Adjuvant Nivolumab and Low Dose Ipilimumab for Stage III and Resected Stage IV Melanoma: A Phase II Brown University Oncology Research Group Trial
Phase: PHASE2
Conditions: Melanoma
Sponsor: Brown University

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
1
BrUOG M324  
 
 
 
 
 
 
 
IND Exempt 129445 
 
Adjuvant Nivolumab and Low Dose Ipilimumab  
for Stage III and Resected Stage IV Melanoma: 
A Phase II Brown University Oncology Research Group Trial 
 
Maria Constantinou, MD 
Principal Investigator  
 
Howard Safran, MD 
Medical Director, Brown University Oncology Group 
 
 
Thomas Miner MD 
Michael Vezeridis, MD 
Peter Barth, MD 
 
 
 
Supported in part by LIFEcycle and Washington Trust Company 
 
Coordinating Center 
Brown University Oncology Research Group 
233 Richmond Street Box G-R001 
Providence, Rhode Island 02903 
Phone: (401) 863-3000 
Fax: (401) 863-3820 
Email:BrUOG@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. 
Original 10/25/15 
Amendment # 1 10-5-16 
Amendment #2 3/1/2017, 3/17/17 (final 4/4/17, updated 6/14/17) 
Amendment # 3 10-19-17 
Amendment # 4 12/26/17 
Amendment #5 7/11/18 
Amendment # 6 12/8/18 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
2
TABLE OF CONTENTS 
Section  
 
 
 
 
 
 
 
 
Page 
1.0 
OBJECTIVES  
 
 
 
 
 
 
3 
2.0 
BACKGROUND 
 
 
 
 
 
 
3 
3.0 
PATIENT ELIGIBILITY 
 
 
 
 
 
7 
 
 
4.0 
TREATMENT 
 
 
 
 
 
 
8 
 
5.0 
TOXICITIES, ASSESSMENT, AND DOSE MODIFICATIONS 
9 
                                                     
6.0 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
 
17 
                          
7.0      RESPONSE ASSESSMENT  
 
 
 
 
18 
 
 
8.0 
PATIENT REGISTRATION  
 
 
 
 
19 
9.0 
PHARMACEUTICAL INFORMATION                                           
19 
10.0 
AGENT ACCOUNTABILITY     
 
 
 
 
22 
 
11.0 
ADVERSE DRUG REACTION REPORTING 
 
 
22 
 
12.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
28 
13.0 
FOLLOW UP    
 
 
 
 
 
 
28 
   
14.0 
REGULATORY CONSIDERATIONS   
 
                           29 
15.0 
DATA MONITORING/QUALITY ASSURANCE/ 
 
 
30 
RECORD RETENTION 
 
 
 
 
 
 
 
16.0 
DATA SAFETY AND MONITORING BOARDS 
 
 
31 
 
17.0 
STATISTICAL CONSIDERATIONS  
 
 
    
32 
18.0 
REFERENCES                                                                        
33 
 
APPENDIX SECTION: 
 
 
 
 
 
APPENDIX A INFORMED CONSENT 
 
 
 
 
 
APPENDIX B ELIGIBILITY CHECKLIST  
 
 
 
APPENDIX C ECOG PERFORMANCE STATUS   
 
 
APPENDIX D CASE REPORT FORMS 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
3
1.0  OBJECTIVES 
1.1 Primary  Objective 
1.1.1. To evaluate the toxicity of nivolumab and low-dose ipilimumab as adjuvant therapy for patients with 
high risk melanoma. 
1.1.2 To evaluate the recurrence-free and survival overall following adjuvant nivolumab and low dose 
ipilimumab for patients with high risk melanoma. 
 
1.2 Secondary  Objective 
 
1.2.1 To evaluate what percentage of patients are able to complete the planned 6 months course of treatment 
without toxicities requiring discontinuation. 
 
2.0  BACKGROUND 
Melanoma: Malignant melanoma is the most common fatal form of skin cancer.1 There were 76,100 new 
cases of melanoma last year and 9,710 deaths.2 There are important, preventable environmental risk 
factors for melanoma such as sun and ultraviolet ray exposure.3,4  Individuals traits such as light skin 
pigmentation, hair color (red or blond), high-density freckling, and light eye color (green, hazel, blue) are 
also associated with increased risk. Genetic features, such as hereditary p16 gene abnormalities, account 
for about 10% of melanoma.5 
 
Adjuvant Therapy for Melanoma:  The curative modality for early stage melanoma is surgical 
resection. Unfortunately, some patients will subsequently relapse with metastatic disease that is generally 
fatal. High-risk features in the primary tumor define subsets that are at increased risk for recurrent 
disease.6 Patients with a deep primary tumor (> 4mm or involved regional lymph nodes have a risk of 
relapse and death of > 50%. 7,8 
 
Agents evaluated in the adjuvant setting include chemotherapy such as dacarbazine, nonspecific immune 
adjuvants such as Bacillus Calmette-Guerin (BCG) vaccine, Corynebacterium parvum and levamisole, 
and hormonal agents such as megace. However, none of these agents have shown benefit in preventing 
recurrence in randomized trials.9-11 
 
Adjuvant Interferon: Interferon alfa appears to be an active agent in melanoma by stimulating the 
immune system against melanoma. 12,13 The phase Eastern Cooperative Oncology Group (ECOG) trial 
ECOG 1684, demonstrated that adjuvant interferon prolongs disease-free and overall survival in selected 
patients at increased risk for disease dissemination. Two-hundred eighty seven patients with melanomas 
>4 mm in depth (stage IIB) or subclinical or clinically apparent regional node involvement (stage III) 
were randomly assigned to one year of high-dose (HD) IFNa-2b or  observation. 14 Interferon treatment 
consisted of intravenous therapy at a dose of 20 million units/m2 five days per week for four weeks 
followed by 10 million units/m2 subcutaneously three times weekly for an additional 11 months. 
Treatment with interferon demonstrated a nine-month prolongation in relapse-free survival and a one-year 
prolongation in median survival (3.8 versus 2.8 years).  However, in a subsequent analysis, the 
improvement in overall survival was no longer statistically significant. 15 Furthermore in a phase III study 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
4
of pegylated interferon, a survival benefit was not seen. 16 Treatment benefit with high dose interferon 
appears to be confined to patients with lymph node involvement as well as those with stage T4B (>4mm  
primary tumor with ulceration). High dose interferon is associated with numerous adverse effects, 
including acute constitutional symptoms, chronic fatigue, myelosuppression, thyroid abnormalities and 
neurologic and psychological effects, which are experienced by the majority of patients. In particular, 
fatigue is common and was present in 70 to 100 percent of patients in large trials. Fatigue can increase in 
severity with duration of therapy and can be debilitating. Mild to moderate depression and impaired 
cognitive function are commonly reported.  
Immune Checkpoint Inhibitors:  The immune checkpoint inhibitors are the most important new class of 
agents in the treatment of advanced melanoma. The immune system can be enhanced to vigorously attack 
melanoma by turning off important immune system inhibitory pathways including the cytotoxic T-
lymphocyte-associated antigen 4 (CTLA-4) pathway and the programmed death 1 (PD-1) pathway. 17 
 
Ipilimumab, an anti–cytotoxic T-lymphocyte– associated antigen 4 (CTLA-4) antibody, acts to up-
regulate antitumor immunity and was the first agent to be associated with an improvement in overall 
survival in a phase 3 study involving patients with metastatic melanoma.17,18 Ipilimumab was associated 
with responses in 10% and 15% of patient;17,18 approximately 20% of treated patients had long-term 
survival.19,20  
 
Two anti–programmed death 1 (PD-1) antibodies, nivolumab and pembrolizumab, were approved by the 
Food and Drug Administration in 2014 for the treatment of metastatic melanoma after progression during 
ipilimumab treatment and, in patients with BRAF-mutated melanoma, after progression during treatment 
with a BRAF inhibitor.20-24 These antibodies were associated with objective responses in 30 to 40% of 
patients, with the majority of responses being durable. Two phase 3 trials have shown superior efficacy of 
nivolumab, as compared with chemotherapy, in previously untreated patients with wild-type BRAF 
tumors21 or in patients with either mutant or wildtype BRAF tumors after progression during ipilimumab 
therapy and, in patients with tumors positive for BRAF mutation, after progression during treatment with 
a BRAF inhibitor.22 Similar results were observed in a phase 2 trial of pembrolizumab versus 
chemotherapy.23 Recently, pembrolizumab was associated with longer progression-free survival and 
overall survival and higher response rates than those associated with ipilimumab in a phase 3 trial 
involving patients with advanced melanoma.24 
 
Ipilimumab and Nivolumab Is the Most Active Regimen In Advanced Melanoma: A phase III study, 
Checkpoint 067, showed that the combination of ipilimumab and nivolumab is more active in advanced 
melanoma that either agent alone. In this trial 945 previously untreated patients with unresectable stage III 
or IV melanoma were randomly assigned 1:1:1 to nivolumab alone, nivolumab plus ipilimumab, or 
ipilimumab. The median progression-free survival was 11.5 months (95% confidence interval [CI],8.9 to 
16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI,2.8 to 3.4) with 
ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 
months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 
99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the 
median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
5
nivolumab group, but in patients with PD-L1–negative tumors, progression-free survival was longer with 
the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 
months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the 
patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of 
those in the ipilimumab group. The most common adverse events in the nivolumab-plus-ipilimumab 
group were diarrhea (in 44.1% of patients), fatigue (in 35.1%), and pruritus (in 33.2%). 
Adjuvant High Dose Ipilimumab: Adjuvant high dose (10mg/kg) ipilimumab is being evaluated as an 
adjuvant in patients at high risk of relapse after initial definitive therapy. In the EORTC 18071 trial, 951 
patients were randomly assigned to either ipilimumab or placebo.26 All patients had stage III melanoma, 
and 80 percent had stage IIIB or IIIC disease. The other 20 percent had stage IIIA disease with melanoma 
>1 mm diameter in the sentinel lymph node. Treatment with ipilimumab was given at a dose of 10 mg/kg 
every three weeks for four doses, then every three months for three years unless toxicity or relapse 
prevented its continuation. Placebo was given on the same schedule. The primary endpoint of the trial was 
relapse-free survival. The median recurrence-free survival (RFS) was significantly increased with 
ipilimumab compared with placebo (median 26 versus 17 months, three-year RFS 46.5 versus 34.8 
percent, hazard ratio [HR] 0.75, 95% CI 0.64-0.90). Toxicity associated with adjuvant ipilimumab was 
quite significant. Immune-related side effects were observed in 90 percent of patients treated with 
ipilimumab, including 36.5 with grade 3 events, and 5.5 percent with grade 4 events. The most common 
treatment-related adverse events were dermatologic, gastrointestinal, endocrine, and hepatic (63, 46, 38, 
and 25 percent of patients, respectively). Primarily because of toxicity, only one-half of the patients 
assigned to ipilimumab received more than the initial 12 weeks of therapy and only 29 percent of the 
patients remained on therapy beyond one year. There were five treatment-related deaths (three due to 
colitis, one to myocarditis, and one due to multiorgan failure with Guillain-Barre syndrome) in patients 
treated on the ipilimumab arm.  
Low Dose Ipilimumab: Wolchok et al evaluated 217 patients over three dose levels of single agent 
ipilimumab at doses of 10mg/kg, 3mg/kg and 0.3 mg/kg. Response rates were 11%, 4.2% and 0%, 
respectively.27 However, prolonged stable disease was seen at all 3 dose levels. At the lowest dose level 
biologic effect was observed with grade 1 and grade 2 toxicities but no grade 3 toxicities. The absolute 
lymphocyte count was similar in the 0.3 and 3mg/kg doses but lower than the 10mg/kg dose. Praeto 
performed a series of protocols with a combination of ipilimumab with other immunologic agents 
including the gp100 vaccine and IL-2.28 Ipilimumab doses were 0.1, 0.3, 1, 2 and 3mg/kg IV every 3 
weeks. Interestingly, among the most active and best tolerated arms was 1mg/kg ipilimumab (after an 
initial 3mg/kg bolus dose). Two patients in this protocol treated with 1mg/kg had a continuous complete 
response with the combination of ipilimumab 1mg/kg and the gp100 vaccine for 94 and 88 months.  
 
Single Agent Nivolumab and in Combination with Ipilimumab in Non-Small Cell Lung Cancer 
(NSCLC): Nivolumab is FDA approved for treatment of advanced NSCLC. In the initial expanded phase 
I study a total of 122 patients with NSCLC were enrolled.29 Patients were heavily pretreated with 55% of 
patients receiving 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 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
6
longer.  Nivolumab is FDA approval to treat metastatic squamous cell lung cancer with progression on or 
after first-line chemotherapy based on Checkmate 017.30 Patients receiving nivolumab experienced 
improved survival and less toxicity as compared with standard second line chemotherapy with docetaxel. 
Nivolumab has also been FDA approved in second line non-squamous cell lung cancer based on 
Checkmate 057. The 12-month overall survival was 51% for nivolumab compared with 39% for 
docetaxel. 31 The response rate was 19% for nivolumab versus 6% for docetaxel. Grade 3/4 toxicities were 
higher with docetaxel (20% versus 7%).  
 
Nivolumab In Combination With Ipilimumab in NSCLC: CheckMate 012 compared several dosing 
schedules of nivolumab and ipilimumab for frontline treatment of advanced NSCLC as follows:32  
• 
Nivolumab at 1mg/kg every 3 weeks x 4 plus ipilimumab at 1mg/kg every 3 weeks x 4 followed 
by nivolumab at 3mg/kg every 2 weeks (n=31).  
• 
Nivolumab at 1mg/kg every 2weeks plus ipilimumab at 1mg/kg every 6 weeks (n=40). 
• 
Nivolumab at 3mg/kg every 2 weeks plus ipilimumab at 1mg/kg every 12 weeks (n=38) 
• 
Nivolumab at 3mg/kg every 2 weeks plus ipilimumab at 1mg/k every 6 weeks (n=39).  
 
Grade 3/4 treatment related adverse events occurred in 28-35% of patients and only 3-10% of patients 
discontinued therapy. Thus the toxicity of low dose ipilimumab appears substantially reduced. Objective 
responses were confirmed in 13-39% of patients with the highest responses rates in the cohorts receiving 
nivolumab 3mg/kg every 2 weeks plus ipilimumab at 1mg/kg every 6-12 weeks.  
 
Protocol Rationale: Effective adjuvant treatment can increase cure in patients with high-risk resected 
melanoma. High dose interferon is a standard of care in the adjuvant setting but is highly toxic and 
marginally effective. The combination of ipilimumab and nivolumab is the most active regimen in 
patients with advanced melanoma so there is clear rationale to test this regimen in the adjuvant setting. 
The M.D. Anderson Cancer Hospital will be testing adjuvant ipilimumab 3mg/kg and with nivolumab 
1mg/kg followed by 3mg/kg maintenance (NCT02519322). This regimen is expected to be quite toxic 
and initially uses low dose of nivolumab – the more active immune checkpoint inhibitor. Praeto et al 
demonstrated that lower dose ipilimumab can be safely combined with other immunologic agents with 
important biologic activity.28 For example, two patients treated in the Praeto study at the 1mg/kg 
maintenance dose level of ipilimumab had prolonged complete responses. In the study by Rizvi et al in 
NSCLC, the regimen of nivolumab 3mg/kg every 2 weeks with ipilimumab 1mg/kg every 6-12 weeks 
appears to be the most promising for further investigation Therefore we will investigate nivolumab 
3mg/kg every 2 weeks with 1mg/kg ipilimumab every 6 weeks in the high risk adjuvant setting. The 
duration of therapy will be six months to be consistent with the M.D. Anderson protocol of 6 months of 
adjuvant ipilimumab 3mg/kg and nivolumab 3mg/kg.  
   
 
 
 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
7
3.0 PATIENT ELIGIBILITY 
3.1 Conditions for patient eligibility 
3.1.1. Histologically or cytologically proven melanoma. The primary site of melanoma may be cutaneous 
or other body site such as ocular or anorectal. Documentation required to be sent to BrUOG. 
3.1.2 Completely resected stage III (patients cannot be N0) or resected stage IV disease. Patients with 
stageT4BN0 are also eligible. Documentation of resection with pathology report to be sent to BrUOG. It 
is required that patients with stage IIIA disease have > 1mm nodal involvement via pathology assessment 
of the resected node. All patients must be disease free to be eligible. Confirmation to be sent to BrUOG. 
3.1.3: No prior treatment for melanoma other than surgical resection or radiation. At least 4 weeks since 
prior surgery and 3 weeks since prior radiation to registration date.  
3.1.4: Age >/= 18 years 
3.1.5: ECOG performance status 0-1 
3.1.6 Patients must have organ and marrow function as defined below within 14 days of study entry:  
Hematologic Absolute neutrophil count (ANC) >/= 1.5 X 109/L;  
Hemoglobin >/= 9.5 g/dL;  
Platelets >/= 100 X 109/L;  
Total Bilirubin ≤ 1.5 x ULN except subjects with normal direct bilirubin or those with known Gilbert’s 
syndrome. Send information to BrUOG if patient has known Gilbert’s syndrome 
AST and ALT </= 2.5 X ULN 
Albumin >/= 2.5 g/dL 
Renal Creatinine OR Calculated creatinine clearance : Creatinine < 1.5 mg/dl or creatinine clearance > 
50ml/min 
3.1.7 No clinically significant coagulation disorder as defined by the treating MD. Therapeutic use of 
anticoagulants is permissible. Add to concomitant medication log if applicable. 
3.1.8. Not pregnant and not nursing. Women of child bearing potential must have a negative serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to Day 1 of 
treatment. Post-menopausal women (surgical menopause or lack of menses >12 months) do not need to 
have a pregnancy test, please document status. 
3.1.9 Confirmation of informed consent. 
3.1.10 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 for 2 months after end of treatment.  
3.2  Exclusion Criteria: 
3.2.1 Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic 
therapy) or investigational anti-cancer drug 
3.2.2 Brain metastases, whether resected or not, and any known leptomeningeal disease or known bone 
metastases. To confirm in writing to BrUOG.  
3.2.3 Pregnant or breastfeeding female. If lactating, must have documentation in writing that patient will 
not breastfeed from time of consent through 2 months post the last dose of drug. 
3.2.4 Unwillingness or inability to follow the procedures required in the protocol, to document 
3.2.5 Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase 
the risk associated with study participation or study drug administration, impair the ability of the subject 
to receive protocol therapy, or interfere with the interpretation of study results. 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
8
3.2.6 Prior malignancy active within the previous 2 years except for locally curable cancers that have 
been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or 
carcinoma in situ of the prostate, cervix, or breast. Documentation required to be sent to BrUOG 
3.2.7 Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, controlled 
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence 
of an external trigger are permitted to enroll.  
3.2.8 Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalents) or other immunosuppressive medications within 14 days of study drug 
administration. Inhaled or topical steroids and adrenal replacement doses >10mg daily of prednisone 
equivalents are permitted in the absence of active autoimmune disease.   
 
 
 
 
 
 
 
 
 
 
3.2.9 Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody 
3.2.10 Any positive test result for hepatitis B or C virus indicating acute or chronic infection  
3.2.11 Known history of testing positive for human immunodeficiency virus or known acquired 
immunodeficiency syndrome 
3.2.12 History of severe hypersensitivity reaction to any monoclonal antibody. To confirm if applicable in 
writing to BrUOG 
3.2.13 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. 
3.2.14 History of autologous transplant or organ allograft even if not taking immunosuppressive 
medications 
 
4.0 TREATMENT 
4.1 Schema:   
Nivolumab and Ipilimumab: 1 cycle = 6 weeks (+/- 8 days) (coinciding with receipt of Ipilimumab). 
Patients will receive 4 cycles of therapy 
 
Ipilimumab:1mg/kg q6weeks (1 dose per cycle, 4 planned treatments over 6 months total) 
Nivolumab: 
Patients who were enrolled and began treatment before Amendment # 2 was IRB approved: Nivolumab: 
3mg/kg q2weeks (+/-3 days) (3 doses per cycle, 12 planned treatments over 6 months total) 
Patients enrolled and who start treatment (cycle 1) based on Amendment #2: Nivolumab: 3mg/kg up to a 
total a total of 240mg IV over approximately 60 minutes (+/- 3 days) (3 doses per cycle, 12 planned 
treatments over 6 months total) 
 
Doses do not need to be recalculated if weight change is less than 10% of total body weight, as per 
institutional standard practice. 
 (In general, when both drugs are due on the same day, it is suggested that ipilimumab be given prior to 
nivolumab, but the study does allow for the reverse to occur if for whatever reason it is more convenient 
and this will not be considered a deviation.) 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
9
Cycles are every 6 weeks (+/- 8 days) however, it will not be considered a deviation if a cycle or pre-
treatment assessments must be adjusted to accommodate scheduling or holidays. Adjustment must be 
documented with reason to BrUOG.  
5.0 TOXICITIES, DOSE MODIFICATIONS, AND MANAGEMENT 
Toxicities will be recorded as adverse events on the Adverse Event case report form and must be graded 
using The National Cancer Institute’s Common Toxicity Criteria (CTCAE) version 4  
5.1        Dose Modifications: 
No dose reductions of nivolumab or ipilimumab are included in the study.   
5.2 The following must be confirmed prior to dosing a patient with nivolumab and ipilimumab: 
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 and 
ipilimumab.  
 
Adverse event management table:  
Event 
Issue 
Action 
Labs: 
1) AST or ALT >3 to 5 times ULN 
(grade 2) or total bilirubin >1.5 to 
3 times ULN (grade 2) 
 
 
 
 
 
 
 
2) AST or ALT >5 times ULN (grade 
3) or total bilirubin >3 times ULN 
(grade 3) 
1) Hold treatment until 
recovery to grade 1 or 
resolution. 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). 
 
2) Permanently discontinue.  
 
Immune mediated hepatitis: 
1) 
Grade 2 or higher 
transaminase elevations that are 
possibly, probably or definitely related 
to nivolumab or ipilimumab (with or 
without total bilirubin elevations) 
 
• 
AST or ALT >3 to 5 times ULN 
(grade 2) 
• 
Total bilirubin >1.5 to 3 times 
ULN (grade 2) 
 
2) Severe (grade 3) or life-threatening 
(grade 4) transaminase elevations 
1) 
Hold treatment until 
recovery to grade 1 or 
resolution and Withhold 
treatment and initiate high-dose 
systemic corticosteroids 
(prednisone 1 to 2 mg/kg daily 
or equivalent) 
 
 
 
2) 
Permanently discontinue 
treatment and initiate high-dose 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
10 
systemic corticosteroids 
(prednisone 1 to 2 mg/kg daily 
or equivalent)  
**document on conmed log* 
 
Kidney 
1) Creatinine >1.5 to 6 times ULN 
(grade 2 or 3) or >1.5 times 
baseline (grade 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
2) Creatinine >6 times ULN (grade 4) 
1) Hold treatment until 
recovery to grade 1 or 
resolution. 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). 
**document on conmed log* 
 
2) Permanently discontinue; 
initiate high-dose systemic 
corticosteroids 
**document on conmed log* 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
11 
Colitis 
1) Grade 2 (duration >5 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
2) Grade 3 
 
 
 
 
 
 
 
3) Colitis: (grade 4) 
 
 
 
 
 
4) Colitis (recurrent) 
1) Hold treatment until 
recovery to grade 1 or 
resolution. 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 
**document on conmed log* 
 
 
2) Permanently discontinue 
drugs.  Also administer 
systemic corticosteroids 
(prednisone 1 to 2 mg/kg 
daily or equivalent) 
followed by a corticosteroid 
taper 
**document on conmed log* 
 
 
 
3) Permanently discontinue 
drugs. Also administer high-
dose systemic 
corticosteroids (prednisone 
1 to 2 mg/kg daily or 
equivalent) followed by a 
corticosteroid taper 
 
 
4) Permanently discontinue 
drugs 
Lung 
1) Pneumonitis (grade 2) 
 
 
 
 
 
 
 
 
 
2) Pneumonitis (grade 3 or 4);  
1) Hold treatment until 
recovery to grade 1 or 
resolution. also administer 
high-dose systemic 
corticosteroids (prednisone 1 
to 2 mg/kg daily or 
equivalent) followed by a 
corticosteroid taper 
**document on conmed log* 
 
 
2) Permanently discontinue. 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
12 
also administer high-dose 
systemic corticosteroids 
(prednisone 1 to 2 mg/kg 
daily or equivalent) followed 
by a corticosteroid taper 
Immune mediated 
1)  
immune mediated toxicity 
1) Hold treatment for all 
grade 2 immune mediated 
clinically significant 
toxicities and >grade 2 
immune mediated 
toxicities, until recovery to 
grade 1 or resolution. 
2) For grade 2 or higher: Also 
administer corticosteroids 
followed by a corticosteroid 
taper  
3) Treatment can be resumed 
once prednisone is 
<10mg/day (or equivalent) 
**document on conmed log* 
 
 
Steroid taper 
1) Inability to reduce corticosteroid 
dose to prednisone ≤10 mg/day (or 
equivalent) within 12 weeks 
1) Permanently discontinue. 
Other adverse reactions that are  
 
1) life-threatening, severe  
or grade 3 treatment related 
adverse reactions that recur,  
2) or grade 3 treatment-related 
toxicity that does not recover to 
grade 1 or resolve within 12 
weeks (not including alopecia)  
1 & 2: Permanently discontinue. 
Thyroid disorder   
1) hyperthyroidism or 
hypothyroidism 
1) There are no recommended 
dosage modifications.  
 
Infusion reactions 
1) For Grade 1 symptoms (mild 
reaction, infusion interruption 
not indicated, intervention not 
indicated): 
 
 
 
 
 
 
 
 
1) 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 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
13 
 
 
 
 
2) 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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
additional nivolumab and 
ipilimumab administrations. 
**document on conmed log* 
 
2) Stop the nivolumab and or 
ipilimumab infusion,  
• 
begin an IV infusion of 
normal saline,  
• 
treat 
the 
subject 
with 
diphenhydramine 50 mg IV 
(or 
equivalent) 
and/or 
paracetamol 325 to 1000 mg 
(acetaminophen) 
• 
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 and or 
ipilimumab 
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 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3) 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): 
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. 
**document all on conmed log* 
 
3) Immediately 
discontinue 
infusion 
of 
nivolumab 
and/or 
ipilimumab 
depending on which agent 
was associated with the 
reaction.  
• 
Begin an IV infusion of 
normal saline and treat the 
subject 
as 
follows: 
recommend 
bronchodilators, 
epinephrine 0.2 to 1 mg of a 
1:1,000 
solution 
for 
subcutaneous 
administration or 0.1 to 0.25 
mg of a 1:10,000 solution 
injected 
slowly 
for 
IV 
administration, 
and/or 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
15 
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.  
• 
Investigators should follow 
their institutional guidelines 
for 
the 
treatment 
of 
anaphylaxis.  
• 
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). 
• 
Patients who develop a 
grade 3 or 4 infusion 
reaction from Ipilimumab 
may continue adjuvant 
therapy with Nivolumab at 
the 
discretion 
of 
the 
treating physician (must 
come off Ipilimumab). 
• 
Patients who develop a 
grade 3 or 4 infusion 
reaction from nivolumab 
to 
permanently 
discontinue all protocol 
treatment.  
**document all on conmed log* 
 
5.3 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 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
16 
AST): No dosage adjustment necessary. 
Moderate (total bilirubin >1.5 to 3 times ULN (grade 2) and any AST) to severe (total bilirubin >3 times 
ULN (grade 3 or higher) and any AST) impairment: There are no dosage adjustments provided in the 
manufacturer’s labeling (has not been studied). See required holds above 
5.4 Treatment of Nivolumab and Ipilimumab Related Infusion Reactions 
Since nivolumab a n d ipili mu ma b  contain only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypo- or hypertension, bronchospasm, or other symptoms.  
All Grade 3 or 4 infusion reactions to be reported within 24 hours/1 working day to BrUOG and 
reported as an SAE if it meets the criteria (as per SAE definitions in section 11). Infusion reactions 
should be graded according to NCI CTCAE (version 4) guidelines. All infusion reactions, regardless of 
grade must be reported to BrUOG via AE log and treatment CRF as well. 
Treatment recommendations are provided below and may be modified based on local treatment standards 
and guidelines as appropriate, see table above for management and action. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
17 
6.0 SCHEDULE OF EVALUATIONS / STUDY CALENDAR *The day an assessment (PE, labs, 
scan etc) is completed is day 0 for counting for example labs drawn on Friday can be used for 
Monday dosing as this is within 3 days* 
Parameter 
Pre-study 
(to be sent to BrUOG 
prior to registration) 
Within 3 days prior to 
each treatment during 
Each Cycle of F 
 
End of Treatment( 
defined as post last 
cycle)(+2 week 
window provided)  
30 days (+7 
days) post last 
dose of drug 
FUD 
Informed Consent (within 
30 days of day 1) *pts are 
to be re-consented if ICF 
outside 30 day window 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Nivolumab and 
Ipilimumab nivolumab 
 
X 
 
 
 
History G 
X 
 
 
 
 
Physical examination with 
performance status 
X 
X 
X 
XI 
 
Weight 
X 
X 
X 
 
 
Vital signs 
X 
X 
X 
 
 
Toxicity Assessment 
X 
X 
X 
XH 
XH 
Conmed log 
X 
X 
X 
X 
 
CBC, diff, platelet count  
X (within 14 days) 
X 
X 
 
 
Na, K, BUN, Cr, AST, 
ALT, Direct and Total 
Bilirubin, Albumin 
X (within 14 days) 
X 
X 
 
 
Ca, Mg, PO4  
X (within 14 days) 
As per institutional 
standard of careK 
X 
 
 
TSH  
X (within 14 days) 
As per institutional 
standard of careK 
X 
 
 
Hep B and C panel 
(HBsAg, Anti-HBs, Hep 
B core and HCV RNA 
and HCV antibody)L 
X 
 
 
 
 
Serum PregnancyE  
X (within 7 days of 
drug) 
 
 
 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
18 
CT scan of  
Chest/abd/pelvis 
XAC(within 12 weeks) 
 
XCJ  
 
XDC 
CT scan or MRI of brain 
with contrast 
X(within 6 weeks) 
 
Only if clinically 
indicated 
 
Only if 
clinically 
indicated 
EKGB 
X 
 
 
 
 
Survival and Disease status  
 
 
 
X 
XD 
Cycles are every 6 weeks (+/- 8 days) however, it will not be considered a deviation if a cycle or pre-treatment assessments must 
be adjusted to accommodate scheduling or holidays. Adjustment must be documented with reason to BrUOG.  
A- CT Scan (C/Abd/P) for disease assessment to be performed within 12 weeks of study entry. Report required. (chest X-ray okay 
with baseline but CT scan should be used during trial). 
B- EKG within 12 weeks of study entry. Report required 
C- An MRI or PET scan may substitute for disease assessment.  
D- Follow-up will be as per institutional standard of care approximately (+/- 2 months) every 6 months for 5 years. Disease status 
and survival to be sent with follow-up. Imaging of chest/abdomen/pelvis to be done approximately every 6-12 months from last 
scan, according to institutional practice, with scans to be sent to BrUOG until disease progression. It required that any assessment 
or pathology showing disease progression be sent to BrUOG 
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). PS, weight, vitals, AE, conmeds, can be used for cycle 1 day 1 if within 14 days. A physical 
exam within 7 days prior to cycle 1 day 1 may be utilized.  Labs, physical exam, PS, weight, vitals, AEs, conmed log for all 
subsequent treatments (post cycle 1 day 1) to be within 3 days prior to treatment days. An additional 1 day window is provided 
for holidays.  
G Physician note required to be sent.  
H Adverse event evaluation, inclusive of SAE evaluation, will be done 30 days post last dose of drug (+1 week window). 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, SAEs will be captured for 30 days post last dose of drug, regardless if patient begins a 
new treatment. SAEs occurring outside this 30 day window must be reported if the relationship to either study drug (or the 
combination) is suspected, even if patient begins a new treatment. It is required to inform BrUOG of patient beginning a new 
treatment and of surgery/pathology. 
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 after completion of all treatment (if patient stops treatment 
early then assessment to be done post all treatment)  
K Any time labs drawn per institutional care, even if not required by study, gradable values must be reported to BrUOG 
L Patient can be registered with a pending HCV RNA value as long as all other hepatitis results are confirmed non-
reactive/negative 
 
7.0 ASSESSMENT OF DISEASE PROGRESSION: 
Any new biopsy proven cutaneous SCC or basal cell carcinomas, should be excised according to standard 
guidelines. It is required that BrUOG received pathology and excision information. This will not require 
patient to be removed from trial. 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
19 
Any diagnosis of melanoma in-situ will not require patient removal from study but site must submit 
pathology and excision to BrUOG.  
 
Any diagnosis of melanoma (not in-situ) will be considered recurrence and patient will be required to be 
removed from study. It is required that all diagnostic information be submitted to BrUOG. 
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. 
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:  
 
 
 
 
 
Brown University Oncology Research Group, 
Brown University 
Box G-R 001 
Providence, RI 02912 
Fax: 401-863-3820 
Phone: 401-863-3000 
Email to: bruog@brown.edu 
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 
9.1 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 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
20 
• 
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. 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: Patients who were enrolled and began treatment before Amendment # 2 was IRB approved: 
Nivolumab: 3mg/kg q2weeks (+/-3 days) (3 doses per cycle, 12 planned treatments over 6 months total) 
Patients enrolled and who start treatment (cycle 1) based on Amendment #2: Nivolumab: 3mg/kg up to a 
total a total of 240mg IV over approximately 60 minutes (+/- 3 days) (3 doses per cycle, 12 planned 
treatments over 6 months total) 
Doses do not need to be recalculated if weight change is less than 10% of total body weight, as per 
institutional standard practice. 
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) 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
21 
9.2 Ipilimumab 
Only commercially available ipilimumab will be utilized.  
Ipilimumab will be stored and administered according to the package insert and institutional standard of 
care.  
Brand Names: US  
• 
Yervoy 
Pharmacologic Category  
• 
Antineoplastic Agent, Monoclonal Antibody 
Dosage Forms: US  
Excipient information presented when available (limited, particularly for generics); consult specific product 
labeling. 
Dosage: Subjects will be treated with 1mg/kg approximately every 6 weeks. Doses do not need to be 
recalculated if weight change is less than 10% of total body weight, as per institutional standard practice. 
Solution, Intravenous [preservative free]:  
Yervoy: 50 mg/10 mL (10 mL); 200 mg/40 mL (40 mL) [contains polysorbate 80] 
Generic Equivalent Available: US  
No Medication Guide and/or Vaccine Information Statement (VIS)  
An FDA-approved patient medication guide, which is available with the product information and at 
http://www.fda.gov/downloads/Drugs/DrugSafety/UCM249168.pdf, must be dispensed with this 
medication. 
 
Storage/Stability 
Store intact vials refrigerated at 2°C to 8°C (36°F to 46°C); do not freeze. Protect from light. Prior to 
preparation, allow vials to sit at room temperature for ~5 minutes. Solutions diluted for infusion are stable 
for up to 24 hours refrigerated or at room temperature. 
Preparation for Administration 
Prior to preparation, allow vials to sit at room temperature for ~5 minutes. Inspect vial prior to use; 
solution may have a pale yellow color or may contain translucent or white amorphous ipilimumab 
particles; discard if cloudy or discolored. Withdraw appropriate ipilimumab volume and transfer to IV 
bag, dilute with NS or D5W to a final concentration between 1-2 mg/mL. Mix by gently inverting, do not 
shake. 
Compatibility 
Stable in NS, D5W 
Administration  
IV: Infuse over approximately 90 minutes through a low protein-binding in-line filter. Flush per 
institutional standard volume with NS or D5W at the end of infusion 
Immune-mediated adverse reactions:  
• 
Ipilimumab can result in severe and fatal immune-mediated adverse reactions due to T-cell 
activation and proliferation. These immune-mediated reactions may involve any organ system; 
however, the most common severe immune-mediated adverse reactions are enterocolitis, 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
22 
hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The 
majority of these immune-mediated reactions initially manifested during treatment; however, a 
minority occurred weeks to months after discontinuation of ipilimumab. 
• 
Permanently discontinue ipilimumab and initiate systemic high-dose corticosteroid therapy for 
severe immune-mediated reactions. 
• 
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and 
endocrinopathy, and evaluate clinical chemistries, including liver function tests and thyroid 
function tests, at baseline and before each dose. 
10.0 
AGENT ACCOUNTABILITY 
All drugs will be administered to eligible patients under the supervision of the investigator or identified 
sub-investigator(s).  The pharmacist will maintain records of drug dispensing via institutional practices.  
 
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 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 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
23 
• 
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. 
 
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). 
 
 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be reported as an 
adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or 
treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
24 
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific judgment 
should be exercised in deciding whether an isolated vital sign abnormality should be classified as an 
adverse event. 
 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high blood 
pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event CRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should not be 
repeatedly recorded on the Adverse Event CRF, unless the etiology changes. The initial severity of the 
event should be recorded, and the severity or seriousness should be updated any time the event worsens. 
 
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. 
 
Serious adverse events occurring more than 30 days after study discontinuation (treatment) need only be 
reported if a relationship to either study drug (or therapy) or combination of drugs is suspected.  
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 email 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 or Ipilimumab must be reported to BrUOG within 24 hours 
of being made aware of the event via the 3500A.  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 related to the in 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
25 
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 pregnancies must be reported to the Brown University Oncology Research Group with 24 hours of the 
Investigator’s knowledge.   
 
Non-pregnancy SAE information and all amendments or additions must be recorded on a MedWatch 
3500A SAE form and are to be faxed or emailed to BrUOG within 5 business days of being made aware 
of the event.  
 
Deaths or life threatening events during treatment thought to be related to either drug or combination of 
the drugs must be reported via Medwatch 3500A to BrUOG within 1 working day of being made aware of 
the event. 
 
All other deaths during treatment or within 30 days following completion of active protocol therapy 
(treatment) must be reported within 5 business days or as soon as the investigator is made aware of the 
event. 
 
Serious adverse events occurring more than 30 days after study discontinuation (treatment) need only be 
reported if a relationship to either study drug (or therapy) or combination of drugs is suspected.  
 
BrUOG fax: 401-863-3820 Email: bruog@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.   
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 
treatment, or until the subject withdraws consent from study participation (declines participation) or at the 
time patient becomes a screen failure, whichever occurs first. If the patient begins a new treatment, AE 
evaluation (not SAE evaluation) will be stopped unless the patient experiences an event that is thought to 
be possibly related to the study treatment. 
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 resolution of the SAE (defined 
as discharge from hospital) is required.   

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
26 
 
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 must be 
reported within 5 business days or as soon as the investigator is made aware of the event. Deaths or life 
threatening events during treatment thought to be related to either drug or combination of the drugs are to 
be reported within 1 working day to BrUOG, from the time of being made aware of the event. 
 
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 (initial or follow-up) contact BrUOG Central Office at via email within 24 
hours upon learning of the event to announce the SAE. Submit notification within 24 hours prior to 
sending signed written MedWatch 3500A. 
 
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. Deaths or life threatening events during 
treatment and thought to be related to either drug or combination of the drugs or pregnancies must be 
reported via Medwatch 3500A to BrUOG within 1 working day of being made aware of the event. All 
Grade 3 or 4 infusion reactions that meet SAE criteria are to be reported within 24 hours/1 working day 
to BrUOG via Medwatch 3500A. All pregnancies must be reported to the Brown University Oncology 
Research Group within 24 hours of the Investigator’s knowledge. 
 
All other deaths during treatment or within 30 days following completion of active protocol therapy 
(treatment) must be reported within 5 business days or as soon as the investigator is made aware of the 
event. 
 
Brown University Oncology Research Group 
Phone : (401) 863-3000, Fax : (401) 863-3820 
Email : BrUOG@brown.edu 
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 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
27 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each product and suspect 
medication 
• 
Expectedness (based on package insert and ICF) and if event is immune mediated 
• 
Must document BrUOG 324 on 3500A 
 
Follow-up information:   
A new Medwatch3500A is required to be used for a follow-up, do not add new information to a 
previously submitted form.  
 
Summarize new information 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). 
 
All requirements for an initial report remain requirements for a follow-up. It is also required that the 
report clearly state what new information is being reported at the time of the follow-up. 
 
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 signed information via the site 
submitted MedWatch 3500A. 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 package insert.  All SAEs will be faxed by BrUOG to the 
FDA as soon as possible but no later than 7 calendar days after BrUOG has received the final signed 
MedWatch from the site.  Each telephone call or fax transmission (see fax number below) should be 
directed to the MedWatch fax number.  
 
Sites are required to submit MedWatch3500A reports no later than 5 business days after being informed 
of an event. 
 
BrUOG will fax reports to the FDA for IND Safety Reports: 1 (800) FDA - 0178 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
28 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a serious 
adverse event according to institutional policy.   
 
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. 
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. 
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. 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
29 
14.0 REGULATORY CONSIDERATIONS 
This research study is sponsored by the Principal Investigator, Dr. Maria Constantinou, 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 by the 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 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  

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
30 
• 
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 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 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
31 
must provide support at all times for these activities. BrUOG will audit sites based on the BrUOG audit 
manual and will monitor sites based on the BrUOG SOP. 
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 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 Principal Investigator with the assistance of the Brown University Oncology Research Group, as 
coordinator of this study, are 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 
(Maria Constantinou, M.D.) and Brown University Oncology Research Group 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. Amgen 
will notify the Principal Investigator if an application is filed.  
16.0 DATA SAFETY AND MONITORING BOARDS 
All trials initiated by the Brown University Oncology Research Group (BrUOG) are subject to 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.   

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
32 
• 
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 
17.1: Toxicity of Adjuvant Ipilimumab and Nivolumab 
The primary goal will be to determine the toxicity of adjuvant ipilimumab and nivolumab in patients with 
melanoma. A rate of 35% or greater grade 3 or grade 4 treatment related non-hematologic toxicities or 
grade 4 neutropenia or thrombocytopenia, or grade 2 treatment related toxicities that prevent the 
completion of treatment will be considered to be unacceptable. According to Flemming’s method59 with a 
maximum overall significance level of 0.05 if there are: 10 or more patients with unacceptable adverse 
events out of 25 evaluable patients, the study will have exceeded the limit for unacceptable adverse 
events.   
17.2 Assessment of disease-free and overall survival 
Disease-free and overall survival will be assessed from the day of study entry. 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
33 
18.0 REFERENCES 
1. Guy GP Jr, Thomas CC, Thompson T, et al. Vital signs: melanoma incidence and mortality trends 
and projections – United States, 1982-2030, MMWR Morb Moral Wkly Rep 2015; 64-591. 
2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014, CA Cancer J Clin 2014; 64:9. 
3. Elwood JM, Jopson J. Melanoma and sun exposure: an overview of published studies. Int j 
Cancer 1997; 73: 198. 
4. Gallagher RP, Spinelli JJ, Lee TK. Tanning beds, sunlamps, and risk of cutaneous malignant 
melanoma. Cancer Epidemiol Biomarkers Prev 2005; 14:562.  
5. Berwick M, Orlow L, Hummer AJ, et al. The prevalence of CDKN2A germ-line mutations and 
relative risk for cutaneous malignant melanoma: an international population-based study. Cancer 
Epidemiol Biomarkers Prev 2006; 15: 1520.  
6. Balch CM, Soong S, Milton GW, et al: A comparison of prognostic factors and surgical results in 
1,786 patients with localized (stage I) melanoma treated in Alabama, USA, and New South 
Wales, Australia. Ann Surg 196:677-684, 1982 
7. Balch CM, Soong S, Murad TM, et al: A multifactorial analysis of melanoma: III. Prognostic 
factors in melanoma patients with lymph node metastases (stage II). Ann Surg 193:377-388, 1981 
8. Balch CM, Murad TM, Soong SJ, et al: A multifactorial analysis of melanoma: Prognostic 
histopathological features comparing Clark's and Breslow's staging methods. Ann Surg 188:732-
742, 1978 
9. Veronesi U, Adamus J, Aubert C, et al. A randomized trial of adjuvant chemotherapy and 
immunotherapy in cutaneous melanoma. N Engl j Med 1982; 307:913. 
10. Lipton A, Harvey HA, Balch CM, et al. Corynebacterium parvum versus bacilli Calmette-Guerin 
adjuvant immunotherapy of stage II malignant melanoma J Clin Oncol 1991:9:1151. 
11. Loutfi A, shakr A, Jerry M, et al. Double blind randomized prospective trial of 
levamisole/placebo in stage I cutaneous malignant melanoma. Clin Invest Med 1987; 10:325. 
12. Lesinski GB, Anghelina M, Zimmerer J et al. The antitumor effects of IFN-alpha are abrogated in 
an STAT1-deficient mouse. J Clin Ivest 2003; 112:170.  
13. Moschos SJ, Edington HD, Land SR, et al. Neoadjuvant treatment of regional stage IIIB 
melanoma with high-dose interferon alfa-2b induces objective tumor regression in association 
with modulation of tumor infiltrating host cellular immune responses J Clinn Oncol 2006; 
24:3164. 
14. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-
risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J 
clin Oncol 1996:14:7. 
15. Kirkwood JM, Manola J, Ibrahim J, et al. A poosled analysis of eastern cooperative oncology 
group and intergroup trials of adjuvant high-dose interferon for melanoma Clin Cancer Res 2004: 
10:1670. 
16. Bouwhuis MG, Suciu S, Testori A, et al. Phase III trial comparing adjuvant treatment with 
pegylated interferonAlfa-2b versus observation: prognostic significance of autoantibodies – 
EORTC 18991. J clin Oncol 2010; 28:2460. 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
34 
17. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with 
metastatic melanoma. N Engl J Med 2010; 363: 711-23. 
18. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated 
metastatic melanoma. N Engl J Med 2011; 364: 2517-26. 
19. Maio M, Grob JJ, Aamdal S, et al. Five year survival rates for treatment-naive patients with 
advanced melanoma who received ipilimumab plus dacarbazine in aphase III trial. J Clin Oncol 
2015; 33: 1191-6. 
20. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II 
and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015 
February 9 (Epub ahead of print). 
21. Robert C, Long GV, Brady B, et al.Nivolumab in previously untreated melanoma without BRAF 
mutation. N Engl J Med 2015; 372: 320-30. 
22. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with 
advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a 
randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; 16: 375-84. 
23. Dummer R, Daud A, Puzanov I, et al. A randomized controlled comparison of pembrolizumab 
and chemotherapy in patients with ipilimumab-refractory melanoma. J Transl Med 2015; 13: 
2062. 
24. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced 
melanoma. N Engl J Med. DOI: 10.1056/NEJMoa1503093. 
25. Larkin J, Chiarion-Sileni V, Gonzalez, R et al. Combined nivolumab and ipilimumab or 
monotherapy in untreated melanoma 2015: 373: 23-34. 
26. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after 
comlete resection of high risk stage III melanoma (EORTC 18071): a randomized, double-blind, 
phase 3 trial. Lancet Oncol 2015; 16:522.  
27. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with previously 
treated, advanced melanoma: A randomized, double-blind, multicenter, phase 2, dose-ranging 
study. Lancet Oncol 2010; 11:155–164. 
28. Prieto PA, Yang JC, Sherry RM, et al: CTLA-4 blockade with ipilimumab: Long-term follow-up 
of 177 patients with metastatic melanoma. Clin Cancer Res 18:2039-2047, 2012 
29. 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 
30. Paz-Ares L, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of 
nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small 
cell lung cancer (NSCLC). J Clin Oncol 33, 2015 (suppl; abstr LBA109). 
31. Spigel DR, Reckamp KL, Rizvi NA, et al. A phase III study (CheckMate 017) of nivolumab 
(NIVO; anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated advanced or 
metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC). J Clin Oncol 33, 2015 
(suppl; abstr 8009). 
32. Rizvi NA, Gettinger SN, Goldman JW, et al. Safety and efficacy of first-line nivolumab and 
ipilimumab in non-small cell lung cancer. 16th World Conference on Lung Cancer. Abstract 
ORAL02.02. Presented September 7, 2015.  

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
35 
APPENDIX A  
 
Agreement to Participate in a Research Study And Authorization for Use and Disclosure of 
Information 
BrUOG 324 Adjuvant Nivolumab and Low Dose Ipilimumab  
for Stage III and Resected Stage IV Melanoma: 
A Phase II Brown University Oncology Research Group Trial 
 
You are being asked to take part in a research study.  All research studies carried out at <INSERT 
HOSPTIAL NAME> are covered by rules of the Federal government as well as rules of the State and 
<INSERT HOSPTIAL NAME>.  Under these rules, the researcher will first explain the study, and then 
he or she will ask you to participate.  You will be asked to sign this agreement that states that the study 
has been explained, that your questions have been answered, and that you agree to participate. 
The researcher will explain the purpose of the study. He or she will explain how the study will be carried 
out and what you will be expected to do.  The researcher will also explain the possible risks and possible 
benefits of being in the study.  You should ask the researcher any questions you have about any of these 
things before you decide whether you wish to take part in the study.  This process is called informed 
consent. 
This form also explains the research study.  Please read the form and talk to the researcher about any 
questions you may have.  Then, if you decide to be in the study, please sign and date this form in front of 
the person who explained the study to you. 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, Dr. Maria 
Constantinou, in collaboration with Brown University Oncology Research Group (BrUOG), which will 
serve as the central coordinating office for the study.  
You are being asked to take part in this study because you have malignant melanoma that has spread to 
lymph nodes or to other parts of your body. While all of the areas involved by the melanoma have been 
removed by surgery there is a high risk that your cancer will recur (come back).  
Treatment options for patients with melanoma at high risk for recurrence include close observation or 
treatment with drugs that are designed to stimulate the immune system in the hope that it will attack any 
remaining melanoma cells. These drugs are interferon and ipilimumab. While ipilimumab has been shown 
to reduce the risk of melanoma recurring, at the dose used in the study that showed it to be effective this 
drug has serious and sometimes life-threatening side effects. In this study we are testing a lower dose of 
ipilimumab. Your doctor will explain these options and the side effects of these options.  
In patients with advanced melanoma, where the cancer has spread to other areas of the body and cannot 
be removed with surgery, the combination of Ipilimumab with another drug that stimulates the immune 
system, Nivolumab has been shown to be both more effective at shrinking melanoma tumors and 
preventing them from growing and to have fewer serious side effects than high dose Ipilimumab by itself.  
Your doctors are studying how well the combination of lower dose Ipilimumab and Nivolumab are 
tolerated and how effective this combination is in preventing melanoma from coming back in patients like 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
36 
you.  While Nivolumab is FDA approved to treat patients with advanced melanoma, it is not FDA 
approved to treat patients like you who are at high risk for their melanoma to recur. In this study you will 
receive the FDA approved dose of Nivolumab for advanced melanoma together with one-third of the 
standard dose of Ipilimumab, and the Ipilimumab will be given approximately once every 6 weeks instead 
of every 3 weeks.  The investigational aspect of the trial is the use of Nivolumab and lower dose 
Ipilimumab to try to prevent recurrence of melanoma after surgery.   
How Many People will take part in the Study?  
Approximately 25 patients will participate 
Explanation of Procedures   
What will happen if I take part in this research study?  
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then 
you will need the following tests, while on the study.  They are part of regular cancer care.  
• 
Medical history prior to starting treatment. 
• 
Physical examination with performance status and toxicity assessment, weight and vitals  
 prior to starting  
• 
Blood tests prior to starting treatment (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 treatment  
• 
CT scan, PET scan, or MRI of the chest, abdomen and pelvis, and a CT or MRI of the brain, prior to 
starting treatment  
• 
EKG prior to starting treatment 
 
While on study: 
You will receive nivolumab by vein (IV) over 60 minutes, approximately every 2 weeks for 12 
treatments.  You will also receive Ipilimumab IV over 90 minutes approximately every 6 weeks for 4 
treatments. The two drugs will be given together at the start of each 6 week cycle, then the nivolumab will 
be given by itself approximately 2 weeks and 4 weeks later. You will be receiving nivolumab and 
ipilimumab for about 6 months. 
You will have the following completed while on study treatment. These assessments are considered a part 
of regular cancer care. 
• 
Physical examination with performance status and toxicity assessment, review of medication list, 
weight and vitals approximately every 2 weeks while on treatment 
• 
Blood tests (approximately 3 tablespoons of blood) approximately every 2 weeks while on treatment 
• 
CT scan, PET scan, or MRI of the chest, abdomen and pelvis at treatment completion. MRI or CT of 
the brain will be performed if clinically indicated by your treating physician 
 
 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
37 
End of study treatment (6-7 months, unless the study treatment has to be stopped early for some 
reason):  
• 
Physical examination, with performance status and toxicity assessment (at the end of treatment and 
again 30 days post the last dose of drug) 
• 
Blood tests (approximately 3 tablespoons of blood) and at the end of treatment and 30 days post last 
dose of drug 
• 
CT scan of the chest, abdomen and pelvis  
• 
CT or Brain MRI as needed 
 
Follow-up: 
• 
CT scan of the chest, abdomen and pelvis approximately every 6-12 months (your doctor may decide 
to do these more frequently) for up to 5 years or until the melanoma recurs (returns or gets worse) 
• 
CT or Brain MRI at the discretion of your doctor  
 
After completion of treatment you will be seen by your doctor approximately every 6 months for 5 years 
so that he/she can document if your melanoma has recurred and that you are still alive.   
Can I stop being in the study?  
Yes. You can decide to stop at any time.  Tell your 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 your doctor if you are thinking about stopping so any risks from the discontinuation 
of treatment can be evaluated. 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.  
Your 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.  
Costs for participating in this study  
All the services you will receive during this research study are considered to be “routine clinical services” 
that you would have received even if you were not participating in the research study. These include all 
study doctor visits, blood tests, Nivolumab and Ipilimumab drugs and administration costs, drugs used to 
reduce side effects, CT scans, MRIs, PET scans and EKGs.  Therefore, all of the services listed in this 
paragraph 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 or your insurance does not cover these services, you will be responsible for 
those costs. 
Contact Information: If you have any questions regarding this study, you may contact your site’s 
Principal Investigator, <INSERT NAME AND CONTACT> 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
38 
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. 
Nivolumab and Ipilimumab are both immunotherapy drugs. The anticipated side effects of each of 
the drugs, at the doses used in this study, are approximately the same. There are also some side 
effects which may not yet be known. 
Possible Side Effects of Ipilimumab  
Ipilimumab is an agent involved in the inhibition of “immune checkpoints,” and may result in severe and 
possibly fatal immune-mediated side effects probably due to activation and growth of immune cells (T-
cells from white blood cells).  Immune-mediated side effects have been reported in patients receiving 
ipilimumab.  In clinical trials, most side effects were reversible and managed by stopping ipilimumab 
temporarily, administration of supportive care. While rare, immune mediated side effects may also occur 
after stopping ipilimumab. These are considered late onset immune mediated toxicities, which may begin 
even months after stopping treatment. Your doctor will closely monitor you after you stop treatment and 
provide supportive care as necessary.  
Common (>20%) 
• 
Diarrhea, nausea 
• 
Tiredness 
• 
Rash which may cause fever and swollen, red, painful bumps in the skin 
Occasional, some may be serious (<20%-4%) 
• 
Abnormal heartbeat 
• 
Hearing loss 
• 
Swelling and redness of the eye 
• 
Pain  
• 
Constipation, vomiting 
• 
Swelling of the body which may cause shortness of breath 
• 
Difficulty swallowing, eating 
• 
Chills, fever 
• 
Reaction during or following infusion of the drug 
• 
Damage to organs leading to prolonged hospitalization (The agent can induce immune reactions 
and inflammation which can cause serious and life-threatening damage to organs including the 
skin, colon, gut, liver, pancreas, heart, brain, muscle, kidney, and endocrine glands) 
• 
Loss of appetite, dehydration 
• 
Abnormal movement of the facial muscles 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
39 
• 
Headache 
• 
Weakness and paralysis 
• 
Kidney damage which may require dialysis 
• 
Itching, hives 
• 
Low blood pressure which may cause feeling faint 
 
Rare and serious (< 3% or fewer) 
• 
Bleeding 
• 
A tear or hole in the stomach that may require surgery 
• 
Severe skin rash with blisters and peeling which can involve mouth and other parts of the body. 
• 
Pericardial effusion 
• 
Adrenal insufficiency (adrenal glands do not produce enough cortisol hormone) 
• 
Hypophysitis (inflammation of pituitary gland) 
• 
Confusion 
• 
Dizziness  
Possible Side Effects of Nivolumab  
Nivolumab is an agent involved in the inhibition of “immune checkpoints,” and may result in severe and 
possibly fatal immune-mediated side effects probably due to activation and growth of immune cells (T-
cells).  Immune-mediated side effects have been reported in patients receiving Nivolumab.  In clinical 
trials, most side effects were reversible and managed by stopping Nivolumab temporarily, administration 
of corticosteroids and supportive care. While rare, immune mediated side effects may also occur after 
stopping Nivolumab. These are considered late onset immune mediated toxicities, which may begin even 
months after stopping treatment. Your doctor will closely monitor you after you stop treatment and 
provide supportive care as necessary.  
Common (>20%) 
• 
Tiredness 
Occasional, some may be serious (<20%-4%) 
• 
Anemia which may require blood transfusion 
• 
Swelling and redness of the eye which may cause blurred vision with a chance of blindness 
• 
Pain 
• 
Constipation, diarrhea, nausea, vomiting 
• 
Dry mouth 
• 
Fever 
• 
Loss of appetite 
• 
Cough, shortness of breath 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
40 
• 
Swelling of the body, including the brain, which may cause shortness of breath, headache, 
tiredness, and nerve pain 
• 
Itching, rash 
 
Rare and serious (<3% or fewer) 
• 
Visual disturbances 
• 
A tear or hole in the stomach that may require surgery 
• 
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• 
Damage to the body by own immune system 
• Weakness and paralysis 
• 
A condition with high blood sugar which may cause tiredness, frequent urination, excessive thirst, 
headache, nausea, vomiting, and can result in coma 
• 
Muscle weakness 
• 
Kidney damage which may require dialysis 
• 
Pericardial effusion 
• 
Edema (including periorbital edema, face edema, generalized edema, gravitational edema, 
localized edema, peripheral edema, pulmonary edema, and lymphedema) 
• 
Pleural effusion 
• 
Adrenal insufficiency (adrenal glands do not produce enough cortisol hormone) 
• 
Hypophysitis (inflammation of pituitary gland) 
• 
Dehydration 
• 
Confusion 
• 
Dizziness 
 
Lung Inflammation (pneumonitis):  It is possible that ipilimumab and 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; 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
41 
• 
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. 
 
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 and ipilimumab 
Nivolumab and ipilimumab 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. 
 
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. 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
42 
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. 
Risk of CT imaging: CT imaging uses x-rays. The radiation dose associated with this procedure is 
estimated to be a small fraction of the annual permissible dose to an x-ray technologist. There is no 
significant risk from this amount of radiation. 
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 
While your doctor hopes that ipilimumab and nivolumab will lower the risk that your melanoma will 
come back, and the side effects of this combination are not too severe, this is not yet known. We do know 
that the information from this study will help doctors learn more about these drugs as a treatment for 
cancer. This information could help future cancer patients. 
Alternative Therapies 
What other choices do I have if I do not take part in this study?  
• 
Treatment with standard (higher) dose ipilimumab  
• 
Treatment with high dose interferon 
• 
Taking part in another study 
• 
Being followed closely for recurrence of melanoma by CT or other scans and not receiving treatment.   
 
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 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
43 
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 Dr. Maria Constantinou nor BrUOG, the coordinating center, have money set 
aside to reimburse you for medical bills from 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 NAME OF IRB> 
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.  
 

1 0/ 2 5/ 1 5, 1 0/ 2 6/ 1 5, 1 0/ 2 8/ 1 5, 1 0/ 2 9/ 1 5, 1 1/ 1 7/ 1 5 a p pr o ve d E xec, 1 1/ 2 7/ 1 5, R N W S re vi e w 1 2/ 4/ 1 5, 1 2/ 1 7/ 1 5 R N, 1 2/ 2 0/ 1 5, 1 2/ 2 3/ 1 5, 
1/ 5/ 1 6 H S re vie w, 1/ 6/ 1 6, 1/ 7/ 1 6, 1/ 1 9/ 1 6, F D A e xe m pti o n, 2/ 1 1/ 1 6, 2/ 2 6/ 1 6 f or L O C R i nitial, A me n d me nt # 1 1 0 - 5-1 6, A me n d me nt # 2 
3/ 1/ 2 0 1 7, 3/ 1 7/ 1 7(fi nal 4/ 4/ 1 7) u p date d 6/ 1 4/ 1 7, A me n d me nt # 3 1 0 -1 9 -1 7, A m e n d me nt # 4 1 2/ 2 6/ 1 7, A me n d me nt # 5 7/ 1 1 / 1 8, A me n d me nt 
# 6 1 2/ 8/ 1 8  
 
4 4  
Ge nerall y, t he e ntire researc h rec or d a n d a n y me dical rec or ds hel d b y t he h os pital ma y be use d a n d 
release d f or researc h p ur p oses. T he f oll o wi n g pe o ple or b usi nesses/c o m pa nies mi g ht use, release, or 
recei ve s uc h i nf or mati o n:  
 T he researc her a n d t heir s u p p ort staff;  
 T he st u d y s p o ns or: Dr. Maria C o nsta nti n o u  a n d ce ntral c o or di nati n g office: T he Br o w n U ni versit y 
O nc ol o g y Researc h Gr o u p a n d its re prese ntati ves 
 D oct ors, n urses, la b orat ories a n d ot hers w h o pr o vi de ser vices t o y o u i n c o n necti o n wit h t his st u d y;  
 T he c o m pa n y or secti o n of t he U. S. g o ver n me nt t hat is pa yi n g f or t he st u d y a n d ot hers t he y hire t o 
o versee, a d mi nister, or c o n d uct t he researc h;  
 T he U nite d States F o o d a n d Dr u g A d mi nistrati o n, t he De part me nt of Healt h a n d H u ma n Ser vices, t he 
Office of I ns pect or Ge neral, a n d t he Office of Ci vil Ri g hts;  
 Pe o ple w h o v ol u nteer t o be patie nt a d v ocates or researc h v ol u nteer pr otect ors;  
 Me m bers of t he h os pital's a d mi nistrati ve staff res p o nsi ble f or re vie wi n g, a p pr o vi n g a n d a d mi nisteri n g 
cli nical trials a n d ot her healt hcare or researc h acti vities.  
 
T here are ti mes w he n t he la w mi g ht re q uire or per mit <I N S E R T H O S PI T A L N A M E > t o release y o ur 
healt h i nf or mati o n wit h o ut y o ur per missi o n. F or e xa m ple, <I N S E R T S T A T E >  la w re q uires researc hers 
a n d healt h care w or kers t o re p ort a b use or ne glect of c hil dre n t o t he De part me nt of C hil dre n, Y o ut h a n d 
Fa milies ( D C Y F) a n d t o re p ort a b use or ne glect of pe o ple a ge 6 0 a n d ol der t o t he De part me nt of El derl y 
Affairs.  
 
All researc hers a n d healt h care pr o vi ders are re q uire d t o pr otect t he pri vac y of y o ur healt h care 
i nf or mati o n. Ot her pe o ple a n d b usi nesses/ or ga nizati o ns t hat are n ot healt h care pr o vi ders are n ot re q uire d 
b y la w t o d o t hat s o it is p ossi ble t he y mi g ht re -release y o ur i nf or mati o n.  
Y o u ha ve t he ri g ht t o ref use t o si g n t his f or m a n d n ot partici pate i n t he researc h. Y o ur ref usal w o ul d ha ve 
n o effect o n y o ur treat me nt, c har ges bille d t o y o u, or be nefits at a n y <I N S E R T H O S PI T A L N A M E > 
healt h care site. If y o u d o n ot si g n, y o u will n ot be a ble t o e nr oll i n t he researc h st u d y a n d will n ot recei ve 
treat me nt as a st u d y partici pa nt.  
If y o u deci de t o q uit t he st u d y after si g ni n g t his f or m (as descri be d i n Sectio n 6) n o ne w i nf or mati o n will 
be c ollecte d a b o ut y o u u nless y o u ga ve us per missi o n t o d o s o. H o we ver, t he h os pital or t he researc hers 
ma y c o nti n ue t o use i nf or mati o n t hat was c ollecte d bef ore y o u q uit t he st u d y t o c o m plete a nal ysis a n d 
re p orts of t his researc h. 
 
A d diti o nall y, a descri pti o n of t his cli nical trial will be a vaila ble o n htt p:// w w w. Cli nic al Tri als. g ov, as 
re q uire d b y U. S. la w. T his We b site will n ot i ncl u de i nf or mati o n t hat ca n i de ntif y y o u. At m ost, t he We b 
site will i ncl u de a s u m mar y of t he res ults. Y o u ca n searc h t his We b site at a n y ti me.  
If after y o u ha ve si g ne d t his f or m y o u ha ve a n y q uesti o ns relati n g t o y o ur ri g hts, please c o ntact <I N S E R T 
I R B C O N A T A C T I N F O R M A TI O N > 
F or m ore detail a b o ut y o ur pri vac y ri g hts see t he <I N S E R T H O S PI T A L N A M E > w h ic h has or will be 
gi ve n t o y o u. 
 
Rese arc h a ut h oriz ati o n f or use a n d discl os ure of i nf or m ati o n.   
T he p ur p ose of t his secti o n of t he d oc u me nt is t o pr o vi de y o u wit h s o me m ore i nf or mati o n a b o ut h o w t he 
i nf or mati o n lear ne d a b o ut y o u d uri n g t he st u d y will be use d a n d s hare d. 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
45 
We understand that your medical information is very personal and we will work hard to keep it private. If 
you sign this form you consent to participate in this research study and are giving us permission to use 
and share your personal health information in the ways described in this form.   
Understandings and notifications 
The main purpose of permitting the use and release of your information is to allow the research project to 
be conducted and to ensure that the information relating to that research is available to all parties who 
may need it for research purposes.  Your information may also be used as necessary for your research-
related treatment, to collect payment for your research-related treatment (when applicable), and to run the 
business operations of the hospital. 
All health care providers are required to protect the privacy of your information.  However, most persons 
or entities (i.e., businesses, organizations) that are not health care providers are not bound by law to 
protect the privacy of your information.  You understand that if the person or entity that receives your 
information is not a health care provider bound to protect your privacy, such person or entity might re-
release your health information.  
You have the right to refuse to sign this form.  If you do not sign this form, none of your health care 
outside the study, or the payment for your health care, or your health care benefits will be affected.  
However, if you do not sign this form, you will not be able to enroll in the research study described in this 
form, and you will not receive treatment as a study participant.  
If you sign this consent form, 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.  This information or action may be needed to complete 
analysis and reports of this research. This permission will never expire unless you cancel it.  To cancel 
this permission, please write to Maria Constantinou, MD c/o the Medical Oncology Clinical Research 
Office at Rhode Island Hospital, 593 Eddy Street, APC Building Rm. 131, Providence, RI 02903. 
If after you have signed this form you have any questions relating to your rights, please contact <INSERT 
IRB CONTACT> 
Uses and releases covered by this authorization (permission) 
Who will release, receive, and/or use your information?  This form will allow the following person(s), 
class(es) of persons, and/or organization(s)* to release,  use, and receive the information listed below in 
connection with this Study, or as required by law: 
 
Every research site for this study, including this hospital, and including each site's research staff 
and medical staff 
 
Health care providers who provide services to you in connection with this study 
 
Laboratories and other individuals and organizations that analyze your health information in 
connection with this study, in accordance with the study’s protocol 
 
The following research sponsors and the people and companies that they use to oversee, 
administer, or conduct the research: The Principal Investigator Maria Constantinou, MD and BrUOG, the 
central coordinating group for the study, and their representatives 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
46 
 
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 
 
The members and staff of the Institutional Review Board(s) or Ethics Committee(s) that approves 
this study 
 
Principal Investigator and other Investigators 
 
Study Coordinator 
 
Additional members of the Research Team 
 
The Patient Advocate or Research Volunteer Protector: _____________________ 
 
Members of the hospital's administrative staff responsible for administering clinical trials and 
other research activities 
 
Contract Research Organization (A contract research organization is an independent organization 
that agrees to oversee and make possible, various aspects of the clinical research process for the research 
sponsor.) 
 
Data and Safety Monitoring Boards and others that monitor the conduct of the Study, for example 
a Clinical Events Committee 
 
The members and staff of the hospitals affiliated Privacy Board (if such a board is used) 
 
Others:  
 
 
 
 
_____________________________ 
* If, during the course of the research, one of the companies or institutions listed above merges with or is 
purchased by another company or institution, this permission to use or release protected health 
information in the research will extend to the new company or institution.  
 
 The entire research record and any medical records held by the hospital may be used and released.   
 The following information: _____________________________________________ 
 
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 
This informed consent document expires on ______________.   
DO NOT sign this document after this expiration date 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
47 
 
__________________________________________ 
 
______________ 
Signature of witness (required if consent  
 
 
 
Date 
is presented orally or at the request of the IRB)  
 
 
 
 
 
 
 
 
__________________________________________ 
 
______________ 
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. 
______________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
48 
APPENDIX B: Checklist 
Adjuvant Nivolumab and Low Dose Ipilimumab for Stage III and  
Resected Stage IV Melanoma: 
A Phase II Brown University Oncology Research Group Trial 
Inclusion Criteria 
________(y/n) Pathologically or cytologically proven melanoma. The primary site of melanoma may be 
cutaneous or other body site such as ocular or anorectal. Document in writing location of cutaneous 
________(y/n) Completely resected stage III (lymph node positive) or resected stage IV disease. Patients 
with stage T4BN0 are also eligible. All patients must be disease free to be eligible. Confirmation to be 
sent to BrUOG. 
 
________(y/n) It is required that patients with stage IIIA disease have > 1mm nodal involvement via 
pathology assessment of the resected node. 
 
________(y/n) No prior treatment for melanoma other than surgical resection or radiation.  
________(y/n) At least 4 weeks since prior major surgery and 3 weeks since radiation from time of 
registration. Submit on prior treatment CRF. 
________(y/n) Voluntary, signed written informed consent, Date signed_____________ 
________(y/n) Age >18  
________(y/n) ECOG PS 0-1 
 
___________(y/n) Must be willing to consent to use effective contraception while on treatment and for 2 
months after the end of treatment.  
___________(y/n) CT scan of the chest/abdomen/pelvis within 12 weeks of study entry. Patients can have 
PET/MRI of the chest/abdomen/pelvis instead. Chest Xray okay baseline. 
________(y/n) MRI or CT brain with contrast within 6 weeks of study entry 
___________(y/n) EKG within 12 weeks study entry 
__________(y/n) Absolute neutrophil count ≥ 1,500/ul, Date_________ Value: ________ 
___________(y/n) Platelet ≥ 100,000/uL, Date_________Value : ________ 
___________(y/n) HGB >/= 9.5 g/dL Date_________Value : ________ 
___________(y/n) Total bilirubin ≤ 1.5 x ULN except subjects with normal direct bilirubin or those with 
known Gilbert’s syndrome, Date_________ Value : ______________ Send information to BrUOG if 
patient has known Gilbert’s syndrome 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
49 
___________(y/n) AST and ALT ≤ 2.5x ULN 
    
____________(y/n) Albumin > 2.5g/dL 
___________(y/n) Creatinine < 1.5 mg/dl or creatinine clearance > 50ml/min 
_______ (y/n) Women of child bearing potential must have a negative serum pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to Day 1 of treatment. Post-
menopausal women (surgical menopause or lack of menses >12 months) do not need to have a pregnancy 
test, please document status. 
Exclusion Criteria: 
_______(y/n) Patients with an active, known or suspected autoimmune disease. Subjects with vitiligo, 
controlled type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in 
the absence of an external trigger are permitted to enroll.  
______    (y/n) Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody  
______    (y/n) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug 
administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone 
equivalents are permitted in the absence of active autoimmune disease. 
________(y/n) Known history of HIV or known acquired immunodeficiency syndrome  
________(y/n) positive test result (chronic or acute) hepatitis B or C 
________(y/n) Clinically significant coagulopathy. Therapeutic use of anticoagulants are allowed (put on 
conmed log). 
________(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 autologous transplant or organ allograft even if not taking immunosuppressive 
medications 
 _______ (y/n) Pregnant or lactating or breastfeeding- see 3.2.3.  
_______ (y/n) Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy) or investigational anti-cancer drug 
_______ (y/n) Unwillingness or inability to follow the procedures required in the protocol, to document 
_______ (y/n) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair the ability of the 
subject to receive protocol therapy, or interfere with the interpretation of study results. 
_______ (y/n) Prior malignancy active within the previous 2 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or 
carcinoma in situ of the prostate, cervix, or breast. Documentation required to be sent to BrUOG 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
50 
_______ (y/n) History of severe hypersensitivity reaction to any monoclonal antibody to confirm in 
writing. 
________(y/n) Brain Metastases (whether resected or not) 
________(y/n) Leptomeningeal disease 
________(y/n) Bone metastases 
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 
It is required that each item from section 6 be submitted to BrUOG along with confirmation via source to 
match each inclusion and confirm each exclusion criteria. 
IRB approval date of protocol:   
  
Date of treatment ____________ 
Hospital where patient will be treated with Oncologist:    
 
 
 
 
Name of treating physician: _____________ 
Your signature:  
 
 
 
 
 
 
 
 
 
 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
51 
APPENDIX C 
 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 
 
 

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
52 
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

10/25/15, 10/26/15, 10/28/15, 10/29/15, 11/17/15 approved Exec, 11/27/15, RNWS review 12/4/15, 12/17/15RN, 12/20/15, 12/23/15, 
1/5/16HS review, 1/6/16, 1/7/16, 1/19/16, FDA exemption, 2/11/16, 2/26/16 for LOCR initial, Amendment #1 10-5-16, Amendment#2 
3/1/2017, 3/17/17(final 4/4/17) updated 6/14/17, Amendment # 3 10-19-17, Amendment # 4 12/26/17, Amendment #5 7/11/18, Amendment 
# 6 12/8/18 
 
53 
APPENDIX D 
CASE REPORT FORMS 
Attached separately are the BrUOG Case Report Forms