
• Tumor imaging of known sites of disease (imaging every 8 weeks ±7 days) 
• Adverse event/serious adverse event review 
• Concomitant medication review 
 
 
 
7.1.4.3 End of Treatment Visit 
• Targeted physical examination 
• Vital Signs and weight 
• ECOG performance status 
• Adverse event review/serious adverse event review 
• Concomitant medication review 
 
7.1.4.4 30-Day Post Last Treatment Visit 
• Targeted physical examination 
• Vital Signs and weight 
• ECOG performance status 
• Adverse event/serious adverse event review 
• Concomitant medication review 
 
 
 
7.1.4.5    Long-Term Follow-Up Visits every 8 weeks (±7 days) for patients without 
documented progression/ have not started new anti-cancer therapy  
 
• ECOG performance status 
• Adverse event/serious adverse event review collection up to 100 days after last dose of 
study treatment 
• Follow-up will continue until end of study 
 
 
7.1.4.6 Survival Follow-Up -Every 12 weeks  for patients with documented disease 
progression/have started new anti-cancer therapy 
• Medical record confirmation or phone contact confirmation to document survival 

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Protocol version 3.0 April 17, 2019 
 
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• Adverse event/serious adverse event review collection up to 100 days after last dose of 
study treatment 
• Follow-up will continue until end of study. 
8. 
SAFETY AND REPORTING 
 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 100 days of last dose of study treatment  must be reported to 
BMS Worldwide Safety, whether related or not related to study drug. If applicable, SAEs must 
be collected that relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy). 
Hospitalizations and/or death related solely to progression of the underlying disease will not be 
considered an SAE. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, are collected, including those thought to be associated with protocol-
specified procedures. The investigator should report any SAE occurring after these 
aforementioned time periods, which 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. 
An appropriate SAE form (e.g.  ex-US = CIOMS form or USA = Medwatch form) should be 
used to report SAEs to BMS. The BMS protocol ID number must be included on whatever form 
is submitted by the Sponsor/Investigator.  
o The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i  
o The MedWatch form is available at: 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
 
• Worldwide.Safety@bmsaepbusinessprocess@bms.com 
• In accordance with local regulations, BMS will notify investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (i.e., not 
previously described in the IB). An event meeting these criteria is termed a Suspected, 
Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of these events 
will be in the form of a SUSAR Report.  

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o Other important findings which may be reported by BMS as an Expedited Safety 
Report (ESR) include: increased frequency of a clinically significant expected SAE, an 
SAE considered associated with study procedures that could modify the conduct of the 
study, lack of efficacy that poses significant hazard to study subjects, clinically 
significant safety finding from a nonclinical (e.g., animal) study, important safety 
recommendations from a study data monitoring committee, or sponsor decision to end 
or temporarily halt a clinical study for safety reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the IB. Where required by local regulations or when there is a central IRB/IEC 
for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information.  
o In addition to the Sponsor Investigator’s responsibility to report events to their local 
HA, suspected serious adverse reactions (whether expected or unexpected) shall be 
reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate 
reports). 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on either CIOMS or MedWatch form & pregnancies 
must be reported on a Pregnancy Surveillance Form or can be submitted on the aforementioned 
SAE form to BMS. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
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 BMS (or designee) 
using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
8.1 
DEFINITIONS FOR 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 participant 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) 

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• 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 [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.)  
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.  
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer 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 should be reported 
as an SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). Hospitalizations and/or death related solely to progression of the underlying disease 
will not be considered an SAE. 
NOTE: (PI determines if this information regarding hospitalizations are considered SAEs and 
should be included in the protocol. This is supplemental information that is included in 
BMS-sponsored trials) 
The following hospitalizations are not considered SAEs in BMS clinical studies:  
− 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 (e.g., 
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 (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
− Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 

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− Hospitalizations and/or death related solely to progression of the underlying disease will 
not be considered an SAE. 
 
8.2 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant 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 investigational product, whether or not considered 
related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual 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.) 
 
 
 
8.3 
NONSERIOUS ADVERSE EVENT 
• Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or 
final study reports as specified in the agreement or, if a regulatory requirement [e.g., IND 
US trial] as part of an annual reporting requirement.  
• Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the 
subjects.  
A non-serious adverse event is an AE not classified as serious.  
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of study drug. All 
non-serious adverse events (not only those deemed to be treatment-related) should be collected 

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continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate.  
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as 
such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• any laboratory test result that is clinically significant or meets the definition of an SAE 
• any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• any laboratory 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 (e.g., anemia versus low hemoglobin value). 
Potential Drug Induced Liver Injury (DILI) 
Specific criteria for identifying potential DILI have not been identified for this protocol. 
Standard medical practice in identifying and monitoring hepatic issues should be followed. 
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:  
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
3) 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. 
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. 

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Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (e.g., dose tapering if 
necessary for participant).  
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either 
the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE 
reporting procedures.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the CIOMS, 
MedWatch or appropriate Pregnancy Surveillance Form.  A BMS Pregnancy Surveillance Form 
may be provided upon request. 
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. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must sign an informed consent form for disclosure of this 
information.  
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious AE, 
as appropriate, and reported accordingly. 
 
8.4 
STUDY STOPPING RULE 
In keeping with the study primary endpoint, a stopping rule will be implemented in the unlikely 
event that the combination under study is deemed to have unacceptably high toxicities. Enrollment 
will be halted if more than 3 patients experience a Grade 4 or higher drug related toxicity (CTCAE 
v. 5) during the trial treatment period or up to 30 days after the last investigational drug infusion. 
The likelihood of observing more than 3 Grade 4+ drug-related adverse events is 80% if the true 

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rate is 20% and the likelihood is 91% if the true rate is 25%.   This rule has an 83% chance of 
prematurely discontinuing trial enrollment after the 1st 10 patients are enrolled if the true rate of 
Grade 4 drug related toxicity is 40%.  The study will be reviewed by the University of 
Washington/Fred Hutch Cancer Consortium Data and Safety Monitoring Committee (DSMC 
STATISTICAL CONSIDERATIONS 
All patients enrolled in the study, including those in the run-in phase will be included in the 
analysis of toxicity and efficacy. 
 
Safety and tolerability is the primary endpoint of this study, and all patients enrolled will be 
assessed for this endpoint. Adverse events will be recorded and graded based on CTCAE v. 5, 
and their relationship to the experimental agents reported.  
 
Similarly, all patients enrolled in the study (i.e., the initial 6 patient cohort, and the additional 14 
patient expansion) will be included in the efficacy analyses.  Clinical responses to the 
combination of nivolumab,  ipiliumumab and hypofractionated radiation will be based on 
RECIST 1.1 criteria.  Oncologic outcome endpoints such as progression free and overall survival 
will be calculated from the date of study enrollment, until disease progression or death from any 
cause, respectively. Survival estimates will be calculated using the Kaplan-Meier method.  
 
Exploratory endpoints of this study include correlative work performed on research serum and 
tissue samples.  
 
Sample size determination 
There are multiple ongoing studies in various tumor types exploring the activity of nivolumab 
and ipilimumab. In a published report of the combination in patients with advanced NSCLC 
treated on a phase I study (Checkmate, 012), treatment related serious adverse events were 
observed in 28% of patients (Hellmann Lancet Oncol 2017). This study plans to accrue 20 
patients, a sample size that would allow us to estimate grade 3 or higher acute drug related 
toxicity rate of 30% with a confidence interval of 20% (95% confidence level) or an upper bound 
of 50%. This would allow us to reasonably exclude a clinically significant increase in toxicity 
with the addition of radiation therapy to the nivolumab and ipilimumab combination as defined 
by the upper bound of the confidence interval. 
9. 
STUDY MANAGEMENT 
All investigators on the protocol will receive formal training in the ethical conduct of human 
research. Institutional support of trial monitoring is provided in accordance with the Cancer 
Consortium’s data and safety monitoring plan 

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Monitoring of the study 
Institutional support of trial monitoring will be in accordance with the Fred Hutch/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the 
provisions of this plan, Fred Hutch Clinical Research Support coordinates data and compliance 
monitoring conducted by consultants, contract research organizations, or Fred Hutch employees 
unaffiliated with the conduct of the study. Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of previous visits per 
the institutional DSMP. 
 
In addition, protocols are reviewed as needed by the Consortium Data and Safety Monitoring 
Committee (DSMC), Fred Hutch Scientific Review Committee (SRC) and the Fred 
Hutch/University of Washington Cancer Consortium Institutional Review Board (IRB). The 
review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating patients. The 
IRB reviews the study progress and safety information to assess continued acceptability of the 
risk-benefit ratio for human subjects. Approval of committees as applicable is necessary to 
continue the study. The trial will comply with the standard guidelines set forth by these regulatory 
committees and other institutional, state, and federal guidelines. 
 
Data Management 
The Protocol Director, or her designees, will prepare and maintain adequate and accurate 
participant case histories with observations and other data pertinent to the study.  Original source 
documents should be transcribed to Case Report Forms (CRFs) and used to analyze the study 
data.  Source documents include hospital records, clinical charts, laboratory and pharmacy 
records, and recorded electronic data. 
 
All data required by the trial will be entered onto paper and electronic case report forms. Any 
corrections to data required into the paper case report forms must be made in such a way that the 
original entry is not obscured. Only designated study staff will enter data for study participants 
after study visits. Case report forms will be checked against source document data by study staff. 
Patient records will be kept in a secure location at the University of Washington accessible only 
to research authorized personnel. The patient identity will be kept as confidential as possible as 
required by law. Except as required by law, the patient will not be identified by name, social 
security number, address, telephone number, or any other direct personal identifier. Study 
subjects will be assigned an ID code. Information about the code will be kept in a secure location 
and access limited to research study personnel. The results of this research study may be 
presented at scientific or medical meetings or published in scientific journals. However, the 
patient identity will not be disclosed. The patient's personal data which may be included in the 
investigator’s database shall be treated in compliance with all applicable laws and regulations. 

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10. 
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