Nivolumab and Ablation For Patients With Advanced Non-Small Cell Lung Cancer Progressing After at Least One Prior Therapy For Metastatic Disease: A Brown University Oncology Research Group Phase II Study
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer, Lung Cancer, Metastatic Lung Cancer, NSCLC
Sponsor: howard safran

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
1
 
BrUOG L317  
 
 
 
 
 
IND Exempt 126924 
 
Nivolumab and Ablation For Patients With Advanced Non-Small Cell Lung Cancer 
Progressing After at Least One Prior Therapy For Metastatic Disease: 
A Brown University Oncology Research Group Phase II Study 
 
Howard Safran, MD Principal Investigator 
Medical Director, Brown University Oncology Research Group 
 
Damian Dupuy, MD 
Humera Khurshid, MD 
Angela Taber, MD 
Anthony Mega, MD 
Kalyan Mantripragada, MD 
Thomas DiPetrillo, MD 
Loren Fast, PhD 
 
 
Financially supported by the Joan DeCotis Foundation 
 
Supported in part by the Smith and Smalley families 
 
Coordinating Center 
Kayla Rosati, EdM 
Brown University Oncology Research Group 
233 Richmond Street Box G-R001 
Providence, Rhode Island 02903 
Phone: (401) 863-3000 
Fax: (401) 863-3820 
Email: Kayla_rosati@brown.edu 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless law 
or regulations require such disclosure.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 
Protocol 3/30/15 
Amendment #1 10/5/15 
Amendment # 2 11/9/15 
Amendment # 3 3/4/16 
Amendment # 4 4/7/16 
Amendment # 5 6/1/16 V2 
Amendment # 6 7/7/16 
Amendment# 7 11/16/16 
Amendment #8 2/22/17 
Amendment #9 5/22/17

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
2
TABLE OF CONTENTS 
Section  
 
 
 
 
 
 
 
 
Page 
1.0 
OBJECTIVES  
 
 
 
 
 
 
3 
2.0 
BACKGROUND 
 
 
 
 
 
 
3 
3.0 
PATIENT ELIGIBILITY 
 
 
 
 
 
5 
 
4.0 
TREATMENT 
 
 
 
 
 
 
6 
 
5.0 
TOXICITIES, ASSESSMENT, AND DOSE MODIFICATIONS 
7 
                                              
6.0 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
 
11 
                          
7.0      RESPONSE ASSESSMENT  
 
 
 
 
14 
 
 
8.0 
PATIENT REGISTRATION  
 
 
 
 
16 
9.0 
PHARMACEUTICAL INFORMATION                                           
17 
10.0 
AGENT ACCOUNTABILITY     
 
 
 
 
18 
 
11.0 
ADVERSE DRUG REACTION REPORTING 
 
 
18 
 
12.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
23 
13.0 
FOLLOW UP    
 
 
 
 
 
 
24 
   
14.0 
REGULATORY CONSIDERATIONS   
 
                           24 
15.0 
DATA MONITORING/QUALITY ASSURANCE/ 
 
 
25 
RECORD RETENTION 
 
 
 
 
 
 
 
16.0 
DATA SAFETY AND MONITORING BOARDS 
 
 
26 
 
17.0 
STATISTICAL CONSIDERATIONS  
 
 
    
27 
18.0 
REFERENCES                                                                        
28 
 
APPENDIX SECTION: 
 
 
 
 
 
APPENDIX A INFORMED CONSENT 
 
 
 
 
 
APPENDIX B ELIGIBILITY CHECKLIST  
 
 
 
APPENDIX C ADVERSE DRUG REACTION MEMORANDUM 
 
 
 
APPENDIX D COMMON TOXICITY CRITERIA  
 
 
APPENDIX E ECOG PERFORMANCE STATUS   
 
 
APPENDIX F CASE REPORT FORMS 
 
 
 

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Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
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1.0  OBJECTIVES 
1.1 Primary  Objective 
1.1.1. To evaluate the response rate of the combination of ablation and the PD-1 inhibitor 
nivolumab for patients with non-small cell lung cancer (NSCLC) who have progressed following 
at least 1 prior chemotherapy regimen for metastatic or locally advanced disease.   
 
1.2 Secondary  Objectives 
1.2.1 To evaluate the disease-free and overall survival for the combination of ablation and the PD-
1 inhibitor nivolumab for patients with NSCLC who have progressed following at least 1 prior 
chemotherapy regimen for metastatic or locally advanced disease.  
1.2.2 To evaluate whether ablation increases tumor PD-L1 expression. 
 
2.0 BACKGROUND: 
 
Lung Cancer: Lung cancer is the most common cause of cancer death. Worldwide, in 2012 there 
were approximately 1.8 million new cases of lung cancer and an estimated 1.6 million deaths. 1 In 
the United States, there will be an estimated 224,000 new cases of lung cancer and 159,000 deaths 
in 2014.2 
 
Chemotherapy for Metastatic NSCLC: First-line treatment for patients with advanced NSCLC 
without an EGFR or ALK mutation is combination chemotherapy generally including a platinum 
compound.3,4,5 Second-line chemotherapy often utilizes a single chemotherapy drug not utilized in 
the first-line regimen such as pemetrexed or docetaxel.6,7 Response rates to second line treatment 
are about 10%. The average survival for patients with metastatic NSLCC with multiple lines of 
chemotherapy is about 1 year.3-7  
 
PD-1/PD-L1 Inhibition: Stimulating the immune system to fight lung cancer represents one of the 
most remarkable clinical achievements in the last decade in thoracic oncology.8 Programmed death 
ligand 1 (PD-L1) is a transmembrane protein that was first identified for its role in the maintenance 
of self-tolerance and prevention of autoimmunity.9 Engagement of PD-L1 on dendritic cells with 
the programmed death 1 (PD-1) receptor on T cells delivers an inhibitory signal that promotes T 
cell anergy or apoptosis.10 This immunoinhibitory checkpoint is often subverted by tumor cells that 
over-express PD-L1 in order to escape immunosurveillance in the tumor microenvironment. There 
is a strong correlation between PD-L1 expression and prognosis in cancer. Blockade of the 
interaction between PD-L1 on tumor cells and PD-1 on T cells with anti PD-1/anti PD-L1 
antibodies reverse T cell suppression within tumors, thereby promoting effective anti-tumor 
immune responses.11 
Nivolumab in NSCLC: Nivolumab is a fully human IgG4 PD-1 monoclonal antibody that binds 
to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 
pathway-mediated inhibition of the immune response, including anti-tumor immune response. 
Patients with advanced NSCLC who had been previously treated with a prior platinum-containing 
regimen received nivolumab at a dose of 1, 3, and 10 mg/kg.12,13 The maximum-tolerated dose 
was not reached in this trial, and all doses were found to be safe. In the initial phase expanded 
phase I study reported in the New England Journal of Medicine (NEJM) a total of 122 patients 
with NSCLC were enrolled.12 The majority of patients with NSCLC were heavily pretreated; 55% 
of patients received at least three prior lines of therapy. Results showed 15 percent of participants 
experienced a partial response, of whom 59 percent had response durations of six months or 

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Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
4
longer.  Disease response was seen in squamous as well as non-squamous histology (six of 18 
patients [RR, 33%] with squamous histology and seven of 56 patients [RR, 12%] with non-
squamous histology). Nivolumab has been well tolerated. Only 8% of the patients with NSCLC 
experienced grade 3 or 4 treatment-related AEs. The most common grade 3 and 4 treatment-
related AEs in patients with NSCLC were fatigue, elevated AST, and pneumonitis. Nine patients 
(3%) of the total trial population developed pneumonitis. 
Tumor PD-L1 expression appeared to be associated with response. Among the first 76 assessable 
patients with NSCLC without tumor expression of PD-L1 there were no documented tumor 
responses, but 36% of patients with tumor PD-L1 expression were objective responders in the 
NEJM article.12,13 However, the FDA granted approval of nivolumab in all patients with 
squamous cell NSCLC regardless of PD-L1 expression based on complete data of the entire 122 
patients with NSCLC in the expanded phase I as well as subsequent BMS trials with nivolumab. 
Similarly, data with the Merck PD-1 antibody MK-3475, suggests that while activity in NSCLC 
is higher in tumors with PD-L1 expression, benefit appears to be present even in tumors without 
expression.14 In KEYNOTE-001 evaluating MK-3475, using the 50% cutoff point for PD-L1 
expression, about 25% of patients with NSCLC were strongly positive for PD-L1 expression. The 
overall response rate to MK-3475 for both PD-L1–positive and –negative groups was 19%. 
Median progression-free survival was 14.1 weeks in the PD-L1–positive patients vs 9.3 weeks in 
the weakly positive (1%–49% cutoff) and negative patients. Overall survival was 9.3 vs 7.3 
months, respectively, following MK-3475 in patients with NSCLC, which was not statistically 
significant between the groups.  
Given the unprecedented response seen in heavily pretreated patients with NSCLC, the following 
phase III studies were initiated: 
 
Nivolumab Compared to Docetaxel in Previously Treated Metastatic Non-squamous 
NSCLC (CheckMate 057) NCT01673867. 
 
Nivolumab Compared to Docetaxel in Previously Treated Advanced or Metastatic 
Squamous Cell Non-small Cell Lung Cancer (NSCLC) (CheckMate 017) NCT01642004 
 
Nivolumab Versus Investigator's Choice Chemotherapy as First-Line Therapy for Stage 
IV or Recurrent PD-L1+ Non-Small Cell Lung Cancer (CheckMate 026) NCT02041533 
On March 4th, 2015 Nivolumab received FDA approval to treat metastatic squamous cell lung 
cancer with progression on or after first-line chemotherapy based on results from Check Mate 
057. Nivolumab’s efficacy to treat squamous NSCLC was established in this randomized trial of 
272 participants, of whom 135 received Nivolumab and 137 received docetaxel. The trial was 
designed to measure the effect on overall survival.  Participants who received Nivolumab lived 
3.2 months longer than those participants who received docetaxel. 
At the annual meeting of the American Society of Clinical Oncology, May 30, 2015, the results 
of Checkmate 057 were released. A survival benefit of nivolumab as compared to docetaxel was 
demonstrated for patients with metastatic non-squamous cell lung cancer. The 12 month overall 
survival was 51% for nivolumab compared with 39% for docetaxel. The response rate was 19% 
for nivolumab versus 6% for docetaxel. Grade 3/4 toxicities were higher with docetaxel (20% 
versus 7%). Patients with tumors with PD-L1 expression had significant benefit with nivolumab 
as compared to docetaxel while tumors without PD-L1 expression had similar outcomes.  
Ablation as a Treatment For Cancer: Ablation is a local modality that involves placing a 
needle or electrode under radiologic guidance into the center of a tumor and using heat or cold to 

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Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
5
destroy a defined area.15 Dupuy et al has demonstrated that ablation is an important treatment for 
lung cancer. 16-18  Radiofrequency ablation (RFA) emits a high frequency alternating current from 
the tip of an electrode into the tissue surrounding that electrode.19 As the ions within the tissue 
attempt to follow the change in the direction of the alternating current, their movement results in 
frictional heating of the tissue. As the temperature within the tissue becomes elevated beyond 
60ºC, cells begin to die, resulting in a region of necrosis surrounding the electrode.19 Ablation can 
be used both to kill tumor cells but also to relieve pain. Dupuy et al pioneered ablation to reduce 
pain from bone metastases and this currently is an FDA indication. 20 
Cryoablation uses cold injury to kill tumors.21 This procedure uses liquefied gases such as argon 
that cool as they expand. This freezing process, unlike other ablative techniques, is unique in 
maintaining intact intracytoplasmic organelles and the cell ultrastructure, while opening up the 
plasma membrane to immune cell exposure thus inducing higher post-ablative immunogenicity.21  
These intact tumor antigens are captured by dendritic cells and macrophages, thereby mounting a 
local and systemic immune response involving IL-1, IL-6 and nuclear factor-κB (NF-κB)-
dependent cytokines such as TNFα.23-25 Histological studies have shown post-cryoablation tumor 
infiltrates of neutrophils, followed by substantial macrophage recruitment; ELISA studies have 
shown systemic elevation of tumor-specific antibodies, NK cell activity, increased tumor-specific 
T cell response in regional lymph nodes and the level of systemic circulating T cells.26,27 Therefore, 
since cryoablation enhances the immunogenicity of tumors, the combination of cryoablation and 
nivolumab may be synergistic.  
 
Recent data from Sloan Kettering suggests that thermal ablation may also activate the immune 
system. Serum interleukin-6 (IL-6) increases after thermal ablation. IL-6 is released by several cell 
types including type-2 helper T-cells (Th2), and plays a role in type-1 helper T-cells (Th1) and Th2 
differentiation.28 Furthermore; heat-based ablation increases the proportions of circulating Th1 and 
CTLs more than cryoablation. Heat-based ablation therefore is another approach to enhance 
systemic anti-tumor immunity by increasing CTL levels and optimizing Th1/Th2 balance. 29 
 
Protocol Rationale: Nivolumab releases the inhibition of the immune system against human 
cancers. Dramatic and sustained activity has been observed in advanced lung cancer. Ablation may 
stimulate the immune system by exposing new tumor antigens. Since tumors that express PD-L1 
may be more likely to respond to nivolumab, if ablation increases PD-L1 expression (which has 
not been studied) this treatment may enhance the activity of nivolumab at both the treated site and 
in other, non-treated, tumors. Ablation is already an FDA approved treatment for cancer. 
Nivolumab was recently FDA approved for second line treatment of advanced squamous cell 
NSCLC. The goal of the study will be to determine if the combination of nivolumab and ablation 
has higher systemic activity than previously reported with nivolumab alone.  
 
3.0 ELIGIBILITY:  
 
3.1 Inclusion Criteria: 
3.1.1  Pathologically or cytologically confirmed NSCLC  
3.1.2 Stage IIIB or stage IV. 
3.1.3 Patient to meet either criterion A or B: 
A) Patient must have progressed after at least 1 line of systemic treatment (IV or oral) for metastatic 
or locally advanced disease. Must provide documentation systemic treatment was for either locally 
advanced or metastatic. Mustalso provide scan or assessment to show most recent progression, pre-
enrollment certifying progression of disease to meet inclusion eligibility of progression. Radiation 
does not count as 1 line. 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
6
B) Patients progressing within 6 months of completion of neoadjuvant or adjuvant chemotherapy 
are also eligible without having treatment for metastatic disease (for example patient with stage I 
disease undergoes resection, receives systemic chemotherapy and then progresses to the liver (now 
stage IV) within 6 months of chemotherapy). Radiation does not count as 1 line.  
3.1.4  Ablation for advanced lung cancer is being considered by the treating physician for treatment 
or prevention of symptoms such as pain, bleeding or obstruction- Documentation is required in 
writing by MD for this criterion.  
3.1.5 At least 1 site of measurable disease that will not be treated with ablation. Sites to send 
confirmation on which lesion of measurable disease will not be ablated for tracking of response. 
3.1.6  At least 3 weeks since prior systemic treatment and/or radiation therapy for patient’s NSCLC 
(from treatment day 1 on study) 
3.1.7. No brain metastases except for patients whose metastases have been removed by surgical 
resection or have had stereotactic radiation or gamma knife with no evidence of active disease on  
MRI within 28 days of starting treatment.  
3.1.8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. 
3.1.9. Life expectancy of at least 12 weeks. 
3.1.10. Required entry laboratory parameters within 14 days of study entry:  Granulocytes ≥ 
1000/µl; platelet count ≥75,000/µl; Creatinine ≤ 1.5x upper limit normal mg/dl; Bilirubin < 1.5x 
upper limit normal; AST ≤ 3 x upper limit of normal. 
3.1.11. Age > 18 years 
3.1.12. Men and women of childbearing potential enrolled in this study must agree to use adequate 
barrier birth control measures during the course of the study and up to 2 months after. 
3.1.13. Written informed consent.  
 
3.2 Exclusion Criteria: 
3.2.1 Patients with a history of clinically significant chronic autoimmune disease 
3.2.2. Prior therapy with antibodies that modulate T-cell function defined as: anti–CTLA-4, anti–
PD-1, and anti–PD-L1 drugs. 
3.2.3. Conditions currently requiring immunosuppressive medications 
3.2.4. Known history of HIV or hepatitis B or C 
3.2.5. Bleeding diathesis or coagulopathy that in the investigators opinion would prevent ablation 
from being safely performed. 
3.2.6. Patients with unstable angina (anginal symptoms at rest) or new-onset angina (began within 
the last 3 months) or myocardial infarction within the past 6 months. 
3.2.7. History of organ allograft even if not taking immunosuppressive medications 
3.2.8. Pregnant or breast-feeding. 
 
3.3 Re-screening: If a patient signs consent and then screen fails (does not meet the eligibility 
criteria) and the treating MD requests that the patient be re-screened outside of the 28 day 
screening window, sites are to contact BrUOG who will assess patients on a case by case basis. 
Depending on many diverse factors including the conditions that are being evaluated, the reasons 
why patient initially screen failed, and the nature of the initial results, re-screening may or may 
not be medically/scientifically appropriate. BrUOG should be made aware of such a situation 
with at least 72 hours and provided with information on screen-failure.  
 
4.0 TREATMENT: 
4.1 Nivolumab: 3mg/kg up to a maximum dose of 240mg IV over approximately 60 minutes 
on Day 1 +/- 3 days every 2 weeks until progression for a maximum of 2 years.  
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
7
It will also not be considered a deviation if a cycle or pre-cycle assessment must be adjusted to 
accommodate scheduling or holidays. Adjustment must be documented with reason to BrUOG. 
While efforts should be made to have cycles be every 2 weeks (+/- 3 days), further allowances are 
allowed as long as cycles are not < 10 days.  
 
4.2 Ablation:  Either cryoablation or thermal ablation may be performed as per standard 
institutional policies. Ablation should be performed within 1 week (7 days) of the initial treatment 
with nivolumab, to occur within the first cycle (14 days) of treatment. Additional ablation 
procedures may be performed as clinically indicated such as for pain control including the 
treatment or prevention of pain or obstruction or as per institutional standard of care.  There must 
be a minimum of 60 days between each ablation (60-90 days is preferable). Standard institutional 
procedures may be used in ablation. One or more than one lesion may undergo ablation as per 
investigator judgement and institutional standard of care. At least one measurable site of disease 
cannot be ablated so that it may be followed for response. This location should be chosen at 
baseline with enrollment-see section 3.1.5 
 
During the same procedural period as ablation, if patient has consented and agreed, a tumor tissue 
biopsy may be obtained prior to each ablation, as per institutional standard of care. This biopsy 
may be assessed for future correlative studies such as assessment of PD-L1 by 
immunohistochemical staining and will allow for correlation to response.  
 
The following treatments must not be administered during the study: Immunotherapy other than 
the study drug, immunosuppressive drugs [i.e., chemotherapy or systemic corticosteroids 
except for short term treatment of allergic reactions or for the treatment of immure related 
adverse events (irAEs)}, or other experimental pharmaceutical products. Short term 
administration of systemic steroid (i.e., for allergic reactions or the management of irAEs is 
allowed). 
 
Growth factors (granulocyte colony stimulating factor or granulocyte macrophage colony 
stimulating factor). Exception: Erythropoietin and darbepoietin alpha may be prescribed at the 
investigator’s discretion. 
 
Requirements For Ablation: 
 
Pre-ablation labs will be done within 2 weeks of ablation (prior to). If the counts are done early 
and would preclude the patient from ablation, labs should be repeated on the day of the procedure 
prior to cancelling.  
 
Ablation cannot occur unless the following criteria are met: 
 
PLT > 50 x109/L (50,000/mm3) 
INR <1.8 
 
5.0 DOSE MODIFICATIONS OF NIVOLUMAB AND TOXICITY MANAGEMENT: 
Adverse events will be graded with the use of the National Cancer Institute Common Terminology 
Criteria for Adverse Events, version 4 
 
 
 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
8
5.1        Nivolumab Dose Modifications: 
 
No dose reductions of nivolumab are included in the study.  Any adverse event, laboratory 
abnormalities, or undercurrent illness which in the judgment of the investigator, can warrant 
delaying the dose of study medication. 
 
5.2 The following must be confirmed prior to dosing a patient with Nivolumab: 
1) Patients experiencing treatment related (drug) grade 4 or treatment related (drug) clinically 
significant grade 3 toxicities must have toxicity resolved to grade 2 or less prior to resuming 
nivolumab.  
 
5.3 Hold treatment until recovery to grade 1 or resolution for:   
1) If AST or ALT >3 to 5 times ULN (grade 2) or total bilirubin >1.5 to 3 times ULN  
(grade 2): Withhold treatment; may resume therapy upon recovery to grade 0 or 1 
toxicity (AST/ALT grade 1 is >ULN-3xULN, Total bilirubin grade 1 is >ULN-
1.5xULN). 
**for possibly, probably or definitely related to nivolumab see section 5.3, 2.I.below 
 
**AST or ALT >5 times ULN (grade 3) or total bilirubin >3 times ULN (grade 3) or severe/life-
threatening immune-mediated hepatitis: Permanently discontinue. **see section 5.3 
(this section), 2** below 
2) Immune-mediated hepatitis:  
I. 
Grade 2 or higher transaminase elevations that are possibly, probably or 
definitely related to nivolumab (with or without total bilirubin elevations): 
Withhold treatment and initiate high-dose systemic corticosteroids 
(prednisone 1 to 2 mg/kg daily or equivalent) 
** Severe (grade 3) or life-threatening (grade 4) transaminase elevations: Permanently 
discontinue treatment and initiate high-dose systemic corticosteroids (prednisone 1 to 2 
mg/kg daily or equivalent)  
3) Colitis:  
I. 
Grade 2 (duration >5 days): Also administer systemic corticosteroids (prednisone 
0.5 to 1 mg/kg daily or equivalent) followed by a corticosteroid taper; may 
increase to prednisone 1 to 2 mg/kg daily (or equivalent) if colitis worsens or 
does not improve despite corticosteroid use 
II. 
Grade 3: Also administer systemic corticosteroids (prednisone 1 to 2 mg/kg daily 
or equivalent) followed by a corticosteroid taper 
 
4) Pneumonitis: Pneumonitis (grade 2); also administer high-dose systemic corticosteroids 
(prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper 
 
5) Other immune-mediated toxicities: Other immune-mediated toxicities; also administer 
high-dose systemic corticosteroids followed by a corticosteroid taper (over 1 month) 
 
6) Creatinine >1.5 to 6 times ULN (grade 2 or 3) or >1.5 times baseline (grade 1): Withhold 
treatment; administer prednisone 0.5 to 1 mg/kg daily (or equivalent) followed by a 
corticosteroid taper; may resume therapy upon recovery to grade 0 or 1 toxicity. If toxicity 
worsens or does not improve, permanently discontinue and increase corticosteroid dose to 
prednisone 1 to 2 mg/kg daily (or equivalent). 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
9
 
5.4 Discontinue treatment (remove patient from study), for following: 
1) AST or ALT >5 times ULN (grade 3) or total bilirubin >3 times ULN (grade 3) or 
severe/life-threatening immune-mediated hepatitis: Permanently discontinue.  
 
2) Colitis  
I. 
Colitis: (grade 4); also administer high-dose systemic corticosteroids (prednisone 
1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper 
II. 
Colitis (recurrent) 
 
3)   Pneumonitis 
Pneumonitis (grade 3 or 4); also administer high-dose systemic corticosteroids 
(prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper 
 
4) Inability to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 
12 weeks. 
 
5)  Other adverse reactions that are life-threatening, severe or grade 3 treatment related 
adverse reactions that recur, or persistent grade 3 treatment-related toxicity that does not 
recover to grade 1 or resolve within 12 weeks (except alopecia)..  
 
6) Creatinine >6 times ULN (grade 4): Permanently discontinue; initiate high-dose systemic 
corticosteroids 
 
7) Severe (grade 3) or life-threatening (grade 4) transaminase elevations: Permanently 
discontinue treatment and initiate high-dose systemic corticosteroids (prednisone 1 to 2 
mg/kg daily or equivalent) 
5.5 Hepatic Impairment  
Hepatic impairment prior to treatment initiation: 
Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin <1 to 1.5 times ULN 
and any AST): No dosage adjustment necessary. 
Moderate (total bilirubin >1.5 to 3 times ULN and any AST) to severe (total bilirubin >3 times 
ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer’s 
labeling (has not been studied). 
Hepatotoxicity during treatment: 
AST or ALT >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN: Withhold treatment; may 
resume therapy upon recovery to grade 0 or 1 toxicity (AST/ALT grade 1 is >ULN-3xULN, Total 
bilirubin grade 1 is >ULN-1.5xULN) . 
AST or ALT >5 times ULN or total bilirubin >3 times ULN or severe/life-threatening immune-
mediated hepatitis: Permanently discontinue.  
Immune-mediated hepatitis:  
Grade 2 or higher transaminase elevations (with or without total bilirubin elevations): Withhold 
treatment and initiate high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or 
equivalent) 
Severe (grade 3) or life-threatening (grade 4) transaminase elevations: Permanently discontinue 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
10 
treatment and initiate high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or 
equivalent)  
5.6 Thyroid Disorders 
Thyroid disorder (hyperthyroidism or hypothyroidism): There are no recommended dosage 
modifications.  
5.7 Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- 
or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should 
be reported within 24 hours to BrUOG and reported as an SAE if it meets the criteria. Infusion 
reactions should be graded according to NCI CTCAE (version 4) guidelines. 
 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
 
For Grade 1 symptoms (mild reaction, infusion interruption not indicated, intervention 
not indicated): Remain at bedside and monitor subject until recovery from symptoms. 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab administrations. 
 
For Grade 2 symptoms (moderate reaction requires therapy or infusion interruption but respond 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory 
drugs, narcotics, corticosteroids, bronchodilators, IV fluids], prophylactic medications 
indicated for < 24 hours) Stop the nivolumab infusion, begin an IV infusion of normal 
saline, and treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor subject 
until resolution of symptoms. Corticosteroid or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor subject 
closely. If symptoms recur then no further nivolumab will be administered at that visit. 
Administer diphenhydramine 50 mg IV and remain at bedside and monitor the subject 
until resolution of symptoms. The amount of study drug infused must be recorded on the 
appropriate page. The following prophylactic medications are recommended for future 
infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional nivolumab 
administration. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
 
Grade 3 or 4 symptoms (severe reaction, Grade 3 prolonged [ie not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening, 
pressor or ventilatory support indicated): Immediately discontinue infusion of nivolumab. 
Begin an IV infusion of normal saline and treat the subject as follows: recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous 
administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
11 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV 
(or equivalent) as needed. Subjects should be monitored until the investigator is comfortable 
that the symptoms will not recur. Nivolumab will be permanently discontinued. 
 
 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor subjects until recovery from symptoms. In case of late-
occurring hypersensitivity symptoms (eg, appearance of a localized or generalized pruritus 
within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine 
or corticosteroids). 
 
6.0 SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
Parameter 
Pre-study 
(to be 
sent to 
BrUOG 
prior to 
registrati
on) 
Within 3 days 
prior to Day 1 
of Each Cycle 
of Nivolumab 
(approximately 
every 2 weeks) F 
While on 
Nivolumab 
therapy 
(Every 12 
weeks 
approximatel
y q 6 cycles) 
Ablation L  
Cycles 1(1 week after 
starting drug) and 
prior to each 
additional ablation (if 
performed) 
End of 
Treatmen
t (2 week 
window 
provided)  
30 
days 
post 
last 
dose of 
drug 
FUD 
Informed Consent 
(within 30 days of 
day 1) *pts are to be 
re-consented if ICF 
will be outside 30 day 
window 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Conmed logP 
X 
X 
X 
X 
X 
 
 
NivolumabK 
 
 
X 
 
 
 
 
 
Optional labs: 3, 6ml 
purple top tubes to 
Dr. Loren Fast at RIH 
at multiple time 
points 
X 
Xo 
 
Xo 
 
 
Xo 
Optional Tissue 
biopsy 
 
 
 
XM 
 
 
 
History G 
X 
 
 
X   
 
 
 
Physical examination  
X 
XQ 
 
 
X 
XI 
 
Weight 
X 
X 
 
 
 
Vital signs 
X 
X 
 
 
 
Toxicity Assessment 
X 
X 
 
 
X 
XH 
 
Performance 
Status  
X 
X 
 
 
X 
 
 
CBC, diff, platelet 
count  
X (within 
14 days) 
X 
 
 
X 
 
 
Na, K, BUN, Cr, 
AST, ALT, Bili  
X (within 
14 days) 
X 
 
 
X 
 
 
Ca, Mg, PO4  
X (within 
14 days) 
X 
 
 
X 
 
 
INR, TSH 
X (within 
14 days) 
 
 
 
 
 
 
Pre-Ablation labs: 
PLT, PT, PTT, INR 
 
 
 
(within 2 weeks of 
ablation up to day of 
(prior to)N 
 
 
 
 
 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
12 
Serum PregnancyE  
X (within 
7 days of 
drug) 
 
 
 
 
 
 
CT scan of  
Chest/abd/pelvis 
XAC(with
in 6 
weeks) 
 
XCJ 
 
XCJ (CT 
does not 
need to 
be 
repeated 
if done in 
prior 2 
months) 
 
XD 
CT scan or MRI of 
brain 
X(within 
6 weeks) 
 
X (only if 
clinically 
indicated) 
 
X (only if 
clinically 
indicated) 
 
X   
EKGB 
X 
 
 
 
 
 
 
Survival and Disease 
status  
 
 
 
 
 
X 
XD 
A- CT Scan for disease assessment to be performed within 6 weeks of study entry. Report required. (chest X-ray okay 
with baseline). 
B- EKG within 8 weeks of study entry. Report required 
C- An MRI or PET scan may substitute for disease assessment.  
D- For patients who are removed from protocol treatment due to toxicity, without progression, Follow-up until disease 
progression will include CT, disease free and overall survival every 3 months (a month window is allotted for 
scheduling). CT scans may be done outside of the 3 month window as per MD discretion; however it is suggested that CT 
scans be done q 3 months. For patients who come off study for progression, overall survival is to be reported every 3 
months (a month window is provided). Follow-up will be for 5 years. 
E post-menopausal women (surgical menopause or lack or menses >12 months) do not need to have a pregnancy test, 
document status. If HCG is not drawn, sites are asked to document menopausal status on lab form. 
F It is appropriate to use labs from screening for cycle 1 day 1, if labs are within 14 days (pregnancy must be within 7 days 
as noted above for applicable patients). A physical exam within 7 days prior to cycle 1 day 1 may be utilized.  PS, weight, 
vitals, conmeds, and AE assessment can be used from screening for cycle 1 if assessments are within 14 days of 
treatment. Labs and physical exam for all subsequent cycles can be within 3 days prior to day 1 of treatment. Another day 
is provided for holidays. 
G Physician note required to be sent. For ablation time points, sites are to submit consult notes from appointment pre-
ablation and if consult occurs post ablation that not is also to be sent. 
H Adverse event evaluation, inclusive of SAE evaluation, will be done 30 days post last dose of drug (+1 week window). 
SAEs occurring outside this 30 day window must be reported if the event is considered to be possibly related to the drug, 
even if patient begins a new treatment. If a patient begins a new treatment, AE evaluation will be stopped unless the 
patient experiences an event that is thought to be possibly related to the study treatment. It is required to inform BrUOG 
of patient beginning a new treatment.  
I Physical to be done in coordination with 30 day toxicity assessment (+ 1 week allowed). Physical post 30 day 
assessments not required per study 
JCT scans (or disease assessment by MRI or PET) to be completed approximately every 12 weeks (approximately every 6 
cycles). For patients staying on study post initial PD – see section 7.3- next scan to confirm PD to be done in 1 month 
time period if patient remains on study. 
K: Cycles are 14 days (+/- 3 days) however, it will not be considered a deviation if a cycle or pre-cycle assessment must 
be adjusted to accommodate scheduling or holidays. Adjustment must be documented with reason to BrUOG. Cycles not 
to be < 10 days.  
L: Sites must submit the procedure report and the imaging report from each ablation procedure to BrUOG and document 
response. The first ablation should be performed within 1 week (7 days) of the initial treatment with nivolumab to occur 
within the first cycle (14 days) of treatment. Additional ablations may be performed as per institutional standard of care. 
There must be a minimum of 60days between each ablation (preference is 60-90 days). This means that the first ablation 
will occur in cycle 1 (post receiving approximately 1 week of drug) and the sixth cycle 
M: During the same procedural period as ablation, a tumor tissue biopsy may be obtained prior to each ablation for future 
correlative studies such as assessment of PD-L1 by immunohistochemical staining.  
N: Pre-ablation labs to be done within 2 weeks of ablation (prior to). If the counts are done early and would preclude the 
patient from ablation, labs should be repeated on the day of the procedure prior to cancelling.  
o. Optional labs: If patient agrees to optional labs; 3, 6ml purple tops will be taken before and after ablation and then post 
treatment. First set to be taken at baseline pre-nivolumab, second set to be taken cycle 1 pre-ablation and post Nivolumab 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
13 
dosing. Third set to be taken post ablation with the pre cycle 2 nivolumab blood work. Fourth set of tubes to be taken 
approximately 3 months post first ablation and then fifth set to be taken approximately 3 months later, approximately 6 
months after first ablation. If patient undergoes a second ablation, one set (3 purple tops) will be taken prior to ablation 
and one set will be taken post ablation.  
P. Conmeds to be collected at baseline and then each cycle. Conmeds to also include documentation of administration of 
agents/drugs/topicals etc for toxicity management. Final conmed log to be sent with off study (end of treatment) 
materials. 
Q- Physical and visit with treating MD is not required prior to each cycle dosing but may be done. It is required that the 
physical and visit with MD occur every other cycle however (i.e. cycle 1(if PE not within time frames allowed from 
screening visit), 3, 5, 7 etc and at end of study treatment and 30 days.) All other pre-dosing assessments are required prior 
to each cycle. 
 
6.1 Correlative Science 
PD-L1 expression may be assessed by immunohistochemistry as previously described. 12,13 
 
Optional Tumor: If optional tumor tissue is collected at the time of ablation, and stored as per 
routine pathology procedures at Rhode Island Hospital/Lifespan, this may be retrospectively 
analyzed for PDL1 expression.  
 
Optional whole blood: Patients will have the option of providing an additional 10 cc of whole blood 
(3 6ml purple top tubes) to be sent to the laboratory of Dr. Loren Fast at Rhode Island hospital to 
assess the effect of nivolumab and ablation on lymphocyte populations. The blood will be drawn 
at study entry with pre-drug cycle lab work, then before and after each ablation at the times 
specified below.   
 
Correlative studies for immune function 
 
The impact of the encounter with damaged and dying cells on the immune system can range from 
induction of tolerance to enhanced immune responses.  One of the consequences of ablation could 
be enhanced tumor immunity.  To test this possibility, the following correlative studies will be 
done at the following time-points: baseline before nivolumab, after nivolumab/ before first 
ablation, after ablation and prior to cycle 2 nivolumab, approximately 3 months post ablation and 
then approximately 6 months post ablation (approximately 3 months later). If patient has a second 
ablation, a set will be taken before and after ablation.  At each time point 3, 6mL purple top tubes 
will be collected and sent to the laboratory.  Initially the samples will be processed and the 
plasma, microvesicles and cells collected and stored at -80˚C for further studies. These samples 
will be used to study the presence of antigen circulating in the blood, the impact of nivolumab 
and ablation on distribution of subpopulations based on immunophenotyping and functional 
studies to determine if anti-cancer immune responses have been induced by these therapeutic 
interventions and if detected changes correlate with response.  
 
The blood samples when collected should be stored at room temperature, the laboratory notified 
(cc BrUOG on email to Dr. Fast’s laboratory) and the samples transported to the laboratory for 
processing the same day.  Research staff will not be processing samples, staff in Dr. Fast’s 
laboratory will be processing. Samples are to be labeled with study number (BrUOG 317), patient 
initials, patient study number and time point.                                           
 
1. Spin at 1000 rpm and collect platelet rich plasma 
2. The plasma will be process further by spinning at 3000 rpm  
3. The supernatant will then be centrifuged at 100000 x g for 1 hour. 
4. The pellet will be resuspended in PBS containing 1% DMSO and stored at -80˚ C. 
5. The plasma will be collected after the ultracentrifuge step and will be stored at -80˚ C.  

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
14 
6. The pellet will be resuspended in PBS containing 1% DMSO and stored at -80˚C.  
7. Resuspend initial cell pellet in PBS and isolate peripheral blood mononuclear cells 
(PBMNC) using Ficoll-Hypaque gradient density centrifugation 
8. The PBMNC will be frozen down for future studies 
 
7.0 RESPONSE ASSESSMENT: 
7.1. Objective Response Rate by RECIST: Response Evaluation Criteria in Solid Tumors 
(RECIST), version 1.1 will be used to assess responses by CT/ MRI but response criteria are 
modified by the immune-related response criteria as described in section 7.3. The first scheduled 
assessment of tumor response will be performed approximately 12 weeks after the first dose of 
nivolumab and approximately every 12 weeks thereafter. Patients in whom a scheduled scan 
showed initial disease progression will be allowed to continue receiving treatment until a 
confirmatory scan was obtained at least 1 month later. (see section 7.3) 
 
Use of RECIST to clinically assess response for patients who progress with sum of target lesion is 
> 20 % then should use IrRC (if patient is asymptomatic, no vital organ involved etc.) 
 
7.2. Overall responses derived from investigator reported data, with assessment according to 
immune-related response criteria. 
 
7.3          Treatment Beyond Disease Progression 
Accumulating evidence indicated a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease (PD). 
 
Subjects treated with nivolumab will be permitted to continue treatment beyond initial 
RECIST 1.1-defined PD as long as they meet the following criteria: (REQUIRED for site to 
document and confirm all are true and submit to BrUOG) 
 
Investigator-assessed clinical benefit and do not have rapid disease progression 
 
Tolerance of study drug 
 
Stable performance status 
 
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases) 
 
A radiographic assessment/scan should be performed within 6 weeks and at least a 
month after original PD to determine whether there has been a decrease in the tumor 
size or continued PD. The assessment of clinical benefit should be balanced by clinical 
judgment as to whether the subject is clinical deteriorating and unlikely to receive any 
benefit from continued treatment with nivolumab 
 
If the investigator feels that the nivolumab subject continues to achieve clinical benefit 
by continued treatment, the subject should remain on the trial and continue to receive 
monitoring according to the Time and Events Schedule. 
 
 
For the subjects who continue nivolumab study therapy beyond progression, further 
progression is defined as an additional 10% increase in tumor burden volume from 
time of initial PD. This includes an increase in the sum of all target lesions and/or the 
development of new measurable lesions. Treatment should be discontinued permanently 
upon documentation of further disease progression. 
        
 
New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes which must have a short 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
15 
axis of at least 15 mm). Any new lesion considered non-measurable at the time of initial 
progression may become measurable and therefore included in the tumor burden volume 
if the longest diameter increases to at least 10 mm (except for pathological lymph nodes 
which must have a short axis of at least 15 mm). 
 
 
 
Global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at the time should be reported as symptomatic 
deterioration. Every effort should be made to document objective progression (ie, 
radiographic confirmation) even after discontinuation of treatment. 
 
 
 
The assessment of clinical benefit should take into account whether the subject is 
clinically deteriorating and unlikely to receive further benefit from continued treatment. 
All decisions to continue treatment beyond initial progression must be discussed in the study 
records. 
 
7.4 Modified immune-related response criteria (irRC), derived from RECIST 1.1 
This new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. The irRC were created using bidimensional measurements (as previously widely 
used in the World Health Organization criteria). For this trial, the concepts of the irRC are 
combined with RECIST 1.1 to come up with the modified irRC. 
 
For modified irRC, only target and measurable lesions are taken into account. In contrast to the 
RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and 
response by imaging at 12 weeks after initial imaging and (b) do not necessarily score the 
appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions 
(minimum of 10 mm per lesion, maximum of 5 targ et lesions, maximum of 2 per organ) and 
measurable new lesions does not increase by ≥ 20%. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. 
All measurements should be recorded in metric notation. The modified irRC based on RECIST 
1.1 are displayed below. 
 
Modified immune-related response criteria are defined as follows:  
New measurable lesions: Incorporated into tumor burden. 
New non-measurable lesions: Do not define progression but precludes (irCR). 
Overall irCR: Complete disappearance of all lesions (whether measurable or not) and no new 
lesions. All measurable lymph nodes also must have a reduction in short axis to 10 mm. 
 
Overall irPR: Sum of the longest diameters of target and new measurable lesions decreases ≥ 
30%. 
 
Overall irSD: Sum of the longest diameters of target and new measurable lesions neither 
irCR, irPR, (compared to baseline) or irPD (compared to nadir). 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
16 
 
Overall irPD:    Sum of the longest diameters of target and new measurable lesion       
      
increases ≥ 20% (compared to nadir). It is recommended that overall irPD be confirmed by a 
follow-up CT at least 4- 1 2  from the date first documented. 
 
Overall responses derived from changes in index, non-index, and new lesions are summarized in 
the table below. 
 
Overall Responses Derived from Changes in Index, Non-Index, and New Lesions 
Measurable Response 
Non-Measurable Response 
Overall Response Using 
Modified irRC 
Index and New, 
Measurable Lesions 
1
Non-Index Lesions 
New, Non- 
Measurable Lesions 
Decrease 100% 
Absent 
Absent 
irCR2 
Decrease 100% 
Stable 
Any 
irPR2 
Decrease 100% 
Unequivocal progression 
Any 
irPR2 
 
 
Decrease ≥ 30% 
Absent / Stable 
Any 
irPR2 
Decrease ≥ 30% 
Unequivocal progression 
Any 
irPR2 
Decrease < 30% to 
increase < 20% 
Absent / Stable 
Any 
irSD 
Decrease < 30% to 
increase < 20% 
Unequivocal progression 
Any 
irSD 
Increase ≥ 20% 
Any 
Any 
irPD 
 
1 Decreases assessed relative to baseline 
2 Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a second, 
consecutive assessment at least 4 weeks apart (normally it should be done 6 weeks apart). 
 
Post Ablation changes observed on radiographic studies that are larger in size than preablation 
masses will not be considered tumor progression if no enhancement within the lesion that suggests 
tumor growth.  
 
8.0 
PATIENT REGISTRATION  
All patients will be registered through the Brown University Oncology Research Group Central 
Office. Eligibility Checklist with supporting documentation, On Study Form and the signed 
Patient Consent Form must be faxed to the BrUOG Central Office, Fax: (401) 863-3820, at the 
time of registration and prior to patient treatment. 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
17 
Details of patient’s study participation should be documented in clinic/file notes. The Brown 
University Oncology Research Group will provide case report forms, for the recording and 
collection of data. In the event of corrections, each correction will be initialed and dated by the 
person making the correction. The investigator will sign the case reports to indicate that, to 
his/her knowledge, they are complete and accurate. Case report forms, flow sheets, off-study 
forms and follow-up forms should be mailed / faxed to:   
 
 
 
 
 
 
Kayla Rosati 
Director, BrUOG 
Brown University Oncology Research Group, 
Brown University 
Box G-R 001 
Providence, RI 02912 
Fax: 401-863-3820 
Phone: 401-863-3000 
 
All support data must be sent in with the corresponding BrUOG forms. It is the treating 
physician’s responsibility to review all data submitted to the BrUOG Central Office for accuracy 
and completeness and he/she must sign the off study form.  Sites are to be sure that elements to 
support all inclusion and exclusion criteria are submitted and that all assessments from the 
schedule of evaluations (section 6) are submitted for registration. 
 
9.0  
PHARMACEUTICAL INFORMATION OF NIVOLUMAB 
 
Only commercially available nivolumab (OPDIVO) will be utilized.  
 
Nivolumab will be stored and administered according to the package insert and institutional 
standard of care.  
 
Preparation and Administration 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard the 
vial if the solution is cloudy, is discolored, or contains extraneous particulate matter other than a 
few translucent-to-white, proteinaceous particles. Do not shake the vial. 
Preparation 
 
Withdraw the required volume of OPDIVO and transfer into an intravenous container. 
 
Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP, to prepare an infusion with a final concentration ranging from 1 mg/mL 
to 10 mg/mL.   
 
Mix diluted solution by gentle inversion. Do not shake.   
 
Discard partially used vials or empty vials of OPDIVO.   
Storage of Infusion 
     The product does not contain a preservative. 
After preparation, store the OPDIVO infusion either: 
 
at room temperature for no more than 4 hours from the time of preparation. 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
18 
This includes room temperature storage of the infusion in the IV container and 
time for administration of the infusion or 
 
under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours from the 
time of infusion preparation. 
Do not freeze. 
Administration 
Administer the infusion over approximately 60 minutes through an intravenous line 
containing a sterile, non- pyrogenic, low protein binding in-line filter (pore size of 0.2 
micrometer to 1.2 micrometer).   
Do not co-administer other drugs through the same intravenous line.   
Flush the intravenous line at end of infusion.   
 
DOSAGE FORMS AND STRENGTHS 
Injection: 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL) solution in a single-use vial. 
 
Dosage: Subjects will be treated with 3mg/kg up to a maximum dose of 240mg  of nivolumab 
as an approximate 60 minute IV infusion every 2 weeks.  
 
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of adverse events 
associated with immuno-oncology agents may mitigate severe toxicity. Immune Toxicities may 
include: 
 
 
Pulmonary (pneumonitis) 
 
Gastrointestinal (colitis with diarrhea) 
 
Endocrinopathies (including inflammation of the thyroid, adrenal and pituitary) 
 
Hepatic (hepatitis) 
 
Renal (nephritis) 
 
Skin (rash) 
 
Neurological (neuritis) 
 
 
10.0 
AGENT ACCOUNTABILITY 
Commercial nivolumab will be used in this trial, therefore there will be no drug accountability.  
 
11.0 ADVERSE DRUG REACTION (ADR) REPORTING 
BrUOG considers the SAE reporting period to begin when the subject signs the study specific 
informed consent. 
 
This study will utilize the descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4 for grading all adverse events. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4. A copy of the 
CTCAE version 4 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have to 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
19 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of Abraxane whether or not considered related to Abraxane. This includes 
any newly occurring event or previous condition that has increased in severity or frequency since 
the administration of drug. 
 
During clinical trials, 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 adverse events.) 
 
Adverse events (AEs) will be recorded in the case report form for the duration of the trial, 
regardless of whether or not the event(s) are considered related to trial medication. All AEs 
considered related to trial medication will be followed until resolution even if this occurs post-
trial. 
 
11.1 Definitions 
An adverse event is any new, undesirable medical experience or change of an existing condition 
that occurs during or after treatment, whether or not considered product-related. 
 
Serious adverse event (SAE) 
An adverse event occurring at any dose that results in any of the following outcomes (CFR 
312.32): 
 
death 
 
a life-threatening adverse drug experience 
 
inpatient hospitalization or prolongation of existing hospitalization excluding  those for study 
drug administration, transfusional support, disease staging/re-staging procedures, 
concomitant radiotherapy, thoracentesis / paracentesis, or placement of an indwelling 
catheter, unless associated with other serious events. 
 
persistent or significant disability or incapacity, 
 
congenital anomaly / birth defect.  
 
The definition of serious adverse event (experience) also includes important medical event. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse. A new diagnosis 
of cancer during the course of treatment should be considered an important medical event. 
 
The definition of “related” being that there is a reasonable possibility that the drug caused the 
adverse experience. 
 
Unexpected adverse event 
An adverse event that is not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the investigator's brochure or package 
insert. 
 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
20 
Life-threatening 
Any adverse drug experience that places the patient or subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred.  It does not include a reaction that, had it 
occurred in a more severe form, might have caused death. 
 
11.2 Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, and deaths that occur during the patient’s study 
participation will be recorded in the source documents.  All SAEs should be monitored until they 
are resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es). 
 
11.3 BRUOG ADVERSE EVENT REPORTING REQUIREMENTS  
Investigators are required by Federal Regulation to report adverse drug reactions. Question 
regarding drugs as used in this study should be directed to the Brown University Oncology 
Research Group (BrUOG) Central Office, Phone: (401) 863-3000 Fax (401) 863-3820, which 
will in turn notify the Principal Investigator. 
 
Intensity for each adverse event will be scored using CTCAE Version 4.  A copy of the CTCAE 
Version 4 can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  All 
appropriate treatment areas have access to a copy of the CTCAE Version 4.  All adverse clinical 
experiences, whether observed by the investigator or reported by the patient, must be recorded, 
with details about the duration and intensity of each episode, the action taken with respect to the 
test drug, and the patient’s outcome.  The investigator must evaluate each adverse experience for 
its relationship to the test drug and for its seriousness. 
 
AEs and SAEs will be captured and reported from when the patient signs consent to 4 weeks post 
last dose of drug or until the subject withdraws consent from study participation (declines 
participation) or at the time patient becomes a screen failure, whichever occurs first.  
 
11.3.1 Pregnancies 
Pregnancies occurring while the subject is on study drug or within 4 weeks after the subject’s last 
dose of study drug are considered expedited reportable events.  If the subject is on study drug the 
study drug is to be discontinued immediately.  The pregnancy must be reported by the Brown 
University Oncology Research Group within 24 hours of the Investigator’s knowledge of the 
pregnancy by phone and facsimile using the SAE Form. 
 
The Investigator will follow the subject until completion of the pregnancy, and must notify 
BrUOG of the outcome as specified below.  The Investigator will provide this information as a 
follow-up to the initial SAE. If the outcome of the pregnancy meets the criteria for immediate 
classification as a SAE (i.e., spontaneous abortion [any congenital anomaly detected in an aborted 
fetus is to be documented], stillbirth, neonatal death, or congenital anomaly), the Investigator 
should follow the procedures for reporting SAEs (i.e., report the event to BrUOG by facsimile 
within 24 hours of the Investigator’s knowledge of the event). 
 
Any suspected fetal exposure to Nivolumab must be reported to BrUOG within 24 hours of being 
made aware of the event.  The patient should be referred to an obstetrician/gynecologist 
experienced in reproductive toxicity for further evaluation and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator suspects to be 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
21 
related to the in utero exposure to the study drug should also be reported. In the case of a live 
“normal” birth, BrUOG should be advised as soon as the information is available. 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. 
 
11.3.2 Serious Adverse Event Reporting Procedures  
All SAEs and pregnancy reports must be reported to the Brown University Oncology Research 
Group to align with 24 hour notification. For pregnancy reporting time frames see section 11.3.1.  
 
All other initial SAE information and all amendments or additions must be recorded on a 
MedWatch 3500A SAE form and be faxed or emailed to BrUOG within 5 business days of being 
made aware of the event. If the SAE is a death thought to be related to the study drug or ablation, 
deaths must be reported to BrUOG within 24 hours/1 business day of the investigator being made 
aware of the event. 
 
BrUOG fax: 401-863-3820 Email: Kayla_Rosati@brown.edu 
Kristen_Mitchell@brown.edu 
 
The treating investigator has the obligation to report all serious adverse events to the Brown 
University Oncology Research Group’s (BrUOG) office who in return will report to the FDA, 
and all sites participating in the trial.   
 
Expedited Reporting by Investigator to BrUOG 
Serious adverse events (SAE) are defined above.  All events must be reported, by FAX or email 
to the Brown University Oncology Research Group.  The initial report must be as complete as 
possible, including an assessment of the causal relationship between the event and the 
investigational product(s), if available.  Information not available at the time of the initial report 
(e.g., an end date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.  A final report to document discharge is required.   
This includes serious, related, labeled (expected) and serious, related, unlabeled (unexpected) 
adverse experiences. All deaths during treatment or within 30 days following completion of 
active protocol therapy (drug or ablation) must be reported within 5 business days of when the 
investigator is made aware of the event or as soon as the investigator is made aware of the event. 
Deaths that are thought to be related to drug are to be reported to BrUOG in 24 hours/1 business 
day of being made aware of the event. SAEs occurring within 30 days following completion of 
active protocol therapy (drug or ablation) will be captured even if patient begins a new treatment. 
AE evaluation will stop once patient begins a new treatment. 
All adverse events and special reporting situations, whether serious or non-serious, related or 
unrelated, will be reported from the time a signed and dated ICF is obtained until 30 days after 
the last dose of nivolumab or ablation (whichever is last), or until the subject withdraws consent 
from study participation (declines participation) or at the time patient becomes a screen failure, 
whichever occurs first. 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the study drug (or therapy/ablation) is suspected.  
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
22 
11.4 Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that treatment caused 
or contributed to an adverse event.  The following general guidance may be used. 
 
Yes: if the temporal relationship of the clinical event to treatment administration makes a  
causal relationship possible, and other drugs, therapeutic interventions or underlying conditions 
do not provide a sufficient explanation for the observed event. 
 
No: if the temporal relationship of the clinical event to treatment administration makes a  
causal relationship unlikely, or other drugs, therapeutic interventions or underlying conditions 
provide a sufficient explanation for the observed event. 
 
11.5 Types of Report: 
Telephone report:  For SAE’s contact BrUOG Central Office at (401) 863-3000 within 24 hours 
upon learning of the event for notification and prior to submitting the SAE report.   
 
Written report: Send the copy of the Medwatch 3500A within 5 business days of being made 
aware of the event to the BrUOG Central Office by email, scan or Fax: 
 
Brown University Oncology Research Group 
Phone: (401) 863-3000, Fax: (401) 863-3820 
Email: Kayla_rosati@brown.edu, Kristen_Mitchell@brown.edu 
 
All deaths during treatment or within 30 days following completion of active protocol therapy 
(last dose of drug or ablation) must be reported within 5 business days of being made aware of the 
event or as soon as the investigator is made aware of the event. If the death is thought to be 
related to the study drug or ablation, deaths must be reported to BrUOG within 24 hours/1 
business day of the investigator being made aware of the event. For pregnancies please refer to 
prior section. 
 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of 
the MedWatch 3500A form: 
 
Treatment regimen (dosing frequency, combination therapy) 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome, if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Must type SAEs 
 
Follow-up information:  *Follow-up SAEs are required to document patient discharge or 
resolution of SAE event* 
Additional Info maybe added to a previously submitted report by any of the following methods. 
 
Adding to the original MedWatch 3500A and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
23 
Summarizing new information and faxing it with a cover letter including subject identifiers (i.e. 
D.O.B. initial, subject number), protocol description and number, if assigned, suspect drug, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted  (The subject identifiers are important so that the new information is added to the 
correct initial report). 
 
11.6 BrUOG Responsibility Regarding Reporting:  
The BrUOG Central Office will notify by phone and/or fax all drug reaction reports to the FDA, 
the Principal Investigator, and the participating sites (who will in turn notify their local IRBs) as 
soon as possible but no later than 7 calendar days after the initial receipt of the information. A 
copy of the form will be kept by the BrUOG Central Office.   
 
 
 
Fax: 1-800-FDA-0178 (1-800-332-0178) For IND exempt study or for IND study the 
SAE will be sent to FDA Division fax line that has responsibility for review of IND) 
 
Mail: For IND studies BrUOG will send the SAE as an amendment to the IND as 
well 
 
11.7 Safety Reporting for IND Holders 
In accordance with 21 CFR 212.32, Sponsor-Investigator of the study conducted under an IND 
must comply with following safety-reporting requirements:  
 
a. Expedited IND Safety Reports: 
7 Day calendar Telephone or Fax Report:   
The Sponsor-Investigator is required to notify the FDA of any event that is serious, 
unlisted/unexpected and assessed by the investigator to be possibly related to the use of study 
drug(s).  An unexpected adverse event is one that is not already described in the Investigator 
Brochure.  Such reports are to be telephoned or faxed to the FDA as soon as possible but no later 
than 7 calendar days of first learning of the event.  Each telephone call or fax transmission (see 
fax number below) should be directed to the appropriate FDA fax number.  
 
Sites are required to submit MedWatch3500A reports no later than 5 business days after being 
informed of an event. 
 
12.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
Extraordinary medical circumstances or withdrawal of consent by the patient: If, at any time, the 
constraints of this protocol are detrimental to the patient's health, and/or the patient no longer wishes 
to continue protocol therapy, the patient shall be withdrawn from protocol therapy.  Patients will also 
be withdrawn from study for the following reasons: 
Disease Progression: Any patient with disease progression should be removed from study.  
Details and tumor measurements should be documented on flow sheets. See section 7 
regarding defining progression on study. 
1. Patient is unable to tolerate the toxicity resulting from the study treatment, even with 
optimal supportive care, in the opinion of the Treating Physician. Adverse event(s) that, in the 
judgment of the investigator, may cause severe or permanent harm or which rule out 
continuation of study drug.  
2. The physician feels it is in the best interest of the patient to stop the treatment. 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
24 
3. Inter current illness that would, in the judgment of the Investigator, affect assessment of 
clinical status to a significant degree or require discontinuation of study treatment 
4. Non protocol chemotherapy or immunotherapy is administered during the study 
5. Noncompliance with protocol or treatment—major violation 
6. Suspected Pregnancy 
7. Patient is lost to follow-up 
8. Patient refuses to continue treatment (patient will continue to be followed for disease-free 
survival and overall survival) 
9. Death 
In this event notify: 
Brown University Oncology Research Group (BrUOG) Central Office, 
Phone:  (401) 863-3000 
Fax:  (401) 860-3820 
The BrUOG Central Office will in turn notify the Principal Investigator. 
*Document the reason(s) for withdrawal on flow sheets.  Follow the patient for five years 
with follow-up forms as dictated by the protocol 
 
13.0 FOLLOW-UP  
All Subjects that discontinue treatment early for any reason as well as patients who complete 
therapy will be followed for five years. At treatment discontinuation, subjects will undergo 
adverse event evaluation and again approximately 30 days post the last dose of study drug. In 
addition off study evaluations will be done when treatment is discontinued -Section 6.0. 
 
14.0 REGULATORY CONSIDERATIONS 
This research study is sponsored by the Principal Investigator, Dr. Howard Safran, in 
collaboration with Brown University Oncology Research Group (BrUOG), which will serve as 
the central coordinating office for the study.  
 
14.1 Protection of Human Subjects 
The Investigator must ensure that patients or their legally acceptable representatives are clearly 
and fully informed about the purpose, potential risks and other critical issues regarding clinical 
trials in which they volunteer to participate.  Preparation of the consent form is the responsibility 
of the Investigator and must include all elements required by CFR 21 Part 50.25 and the local 
IRB. 
 
14.2 Compliance with the Protocol and Protocol Revisions: 
The study must be conducted as described in this approved protocol.   
All revisions to the protocol must be provided to Brown University Oncology Research Group.  
The Investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion from the IRB/IEC of an Amendment, except 
where necessary to eliminate an immediate hazard(s) to study patients. 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to Brown University Oncology Research Group.  If the revision is an Administrative Letter, 
Investigators must inform their IRB(s)/IEC(s).  
The Investigator must ensure that patients or their legally acceptable representatives are clearly 
and fully informed about the purpose, potential risks and other critical issues regarding clinical 
trials in which they volunteer to participate.  Preparation of the consent form is the responsibility 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
25 
of the Investigator and must include all elements required by CFR 21 Part 50.25 and the local 
IRB. 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative prior to study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent will comply 
with ICH-GCP and all applicable regulatory requirement(s). 
14.3 Protocol amendments or changes in study conduct:  
 
Any change or addition (excluding administrative) to this protocol requires a written 
protocol amendment that must be reviewed and approved by Brown University Oncology 
Research Group, and the investigator before implementation. Amendments significantly 
affecting the safety of subjects, the scope of the investigation or the scientific quality of 
the study require additional approval by the IRB at each study center.  A copy of the 
written approval of the IRB must be provided to Brown University Oncology Research 
Group 
Examples of amendments requiring such approval  
 
Increases in drug dose or duration of exposure of subjects 
 
Significant changes in the study design (e.g. addition or deletion of a control group) 
 
Increases in the number of invasive procedures 
 
Addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Brown University Oncology Research Group in the interests of 
preserving the safety of all patients included in the trial.  If an immediate change to the protocol is 
felt to be necessary by the investigator and is implemented for safety reasons Brown University 
Oncology Research Group must be notified and the IRB at the center must be informed 
immediately. Amendments affecting only administrative aspects of the study do not require 
formal protocol amendments or IRB approval but the IRB must be kept informed of such 
administrative changes.  
15.0 DATA MONITORING / QUALITY ASSURANCE/ RECORD RETENTION 
15.1 Good Clinical Practice: The study will be conducted in accordance with the International 
Conference on Harmonisation (ICH) for Good Clinical Practice (GCP) and in the US Code of 
Federal Regulations.  The investigator will be thoroughly familiar with the appropriate use of the 
drug as described in the protocol.  Essential clinical documents will be maintained to demonstrate 
the validity of the study and the integrity of the data collected.  Master files should be established 
at the beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations.   
 
15.2 Patient Confidentiality: In order to maintain patient privacy, all data capture records, drug 
accountability records, study reports and communications will identify the patient by initials and 
the assigned patient number.  The investigator will grant monitor(s) and auditor(s) from BrUOG 
or its designees and regulatory authority (ies) access to the patient’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection process.  
The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
 
15.3 Protocol Compliance: The investigator will conduct the study in compliance with the 
protocol given approval/favorable opinion by the IRB/IEC and the appropriate regulatory 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
26 
authority(ies).  Changes to the protocol will require approval from BrUOG and written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory 
authority(ies) permit, expedited review and approval/favorable opinion for minor change(s) in 
ongoing studies that have the approval /favorable opinion of the IRB/IEC.  The investigator will 
submit all protocol modifications to BrUOG and the regulatory authority(ies) in accordance with 
the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.   
 
15.4 On-site Audits: Regulatory authorities, the IEC/IRB and/or BrUOG clinical quality 
assurance group may request access to all source documents, data capture records, and other 
study documentation for on-site audit or inspection.  Direct access to these documents must be 
guaranteed by the investigator, who must provide support at all times for these activities. 
 
15.5 Drug Accountability: Accountability for the drug at all study sites is the responsibility of 
the principal investigator.  The investigator will ensure that the drug is used only in accordance 
with this protocol.  Drug accountability records indicating the drug’s delivery date to the site (if 
applicable), inventory at the site (if applicable), use by each patient will be maintained by the 
clinical site.  Accountability records will include dates, and patient numbers.   
 
15.6 Premature Closure of the Study: This study may be prematurely terminated, if in the 
opinion of the investigator or BrUOG, there is sufficient reasonable cause.  Written notification 
documenting the reason for study termination will be provided to the investigator by the 
terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to patients 
 
Failure to enter patients at an acceptable rate 
 
Insufficient adherence to protocol requirements 
 
Insufficient complete and/or evaluable data 
 
Plans to modify, suspend or discontinue the development of the drug 
 
15.7 Record Retention:  
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
The Brown University Oncology Research Group, as coordinator of this study, is responsible for 
ensuring proper conduct of the study with regard to protocol adherence and the validity of the 
data recorded on the case report forms. The Principal Investigator (Howard Safran, M.D.) and 
Brown University Oncology Research Group Director of Operations (Kayla Rosati) will monitor 
this study. The case report forms will be monitored for accuracy, completeness, adherence to the 
protocol and regulatory compliance.  
U.S. FDA regulations (21CFR312.62[c] require all records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consents 
forms, laboratory test results and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these 
records must be kept 2 years after the investigation is discontinued and the FDA and the 
applicable local health authorities are notified.  
 
16.0 DATA SAFETY AND MONITORING BOARDS 
All trials initiated by the Brown University Oncology Research Group (BrUOG) are subject to 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
27 
oversight by the Data Safety Monitoring Board (DSMB).  This board meets two times per year 
with any additional meetings scheduled when needed.  The responsibilities are as follows: 
 
Familiarize themselves with the research protocol (s)  
 
The DSMB reviews trial performance information such as accrual information.   
 
Review interim analyses of outcome data and cumulative toxicity data summaries to 
determine whether the trial should continue as originally designed, should be changed, or 
should be terminated based on these data.   
 
The DSMB also determines whether and to whom outcome results should be released 
prior to the reporting of study results. 
 
All adverse events are reviewed by the committee, with assurances that these have been 
in fact sent for review to all pertinent IRBs. 
 
Review of reports of related studies to determine whether the monitored study needs to be 
changed or terminated. 
 
Review major proposed modifications to the study prior to their implementation (e.g., 
termination, dropping an arm based on toxicity results or other reported trial outcomes, 
increasing target sample size). 
 
Following each DSMB meeting, provide the study leadership with written information 
concerning findings for the trial as a whole related to cumulative toxicities observed and 
any relevant recommendations related to continuing, changing, or terminating the trial.  
 
The study leadership will provide information on cumulative toxicities and relevant 
recommendations to the local principal investigators to be shared with their IRB’s. 
 
 
17.0 STATISTICS 
The primary goal will be to determine the response rate of the combination of nivolumab and 
ablation. 
17.1 Statistical Methods: 
Let ‘p’ be the probability of response to treatment 
           Null hypothesis              H0:p=p0 
          Alternate hypothesis       H1:p>=p1 
  
This study is a phase II non-randomized clinical trial. The primary endpoint of this trial is to 
determine the response rate for patients with metastatic non-small cell lung cancer treated with a 
combination of nivolumab and ablation, in the second line setting. Historically, the response rate 
of nivolumab alone in this setting has been about 20%. 
  
Simon's minimax two-stage design (Simon, 1989) will be used. The null hypothesis that the true 
response rate is 20% will be tested against a one-sided alternative. In the first stage, 18 patients will 
be accrued. If there are 4 or fewer responses in these 18 patients, the study will be stopped early 
for futility. If at least 5 responses are obtained, additional patients will be accrued for a total of 33. 
The null hypothesis will be rejected if 11 or more responses are observed in 33 patients. This design 
yields a type I error rate of 0.05 and power of 80% when the true response rate is 40%. 
  
17.2 Assessment of disease-free and overall survival 
Disease-free and overall survival will be assessed from the day of study entry. 
 
17.3 Laboratory Correlative Studies:  
Fisher's exact test will be used to assess the association between PD-L1 expression and objective 
response. 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
28 
 
18.0 References: 
1.Brambilla E, Travis WD. Lung cancer. In: World Cancer Report, Stewart BW, Wild CP (Eds), 
World Health Organization, Lyon 2014. 
2. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014:64:9. 
3. Sandler A, Gray R, Perry MC, et al. Paclitaxel–Carboplatin Alone or with Bevacizumab for 
Non–Small-Cell Lung Cancer. N Engl J Med2006; 355:2542-2550 
4. Fossella F, Pereira JR, Pawel V et al. Randomized, multinational, phase III study of docetaxel 
plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small cell lung 
cancer: The TAX 326 Study Group. J Clin Oncol 21:3016-3024, 2003 
5. Scagliotti GV, De Marinis F, Rinaldi M, et al,  Phase III randomized trial comparing three 
platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 20:4285-4291, 
2002. 
6. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus 
docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy J Clin 
Oncol 2004:22-1589-1597.  
7. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus  
best supportive care in patients with non-small-cell lung cancer previously treated with platinum 
based chemotherapy J Clin Oncol 2000: 18:2095-2103 
8. Brahmer JA. Harnessing the Immune System for the Treatment of Non–Small-Cell Lung 
Cancer J Clin Oncol 31:1021-1028, 2013 
9. Fife BT and Pauken KE. The Role of the PD-1 Pathway in Autoimmunity and Peripheral 
Tolerance. Ann NY Acad Sci 2011; 1217: 45-59. 
10. Riley JL. PD-1 Signaling in primary T cells. Immunological Reviews 2009; 229: 114-25. 
11. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L1 is a 
second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2(3): 261-68. 
12. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-
1 antibody in cancer. N Engl J Med 366:2443-2454, 2012 
13. Brahmer JR, Horn L, Antonia S, et al: Clinical activity and safety of anti-PD1 (BMS-936558, 
MDX- 1106) in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 
30:482s, 2012 (suppl; abstr 7509). 
14. Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial 
therapy in patients with advanced non-small cell lung cancer. J Clin Oncol (suppl 15s):32, abstr 
8007, 2014. 
15. Image-Guided Cancer Therapy: A Multidisciplinary Approach Damian E. Dupuy, Yuman 
Fong and William N. McMullen (eds) Springer Verlag NYC, 2013 
16. Dupuy DE, Schirmang TC. Image-Guided Thermal Ablation of Nonresectable Hepatic 
Tumors Using the Cool-Tip Radiofrequency Ablation System. Expert Review of Medical 
Devices 2007; 4:803-814. 
 17. Mctaggart RA, Dupuy DE, DiPetrillo T. Image Guided Ablation in the Thorax in 
Interventional Oncology Principles and Practice. Geschwind JH, Soulen MC (eds). Cambridge 
Press New York 2008 
18 Healey TT, Dupuy DE. Radiofrequency ablation: a safe and effective treatment in 
nonoperative patients with early-stage lung cancer.  Cancer J. 2011 Jan-Feb; 
17(1):33-7. 
19. Dupuy DE, Schirmang TC. Image-Guided Thermal Ablation of Nonresectable Hepatic Tumors 
Using the Cool-Tip Radiofrequency Ablation System. Expert Review of Medical Devices 2007; 
4:803-814. 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
29 
20. Dupuy DE, Liu D, Hartfeil D, Hanna L, Blume JD, Ahrar K, Lopez R, Safran H, DiPetrillo T. 
Percutaneous radiofrequency ablation of painful osseous metastases: a multicenter American 
College of Radiology Imaging Network trial. Cancer 2010; 116:989-997. 
 
21. Chu, Katrina F., and Damian E. Dupuy. "Thermal ablation of tumours: biological mechanisms 
and advances in therapy." Nature Reviews Cancer 14.3 (2014): 199-208. 
22. Hoffmann, N. E. & Bischof, J. C. The cryobiology of cryosurgical injury. Urology 60, 40–49 
(2002). 
23. Jansen, M. C. et al. Cryoablation induces greater inflammatory and coagulative responses than 
radiofrequency ablation or laser induced thermotherapy in a rat liver model. Surgery 147, 686–695 
(2010). 
24. Erinjeri, J. P. et al. Image-guided thermal ablation of tumors increases the plasma level of 
Interleukin-6 and Interleukin-10. J. Vasc. Interv. Radiol. 24, 1105–1112 (2013). 
25. Chapman, W. C. et al. Hepatic cryoablation, but not radiofrequency ablation, results in lung 
inflammation. Ann. Surg. 231, 752–761 (2000). 
26. Gazzaniga, S. et al. Inflammatory changes after cryosurgery-induced necrosis in human 
melanoma xenografted in nude mice. J. Invest. Dermatol. 116, 664–671 (2001). 
27. Sabel, M. S. et al. Immunologic response to cryoablation of breast cancer. Breast Cancer Res. 
Treat. 90, 97–104 (2005). 
28. Erinjeri JP, Thomas CT, Samoila A, et al. Image guided thermal ablation of tumors increases 
the plasma level of IL-6 and IL-10. J Vasc Interv Radiol. 2013 Aug; 24(8): 1105–1112. 
29. Takaki H, Thomas CT, Srimathveeravalli G, et al.  Heat-based ablation increases the 
proportions of circulating Th1 and cytotoxic lymphocytes more than cryoablation  Society of 
Interventional Radiology, March 2015. 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
30 
APPENDIX A  
 
Agreement to Participate in a Research Study and Authorization for Use and Disclosure of 
Information 
 
BrUOG 317: Nivolumab and Ablation For Patients With Advanced Non- 
Small Cell Lung Cancer (NSCLC) Progressing After at Least One Prior Therapy For 
Metastatic Disease: 
A Brown University Oncology Research Group Phase II Study 
 
You are being asked to take part in a research study.  All research studies at <INSERT 
HOSPITAL NAME> hospitals follow the rules of the state of <INSERT STATE>, the United 
States government and <INSERT HOSPITAL NAME>.  Before you decide whether to be in the 
study, you and the researcher will engage in the “informed consent” process.   During this 
process, the researcher will explain the purpose of the study, how it will be carried out, and what 
you will be expected to do if you participate.  The researcher will also explain the possible risks 
and benefits of being in the study, and will provide other information.  You should feel free to ask 
any questions you might have.  The purpose of these discussions is for you to decide whether 
participating in the study is the best decision for you. 
 
If you decide to be in the study, you will be asked to sign and date this form in front of the person 
who explained the study to you.  This form summarizes the information you discussed.  You will 
be given a copy of this form to keep.   
 
Nature and Purpose of the Study      
 
Your doctors are participating in this research study sponsored by the Principal Investigator 
Howard Safran MD, which is coordinated by the Brown University Oncology Research Group 
(BrUOG). 
 
You are being asked to participate in this study because you have advanced non-small cell lung 
cancer. You have already received chemotherapy but your cancer has grown or spread despite 
this chemotherapy. The purpose of this study is to study the effects, good and bad, of treating one 
of your cancer tumors with a procedure called ablation to see if this will improve your response to 
a recently approved treatment for advanced lung cancer called nivolumab.   
 
Nivolumab is an antibody (a type of human protein) that can stimulate your immune system to 
fight your lung cancer. Nivolumab is FDA approved to treat squamous non-small cell lung 
cancer.   
Ablation is an FDA approved procedure to treat one or two cancer tumors in patients with limited 
advanced lung cancer,  in which a radiologist tries to destroy a tumor by freezing it (cryoablation) 
or heating it (thermal ablation). The radiologist will place needles into the tumor to transmit cold, 
to freeze the tumor, or heat to burn the tumor.   
 
Your doctor has suggested that you undergo ablation to treat a tumor that is causing pain or other 
symptoms. Ablation by itself would not be expected to extend life in patients like you with more 
extensive lung cancer. You and your doctor will discuss whether freezing the tumor 
(cryoablation) or heating the tumor (thermal ablation) is better for you. We are studying if 
ablation, the freezing or heating of a tumor, may make nivolumab more effective helping your 
immune system recognize other cancer cells and tumors as being abnormal.   
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
31 
We expect to enroll 33 subjects into this study and X number of patients at <INSERT 
HOSPITAL NAME> hospital. The study is sponsored by the Principal Investigator Howard 
Safran, MD and it is being coordinated by the Brown University Oncology Research Group.  
 
Explanation of Procedures   
What will happen if I take part in this research study? If you take part in this study, you will 
have exams, tests and procedures to show that you can be in the study. They are part of regular 
cancer care.  
 
Screening: 
 
Medical history prior to starting treatment. 
 
Physical examination, with performance status and toxicity assessment, weight and vitals  
 
Blood tests (approximately 3 tablespoons of blood). If you are a female of childbearing age 
you will also have a pregnancy test within 7 days of study entry 
 
CT scan of the chest, abdomen and pelvis within 6 weeks prior to study entry 
 
CT or Brain MRI within 6 weeks prior to study entry  
 
EKG prior to study entry, within 8 weeks 
 
While on study:  
A cycle of treatment is considered 2 weeks. You will have the following approximately every 2 
weeks or as otherwise noted below: 
 
Performance status and toxicity assessment, weight and vitals prior to each cycle. Physical 
exam is required prior to every other cycle, but it may be done more frequently if the treating 
investigator feels it is in your best interest. 
 
Blood tests (approximately 3 tablespoons of blood) prior to each cycle  
 
CT scan of the chest, abdomen and pelvis approximately every 12 weeks (6 cycles) 
 
CT or Brain MRI as needed 
 
You will receive Nivolumab through an IV (in your vein) over 1 hour in the outpatient 
chemotherapy clinic approximately every 2 weeks, as long as your cancer tumors do not grow or 
the cancer spreads to new areas of your body, for up to 2 years. Even if you are found to have 
progressive disease (your cancer has grown or spread), your doctor will evaluate you to see if 
there may be potential benefit to keeping you on the study drug. This will be discussed with you 
when necessary.  
 
Ablation is performed as an outpatient in the department of radiology with both intravenous 
sedation and local anesthesia. The procedure takes approximately 60-90 minutes. Using CT 
guidance, a needle will be placed into one of your tumor masses. Your doctors will discuss with 
you which tumor mass in your body will undergo ablation. Ablation of a tumor mass can be 
performed in the lung, liver, lymph nodes, bone, and other organs.  
 
The ablation may be performed within 7 days after the first treatment with nivolumab. Additional 
ablation procedures may be suggested by your doctors as part of standard treatment for your 
cancer if your doctors think additional ablation procedures may be of help such as to treat or 
prevent pain, bleeding or blockage of an organ. Each ablation must be separated by at least 60 
days.  
 
Optional Tumor Biopsy at Time of Ablation: 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
32 
If you agree, during the ablation procedure, a small piece of the tumor being ablated will be taken 
to test the cancer cells for a protein call PD-L1, which is the target for nivolumab.  These biopsies 
are optional and you will be given the chance to make your choice at the end of this document. 
The biopsy is performed under CT or ultrasound guidance using the same intravenous sedation 
and local anesthesia you receive for the ablation. The biopsy needle is smaller than the ablation 
needle. 
 
Optional Blood: 
 
You will be asked to choose if you would allow additional blood to be taken for research 
purposes. If you agree, an additional 1-2 tablespoons of blood will be taken with your screening 
blood tests before study entry and before and after ablation. Additional blood will also be taken at 
approximately 3 and 6 months post the first ablation. The blood will be sent to the research 
laboratory of Dr. Loren Fast at Rhode Island Hospital who will be researching how nivolumab 
and ablation affect your white blood cells.  
 
Off study/Follow-up: 
When you stop taking the study drug you are considered “off study” and you will then move into 
the follow-up portion of this trial. You will have the following exams done: 
 
Off study: 
 
Physical examination, with performance status and toxicity assessment (and again 30 days 
post the last dose of drug) 
 
Blood tests (approximately 3 tablespoons of blood)  
 
CT scan of the chest, abdomen and pelvis if one has not been done in the prior 2 months 
 
CT or Brain MRI as needed 
 
Follow-up: 
 
CT scan of the chest, abdomen and pelvis approximately every 3 months until your disease 
progresses 
 
CT or Brain MRI as needed 
 
All patients will be followed approximately every 3 months for disease status and overall survival 
information, for up to 5 years. 
 
How long will I be in the study?  
You will receive nivolumab until your cancer starts to grow or spread for up to 2 years. An 
average time people will be in the study will be 6-24 months. All patients will be followed 
approximately every 3 months after completing or being taken off of the study treatment for up to 
5 years. 
 
Can I stop being in the study?  
Yes. You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping 
or decide to stop.  He or she will tell you how to stop safely.   
It is important to tell the study your doctor can evaluate doctor if you are thinking about stopping 
so any risks from the discontinuation of treatment can be discussed.  Another reason to tell your 
doctor that you are thinking about stopping is to discuss what follow-up care and testing could be 
most helpful for you.  
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped.  

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
33 
 
 
Costs for participating in this study  
Taking part in this study may lead to added costs to you or your insurance company. Please ask 
about any expected added costs or insurance problems regarding the costs of treating your cancer 
during this study. 
Some of the services you will receive are being performed only because you are participating in 
this research study. Examples of these ‘research only’ services include the assessment of PD-L1 
in the optional tumor biopsy(ies) being collected at the time of ablation and the optional additional 
blood.  Those services will be paid for by the study and will not be billed to you or your health 
insurance company. 
 
Other services you will receive during this research study are considered "routine clinical 
services" that you would have received even if you were not in the research study. Examples are 
all study doctor visits, blood tests, treatment with nivolumab, including the drug itself and 
administration of the drug, ablation, drugs used to reduce side effects from nivolumab and 
ablation, CT scans (or MRIs) and EKGs. These services will be billed to your health insurance 
company, but you will be responsible for paying any deductibles, co-payments, or co-insurance 
that are a normal part of your health insurance plan.  If you do not have health insurance, you will 
be responsible for those costs.  
 
Contact Information: If you have any questions regarding this study, you may contact the site 
Principal Investigator, <INSERT NAME>, MD at <INSERT PHONE NUMBER>. 
 
Discomforts and Risks 
You may have side effects while on this study.  We will monitor everyone in the study for any 
side effects. Contact your study doctor if you experience a side effect or have any questions about 
possible side effects. 
 
Side effects may be mild or serious.  We may give you medicines to help lessen side effects.  
Some side effects will go away as soon as you stop taking the drug.  In some cases, side effects 
can be serious, long-lasting, or may never go away. Taking part in this study may lead to time 
away from work. 
 
The most common side effects (> 20%) of nivolumab are: 
 
Fatigue  
 
Skin reactions: including rash, itching, hives, redness, and dry skin. 
 
Diarrhea or colitis (swelling of large intestine) with diarrhea 
 
Nausea 
 
Abdominal pain 
 
Decreased appetite 
 
Low red blood cells 
 
Fever 
 
Joint pain or stiffness 
 
 
Less common side effects (1-20%) of nivolumab include:  
 
Bowel inflammation 
 
Liver function blood test abnormalities 
 
Loss of color (pigment) from areas of skin 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
34 
 
Dry mouth 
 
Stomach pain 
 
Vomiting 
 
Weight loss 
 
Thyroid gland abnormalities and inflammation 
 
Blood chemistry abnormalities, including low blood phosphate, magnesium, and 
potassium levels. 
 
High blood uric acid level 
 
Lung inflammation (pneumonitis - see details below) 
 
Cough 
 
Dizziness 
 
Headache 
 
Low white blood cells 
 
Chills 
 
Muscle soreness, weakness, stiffness or spasms 
 
Pain in arms or legs 
 
Tingling, burning, or numbness in hands and feet, neuropathy (including tingling, cold 
sensitivity, numbness, pain) 
 
Shortness of breath 
 
Abnormal taste  
 
Flushing 
 
High or low blood pressure 
 
Allergic reaction during or between study drug infusions 
 
Increased sensitivity of skin to sunlight 
 
Constipation 
 
Difficulty swallowing 
 
Heartburn 
 
Low blood platelets (may increase risk of bleeding) 
 
Rare (<1%) but potentially serious side effects of nivolumab include: 
 
Low blood oxygen level 
 
Acute lung injury or failure 
 
Collection of fluid around the lungs 
 
Inflammation of the appendix 
 
Increase in inflammatory blood proteins (e.g., lipase) 
 
Adrenal gland abnormalities 
 
Pituitary gland inflammation 
 
Changes in vision (including decreased or blurry vision), inflammation of the eye, or 
bleeding into the eye 
 
Liver inflammation 
 
Acute kidney injury, failure, inflammation (nephritis) 
 
Abnormal blood cell production 
 
Inflammation of the mouth and lining of the digestive tract  
 
Swelling of the face, arms, or legs 
 
Inflammation of the pancreas 
 
Back pain 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
35 
 
Autoimmune disorders, including Guillain-Barre syndrome (associated with progressive 
muscle weakness or paralysis)  
 
Chest discomfort 
 
Heart palpitations 
 
Inflammation of the heart or its lining 
 
Collection of fluid around the heart 
 
Increased blood sugar 
 
Dehydration 
 
Infections: including sepsis, lung infections, and skin infections.  
 
Decreased movement of the intestines 
 
Disorientation 
 
Swelling of the optic disc 
 
Inflammation of the optic nerve 
 
Inflammation of the lining of the brain and spinal cord 
 
Drug reaction with rash, blood cell abnormalities, enlarged lymph nodes, and internal 
organ involvement (including liver, kidney, and lung); known as Drug Reaction with 
Eosinophilia and Systemic Symptoms (DRESS) 
 
Hepatitis 
 
Lung Inflammation (pneumonitis):  It is possible that nivolumab may cause inflammation of 
the tissues of the lung.  This adverse effect has been reported infrequently in patients treated with 
nivolumab.  While many patients with x-ray or CT abnormalities have not developed any 
symptoms, some patients have developed mild to severe symptoms and in rare cases, death has 
occurred as a result of their lung inflammation.  Signs and symptoms of lung inflammation may 
include difficulty breathing, pain or discomfort while breathing, chest pain, cough, shortness of 
breath, increased rate of breathing, fever, low blood oxygen levels, or fatigue.   
Your study doctor and nurse will watch you closely for changes in your ability to breathe and for 
other signs or symptoms that might show you are developing this type of lung inflammation and 
will perform regular tests including physical exams, measurement of oxygen levels through non-
invasive testing (i.e., pulse oximeter), blood tests, chest x-rays and/or CT scans. 
 
Please inform your study doctor or nurse AT ONCE if you experience any of the following: 
 
Any new or increased shortness of breath; 
 
Any new or increased chest pain; 
 
Any new or increased pain/difficulty while breathing; 
 
Any new or increased cough or any significant change in your type of cough; for example 
any new or increased mucous or blood in your cough;   
 
Any change in the amount of oxygen you require; 
 
Any fever, fatigue, or other symptoms that occur at the same time as any changes to your 
breathing or other lung symptoms.  
 
If you start to develop symptoms, your study doctor will ask you to return to the clinic for 
additional tests, which could include a physical exam, measurement of oxygen levels, blood tests, 
chest x-rays, and/or CT scans. You will be monitored very closely for changes in your overall 
lung symptoms, monitoring may require hospitalization. You may require specific treatment in 
order to control pneumonitis. You may also be seen by a special doctor called a pulmonologist, 
who has special training to be an expert in how your lungs work. 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
36 
Prolonged treatment with medicines that suppress inflammation, sometimes needed to manage the 
side effects of nivolumab treatment, may lower your body’s ability to fight off certain infections 
(i.e., opportunistic infections). These infections may require treatment with antibiotic or 
antifungal medications and may be fatal. 
 
Reproductive Risks From Nivolumab 
Nivolumab may decrease sperm count. This is usually temporary but can be permanent, which 
would result in sterility (not being able to father a baby).  
 
Because the drugs in this study can affect an unborn baby, you should not become pregnant while 
on this study. 
 
If you are a woman or man of childbearing potential you must practice an effective method of 
birth control while receiving study treatment and for at least 2 months after completing or 
discontinuing study treatment. Ask your study doctor for more information regarding preventing 
pregnancy during the study treatments. 
 
 You should not nurse your baby while on this study. If you are premenopausal, your periods are 
likely to stop temporarily and may stop permanently due to the study treatments, which may lead 
to symptoms of menopause, such as hot flashes, and the inability to become pregnant, which may 
be permanent. If you are concerned about this, ask your study doctor about options for preserving 
your reproductive choices, which may include referral to a specialist in this field.   
 
By signing this document you are acknowledging that you understand and agree to the 
information presented in this Reproductive Risk section. 
 
By signing this document you understand that there is no known potential for the use of ablation 
(ablating one lesion in a patient who may have diffuse metastatic disease) to increase your 
survival.  It is hoped that ablation may increase the likelihood of your cancer responding to 
nivolumab. By signing this form you agree to accept the risks of the ablation procedure without 
any known survival benefit. 
 
Risks From Ablation: 
Side effects from ablation differ depending on the location in the body the ablation is being 
performed. Please review with your doctor the expected risks to you of ablation. General risks of 
ablation include the following: 
 
The most common side effects (> 20%) of ablation are: 
Pain 
Bruising 
Bleeding 
Fatigue 
Weakness 
 
Less common side effects (1-20%) of ablation include:  
Shortness of breath 
Collapse of a lung that will need temporary placement of a chest tube. 
Infection 
Temporary changes in your body chemistries such as your potassium or other electrolytes 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
37 
Rare (<1%) but potentially serious side effects of ablation include: 
Damage to nerves 
Liver or kidney damage 
 
Antiemetics (anti-nausea medications): Various medications used to prevent nausea and 
vomiting may cause drowsiness, dry mouth, diarrhea, constipation, headache, restlessness, 
agitation, anxiety, dizziness, involuntary tremors, skin rash, and possible allergic reaction. 
You will receive pre-medication to reduce the risk of infusion/injection reactions on your 
treatment days. Overall, the pre-medications you will be given are well tolerated. 
 
Venipuncture (inserting a needle into a vein to obtain blood or give medication): May cause 
inflammation, pain, bruising, bleeding, or infection. 
When you receive chemotherapy by vein, there is a slight risk that some of the drug may leak out 
around the needle at the injection site. A skin burn may result. Most skin burns are treatable and 
heal well. 
In order to monitor the side effects, your physician will examine you frequently and obtain 
laboratory tests (blood tests, chest x-rays, or CT scans as needed) to determine the effects of your 
treatment and alter the drug dosages if necessary. 
 
Radiation Risks 
If you participate in this study, you receive several medical imaging scans that involve radiation 
exposure: 
 
CT guidance during ablation procedure  
 
Chest-abdomen-pelvis CT scan at screening, every 12 weeks thereafter, possibly at the 
end of treatment, and then every 3 months until progression of your disease.  
 
CT scan of your brain at screening and whenever clinically indicated 
You may be wondering if this amount of radiation exposure carries any additional risk of cancer 
in the future.  
 
The State and Federal government has established yearly limits of radiation exposure for 
people (radiation workers) who work around radiation every day 
 
There has been no increased rate of cancer for radiation workers compared to others  
 
If enrolled into this study, the maximum radiation exposure you are expected to receive 
during your first year on the study is about equal to the annual radiation exposure limit 
for a radiation worker 
 
The maximum radiation exposure you are expected to receive during your second and 
following years on the study is about one half (1/2) of the annual radiation exposure limit 
for a radiation worker 
 
At this level of radiation exposure, your increased risk of cancer due to this radiation is 
low 
 
Please note that this is a long-term risk; that is, cancers that are known to be caused by 
radiation generally do not appear for 7 to 50 years after the exposure 
 
If you have concerns about the radiation exposure associated with this study, please speak 
with your doctor 
Risk of Biopsies: Risks associated with biopsies include pain, redness, swelling, excessive 
bleeding, bruising, or draining at the needle site, abnormal wound healing, fever, infection, and 
allergic reaction to the medication used to numb the skin over the biopsy site. In patients who 
undergo a biopsy during a procedure called a bronchoscopy, the risks also include lung collapse. 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
38 
 
There may be other side effects that have not been reported. If you have any unusual symptoms, 
you should report them immediately to your doctor or nurse. 
 
Benefits 
It is hoped that the combination of nivolumab and ablation will be able stimulate your immune 
system against your cancer. Taking part in this study may or may not make your health better. 
This information could help future cancer patients. The benefits of this research include learning 
more about Nivolumab and ablation in treating certain lung cancer tumors.  
 
Alternative Therapies 
What other choices do I have if I do not take part in this study?  
 
Getting treatment or care for your cancer without being in a study such as receiving other 
chemotherapy or  nivolumab alone   
 
Receiving radiation treatments. 
 
Taking part in another study 
 
Getting no treatment 
 
Being followed closely and deciding about being treated when the disease progresses further    
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Refusal/Withdrawal 
It is up to you whether you want to be in the study.  You are not required to enroll or participate.  
If you decide to participate, you can always change your mind and quit at any time.  If you decide 
not to be in the study, or if you quit later, you will still be able to get the health care services you 
normally get.  If you join, but later on the researcher or your doctor feels being in the study is no 
longer good for you, they may choose to take you out of the study before it is over.  If new 
information becomes available that might change your mind about whether you want to stay in 
the study the researcher will share this information with you as soon as possible. 
 
If you make the decision to withdraw from this study (stop taking study medication) for any 
reason, tell your doctor immediately. You will be asked to sign a form indicating whether you 
give your permission for your doctor and the research staff to continue to collect and submit 
follow-up information on your health status from your physicians and medical record. After 
signing the form, you still have the right to change your mind, at any time, regarding follow-up 
after withdrawal. 
 
Medical Treatment/Payment in Case of Injury 
A research injury is any physical or mental injury or illness caused by being in the study. If you 
are injured by a medical treatment or procedure you would have received even if you were not in 
the study that is not a research injury. To help avoid research injury and added medical expenses, 
it is very important to follow all study directions carefully. If you do experience a research injury, 
<INSERT HOSPITAL NAME> or the study doctor can arrange medical treatment for you. Such 
treatment will be paid for as described below.  
 
Medical treatment will be available if you suffer a research related injury; however, you and/or 
your health insurance company will be charged for this treatment. The study will not pay for this 
medical treatment. Neither the Principal investigator and sponsor, Dr. Howard Safran nor 
BrUOG, the coordinating center, have money set aside to reimburse you for medical bills from 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
39 
treatment of a research related injury or otherwise compensate you in the event of a study-related 
injury.  
 
If you have insurance and have a research injury that is not covered by the study, it is possible 
that some or all of the cost of treating you could be billed to your insurer. If your health insurance 
will not cover such costs, it is possible you would have to pay out of pocket. In some cases, 
<INSERT HOSPITAL NAME> might be able to help you pay if you qualify for free care under 
<INSERT HOSPITAL NAME> policy. However, <INSERT HOSPITAL NAME> has no policy 
to cover payment for such things as lost wages, expenses other than medical care, or pain and 
suffering. 
 
 
 
Rights and Complaints 
Signing this form does not take away any of your lawful rights. If you have any complaints about 
this study, or would like more facts about the rules for research studies, or the rights of people 
who take part in research studies you may contact <INSERT CONTACT>, in the <INSERT 
HOSPITAL NAME> Office of Research Administration, at <INSERT PHONE NUMBER> 
 
Confidentiality 
Your research records will be treated as private health care records and will be protected 
according to <INSERT HOSPITAL NAME> privacy practices and policies that are based on 
state and federal law. In particular, federal law requires us to get your permission to use or 
disclose (release your information to someone outside of <INSERT HOSPITAL NAME>) your 
health information for research purposes. If you sign this form you agree to be in this research 
study and you permit the use and disclosure of your health information for the purpose of 
conducting the research, providing treatment, collecting payment and running the business of the 
hospital. This permission has no expiration date. You may withdraw from the study at any time. 
However, if you do not want the researchers to use or disclose any further information in this 
study you must cancel permission in writing and may do so at any time. If you cancel your 
permission, you will stop taking part in the study and no new information will be collected about 
you. However, if you cancel your permission, it will not apply to actions already taken or 
information already collected about you by the hospital or the researchers before you canceled 
your permission.  
 
Generally, the entire research record and any medical records held by the hospital may be used 
and released for research purposes. The following people or businesses/companies might use, 
release, or receive such information:  
 
The researcher and their support staff;  
 
The study sponsor: The Sponsor: Principal Investigator Howard Safran, MD, BrUOG, the 
coordinating office, or their representatives. 
 
Doctors, nurses, laboratories and others who provide services to you in connection with this 
study;  
 
The company or section of the U.S. government that is paying for the study and others they 
hire to oversee, administer, or conduct the research;  
 
The United States Food and Drug Administration, the Department of Health and Human 
Services, the Office of Inspector General, and the Office of Civil Rights;  
 
People who volunteer to be patient advocates or research volunteer protectors;  
 
Members of the hospital's administrative staff responsible for reviewing, approving and 
administering clinical trials and other healthcare or research activities.  

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
40 
 
There are times when the law might require or permit <INSERT HOSPITAL NAME> to release 
your health information without your permission. For example, <INSERT STATE> law requires 
researchers and health care workers to report abuse or neglect of children to the Department of 
Children, Youth and Families (DCYF) and to report abuse or neglect of people age 60 and older 
to the Department of Elderly Affairs. 
 
All researchers and health care providers are required to protect the privacy of your health care 
information. Other people and businesses/organizations that are not health care providers are not 
required by law to do that so it is possible they might re-release your information.  
You have the right to refuse to sign this form and not participate in the research. Your refusal 
would have no effect on your treatment, charges billed to you, or benefits at any <INSERT 
HOSPITAL NAME> health care site. If you do not sign, you will not be able to enroll in the 
research study and will not receive treatment as a study participant.  
 
If you decide to quit the study after signing this form (as described in Section 6) no new 
information will be collected about you unless you gave us permission to do so. However, the 
hospital or the researchers may continue to use information that was collected before you quit the 
study to complete analysis and reports of this research. 
 
Additionally, a description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at any 
time.  
 
For more detail about your privacy rights see the <INSERT HOSPITAL NAME> Joint Privacy 
Notice which has or will be given to you.   

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
41 
RELATED STUDIES 
Please note:  This section of the informed consent form is about additional research that is 
being done with people who are taking part in the main study.   You may take part in this 
additional research if you want to.  You can still be a part of the main study even if you say 
‘no’ to taking part in this additional research. 
You can say “yes” or “no” to the following studies.  Below, please mark your choice for each 
question.   
 
When having ablation your doctors may want to take a biopsy of your tumor to test it for the 
expression of a protein called, PDL-1. They may also check the tumor for other immune cells.  
Your doctors are hoping that they may be able to see if the levels of the protein, PD-L1 other 
immune markers and immune cells are related to how you respond to this treatment with 
Nivolumab and ablation. Leftover tissue may be saved in a specimen bank to allow for future 
unknown testing on your tumor tissue. This may allow your doctors to use some of your collected 
tissue for research to learn more about your disease and potential treatment options and 
responses.  
 
Benefits  
 
The benefits of this research include learning more about Nivolumab and ablation in treating certain 
lung cancer tumors. 
 
Risks  
Risks associated with taking a biopsy at the time of ablation include: 
 
Unlikely risks include bleeding, pain and unsuccessful biopsy (your doctor is not able to obtain 
enough tissue). 
 
GINA STATEMENT  
This study involves ‘genetic testing’ as defined by the Genetic Information Nondiscrimination 
Act of 2008 (GINA). GINA generally makes it illegal for health insurance companies, group 
health plans, and most employers to discriminate against you based on your genetic 
information.  There are some limitations to GINA’s protections (it does not apply to all insurers 
or employers, nor does it apply to all genetic information, such as information related to a genetic 
disease that you already have).  In addition to GINA’s protections regarding the ultimate use to 
which your genetic information is put, <INSERT HOSPITAL NAME>’s privacy policies 
generally protect the privacy of such information and restrict its release outside of <INSERT 
HOSPITAL NAME>, unless you specifically authorize its disclosure or unless disclosure without 
your authorization is permitted under applicable privacy laws.  
 
Making Your Choice  
Please read each sentence below and think about your choice. After reading each sentence, circle 
"Yes" or "No". If you have any questions, please talk to your doctor or nurse at <INSERT PHONE 
NUMBER>.  
These reports will not be put in your health record. No matter what you decide to do, it will not 
affect your care. 
Optional tumor tissue: 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
42 
1. A biopsy of my tumor tissue may be taken at the time of my ablations to evaluate for PD-
L1, other immune markers and immune cells.  
  Yes  No 
2. A portion of my tumor tissue may be saved for specimen banking at Rhode Island 
Hospital and for additional future testing. I understand that I will not be informed of any 
information that is discovered from these tests. 
 
  Yes  No 
 
Optional Blood: 
1. Additional laboratory samples, (approximately two tablespoons of blood) can be drawn at 
the following time points: at baseline when I am being evaluated for this trial, before and 
after ablation and approximately 3 and 6 months after my first ablation. If I undergo 
additional ablation procedures additional laboratory samples (approximately two 
tablespoons of blood) may also be taken before and after ablation. I understand that the 
additional blood work will be sent to the research laboratory of Dr. Loren Fast at Rhode 
Island Hospital to study the effect of nivolumab and ablation on my blood cells.  
  Yes  No 
 
 
Participation in Specimen Banking  
You are agreeing to participate in this research study by signing this form (the “Main Study”) 
tissue samples will be collected from you, which will be referred to here as your ‘Specimen.’  In 
addition to being analyzed as part of the Main Study, your Specimen may be useful for future 
research purposes.  You are being asked to agree to this optional component (the “Specimen 
Banking Component”) of the study if you are willing to allow your Specimen to be saved or 
‘banked’ for use in future research studies.  If you agree to this optional Specimen Banking 
Component, you give permission for your Specimen to be stored in a specimen bank indefinitely, 
until it is no longer usable. The Specimen may also be used to create a cell line, which would also 
be stored for an indefinite period of time.  . Along with the specimens, portions of your personal 
health information collected as part of the Main Study will also be stored.  Your Specimen and 
personal health information may be stored and analyzed at Lifespan; or, they may be shared with 
researchers at other institutions or companies that may store them and use them for their own 
research.  It is very unlikely that any future research performed using your Specimen would 
benefit you directly.  However, the research may provide important medical knowledge that in the 
future could help other patients with your medical condition or other medical problems.     
 
At this time, we do not know what future research studies may be done using your Specimen.  
Such research studies may include genetic tests that would analyze your DNA, RNA or other 
gene products, like proteins and metabolites.  These genetic tests may be done by Lifespan, or 
they may be done by other researchers with whom your Specimen and data have been shared.  
Because any genetic testing of your Specimen would be for research purposes, the results would 
have no clear implications for your health or medical condition, or that of your family members.  
Any testing results would not be made available to you or to any insurance company, your 
employer, your family, or any physician who treats you in the future.       
 
There is a very remote possibility that your Specimen and some associated data may become part 
of a process or product that ultimately has commercial value.  For instance, the Specimen could 
be used to establish a cell line (a group of cells that are able to reproduce, sometimes indefinitely) 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
43 
that could be patented and licensed.  There are no plans to provide financial compensation to you 
should this occur. 
 
If you decide at some time in the future that you no longer wish your stored Specimen to be used 
in future studies, you have the right to request that the Specimen be withdrawn from the specimen 
bank.  However, withdrawal cannot be guaranteed and may be impossible.  For example, it is 
possible that the Specimen might no longer be identifiable as belonging to you, or it may have 
been used up, or it may already have been shared with other institutions or companies for their 
own research.  To request withdrawal of your Specimen, please write to: Howard Safran, MD 593 
Eddy Street APC1 Providence, RI 02903. 
 
Refusal to participate in this optional Specimen Banking component will in no way affect your 
ability to receive any treatment or services offered as part of the Main Study, and will not have 
any effect on your other health care, the payment for your health care, or your health care 
benefits.  
 
If you are willing to allow your Specimen to be banked for future research purposes, please 
indicate your consent by signing below. 
 
______________________________________  
 
__________ 
 
      
Signature of study volunteer/authorized representative 
 
 
Date          
 
 
SIGNATURE 
 
I have read this informed consent and authorization form.  ALL OF MY QUESTIONS HAVE 
BEEN ANSWERED, AND I WANT TO TAKE PART IN THIS RESEARCH STUDY. 
 
By signing below, I give my permission to participate in this research study and for the described 
uses and releases of information.  I also confirm that I have been now or previously given a copy 
of the <INSERT HOSPITAL NAME> Privacy Notice 
 
 
 
 
 
The Researcher is required to provide a copy of this consent to you.  
 
_________________________________________ 
________          ____________ 
Signature of study volunteer/authorized representative* Date         and    Time when signed 
 
 
 
I was present during the consent PROCESS AND signing of this agreement by the study 
volunteer or authorized representative 
 
__________________________________________ 
 
______________ 
Signature of witness (required if consent  
 
 
 
Date 
is presented orally or at the request of the IRB)  
 
 
 
 
 
 
 
 
__________________________________________ 
 
______________ 
This informed consent document expires on ______________.   
DO NOT sign this document after this expiration date 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
44 
Signature of Translator  
 
 
 
 
Date 
 
___________________________________________ 
________          __________ 
Signature of researcher or designate 
 
 
 
Date         and    Time when 
signed 
 
* If signed by agent other than study volunteer, please explain below. 
______________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
45 
 
 
APPENDIX B: Checklist  
 
Nivolumab and Ablation For Patients With Advanced Non-Small Cell Lung Cancer 
(NSCLC) Progressing After at Least One Prior Therapy For Metastatic Disease: 
A Brown University Oncology Research Group Phase II Study 
 
Inclusion Criteria 
________(y/n) Pathologically or cytologically confirmed NSCLC 
________(y/n) Stage IIIB or stage IV. 
________(y/n) Progression after at least 1 line of systemic treatment (IV or oral) for metastatic or 
locally advanced disease. Patients progressing within 6 months of completion of neoadjuvant or 
adjuvant chemotherapy are also eligible. Radiation does not count as 1 line. 
OR 
_________(y/n) Patients progressing within 6 months of completion of neoadjuvant or adjuvant 
chemotherapy are also eligible without having treatment for metastatic disease (for example 
patient with stage I disease undergoes resection, receives systemic chemotherapy and then 
progresses to the liver (now stage IV) within 6 months of chemotherapy). Radiation does not 
count as 1 line. 
________(y/n) At least 1 site of measurable disease that will not be treated with ablation 
________(y/n) Ablation for advanced lung cancer is being considered by the treating physician for 
treatment or prevention of symptoms such as pain, bleeding or obstruction. Documentation to be 
sent in writing from MD to confirm criterion. 
________(y/n) At least 3 weeks since prior systemic treatment and/or radiation therapy for patient’s 
NSCLC (from treatment day 1 on study) 
________(y/n) No brain metastases except for patients whose metastases have been removed by 
surgical resection or have had stereotactic radiation or gamma knife with no evidence of active 
disease on MRI within 28 days of starting treatment. 
________(y/n) Voluntary, signed written informed consent, Date signed_____________ 
________(y/n) Age >18  
________(y/n) ECOG PS 0-2 
________(y/n) Life expectancy > 12 weeks (must be confirmed by treating MD in writing) 
________(y/n) Must be willing to consent to use effective contraception while on treatment and 
for at least 2 months afterwards.  
________(y/n) CT scan of the chest/abdomen/pelvis within 6 weeks of study entry. Patients can 
have PET/MRI of the chest/abdomen instead. Chest Xray okay. 
________(y/n) EKG within 8 weeks study entry 
________(y/n) Absolute neutrophil count ≥ 1,000/ul, Date_________  
________(y/n) Platelet ≥ 75,000/uL,  Date_________ 
 
________(y/n) Total bilirubin ≤ 1.5 x ULN, Date_________ 
________(y/n) AST≤  3x ULN     
________(y/n) Creatinine < 1.5 mg/dl or creatinine  
 
Exclusion Criteria: 
_______(y/n) Patients with a history of clinically significant chronic autoimmune disease 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
46 
______  (y/n) Prior therapy with antibodies that modulate T-cell function (e.g., anti–CTLA-4, 
anti–PD-1, and anti–PD-L1) 
______    (y/n) Conditions currently requiring immunosuppressive medications 
________(y/n)  Known history of HIV or hepatitis B or C 
________(y/n) Bleeding diathesis or coagulopathy that would prevent cyroablation from being 
safely performed. 
________(y/n) Patients with unstable angina (anginal symptoms at rest) or new-onset angina 
(began within the last 3 months) or myocardial infarction within the past 6 months. 
________(y/n)  History of organ allograft even if not taking immunosuppressive medications 
 _______ (y/n) Pregnant or breastfeeding. 
 
 
Optional tumor tissue:  
 
Did patient agree to optional biopsy of tumor tissue at time of ablation? 
 
Yes  No 
 
Did patient agree that a portion of the tumor tissue could be saved in the specimen bank at RIH? 
 
Yes  No   N/A 
 
Did patient agree to optional laboratory correlative samples?  Yes 
 No 
 
Document if patient will undergo Cryoablation or thermal ablation: ________________ 
**Remember to document which lesion will not be ablated for registration** 
 
Signed informed consent: The patient must be aware of the neoplastic nature of his/her disease 
and must willingly consent after being informed of the procedure to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and 
discomforts. 
The support documentation, per the requirements under the study parameters section of this 
study, as well as the consent form and this checklist, must be faxed to the BrUOG Central Office 
at the time of registration.  Please check if “Enclosed”, state reason when “Not Enclosed,” or 
check if "Not Applicable."  
1) Eligibility Form  
 
Enclosed __Not Enclosed   
___ Not Applicable  __ 
2) Heme/Onc initial note 
Enclosed __Not Enclosed   
___ Not Applicable  __ 
3) Pathology Report(s)         
Enclosed __Not Enclosed   
___ Not Applicable  __ 
4) MRI/CT Report(s)   
Enclosed __Not Enclosed   
___ Not Applicable  __ 
5) Lab Source Document        Enclosed __Not Enclosed   
___ Not Applicable  __ 
6) ICF signature page 
 
7) Other documentation 
 
IRB approval date of protocol:   
  
 
Hospital where patient will be treated with Oncologist:    
 
 
 
 
 
Hospital where ablation will occur:_____________ 
 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
47 
Date patient will begin treatment:  
 
  Date patient to undergo ablation:________ 
Primary Physician: 
 
 
 Primary Diagnostic Radiologist:____________ 
 
 
Your signature:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX C 
NCI CTC Version 4 
 
Toxicity will be scored using NCI CTC Version 4 for toxicity and adverse event reporting.  A 
copy of the NCI CTC Version 4 can be downloaded from the CTEP homepage: 
(http://ctep.info.nih.gov).  All appropriate treatment areas have access to a copy of the CTC 
Version 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
48 
APPENDIX D 
 ECOG PATIENT PERFORMANCE STATUS 
STATUS 
KARNOFSKY 
ZUBROD-ECOG-
WHO 
Description 
No complaints 
100 
0 
Normal activity 
 
Able to carry on 
normal activities 
90 
1 
Symptoms, but fully 
ambulatory 
 
Normal activity with 
effort 
 
80 
 
 
 
Cares for self.  Unable 
to carry on normal 
activity or to do active 
work 
 
70 
2 
Symptomatic, but in 
bed <50% of the day 
Requires occasional 
assistance, but able to 
care for most of his 
needs 
 
60 
 
 
Requires considerable 
assistance and 
frequent medical care 
 
50 
3 
Needs to be in bed 
>50% of the day, but 
not bedridden 
Disabled, requires 
special care and 
assistance 
 
40 
 
 
Severely disabled.  
Hospitalization 
indicated though 
death non imminent 
 
30 
4 
Unable to get out of 
bed 
Very sick.  
Hospitalization  
Necessary.  Active 
support treatment 
necessary 
 
20 
 
 
Moribund 
 
10 
 
 
Dead 
0 
 
 
From: Minna J.D., Higgins G.A and Glapstein E.J.  Cancer of the lung:  In: DeVita V, Hellman 
S., Rosenberg S., (Eds.).  Cancer: Principles and Practice of Oncology, Lippincott, Philadelphia, 
1984, p. 536

FDA exemption 6/30/15, 6/30/15, 8/17/15 (for LOCR initial), Amendment #1 10/5/15 v 2 HS approval, Amendment # 2 11/9/15, 
Amendment #3 3/4/16, Amendment # 4 4/7/16, Amendment # 5 6/1/16 V2, Amendment # 6 7/7/16, Amendment # 7 11/16/16, 
Amendment # 8 2/22/17, Amendment #9 5/22/17 
 
 
49 
APPENDIX E 
CASE REPORT FORMS 
Attached separately are the BrUOG Case Report Forms