Phase II Study of Optimized Management of NIVOlumab Based on REsponse in Patients With Advanced Renal Cell Carcinoma (OMNIVORE Study)
Phase: PHASE2
Conditions: Renal Cancer
Sponsor: Toni Choueiri, MD

TITLE: Phase II study of Optimized Management of NIVOlumab based on Response in patients with 
advanced renal cell carcinoma (OMNIVORE study)  
 
NCT Number: NCT03203473 
 
Protocol Version Date: January 07, 2020 

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  DF/HCC Protocol #: 17-064 
 
 
 
TITLE: Phase II study of Optimized Management of NIVOlumab based on REsponse in 
patients with advanced renal cell carcinoma (OMNIVORE study) 
 
Coordinating Center: 
Dana-Farber Cancer Institute 
 
 
 
Principal Investigator (PI): 
 
 
 
  
 
 
 
Co-Investigators: 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
 
 
 
Trial Supported by: 
Bristol-Myers Squibb 
 
NCI-Supplied Agent: 
N/A 
Other Agents: 
Nivolumab and Ipilimumab; Bristol-Myers Squibb 
 
IND #: 
135115 
IND Sponsor: 
 

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TABLE OF CONTENTS 
1. 
SCHEMA ................................................................................................................... 4 
2. 
BACKGROUND AND RATIONALE ...................................................................... 5 
2.1 Disease Background……………………………………………………………..5 
2.2 Nivolumab………………………………………………………………….……7 
2.3 Ipilimumab……………………………………………………………………....8 
2.4 Nivolumab and Ipimumab…………………………………………...……….…9 
2.5 Rationale…………………………………………………………………….....10 
2.6 Correlative Studies Backgroud………………………………………………...10 
2.7 Study Design…………………………………………………………………...11 
3. 
STUDY OBJECTIVES. ...................................................................................... .....12 
3.1 Objectives………………………………………………………………………12 
4. 
ELIGIBILITY CRITERIA ....................................................................................... 13 
4.1 Inclusion Criteria…………………………………………………………….....13 
4.2 Exclusion Criteria……………………………………………………………....15 
5. 
SUBJECT REGISTRATION ................................................................................... 18 
5.1 General Guidelines for DF/HCC Institutions……………………………..……18 
5.2 Registration Process for DF/HCC Institutions…………………………………18 
5.3 General Gudielines for Other Investigative Sites………………………………18 
5.4 Registration Process for other Investigative Sites……………………….……..18 
6. 
TREATMENT PLAN. ............................................................................................. 19 
6.1 Drug Administration…………………………………………………………...20 
6.2 Pre-Treatment Criteria………………………………………………………....21 
6.3 Concomitant Medications……………………………………………………...22 
6.4 Supportive Care………………………………………………………………..23 
6.5 Criteria for Taking a Participant Off Protocol Therapy……………………….25 
6.6 Duration of Follow Up…………………………………………………….…..25 
6.7 Treatment Beyond Disease Progression………………………………………26 
6.8 Criteria for Taking a Participant Off Study…………………………………...26 
6.9 Replacement…………………………………………………………………...26 
7. 
DOSING DELAYS/DOSE MODIFICATIONS……………………………..……27 
7.1 Dosing Delays/Dose Modifications…………………………………………....27 
 
7.2 Criteria to Resume Treatment with Nivolumab with or without Ipilimumab....27 
 
7.3 Criteria to Discontinue Treatment with Nivolumab with or without Ipilimumab..28 
 
7.4 Managemnt Algorithms for Immune-Mediated Adverse Events………………29 
8. 
STUDY CALENDARS & EVALUATIONS .......................................................... 30 
8.1 Duration of Follow Up…………………………………………………………39 
9. 
BIOSPECIMEN STUDIES AND PROCEDURES ................................................. 39 
9.1 Blood for Germline DNA……………………………………………………...39 
9.2 Blood for Research Analysis…………………………………………………..39 
9.3 Tissue Studies………………………………………………………………….40 
9.4 Radiology Imaging Studies……………………………………………………41 
9.5 Storage of Biospecimens………………………………………………………41 
9.6 Confidentiality of Biospecimens………………………………………………41 
10. CRITERIA FOR DISEASE EVALUATION……………………………………..41 
10.1 Definitions……………………………………………………………………42 
10.2 Disease Parameters…………………………………………………………...42 
10.3 Response Criteria…………………………………………………………….43 

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10.4 Duration of Response………………………………………………………….45 
10.5 Immune-Related Response Criteria (irRC)…………………………………....46 
10.6 Response Review……………………………………………………………...48 
11. DRUG INFORMATION ........................................................................................ .48 
11.1 Nivolumab…………………………………………………………………….48 
11.2 Ipilumab……………………………………………………………………….51 
12. ADVERSE EVENTS ............................................................................................... 54 
12.1 Adverse Event List for Nivolumab…………………………………………...55 
12.2 Adverse Event Characteristics………………………………………………..55 
12.3 DF/HCC and BMS Expeditied Adverse Event Reporting……………………55 
12.4 Expedited Reporting to the Food and Drug Administration (FDA)………….57 
12.5 Expedited Reporting to Hospital Risk Management…………………………57 
12.6 Routine Adverse Event Reporting……………………………………………58 
12.7 Pregnancy…………………………………………………………………….58 
13. STATISTICAL METHODS .................................................................................... 59 
13.1 Study Design………………………………………………………………….59 
13.2 Endpoints……………………………………………………………………..59 
13.3 Sample Size and Accrual……………………………………………………..60 
13.4 Analysis Datasets……………………………………………………………..61 
13.5 Assessment of Safety…………………………………………………………62 
13.6 Operating Characteristics of Early Futility Stopping………………………...62 
13.7 Efficacy Analysis……………………………………………………………..63 
14. DATA REPORTING/REGULATORY REQUIREMENTS ................................... 66 
14.1 Data Reporting………………………………………………………………..66 
14.2 Data Safety Monitoring………………………………………………………66 
14.3 Multicenter Guidelines……………………………………………………….66 
14.4 Data Quality Oversight Activites…………………………………………….67 
14.5 Compliance with Trial Registration and Result Posting Requirement……….67 
15. DATA HANDLING AND RECORD KEEPING ................................................... 67 
15.1 Data Management…………………………………………………………….67 
15.2 Case Report Forms and Submission……………………………………….…67 
15.3 Record Retention……………………………………………………………..68 
15.4 Confidentiality………………………………………………………………..68 
16. PUBLICATION PLAN ........................................................................................... 68 
17. REFERENCES ........................................................................................................ 69 
18. APPENDICES ......................................................................................................... 72 
19. APPENDIX A: Performance Status Criteria…………………………………….....73 
20. APPENDIX B: Information on Possible Drug Interactions. ………………………....77 
21. APPENDIX C: Management Algorithms for Immune-Mediated AEs .................... 75 
22. APPENDIX D: DF/HCC Multi-Center Data and Safety Monitoring Plan .............. 82 

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2.2 
Nivolumab 
Programmed death receptor-1 (PD-1, CD279), a 55 kD type I transmembrane protein, is a 
member of the CD28 family of T-cell costimulary receptors that also includes CD28, CTLA-4, 
ICOS, and BTLA. PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine 
inhibitory motif (ITIM) and a membrane distal immunoreceptor tyrosine-based switch motif 
(ITSM). Two ligands specific for PD-1 have been identified: PD-L1 (B7-H1/CD274) and PD-L2 
(B7-DC/CD273). PD-L1 and PD-L2 have been shown to down-regulate T-cell activation upon 
binding to PD-1 in both murine and human systems22, 23. PD-1 delivers a negative signal by the 
recruitment of a protein tyrosine phosphatase SHP-2 to the phosphorylated tyrosine residue in 
the ITSM in its cytoplasmic region24, 25. PD-1 is primarily expressed on activated T cells, B cells 
and myeloid cells26. 
 
Nivolumab is a fully human, IgG4 (kappa) isotype, mAb that binds PD-1. Blockade of the PD-1 
pathway by nivolumab was studied using the mixed lymphocyte reaction (MLR). PD-1 blockade 
resulted in a reproducible enhancement of both proliferation and IFN- release in the MLR. 
 
Nivolumab monotherapy has been studied in subjects with RCC. In a phase 1 dose escalation 
followed by dose expansion study, the safety and clinical activity of nivolumab was 
investigated27. A total of 34 patients with previously treated RCC were enrolled between 2008 
and 2012 and received nivolumab (1-10 mg/kg) in an outpatient setting once every 2 weeks for 
up to 96 weeks. Ten patients (29%) achieved an objective response by RECIST 1.0 with median 
response duration of 12.9 months. Nine additional patients (27%) demonstrated SD lasting > 24 
weeks. Three of five patients who stopped treatment while in response continued to respond for 
≥ 45 weeks. Median OS in all patients (71% with 2-5 prior lines of therapy) was 22.4 months. 
And the 1, 2, and 3 year survival rates were 71%, 48%, and 44%. Grade 3-4 treatment-related 
adverse events (AEs) occurred in 18% of patients and all were reversible. 
 
In a phase II study, 168 patients with clear cell RCC who received at least one prior-anti- 
angiogenic therapy (70% received ≥2 prior systemic therapy regimens) were randomized to 
receive nivolumab 0.3 mg/kg (n=60), 2 mg/kg (n=54), and 10 mg/kg (n=54).21 Median PFS was 
2.7 months, 4.0 months, and 4.2 months at 0.3, 2, and 10 mg/kg respectively. The median OS 
was 18.2 months, 25.5 months, and 24.7 months, respectively. The ORR ranged from 20-22% 
across dose levels. 
 
Most of the 167 patients (n=122, 73%) experienced treatment-related AEs (any grade) and 19 
patients (11%) experienced grade 3-4 treatment-related AEs. The incidence of treatment-related 
AEs of any grade was similar across the dose arms: 75%, 67%, and 78% in the 0.3, 2, and 10 
mg/kg respectively. Grade 3-4 events occurred in 5%, 17%, and 15%, respectively. The most 
common any grade treatment-related AEs were fatigue, nausea, pruritis, rash, decreased appetite, 
diarrhea, dry mouth, arthralgia, dry skin, and hypersensitivity. Systemic corticosteroids were 
administered in 9 (15%), 10 (19%), and 18 (33%) patients in the 0.3, 2, and 10 mg/kg arms, 
respectively. Treatment-related AEs leading to discontinuation of study drug occurred in 7% 
(n=11), the most common reason being elevated serum aspartate aminotransferase (AST), 
occurring in two patients. 

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The efficacy of nivolumab in RCC was demonstrated in a randomized, open-label, phase III 
study of nivolumab compared to everolimus in patients with RCC who had received previously 
treatment.19 In this study, a total of 821 patients with advanced clear cell RCC were randomized 
1:1 to received 3 mg/kg of nivolumab IV every 2 weeks of 10 mg of everolimus orally. The 
primary endpoint was OS. 
 
The median OS was 25.0 months (95% CI 21.8 to NR) with nivolumab and 19.6 months (95% 
CI 17.6-23.1) with everolimus (HR 0.73, 95% CI 0.57-0.93, p=0.002). The ORR was 25% in the 
nivolumab arm and 5% in the everolimus arm (OR 5.98, 95% CI 3.68-9.72, p<0.001). PR were 
observed in 99 patients (24%) in the nivolumab group and in 20 patients (5%) in the everolimus 
group. CR were observed in 4 patients (1%) in the nivolumab group and 1 patient (<1%) in the 
everolimus group. The median time to response was 3.5 months (range 1.4-24.8 months) among 
the 103 patients with a response in the nivolumab group and 3.7 months (range 1.5-11.2 months) 
among the 22 patients with a response in the everolimus group. The median duration of response 
was 12 months (range 0-27.6 months) in the nivolumab group and 12 months (0-22.2 months) 
with everolimus. The median PFS was 4.6 months (95% CI 3.7-5.4) with nivolumab and 4.4 
months (95% CI 3.7-5.5) with everolimus (HR 0.88, 95% CI 0.75-1.03, p=0.11). 
 
Treatment-related AEs of any grade occurred in 319 of the 406 patients (79%) treated with 
nivolumab and in 349 of the 397 patients (88%) treated with everolimus. The most common 
treatment-related AEs among patients who received nivolumab were fatigue (134 patients, 33%), 
nausea (57 patients, 14%), and pruritus (57 patients, 14%); among patients who received 
everolimus, the most common events were fatigue (134 patients, 34%), stomatitis (117 patients, 
29%), and anemia (94 patients, 24%). Grade 3 or 4 treatment-related AEs occurred in 76 of the 
406 patients (19%) treated with nivolumab and in 145 of the 397 patients (37%) treated with 
everolimus; the most common grade 3 or grade 4 event was fatigue (10 patients, 2%) with 
nivolumab and anemia (31 patients, 8%) with everolimus. Treatment-related adverse events 
leading to treatment discontinuation occurred in 31 of the 406 patients (8%) treated with 
nivolumab and in 52 of the 397 patients (13%) treated with everolimus. 
 
2.3 
Ipilimumab 
Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), an activation-induced T-cell surface molecule, is 
a member of the CD28:B7 immunoglobulin superfamily that competes with CD28 for B7. 
CTLA-4-mediated signals are inhibitory and turn off T cell-dependent immune responses28, 29. 
 
Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a 
subset of T cells from human and nonhuman primates. The proposed mechanism of action for 
ipilimumab is interference of the interaction of CTLA-4 with B7 molecules on antigen 
presenting cells (APCs), with subsequent blockade of the inhibitory modulation of T-cell 
activation promoted by the CTLA-4/B7 interaction. 
 
Ipilimumab monotherapy for the treatment of metastatic RCC was studied in a phase 2 clinical 
trial. Two sequential cohorts were studied, each with a loading dose of 3 mg/kg followed by 3 
doses of either 1 mg/kg (group 3-1; n = 21) or 3 mg/kg (group 3-3; n = 40). Subjects with stable 
disease or partial or complete response were allowed additional treatment. In group 3-1 (n = 21), 
one subject (5%) had a PR. In group 3-3 (n = 40), 5 subjects (12.5 %) had a PR. Among 14 

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treatment-naive subjects in group 3-3, 3 (21%) had a PR. The major toxicities were colitis (all 
grade 3-4; 14% in group 3-1, 33% in group 3-3) and hypophisitis (1 grade 3-4, 1 grade 1-2 in 
group 3-3; none in group 3-1). Most reported AEs were grade 1-2 (57% in group 3-1, 35% in 
group 3-3) or grade 3 (38% in group 3-1, 48 % in group 3-3). There were 6 subjects (15%) with 
grade 4 AEs in group 3-3. The most common treatment-related AEs in group 3-1 (total 81%) and 
group 3-3 (total 93%) were diarrhea (38% and 40%, respectively) and fatigue (33% and 38%, 
respectively). Most AEs were manageable with appropriate treatment, including high dose 
corticosteroids and hormone replacement. 
 
2.4 
Nivolumab and Ipilimumab 
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN- 
production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased 
antitumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer 
models. In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies 
increased the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector 
cells, and dual blockade increased tumor infiltration of T effector cells and decreased 
intratumoral T regulatory cells, as compared to either agent alone30. 
 
A phase I study investigated the safety and activity of nivolumab and ipilimumab in RCC31. 
Subjects with metastatic RCC (favorable/intermediate Memorial Sloan Kettering Cancer Center 
(MSKCC) score; Karnofsky performance status ≥ 80%; untreated or any number of prior 
therapies) were randomized to receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg (arm N3 + I1) 
or nivolumab 1 mg/kg + ipilimumab 3 mg/kg (arm N1 + I3) IV every 3 weeks for 4 doses then 
nivolumab 3 mg/kg IV every 2 weeks until progression/toxicity. The primary objective was to 
assess safety/tolerability and the secondary objective was to assess antitumor activity. Subjects 
were randomized to N3 + I1 (n = 21) and N1 + I3 (n = 23). Most patients (n=34; 77%) had prior 
systemic therapy (N3 + I1: 16; N1 + I3: 18). The confirmed ORR was 43% (N3 + I1) and 48% 
(N1 + I3). Duration of response was 4.1+ to 42.1+ weeks (7 of 9 responses ongoing) in N3 + I1, 
and 12.1+ to 35.1+ wks (9 of 11 responses ongoing) in N1 + I3. Best response of SD was seen in 
5 (24%) patients (N3 + I1) and 8 (35%) pts (N1 + I3). Median PFS was 36.6 weeks (N3 + I1) 
and 38.3 weeks (N1 + I3). These data are still immature, with 11 of 21 events reported for 
N3 + I1 and 10 of 23 events reported for N1 + I3. 
 
The safety of nivolumab combined with ipilimumab was assessed in the phase 1 study. 
Treatment-related AEs were seen in 39/44 patients (89%), including 16/21 (76.2%) in N3 + I1 
and 23/23 (100%) in N1 + I3. Across the N3 + I1 and N1 + I3 arms, the most common (≥ 20%) 
treatment related AEs of any grade were fatigue (61%), diarrhea (32%), nausea (30%), rash 
(27%), pruritis (25%), ALT increased (23%), AST increased (20%), hypothyroidism (20%), and 
lipase increased (20%). Grade 3–4 related AEs occurred in 19 patients (29%), including 6/21 
(29%) at N3 + I1 and 14/23 (61%) at N1 + I3. The most common (≥ 5%) drug-related grade 3-4 
events were lipase increased (21%), ALT increased (14%), AST increased (7%), diarrhea (9%), 
fatigue (5%), amylase increased (5%), colitis (5%), lymphocyte count decreased (5%). No grade 
3–4 pneumonitis was seen. No treatment-related deaths were reported. 

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Treatment-related AEs (including Grade 3-4), treatment-related AEs leading to discontinuation, 
and treatment-related SAEs all occurred more commonly in subjects in the N1 + I3 arm than in 
the N3 + I1 arm: treatment related AEs 76.2% N3 + N1 versus 100% N1 + I3; treatment related 
grade 3-4 AEs 28.6% versus 60.9%, treatment related AEs leading to discontinuation 9.5% 
versus 26.1%. 
 
2.5 
Rationale 
Patients with metastatic RCC have multiple treatment options however the only one currently 
demonstrated to improve OS is nivolumab. Little information is known about whether treatment 
can safely be discontinued in patients who experience a response. Data from early drug trials of 
nivolumab suggest that some patients who discontinued therapy while demonstrating a response 
continue to derive benefit from therapy for a durable period of time. This study will plan to 
formally investigate this question. Nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg has 
demonstrated substantial clinical activity, as measured by ORR, while still exhibiting an 
acceptable safety profile. Given the promising data of the combination of nivolumab and 
ipilmumab, this study will investigate whether ipilimumab can be used to improve ORR for 
patients who experience SD or PD initially. In this study, we are evaluating the efficacy of 
nivolumab when given in combination with a total of 2 doses of ipilimumab every 3 weeks (± 3 
days). The efficacy of 2 doses compared to 4 doses of ipilimumab when given in combination 
with nivolumab is unknown. Furthermore, the efficacy of re-treatment with nivolumab combined 
with ipilimumab is unknown. Studies exploring differing treatment schedules are lacking in 
RCC. The responses induced by immunotherapy are expected to be more durable than those 
induced by VEGF receptor therapy, and are therefore likely to translate into improvements OS, 
as seen with nivolumab alone. 
 
2.6 
Correlative Studies Background 
PD-L1/PD-1 pathway activation in tumors, as determined by PD-L1 levels, may be an important 
predictive diagnostic for checkpoint inhibition. Published results suggest that expression of PD- 
L1 in tumors correlates with response to anti-PD-1 therapy32. This correlation was also observed 
with nivolumab in data from the phase II study of nivolumab alone. Tumor specimens (collected 
from baseline fresh tumor specimens) from patients meeting eligibility criteria will be tested for 
PD-L1 expression and other markers of immunogenicity and angiogenesis. In addition, PD-L1 
status (as defined by expression of PD-L1 on tumor cells or TIMC) will be correlated with 
outcomes. Because the expression of PD-L1 on the surface of both tumor cells and TIMC can be 
a dynamic process and because PD-L1 expression on these cells may vary between primary and 
metastatic sites, mandatory fresh tumor specimens will be collected at baseline. Additionally, to 
investigate mechanisms of acquired resistance to therapy, we will obtain progression biopsies. 
For patients in Arm A who experience an initial CR/PR to nivolumab alone, we will obtain an 
optional biopsy at time of progression prior to re-initiation of nivolumab . From patients who 
demonstrate progression to nivolumab and ipilimumab we will obtain an optional tumor biopsy 
at progression on both agents. 
 
Changes in biomarkers in the blood may provide evidence for the biological activity of 
nivolumab alone or in combination with ipilimumab in humans and may allow for the developed 
of a blood based biomarkers to help predict which patients may benefit from therapy. A 
secondary objective is to assess the immunomodulatory properties of nivolumab alone or in 

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combination with ipilimumab by evaluating baseline levels and changes in levels upon 
treatment of surrogate pharmacodynamic markers in the blood. In addition, we will correlate 
levels with the anti-tumor activity of the combination of these agents. 
 
2.7 
Study Design 
This is a phase II study investigating a response-based approach to therapy with nivolumab 
and ipilimumab in subjects with advanced renal cell carcinoma (RCC). All subjects will 
initiate therapy with nivolumab. After 8 weeks (± 7 days), subjects will undergo the first 
response assessment, as well as additional assessments for the response confirmations if 
applicable, then be assigned to the study arms A and B. Confirmation scans for patients with 
CR/PR/SD will occur following an additional 8 weeks (± 7 days). For patients with PD, 
initial confirmation scans will be obtained at 4 weeks (± 7 days) at the discretion of the 
treating investigator if the patient is stable to wait for confirmatory imaging. Arm allocation 
will occur within the first 6 months of the study. For subjects to be allocated to Arm A, they 
need to have a confirmed CR/PR on two serial and consecutive imaging assessments within 
the first 6 months of the study while on nivolumab treatment alone. All other subjects who 
are not able to demonstrate a persistent confirmed CR/PR within the first 6 months of the 
study, will be allocated to Arm B. 
 
 
Single Cell Sequencing Cohort: An additional subset of patients (n=25) will be enrolled to 
the study at DFCI and selected sites with capability for single cell molecular transcriptomic 
assessment. These patients will receive the same treatment at detailed above and will be 
allocated in Arm A and B as detailed above. All patients will undergo a mandatory baseline 
biopsy. Biopsy schedule by treatment arm is detailed below: 
 
Arm A: 
Mandatory biopsy at baseline 
Optional biopsy at time of response following discontinuation of nivolumab 
Mandatory biopsy at final treatment disconuation/off study 
 
Arm B: 
Mandatory biopsy at baseline 
Mandatory biopsy at final treatment disconuation/off study 
 
Arm A (persistent PR/CR) includes the following patient scenarios: 
 
• Subjects who experience a partial response (PR) or complete response (CR) at 8 
weeks (initial response assessment) from initiation of primary nivolumab therapy and 
who maintain a persistent PR or CR at the subsequent imaging assessment in 8 weeks 
(+/- 7 days) (i.e.,~16 weeks from initiation of nivolumab); 
OR 
• Subjects who experience stable disease (SD) at the initial response assessment at 8 
weeks from initiation of primary nivolumab therapy, with the subsequent scan in 8 
weeks (+/- 7 days) documenting CR/PR which is maintained at the next imaging 
assessment in 8 weeks (+/- 7 days) (i.e, ~24 weeks from initiation of nivolumab). 
 

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Patients who have SD on initial assessment followed by CR/PR on first confirmatory 
assessment which does not persist on the second confirmatory imaging assessment will be 
allocated to Arm B as CR/PR was not persistent and confirmed on consecutive imaging 
assessments. 
 
Subjects with confirmed PR/CR (arm A) will discontinue nivolumab and be followed with 
serial imaging assessments every 8 weeks. If progressive disease (PD) develops, therapy with 
nivolumab will be resumed and will not be discontinued if a subsequent PR or CR were to 
occur. Subjects who experience subsequent PD following re-initiation of nivolumab, will be 
treated with nivolumab + ipilimumab every 3 weeks x 2 doses and will continue nivolumab. 
All patients will continue on treatment with nivolumab alone every 4 weeks which will begin 
5 weeks ± 3 days after the last dose of nivolumab + ipilimumab. For subjects who experience 
a PD on nivolumab and ipilimumab, treatment will be discontinued. 
 
If by 24 weeks, subjects have not demonstrated a persistent CR/PR confirmed on at least two 
serial scan assessments, then subjects will be allocated to Arm B at the 24 week time point.  
 
Arm B (persistent PD/SD) includes the following patient scenarios:  
• Subjects who experience PD at 8 weeks (initial response assessment) on primary 
nivolumab therapy which is then confirmed by a second scan within 4 weeks (+/- 7 
days). The confirmatory scan is not required if the site investigator determines that 
this is clinically detrimental; 
• Subjects who initially experience SD at 8 weeks (initial response assessment), which 
is confirmed with a second scan showing SD in 8 weeks (± 7 days) 
• Subjects who have receive at least 3 doses of nivolumab and may have signs and/or 
symptoms concerning for early clinical progression with  radiographic evidence of PD 
before 8 weeks 
• Subjects who do not meet the criteria for allocation into Arm A given lack of 
persistent CR/PR confirmation on serial and consecutive imaging within the first 6 
months of the study will be allocated to Arm B by the 6-month time point. 
 
Subjects in Arm B will receive ipilimumab every three weeks x 2 doses in addition to 
nivolumab. Treatment with nivolumab alone every 4 weeks will begin 5 weeks ± 3 days after 
the last dose of nivolumab + ipilimumab. Subjects will be followed with serial imaging 
assessments every 8 weeks (except the first imaging assessment which will take place at 12 
weeks since ipilimumab addition). If PD persists or develops, all treatments will be 
discontinued. If PR/CR/SD is observed subjects will continue nivolumab. 
 
3. STUDY OBJECTIVES 
 
3.1 Objectives 
 
3.1.1 Primary Objectives 
• 
Assess the proportion of subjects with persistent complete 
response (CR) or partial response (PR) at one year after 

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nivolumab discontinuation (Arm A) 
• 
Assess the proportion of subjects with progressive disease 
(PD)/stable disease (SD) that convert to PR/CR at one 
year upon the addition of ipilimumab to nivolumab (Arm 
B) 
 
3.1.2 Secondary Objectives 
• 
Assess progression-free survival (PFS) and overall survival 
(OS) rates in Arm A and Arm B 
• 
To assess the rate of re-initiation of nivolumab (salvage) 
therapy (arm A) 
• 
Assess the immune-related ORR (irORR) in subjects in Arm A 
and B 
• 
Assess safety and toxicity in study arms A and B 
• 
Summarize PR/CR rate, PFS, and OS in the overall cohort 
and by each arm according to subgroups: 
o 
International mRCC Database Consortium (IMDC) 
risk groups. 
o 
Untreated versus previously treated subjects 
o 
Histologic subtype (clear cell versus non-
clear cell renal cell carcinoma (RCC) 
subtypes; sarcomatoid components present 
versus absent) 
 
3.1.3 Correlative/Exploratory Objectives 
• 
Evaluate the relationship between tumor-infiltrating 
lymphocytes (TILs), programmed death-ligand 1 (PD-
L1) tumor expression, and other tissue biomarkers with 
efficacy outcomes (proportion of PR/CR, PFS, OS) 
• 
Evaluate the relationship between PD-L1 status in 
archival tissue and in fresh tumor specimens 
• 
Evaluate mechanisms of response to nivolumab in fresh 
tumor specimens obtained at baseline in subjects with a 
durable response to treatment (≥1 year) 
• 
Evaluate mechanisms of intrinsic and acquired resistance 
to nivolumab and ipilimumab treatments in fresh tumor 
specimens obtained at time of radiographic progression 
• 
Assess molecular mechanisms of resistance to treatment via 
circulating free DNA (cfDNA) assessment and to correlate 
cfDNA molecular profile with metastasis biopsy molecular 
profile 
• 
Assess molecular mechanisms of resistance to treatment via 
circulating tumor cell (CTC) assessment  
• 
Correlate CTC molecular profile with metastasis biopsy 
molecular profile 

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• 
Assess mechanisms of response and resistance to treatment 
via single cell molecular assessment (transcriptome 
assessment)  
• 
Correlate single cell molecular profile with metastasis 
biopsy molecular profile 
 
4 ELIGIBILITY CRITERIA 
 
4.1    Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Age ≥ 18 years at the time of consent. 
 
2. ECOG Performance Status of ≤ 2 within 28 days prior to registration. 
3. Unresectable advanced or metastatic RCC to include both clear cell and non-clear 
histologies.  
 
Patients who have suspected metastatic RCC, which has not yet been pathologically 
proven, may be enrolled if they plan to undergo a cytoreductive nephrectomy, 
metastectomy, or biopsy. Fresh tissue from one of these procedures can be used for the 
clinical trial requirements (eligibility #) as well as serve as pathologic confirmation of 
RCC. The pathologic confirmation must be documented prior to C1D1. 
 
Single Cell Sequencing Cohort only: Histology must have predominant clear cell 
component. 
 
4. Availability at the study site of formalin-fixed, paraffin-embedded (FFPE) archival 
tumor specimens, when available, and willingness of the subject to undergo mandatory 
fresh tumor biopsy prior to treatment initiation. If a target lesion is biopsied at 
screening, this lesion must be followed as non-target lesion after the biopsy unless it is 
the patient’s only target lesion. If there is only one target lesion, it should be followed 
as a target lesion regardless. 
a. The archival specimen must contain adequate viable tumor tissue. 
b. The specimen may consist of a tissue block (preferred and should contain 
the highest grade of tumor) or at least 30 unstained serial sections. Fine-
needle aspiration/ biopsy, brushings, cell pellet from pleural effusion, 
bone lesion, bone marrow aspirate/biopsy are not acceptable. 
  
Previously untreated or treated subjects with no limit on prior lines of systemic therapies are 
allowed. Patient may have received prior adjuvant therapy.  
 
Single Cell Sequencing Cohort only: Can either have had no prior systemic therapy 
(treatment naïve) for RCC, prior IFN-α or IL-2,  or a maximum of 1 prior VEGF 
targeted therapy (VEGFR TKI-based regimen or bevacizumab) for RCC. Agents given 
in combination in the first line would count as 1 regimen (e.g,. Lenvatinib + 

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4.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Prior use of systemic checkpoint inhibitors for the management of metastatic RCC is 
excluded. Prior IFN-α or IL-2 is allowed. 
 
2. Single Cell Sequencing Cohort only: Non-clear cell histology. 
 
3. Receipt of any type of small molecule kinase inhibitor (including investigational 
kinase inhibitors) within 2 weeks of enrollment or receipt of any anti-cancer therapy 
(including investigational therapy, monoclonal antibodies) within 4 weeks of 
enrollment. 
 
4. Treatment with systemic immunosuppressive medications including but not limited 
to: 
prednisone, dexamethasone, cyclosporin, azathioprine, methotrexate, thalidomide, anti- 
tumor necrosis factor (TNF) agents within 2 weeks of first study dose. 
• Subjects who have received acute, low-dose systemic immunosuppressant 
medications may be enrolled (such as steroids for acute nausea or cancer-related 
pain ≤ 10 mg prednisone) may be enrolled sooner than 2 weeks of first study dose. 
• Subjects with adrenal insufficiency on physiologic replacement doses of steroids 
may be enrolled (≤ 10 mg prednisone). 
• The use of inhaled, topical, ocular or intra-articular corticosteroids and 
mineralocorticoids are allowed. 
 
5. Treatment with a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor 
(e.g. denosumab) within 2 weeks of first study dose. 
 
6. Radiotherapy for RCC within 14 days of first study treatment with the exception of a 
single fraction of radiation administered for palliation of symptoms. 
 
7. Known active metastases to the brain, spinal cord or leptomeninges unless adequately 
treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks of first 
study treatment as documented by magnetic resonance imaging (MRI) or computerized 
tomography (CT) imaging and having no ongoing requirement for steroids. 
 
8. Malignancies other than RCC within 5 years of first study treatment with the exception of 
those with negligible risk of metastases or death and/or treated with expected curative 
outcome (included but not limited to carcinoma in situ of the cervix, basal or squamous 
cell skin cancer, localized prostate cancer, ductal carcinoma in situ of the breast, non-
muscle invasive urothelial carcinoma). 
 
9. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion protein. 

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10. Known hypersensitivity to any component of the nivolumab or ipilimumab product. 
 
11. Any active or recent history (within 6 months of first study dose) of autoimmune disease 
or syndrome that requires systemic corticosteroids (>10 mg daily prednisone equivalent) 
or immunosuppressive medications including but not limited to: myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid 
syndrome, Wegner’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, 
multiple sclerosis, vasculitis, or glomerulonephritis. Subjects with vitiligo, controlled 
type I diabetes mellitus, hypo- or hyperthyroid disease, or surgical adrenal insufficiency 
requiring hormone replacement therapy are permitted to enroll. 
 
12. Any condition requiring treatment with corticosteroids (>10 mg daily prednisone 
equivalent) or other immunosuppressive medication within 14 days of the first dose of 
study drug. Inhaled, topical, ocular or intra-articular steroids and adrenal replacement 
steroid doses ≤ 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease. 
 
13. Uncontrolled adrenal insufficiency. 
 
14. History of idiopathic pulmonary fibrosis, organized pneumonia, drug-induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening 
imaging CT of the chest. History of radiation pneumonitis in the radiation field is 
permitted. 
 
15. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome. 
 
16. Known active or chronic hepatitis B infection (defined as having a positive hepatitis B 
surface antigen (HBsAg) test at screening). Subject with past or resolved hepatitis B 
infection (defined as having a negative HBsAg test and positive antibody to hepatitis B 
core antigen test) are eligible. Hepatitis B viral DNA must be obtained in subjects with 
positive hepatitis B core antibody prior to first treatment start. 
 
17. Active hepatitis C infection. Subjects positive hepatitis C antibody test are eligible if PCR 
is negative for hepatitis C viral DNA. 
 
18. Severe infections within 4 weeks of first study treatment including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
 
19. Receipt of therapeutic oral or IV antibiotics within 2 weeks of first study treatment. 
Subjects receiving routine antibiotic prophylaxis (for dental extractions/procedures) are 
eligible. 
 
20. Significant cardiovascular disease such as New York Heart Association (NYHA) class III 
or greater, myocardial infarction within the previous 3 months, unstable arrhythmias, 

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unstable angina. Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or left ventricular ejection fraction < 45% must be on a stable 
regimen that is optimized in the opinion of the treating physician, in consultation with a 
cardiologist when appropriate. 
 
21. Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on 
screening EKG > 500 msec. 
 
22. History of abdominal or tracheoesophageal fistula or GI perforation within 6 months of 
first study treatment. 
 
23. Clinical signs or symptoms of GI obstruction or requirement of routine parenteral 
nutrition. 
 
24. Evidence of abdominal free air not explained by paracentesis or recent surgical 
procedure.  
 
25. Serious, non-healing or dehiscing wound or active ulcer. 
 
26. Major surgical procedure within 4 weeks of first study treatment. 
 
27. Presence of any toxicities attributed to prior anti-cancer therapy that are not 
resolved to grade 1 (National Cancer Institute Common Terminology Criteria 
for Adverse Events version 4.0) or baseline before administration of study drug. 
 
28. Prior allogenic stem cell or solid organ transplant. 
 
29. Administration of a live, attenuated vaccine within 4 weeks for first study 
treatment. 
 
4.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
5. 
SUBJECT REGISTRATION 
 
5.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System 
(CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. Any 
participant not registered to the protocol before protocol therapy begins will be considered 
ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete 
the protocol-specific eligibility checklist. 

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Following registration, participants will undergo a mandatory fresh tumor biopsy prior to 
starting  protocol therapy. Issues that would cause treatment delays should be discussed with 
the Overall Principal Investigator (PI). If a participant does not receive protocol therapy 
following registration, the participant’s registration on the study must be canceled. 
Registration cancellations must be made in OnCore as soon as possible. 
 
5.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) must be followed. 
 
5.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the DFCI by the Project Manager. All 
sites should call the Project Manager to verify treatment availability. 
 
Following registration, participants should begin protocol therapy within two weeks (14 days). 
Issues that would cause treatment delays should be discussed with the Overall PI.  If a 
participant does not receive protocol therapy following registration, the participant’s 
registration on the study must be canceled.  The Project Manager should be notified of 
cancellations as soon as possible. 
 
5.4 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the research nurse 
or data manager and emailed/faxed to the Project Manager: 
 
• Informed consent 
• HIPAA authorization form (if not included in consent form). 
• Medical History 
• Diagnosis and staging assessment 
• Physical Examination including review of medications (over-the-counter or 
prescribed) and side effects the subject is experiencing 
• Vital signs (including temperature, heart rate, blood pressure, weight, height and 
oxygen saturation) and ECOG performance status 
• ECG 
• Laboratory Testing 
• Documentation of at least one prior anti-cancer therapy 
• Eligibility Checklist 
 
The research nurse or data manager at the participating site will then e-mail the Project 
Manager to verify eligibility. To complete the registration process, the Project Manager will 
follow DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) and register the participant on the protocol. The 
Project Manager will fax or e-mail the participant study number, and if applicable the dose 

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20 
 
treatment level, to the participating site. The Project Manager will also call the research nurse 
or data manager at the participating site and verbally confirm registration. 
 
6. 
TREATMENT PLAN 
After informed consent has been obtained in writing, the subject will then undergo screening 
procedures and will enter the trial after successful screening. The subject must be willing to 
undergo a MANDATORY fresh tumor biopsy prior to treatment following successful 
screening and registration unless the site investigator deems the procedure medically unsafe. 
 
Subjects who have signs and/or symptoms concerning for early clinical progression can 
undergo imaging before the initial 8 week imaging time point.  In this scenario, if there is 
evidence of radiographic progression as per RECIST version 1.1, subjects will be allocated 
immediately to Arm B as long as they have received at least 2 doses of nivolumab (two doses 
of 480mg IV q 4 wks). Subjects who received fewer than 2 doses of nivolumab (480mg 
dosing) with early progression can either discontinue from study or may continue on to 
receive at least 2 doses of nivolumab before reassessing response at treating investigator’s 
discretion. The per protocol 8 week scans should still be done on schedule even if earlier 
scans are done and compared to baseline for initial response assessment which should then be 
confirmed at the 16 week time point per protocol.  
 
 
Primary Treatment with Nivolumab 
Eligible subjects will be enrolled and will receive primary treatment with nivolumab 480 mg IV 
(D1) for 2 cycles. Each Cycle = 28 days. After 2 cycles (8 weeks +/- 7 days), all subjects will 
have initial disease assessment scans. 
 
Arm A: CR or PR Response after Primary Treatment with Nivolumab: 
• For subjects allocated to Arm A, nivolumab will be discontinued and subjects will be 
followed with serial imaging assessments every 8 weeks (Observation). 
• If PD develops, therapy with nivolumab 480 mg IV every 4 weeks will be resumed. At 
this time, subjects will be asked to undergo an optional fresh tumor biopsy. Subjects 
will have disease assessment scans every 8 weeks (+/- 7 days). Nivolumab will 
continue until PD is documented. 
• Subjects who experience subsequent PD following re-initiation of nivolumab will have 
ipilimumab 1 mg/kg IV every 3 weeks x 2 doses added. During this time, nivolumab 3 
mg/kg IV will be administered every 3 weeks to coincide with ipilimumab 1 mg/kg x 
2 doses. Treatment with nivolumab alone 480 mg IV every 4 weeks will begin 5 
weeks ± 3 days after the last dose of nivolumab + ipilimumab. NOTE: When 
ipilimumab is added, the first radiology imaging from the time that combination 
therapy with nivolumab and ipilimumab is initiated will be obtained after 3 cycles (12 
weeks ± 7 days) instead of 2 cycles (8 weeks). Subsequent imaging assessments after 
this first imaging assessment will occur every 2 cycles (8 weeks +/- 7 days). 
• Subjects with CR/PR/SD after nivolumab plus ipilimumab will continue nivolumab 
alone starting 5 weeks +/- 3 days after the last dose of combination therapy with 
nivolumab and ipilimumab. When given alone, nivolumab will be given at 480 mg IV 

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every 4 weeks. If disease assessment scans after 3 cycles (12 weeks) from the time of 
initiation of combination therapy with nivolumab and ipilimumab show CR/PR/SD, 
subjects will continue nivolumab alone until PD is documented. Subsequent imaging 
assessments after this first imaging assessment will occur every 2 cycles (8 weeks ± 7 
days). 
• For subjects who experience a PD on nivolumab and ipilimumab, treatment will 
be discontinued. 
 
 
Arm B: SD/PD Response after Primary Treatment Nivolumab: 
• For subjects allocated to Arm B, ipilimumab 1 mg/kg IV every 3 weeks x 2 doses will 
be added. During this time, nivolumab 3 mg/kg IV will be administered every 3 weeks 
to coincide with ipilimumab dosing x 2 doses and then nivolumab will be continued at 
480 mg IV every 4 weeks thereafter. Treatment with nivolumab alone every 4 weeks 
will begin 5 weeks ± 3 days after the last dose of nivolumab + ipilimumab at the start 
of Cycle 3/Day 1 following primary treatment with nivolumab. Subjects will be 
followed with serial imaging assessments every 8 week (+/- 7 days) and will continue 
nivolumab.  If PD develops, treatment will be discontinued.  
NOTE: When ipilimumab is added, the first radiology imaging from the time that 
combination therapy with nivolumab and ipilimumab is initiated will be obtained after 
3 cycles (12 weeks ± 7 days) instead of 2 cycles (8 weeks +/- 7 days). Subsequent 
imaging assessments after this first imaging assessment will occur every 2 cycles (8 
weeks +/- 7 days). 
 
 
• In certain cases if a patient is recovering from a recent hospitalization for a study irAE 
or comorbidity (unrelated to study intervention) at the time of transition to Arm B but 
has confirmed persistent stable disease on Initial treatment or is felt to be receiving 
clinical benefit, then the patient may be allowed to stay on Initial treatment with 
nivolumab alone. This must be confirmed with the sponsor-investigator. If ipilimumab is 
to be added it should be done at the next cycle (after 2 more doses of nivolumab). If 
prior irAE or non-study drug co-morbidity precludes addition of ipilimumab for safety 
concerns, the patient may continue on nivolumab monotherapy if thought to be 
achieving clinical benefit. This must be confirmed with the sponsor-investigator. 
 
 
For either arm: 
• Subjects will continue on therapy until radiographic progression on study 
therapy or withdrawal for some other reason as detailed in section 6.7. Subjects 
will be asked to undergo an OPTIONAL fresh tumor biopsy at the time of 
progression. Subjects will be permitted to continue treatment beyond progression 
as long as they meet the following criteria: (1) Site investigator-assessed clinical 
benefit AND (2) Subject is tolerating study drug. 
• If brain metastases are identified on brain imaging, patients may continue on 
study therapy if: 
o All brain lesion(s) are amenable to focal therapy (e.g. stereotactic body 

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radiation therapy (SBRT) or metastectomy) 
o They meet other criteria to continue on study therapy 
o If the only site of progression is intracranial, the patient may continue on 
nivolumab monotherapy without transitioning to adding ipiliumumab at 
investigator discretion  
 
6.1 
Drug Administration 
 
Table 1A 
Nivolumab Monotherapy Administration 
Regimen Description 
Agent* 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle Length 
Nivolumab 
None 
480 mg 
flat dose 
IV 
Every 4 weeks (± 
3 days) 
4 weeks (28 
days) 
*Nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution.  
Table 1B 
Nivolumab and Ipilimumab Administration 
Regimen Description 
Agent* 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle Length 
Nivolumab 
None 
3 mg/kg 
IV before 
ipilimumab 
When 
administered 
concurrently with 
ipilimumab will be 
administered every 
3 weeks** (± 3 
days) 
4 weeks (28 
days) 
Ipilimumab 
None 
1 mg/kg 
IV after 
nivolumab 
Every 3 weeks for 
a total of 2 
maximum doses 
based on response 
(± 3 days) 
*Nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution. 
Ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution. 
**Nivolumab will be administered first followed by ipilimumab with a minimum of 30 minutes 
from the end of nivolumab infusion to beginning of ipilimumab infusion. 
 
Nivolumab is to be administered as an approximately 30-minute IV infusion when given 
as a flat dose of 480 mg. When nivolumab is given concurrently with ipilimumab at 3 
mg/kg it will be administered as an approximately 30-minute IV infusion. At the end of 
the infusion, flush the line with a sufficient quantity of normal saline. 
 
Ipilimumab is to be administered as an approximately 30-minute IV infusion. At the end 
of the infusion, flush the line with a sufficient quantity of normal saline or 5% dextrose 
solution. 

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When both study drugs are to be administered on the same day, separate infusion bags and 
filters must be used for each infusion. Nivolumab is to be administered first. The nivolumab 
infusion must be promptly followed by a saline flush to clear the line of nivolumab before 
starting the ipilimumab infusion. The second infusion will always be ipilimumab, and will 
start at least 30 minutes after completion of the nivolumab infusion. 
 
The dosing calculations should be based on the body weight from the initiation of treatment 
with nivolumab. If the subject’s weight on the day of dosing differs by > 5% from the 
weight used to calculate the dose, the dose should be recalculated based on the current day 
of treatment weight. All doses should be rounded to the nearest milligram. There will be no 
dose modifications allowed. 
 
Antiemetic premedications should not be routinely administered prior to dosing of drugs.  
 
6.2 
Pre-Treatment Criteria 
Prior to every cycle 1 day 1: Initial treatment, day 1 Nivolumab plus Ipilimumab 
Ipilimumab and day 1 of resuming nivo post discontinuation after response 
6.2.1 Cycle 1, Day 1 
 
  Cycle 1, day 1 the following parameters must be met: 
• Absolute Neutrophil Count (ANC) ≥1500 cells/ µL 
• Platelet count ≥100,000/ µL 
• Hemoglobin (Hgb) ≥9g/dl (transfusions allowed) 
• Serum creatinine ≤ 1.5 x ULN OR Calculated creatinine clearance1 ≥ 40 mL/min 
• Bilirubin ≤1.5 x upper limit of normal (ULN)2  
• Aspartate aminotransferase (AST)3 ≤2.5 x ULN 
• Alanine aminotransferase (ALT)3 ≤2.5 x ULN 
 
1. Cockcroft-Gault formula will be used to calculate creatinine clearance 
2. Subjects with known Gilbert’s disease should have a serum bilirubin ≤ 3 x ULN. 
3. Subjects with documented liver metastases should have AST and ALT ≤ 5 x ULN. Subjects 
with documented liver or bone metastases should have alkaline phosphatase ≤ 5 x ULN 
 
For patients that had fresh tissue collected at baseline (via biopsy or surgery) with no prior 
pathology review, the final pathology from baseline procedures must be reviewed and 
documented in the patient’s medical records prior to initiating therapy (finalization of a 
pathology report is sufficient).  
 
6.3 
Concomitant Medications 
 
6.3.1 Allowed Concomitant Medications 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a subject after 7 days preceding the screening evaluation and prior to the end of 
treatment visit. All concomitant medications administered within 14 days preceding Cycle 1 
Day 1 and throughout the study until the treatment termination visit will be collected on 

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study- specific electronic Case-Report Forms (eCRFs). The reason(s) for treatment and dates 
of treatment should be reported to the site investigator and recorded as instructed on the 
study- specific eCRFs. 
 
Subjects who experience treatment related infusion reactions should be managed as 
per guidelines in Section 6.4.1. 
 
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of 
systemic corticosteroids for treatment of non-irAEs are permitted but a dose that exceeds 10 
mg/day prednisone equivalents must be discussed with the sponsor-investigator. At 
eligibility, subjects must be on ≤ 10 mg/day prednisone equivalent. Use of steroids exceeding 
prednisone 10 mg/day equivalent to treat irAEs is permitted. A brief course of corticosteroids 
for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by contact allergen) is permitted. Megestrol 
administered as an appetite stimulant is acceptable while the patient is enrolled in the study. 
Mineralocorticoids for orthostatic hypotension or adrenal cortical insufficiency are 
acceptable. Use of osteoclast targeted therapy (including bisphosphonates and denosumab) is 
permitted and these agent are allowed to be newly initiated for patients while on study.  
 
Influenza vaccination should be given during influenza season only (approximately October 
to March). Subjects must not receive live attenuated influenza vaccine within 4 weeks prior to 
Cycle 1 Day 1 or at any time during the study but may receive inactivated influenza vaccines. 
Subjects who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as low molecular-weight heparin at a stable dose 
level or oral anticoagulants (eg.warfain, rivaroxaban)) should continue their use. Males and 
females of reproductive potential should use highly effective means of contraception. The use 
of denosumab is allowed on study once treatment has been initiated. 
 
All concomitant medications should be reported to the site investigator and recorded on 
the appropriate eCRF. 
 
6.3.2 Prohibited Concomitant Medications 
Instructions for subjects regarding concomitant therapies can be found in Appendix B. 
 
• Any concomitant therapy intended for the treatment of cancer, whether health 
authority−approved or experimental, is prohibited. This includes but is not 
limited to the following: 
o Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, i-
nvestigational agents, or herbal therapy. Radiotherapy may be considered for 
pain palliation if subjects are deriving benefit (such as treatment of known 
bony metastases, see eligibility). 
▪ In the event that the investigator chooses to wait to add ipilimumab until 
after radiation completion, patient may continue on single agent 
nivolumab in the meantime. Restaging scans will occur 12 weeks (+/- 7 
days) AFTER ipilimumab starts.  

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o Subjects experiencing a mixed response requiring local therapy (such as 
surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) for 
control of three or fewer lesions may still be eligible to continue study 
treatment. Subjects who receive local therapy directed at a target lesion will no 
longer be evaluable for radiographic response but will remain evaluable for 
progression. Such cases must be discussed with and approved by the sponsor-
investigator. 
 
• Traditional herbal medicines should not be administered because the ingredients of 
many herbal medicines are not fully studied and their use may result in unanticipated 
drug-drug interactions that may cause or confound assessment of toxicity. 
 
• Initiation or increased dose of granulocyte colony-stimulating factors (such as 
granulocyte colony-stimulating factor, granulocyte/macrophage colony-
stimulating factor, and/or pegfilgrastim) is prohibited. 
 
• Concomitant immunostimulatory agents, including but not limited to IFN- α or IL-2, 
are not permitted during the entire study. These agents, in combination with nivolumab 
and/or ipilimumab, could potentially increase the risk for autoimmune conditions. 
 
• Immunosuppressive medications (except to treated drug-related AE), including but not 
limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide, are not 
permitted. These agents could potentially alter the activity and the safety of nivolumab 
and/or ipilimumab. Systemic corticosteroids (>10 mg daily prednisone equivalent) and 
anti-TNF-α agents may attenuate potential beneficial immunologic effects of treatment 
with nivolumab and/or ipilimumab but may be administered for the treatment of non 
irAEs only after consultation with the sponsor-investigator. If feasible, alternatives to 
these agents should be considered. In addition, all subjects (including those who 
discontinue the study early) should not receive other immunostimulatory agents for 10 
weeks after the last dose of nivolumab and/or ipilimumab. Use of systemic 
corticosteroids (>10 mg daily prednisone equivalent) and anti-TNF- α is permitted for 
management of irAEs as detailed in Appendix C. 
 
• Elective major surgery should be delayed whenever possible. No data are available to 
define a safe interval. Re-initiation of nivolumab and/or ipilimumab following 
surgery requires documented approval from the sponsor-investigator. 
 
6.4 Supportive Care 
Subjects should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, anti-emetics, etc., when appropriate. Subjects who require therapeutic 
anticoagulation with low molecular weight heparin (e.g., enoxaparin and tinzaparin), 
coumadin or other oral anticoagulants at study entry will be eligible for enrollment. In 
addition, subjects requiring therapeutic anticoagulation with these agents during study 
participation will be allowed to remain on study therapy. 
 
6.4.1 Treatment of Nivolumab or Ipilimumab-Related Infusions Reactions 

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Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, 
each is unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, rigors, 
headache, rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. 
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the BMS Medical 
Monitor and reported as an SAE if criteria are met. Infusion reactions should be graded 
according to NCI CTCAE (v4) 
guidelines. Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines as appropriate: 
 
Grade 1 Symptoms: Mild reaction; infusion interruption not indicated; intervention 
not indicated. 
• Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at least 30 minutes 
before additional nivolumab or ipilimumab administrations. 
 
Grade 2 Symptoms: Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory 
drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications 
indicated for ≤ 24 hours. 
• Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, 
and treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen 325 to 1000 mg. Remain at bedside and monitor subject until 
resolution of symptoms. Corticosteroid or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 
50% of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor subject closely. If symptoms recur then no further nivolumab or 
ipilimumab will be administered at that visit. Administer diphenhydramine 50 mg IV, 
and remain at bedside and monitor the subject until resolution of symptoms. The 
amount of study drug infused must be recorded on the electronic case report form 
(eCRF). The following prophylactic premedications are recommended for future 
infusions: diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 
mg should be administered at least 30 minutes before additional nivolumab or 
ipilimumab administrations. If necessary, corticosteroids (recommended dose: up to 
25 mg of IV hydrocortisone or equivalent) may be used. 
 
Grade 3 or Grade 4 symptoms: Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; pressor or 
ventilatory support indicated). 
• Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion 
of normal saline, and treat the subject as follows. Recommend bronchodilators, 
epinephrine 

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0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of 
a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 
mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should 
be monitored until the investigator is comfortable that the symptoms will not recur. 
Nivolumab or ipilimumab will be permanently discontinued. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at 
bedside and monitor subject until recovery from symptoms. In the case of late-
occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritis within 1 
week after treatment), symptomatic treatment may be given (eg, oral antihistamine, 
or corticosteroids). 
 
6.5 Criteria for Taking a Participant Off Protocol Therapy 
Duration of therapy will depend on individual response, evidence of disease progression 
and tolerance. In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
 
• Disease progression (unless otherwise specified in section 6.7) 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Subject demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• Subject decides to withdraw from the protocol therapy 
• General or specific changes in the subject's condition render the subject unacceptable 
for further treatment in the judgment of the site investigator 
• 
Female subject becomes pregnant 
• 
Protocol therapy is interrupted for > 6 weeks (unless otherwise specified in 6.3). 
 
Participants will be removed from the protocol therapy when any of these criteria apply. 
The reason for removal from protocol therapy, and the date the participant was removed, 
must be documented in the case report form (CRF). Alternative care options will be 
discussed with the participant. 
 
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed 
from protocol therapy. This form can be found on the DF/HCC website at 
http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-forms-
sops- etc/. 
 
In the event of unusual or life-threatening complications, treating investigators must 
immediately notify the Overall PI, 
 
 
6.6 Duration of Follow Up 
Subjects will have safety follow up visits at D30 following the last dose of study drug. 
Subjects who have an ongoing study treatment-related AE upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline grade, 
the event is assessed by the site investigator as stable, new anticancer treatment is initiated, 

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the subject is lost to follow-up, the subject withdraws consent, or until it has been determined 
that study treatment or participation is not the cause of the AE. If not seen in clinic, subjects 
will be called on day 100 (+/-3) following the last dose of study drug for assessment of 
adverse events.  
 
After progression/treatment discontinuation, subjects will be followed for survival and receipt 
of next line therapies every 6 months until death or 2 years after end of treatment visit. 
Follow-up will be via phone calls and through review of medical records. 
 
6.7 Treatment Beyond Disease Progression 
 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. Subjects will be permitted to continue 
treatment beyond site investigator assessed progression after the administration of ipilimumab 
for rescue as detailed in the study schema and continued nivolumab as long as they meet the 
following criteria: 
• Site investigator-assessed clinical benefit 
AND 
• Subject is tolerating study drug(s). 
 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. All decisions 
to continue treatment beyond progression on nivolumab after addition of ipilimumab 
should be discussed with the sponsor-investigator and documented in the study records. 
 
Subjects should discontinue study therapy upon evidence of further progression on 
nivolumab after administration of ipilimumab, defined as an additional 10%  or greater 
increase in tumor burden volume from time of initial progression (including all target lesions 
and new measurable lesions). 
 
New lesions are considered measurable at the time of progression if the longest diameter is at 
least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm). Any new lesion considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden measurement if the longest 
diameter increases to at least 10 mm (except for pathological lymph nodes, which must have 
an increase in short axis to at least 15 mm) on followup imaging. 
 
 
6.8 Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must 

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be documented in the case report form (CRF). 
 
For Decentralized Subject Registrations, the research team updates the relevant 
Off Treatment/Off Study information in OnCore. 
 
6.9 Replacement 
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been assigned to treatment or administered at least one 
dose of the study drug. Subjects who have dropped out but have not received at least one 
dose of treatment will be replaced. Subjects who have not received at least one dose of 
treatment will not be included in data analysis and thus will not require data entry.  
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 will be used to 
grade adverse events.  Subjects enrolled in this study will be evaluated clinically and with 
standard laboratory tests before and at regular intervals during their participation in this study 
as specified in Study Calendar & Evaluations. Subjects will be evaluated for adverse events 
(all grades), serious adverse events, and adverse events requiring study drug interruption or 
discontinuation. 
 
There will be no dose reductions or dose escalations for either nivolumab or ipilimumab on 
this study, however, dose delays will be permitted as detailed below for each agent. The 
descriptions and grading scales found in the revised NCI CTCAE v4 will be utilized for dose 
delays. 
 
7.1 
Dose Delays for Nivolumab with or without Ipilimumab 
Nivolumab with or without ipilimumab administration should be delayed for the following: 
• Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not 
require a treatment delay 
• Any Grade 3 skin, drug-related adverse event 
• Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
AST, ALT, or total bilirubin: 
o If a subject has a baseline AST, ALT, or total bilirubin that is within 
normal limits, delay dosing for drug-related Grade ≥ 2 toxicity 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 
toxicity range, delay dosing for drug-related Grade ≥ 3 toxicity 
• Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis do not require a dose delay. It is recommended 
to consult with the PI for Grade 3 amylase or lipase abnormalities. 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication. 
 
 
7.2 
Criteria to Resume Treatment with Nivolumab with or without Ipilimumab 

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Nivolumab and/or ipilimumab should be administered as soon as the subject meets criteria to 
resume treatment. If a dose has been missed for combination therapy, the subject should not 
wait until the next scheduled dosing date but can restart when clinically safe as long as it has 
been at least 3 weeks from last ipilimumab. If a dose is held or missed for single agent 
nivolumab, the subject should resume treatment at the next scheduled dosing date. Efforts 
should be made to administer as many doses as possible, if a subject cannot be treated on a 
particular day the cycle should either be skipped or frame shifted to a point when the patient 
is able to be treated. All efforts should be made to refrain from skipping doses of Ipilimumab. 
If a subject has been holding for an extended period of time or clarifying questions are 
needed in regards to resuming treatment please reach out to the Principal Investigator  
 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤ 1 or baseline value, with the following EXCEPTIONS: 
• Subjects may resume treatment in the presence of Grade 2 fatigue. 
• Subjects who have not experienced a Grade 3 drug-related skin AE may 
resume treatment in the presence of Grade 2 skin toxicity. 
• Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays 
for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin. 
• Subjects with combined Grade 2 AST/ALT AND total bilirubin values 
meeting discontinuation parameters (Section 7.3) should have treatment 
permanently discontinued. 
• Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to 
baseline before treatment is resumed. 
• Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. 
 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Section 7.3. If irAEs require management with systemic 
steroids, dosing may resume once patient is tolerating prednisone 10 mg/day equivalent or 
lower. 
 
For the period in which ipilimumab is administered with nivolumab, treatment must be 
resumed on the same day. If a subject is unable to resume both nivolumab and ipilimumab 
within 6 weeks of dose interruption, permanent discontinuation is required. 
 
7.3 
Criteria to Discontinue Treatment with Nivolumab with or without Ipilimumab 
Treatment with nivolumab with or without ipilimumab should be permanently discontinued 
for any of the following: 
• Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment 
• Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, 
pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, hypersensitivity 
reactions, and infusion reactions: 

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o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic toxicity, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require 
treatment discontinuation except: 
▪ Grade 3 drug-related thrombocytopenia > 7 days or associated 
with bleeding requires discontinuation 
▪ Any drug-related liver function test (LFT) abnormality that meets 
the following criteria require discontinuation: 
 AST or ALT > 8 x ULN 
 Total bilirubin > 5 x ULN 
 Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any Grade 4 drug-related adverse event or laboratory abnormality, except for 
the following events which do not require discontinuation: 
o Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis. It is recommended to consult with the 
PI for Grade 4 amylase or lipase abnormalities. 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
• Any dosing interruption lasting > 6 weeks unless the sponsor-investigator is 
consulted and agrees with the rationale for resuming therapy after a delay > 6 
weeks. Note that tumor assessments should continue as per protocol even if dosing 
is interrupted. 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the site investigator, presents a substantial clinical risk to the subject with 
continued nivolumab with or without ipilimumab dosing.   
 
 
7.4 
Management Algorithms for Immune-Mediated Adverse Events 
Appendix C provides general management algorithm for immune-mediated AEs to 
provide guidance to the site investigator and may be supplemented by discussions with 
the sponsor- investigator. The guidance applies to all immuno-oncology agents and 
regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory subjects with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic 
or therapeutic procedure, is recommended. 

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The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 

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CALENDAR FOR ALL SUBJECTS 
PRIMARY TREATMENT 
Initial Primary Treatment 
Continued Primary Treatment 
During Period to Confirm 
Response14 
While on Primary Treatment 
Study Evaluation 
Cycle = 28 days 
Screening 
Nivolumab ALONE 
Cycle 1 
Nivolumab ALONE 
Cycle 2 + 
Nivolumab ALONE 
Every 2 cycles 
-28 days 
Day 1 
± 3 days 
Day 15 
± 3 days 
Day 1 
± 3 days 
Every 2 cycles (8 weeks +/- 
7 days) 
Research Blood Sample- cfDNA and 
CTCs13 
X 
X 
 
X 
 
 
Key to Footnotes 
1: Vital signs to include blood pressure, heart rate, respiratory rate, temperature, oxygen saturation, body weight (kg) and height (cm). Height 
at SCREENING ONLY. 
2: If the initial QTcF is found to be > 500 msec, two additional EKGs separated by at least 3 minutes should be performed. If the average of these 
three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility  in this regard. For Single Cell Sequencing Cohort ECHO will not be 
required at screening.  
3: Hematology testing to include full CBC with WBC, ANC, hemoglobin, and platelet count and differential. Serum chemistry to include full 
comprehensive metabolic panel with sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, albumin, AST, ALT, alkaline 
phosphatase, total bilirubin, and LDH (baseline LDH only). C1D1 laboratory assessments do not need to re-meet eligibility criteria. 
4: TSH and free T4 will be done at screening and every 2 cycles (8 weeks ± 7 days). 
5: For women of childbearing potential (WOCBP): urine or serum βhCG. If a urine test is done and it is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. WOCBP should be counseled regarding the importance of contraception from the time of 
screening until 180 days after last dose of study drug(s). If a subject communicates that pregnancy is possible, a serum βhCG should be performed 
per site investigator’s discretion. 
6: Hepatitis B virus (HBV) serology (HBsAg, antibodies against HBsAg, antibodies against hepatitis B core antigen), and HCV serology (anti- 
HCV) will be performed. HBV DNA test is required for subjects who have known positive serology for anti HBc. HCV RNA test is required for 
subjects who have known positive serology for anti HCV.  
7: Radiology Imaging at screening to include: Diagnostic CT chest and CT or MRI of the abdomen and pelvis and MRI of the brain. If a subject is 
not able to obtain an MRI, CT imaging with contrast is acceptable. If a subject is not able to receive contrast, CT head without contrast is 
acceptable.  Radiology Imaging during Primary Treatment: Initial scans will be done after 2 cycles (8 weeks +/- 7 days) of nivolumab.  Subjects 
with PR/CR/SD will have confirmatory scans 8 weeks later (+/- 7 days). Confirmatory scans for subjects with PD are not mandatory but may be 
attained 4 weeks later if clinically feasible (+/- 7 days). Subjects who have two serial consecutive imaging assessments (8 weeks +/- 7 days apart) 
which demonstrate CR/PR within the first 6 months of study will be allocated to Arm A. All other subjects who do not meet this criteria will enter 
Arm B by the 6 month time point. Subjects have who signs and/or symptoms concerning for early clinical progression can undergo imaging 
before 8 weeks (+/- 7 days). In this scenario, if there is evidence of radiographic progression, subjects may be allocated to Arm B immediately, 
assuming they have received at least 3 doses of nivolumab. For Single Cell Sequencing Cohort MRI or CT of the Brain will not be collected at 
screening.  
8: Primary Treatment: Nivolumab will be administered on Day 1 (+/- 3 days) of each 28-day cycle for 2 cycles. After 2 cycles, disease assessment 
will occur. Nivolumab alone will continue until disease status documented with confirmatory scans (See Footnote 7) or site investigator 

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confirmation of PD and inability to wait for confirmatory scan. 
9: MANDATORY if available: Archival tissue will be requested and received prior to Cycle 1 Day 1. Formalin-fixed, paraffin-embedded (FFPE) 
tumor tissue block is preferred. Alternatively, a minimum of 30 unstained, charged, paraffin coated slides will suffice. Fine-needle aspiration, 
brushings, cell pellet from pleural effusion, bone marrow aspirate/biopsy are not acceptable. Please see the laboratory manual for additional 
collection, labeling and shipping information. 
10: MANDATORY: Pre-treatment biopsy. Given that fresh tumor tissue is required for correlative assessments, archival tissue cannot take the place 
of the pre-treatment biopsy. The pre-treatment biopsy will take place following confirmation of eligibility, after registration and prior to Cycle 1 
Day 1. In the case that a patient will be undergoing a cytoreductive nephrectomy, or metastatectomy, or biopsy within 12 months of enrolling on the 
study with no intervening systemic therapy from the time of surgery to study enrollment, fresh tissue obtained from the surgical specimen may be 
used to replace the mandatory baseline fresh tumor biopsy. 
11: MANDATORY: Blood for germline DNA analysis collected once between screening to prior to treatment Cycle 1 Day 1 
12: MANDATORY: Blood samples for biomarkers will be collected (1) once between screening to prior to treatment C1D1 then (2) every 2 cycles 
(± 7 days) prior to treatment and corresponding to all imaging assessment time points and (3) at time of EOT visit. Additionally, blood samples for 
biomarkers will be collected at confirmatory imaging assessment time points. If EOT collection is within 2 weeks of prior collection, research 
samples do not need to be collected. For patients enrolled on the Single Cell Sequencing Cohort, whole blood for CTC collection and whole blood 
for plasma/PBMC isolation will not be collected. 
13: MANDATORY: Blood samples for cfDNA and CTCs will be collected at screening and prior to C1D1 treatment, every 2 cycles (± 7 days) 
prior to treatment and corresponding to all imaging assessment time points, and at time of EOT visit. Additionally, blood samples for cfDNA and 
CTCs will be collected at confirmatory imaging assessment time points. If EOT collection is within 2 weeks of prior collection, research samples 
do not need to be collected. For patients enrolled on the Single Cell Sequencing Cohort, whole blood for CTC collection and whole blood for 
plasma/PBMC isolation will not be collected. 
14: Nivolumab will continue to be administered on D1 of each 28-day cycle. Once confirmatory scans are complete subjects will either be 
followed per Arm A or Arm B calendar. Subjects that show SD/PD with confirmatory scans after Primary Treatment with nivolumab will be 
assigned to Arm B. Subjects with SD after initial scans with Primary Treatment with nivolumab and CR/PR with confirmatory scans will have 
additional scans 8 weeks later (± 7 days) to confirm CR/PR.  If CR/PR is confirmed, these subjects will be assigned to Arm A, go into observation 
and be followed as described in the calendar titled “Arm A: CALENDAR FOR SUBJECTS WITH CR/PR AFTER PRIMARY TREATMENT.” Subjects 
that show CR/PR with confirmatory scans after Primary Treatment with nivolumab will be assigned to Arm A. 

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Key to Footnotes: 
1: Vital signs to include upright blood pressure, heart rate, respiratory rate, temperature, oxygen saturation, body weight (kg) and height (cm). Height 
at SCREENING ONLY. 
2: Hematology testing to include full CBC with WBC, ANC, hemoglobin, and platelet count and differential. Serum chemistry to include full 
comprehensive metabolic panel with sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, albumin, AST, ALT, alkaline 
phosphatase, and total bilirubin. C1D1 laboratory assessments do not need to re-meet eligibility criteria. TSH and free T4 will be done every two cycles 
(8 weeks ± 7 days), except when ipilimumab is added, TSH and free T4 will be obtained after 3 cycles (12 weeks ± 7 days) instead of 2 cycles (8 weeks) 
to align with scans. 
3: Diagnostic CT chest and CT or MRI of the abdomen and pelvis should be obtained every 2 cycles (± 7 days). NOTE: When ipilimumab is added, 
the first set of post-ipilimumab imaging will be obtained after 3 cycles (~12 weeks ± 7 days) instead of 2 cycles.  After the initial set of scans after 
ipiliumumab initiation, the scan timing will revert back to every 2 cycles (+/- 7 days). If dosing is delayed, imaging should follow guidelines of 
cycles over absolute weeks. 
4: OBSERVATION: Subjects with a CR/PR (Arm A) after Primary Treatment with nivolumab will have nivolumab discontinued and go onto 
Observation. Radiology imaging will be done every 2 cycles (8 weeks ± 7 days) as described in bullet 3. Subjects will continue observation until PD. 
During the observation period subjects will be seen in clinic once per cycles (28 days +/- 3 days).  
For subjects who have shown persistent CR/PR while on observation, in clinic study visits can be extended to every 8 weeks. A nurse, NP/PA, or 
physician will call subjects in between visits for assessment of symptoms (at least every 4 weeks). This must be approved by sponsor-investigator prior to 
modifying subjects visit schedule. 
5: RE-INITIATION OF NIVOLUMAB: Subjects that experience PD during observation will re-initiate nivolumab. Radiology imaging will be done 
every 2 cycles (8 weeks +/- 7 days) as described in bullet 3.  Subjects will continue nivolumab until PD. 
6: ADDITION OF IPILIMUMAB: Subjects that show PD after re-initiation of nivolumab will have ipilimumab added for 2 doses ONLY. During this 
time, nivolumab will be given every 3 weeks to match ipilimumab administration. Disease assessment scans will occur after completion of 3 cycles (12 
weeks ± 7 days) from the time ipilimumab is added to nivolumab. Nivolumab ALONE will be continued starting 5 weeks +/- 3 days after last dose of 
nivolumab PLUS ipilimumab at the start of cycle 3/day 1 from when ipilimumab is added to nivolumab.  
7: CONTINUATION OF NIVOLUMAB: Subjects with CR/PR/SD after initial scans following the addition of ipilimumab to nivolumab will continue 
nivolumab ALONE until PD. During this time nivolumab will be given every 4 weeks and disease assessment scans will occur every 2 cycles (8 weeks +/- 
7 days). Subjects will be permitted to continue treatment beyond site investigator assessed progression as long as they meet the following criteria: (1) Site 
investigator-assessed clinical benefit AND (2) Subject is tolerating study drug. 
8: End of treatment (EOT) visit will occur 30 days (± 7 days) after last dose of study drug. Subjects will come off study treatment if they have PD as 
described in bullet #6 or for other reasons such as toxicity or subject choice. Subjects who (1) had study drugs delayed or modified due to toxicity or other 
factors and (2) were then discontinued from study treatment can use a study visit as EOT visit. Subjects who have an ongoing study treatment-related AE 
upon discontinuation from the study treatment will be followed until the event has resolved to baseline grade, the event is assessed by the site investigator 
as stable, new anticancer treatment is initiated, the subject is lost to follow-up, the subject withdraws consent, or until it has been determined that study 
treatment or participation is not the cause of the AE. If not seen in clinic, subjects will be called on day100 following the last dose of study drug for 
assessment of adverse events. 
9: Long term follow-up for survival and initiation of a new anti-cancer treatment will occur every 6 months (± 14 days) until death or 2 years after EOT 
visit whichever comes first.  This follow up may be via phone calls and through review of medical records. 
10: An OPTIONAL tumor biopsy at time of progression will be requested from subjects unless the procedure is deemed medically unsafe or not feasible. 

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ARM A subjects will have biopsies (1) following progression off nivolumab prior to reinitiation of nivolumab (ideally prior to restart but within 10 days of 
re-starting nivolumab is permitted if scheduling issues and clinical need to start sooner than biopsy can be obtained), (2) at progression following treatment 
with both nivolumab and ipilimumab. For patients enrolled on ARM A in the Single Cell Sequencing Cohort a mandatory biopsy will be performed at 
baseline, an optional biopsy at the time of response following discontinuation of nivolumab and a mandatory biopsy at time of permannent treatment 
discontinuation/off study if deemed safe and feasible. Biopsies should be performed per institutional standards and/or operator preference. Blood samples 
should be drawn within 2 weeks of the biopsy to document an acceptable coagulation profile (INR ≤ 1.5, PTT ≤ 60, platelets > 50,000). Aspirin and 
NSAIDS should be discontinued 5 days prior to the biopsy. Please see the laboratory manual for additional collection, labeling and shipping information. 
11: MANDATORY: Blood samples for Biomarkers will be collected every 2 cycles (± 7 days) prior to treatment, corresponding to all imaging assessment 
time points and at time of EOT visit. Additionally, blood samples for biomarkers will be collected at confirmatory imaging assessment time points. If EOT 
collection is within 2 weeks of prior collection, research samples do not need to be collected. For patients enrolled on the Single Cell Sequencing Cohort, 
whole blood for CTC collection and whole blood for plasma/PBMC isolation will not be collected. 
12: MANDATORY: Blood samples for cfDNA and CTCs will be collected every 2 cycles (± 7 days) prior to treatment, corresponding to all imaging 
assessment time points and at time of EOT visit. Additionally, blood samples for cfDNA and CTCs will be collected at confirmatory imaging 
assessment time points. If EOT collection is within 2 weeks of prior collection, research samples do not need to be collected. For patients enrolled on 
the Single Cell Sequencing Cohort, whole blood for CTC collection and whole blood for plasma/PBMC isolation will not be collected. 
 
 

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Key to Footnotes 
1: Vital signs to include upright blood pressure, heart rate, respiratory rate, temperature, oxygen saturation, body weight (kg) and height (cm). 
Height at SCREENING ONLY. 
2: Hematology testing to include full CBC with WBC, ANC, hemoglobin, and platelet count and differential. Serum chemistry to include full 
comprehensive metabolic panel with sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, albumin, AST, ALT, alkaline 
phosphatase, and total bilirubin. C1D1 laboratory assessments do not need to re-meet eligibility criteria. TSH and free T4 will be done every two 
cycles (8 weeks ± 7 days), except when ipilimumab is added, TSH and free T4 will be obtained after 3 cycles (12 weeks ± 7 days) instead of 2 
cycles (8 weeks) to align with scan visits 
3: Diagnostic CT chest and CT or MRI of the abdomen and pelvis should be obtained every 2 cycles (- 7 days). NOTE: When ipilimumab is 
added, imaging will be obtained after 3 cycles (~12 weeks ± 7 days) instead of 2 cycles. If dosing is delayed, imaging should follow 
guidelines of cycles over absolute weeks. 
 
4: ADDITION OF IPILIMUMAB: Subjects that show SD/PD with confirmatory scans after Primary Treatment (Arm B) will have ipilimumab 
added for 2 doses ONLY. During this time, nivolumab will be given every 3 weeks to match ipilimumab administration. Disease assessment 
scans will occur after completion of 3 cycles from the addition of ipilimumab to nivolumab. Nivolumab ALONE will be continued starting 5 
weeks +/- 3 days after last dose of nivolumab PLUS ipilimumab at the start of cycle 3/day 1 from when ipilimumab is added to nivolumab.  
5: CR/PR/SD AFTER ADDITION OF IPILIMUMAB: Subjects will continue nivolumab ALONE until PD. During this time nivolumab will 
be given every 4 weeks and disease assessment scans will occur every 2 cycles (8 weeks +/- 7 days). 
6: PD AFTER ADDITION OF IPILIMUMAB: Subjects that experience PD after nivolumab PLUS ipilimumab will be taken off study 
treatment and continue follow up per protocol. Confirmatory scans for subjects with PD are not mandatory but may be attained 4 weeks later if 
clinically feasible. Subjects will be permitted to continue treatment beyond site investigator assessed progression as long as they meet the 
following criteria: (1) Site investigator-assessed clinical benefit AND (2) Subject is tolerating study drug. 
7: End of treatment (EOT) visit will occur 30 days (± 7 days) after last dose of study drug. Subjects will come off study treatment if they have PD 
as described in bullet #6 or for other reasons such as toxicity or subject choice. Subjects who (1) had study drugs delayed or modified due to 
toxicity or other factors and (2) were then discontinued from study treatment can use a study visit as EOT visit. Subjects who have an ongoing 
study treatment-related AE upon discontinuation from the study treatment will be followed until the event has resolved to baseline grade, the event 
is assessed by the site investigator as stable, new anticancer treatment is initiated, the subject is lost to follow-up, the subject withdraws consent, or 
until it has been determined that study treatment or participation is not the cause of the AE. If not seen in clinic, subjects will be called on day 100 
(+/- 3) following the last dose of study drug for assessment of adverse events. 
8: Long term follow-up for survival and initiation of a new anti-cancer treatment will occur every 6 months (± 14 days) until death or 2 years after 
EOT visit whichever comes first.  This follow up may be via phone calls and through review of medical records. 
9: An OPTIONAL tumor biopsy at time of progression will be requested from subjects unless the procedure is deemed medically unsafe or not 
feasible. For patients enrolled on the Single Cell Sequencing Cohort a mandatory biopsy will be performed at the time of treatment 
discontinuation/off study following treatment with nivolumab and ipilimumab if deemed safe and feasible. Arm B (1) following progression on 
treatment with BOTH nivolumab and ipilimumab. Biopsies should be performed per institutional standards and/or operator preference. Blood 
samples should be drawn within 2 weeks of the biopsy to document an acceptable coagulation profile (INR ≤ 1.5, PTT ≤ 60, platelets > 50,000). 
Aspirin and NSAIDS should be discontinued 5 days prior to the biopsy. Please see the laboratory manual for additional collection, labeling and 
shipping information. 

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10: MANDATORY: Blood samples for Biomarkers will be collected every 2 cycles (± 7 days) prior to treatment, corresponding to all imaging 
assessment time points and at time of EOT visit. Additionally, blood samples for biomarkers will be collected at confirmatory imaging assessment 
time points. If EOT collection is within 2 weeks of prior collection, research samples do not need to be collected. For patients enrolled on the Single 
Cell Sequencing Cohort, whole blood for CTC collection and whole blood for plasma/PBMC isolation will not be collected. 
11: MANDATORY: Blood samples for cfDNA and CTCs will be collected every 2 cycles (± 7 days) prior to treatment, corresponding to all 
imaging assessment time points and at time of EOT visit. Additionally, blood samples for cfDNA and CTCs will be collected at confirmatory 
imaging assessment time points. If EOT collection is within 2 weeks of prior collection, research samples do not need to be collected. For patients 
enrolled on the Single Cell Sequencing Cohort, whole blood for CTC collection and whole blood for plasma/PBMC isolation will not be collected. 

   
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8.1 
Duration of Follow Up 
Subjects who have an ongoing study treatment-related AE upon end of treatment visit will be 
followed until the event has resolved to baseline grade, the event is assessed by the site 
investigator as stable, new anticancer treatment is initiated, the subject is lost to follow-up, the 
subject withdraws consent, or until it has been determined that study treatment or participation is 
not the cause of the AE. After progression/treatment discontinuation, subjects will be followed 
for survival and receipt of next line therapies every 6 months until death or 2 years after 
treatment discontinuation. Follow-up will be via phone calls and through review of medical 
records. 
 
9. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Correlative studies will be exploratory in nature. In this study, we will evaluate the 
immunomodulatory properties of nivolumab in combination with ipilimumab and correlate 
findings with outcomes. In addition, we will evaluate tumor tissue and TIMC for expression of 
PD-L1 in mandatory baseline biopsies and optional progression biopsies and correlate with 
outcomes. Lastly, we will evaluate mechanisms of resistance to therapy in optional progression 
biopsy specimens. Please see the Laboratory Manual for collection, processing, labeling and 
shipping instructions. 
 
Whole blood for germline DNA and cfDNA plasma samples will be analyzed by investigators 
at   collaborating institutions, such as the Broad Institute, for all patients enrolled on this trial. 
From  these samples, the data will be submitted to the National Institutes of Health’s Database 
for  Genotypes and Phenotypes (dbGaP) and other public databases. Samples and data will be 
de-identified. 
 
9.1 
Blood for Germline DNA 
• This sample will be drawn once prior to C1D1 treatment 
• Five (5) mL of blood will be drawn into purple top vacutainers with EDTA. DO NOT 
use heparin as anticoagulant, since the polymer will tightly bind downstream PCR 
enzyme during sequencing. 
 
9.2 
Blood for Research Analysis 
 
9.2.1 Biomarker Analysis 
Blood will be collected for flow cytometry studies to analyze peripheral blood mononuclear 
cells. Additionally, plasma will be collected to analyze soluble biomarkers to include 
cyotkines/chemokines and angiogenic/growth factors. This analysis will require 30 mL of blood 
in green or purple top tubes at each time point. These samples are to be collected prior to 
treatment C1D1, every 2 cycles corresponding with radiology imaging. If off treatment 
collection is within 2 weeks of prior collection, research samples do not need to be collected. 
 
9.2.2 cfDNA Plasma 
Plasma will be collected for genomic analysis of circulating free DNA (cfDNA). cfDNA assessments will 
require 10 mL of blood in an EDTA tube at each time point. These samples are to be collected prior to 
treatment C1D1, every 2 cycles corresponding with radiology imaging. If off treatment collection is within 2 
weeks of prior collection, research samples do not need to be collected.  
 

   
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The cfDNA from each time point will be subjected to low pass whole genome sequencing 
to assess DNA quality, tumor purity (i.e. the approximate percentage of DNA isolated from 
peripheral blood originating from tumor rather than normal cells), and copy number profile 
of tumor DNA. For subjects with cfDNA of adequate quality and purity, we will also 
perform whole exome sequencing from cfDNA isolated at baseline, at best tumor response, 
and at progression. 
 
9.2.3 CTC Analysis 
CTC analysis will require 20mL of blood in EDTA tubes at each time point. These samples 
are to be collected during screening, prior to treatment C1D1, every 2 cycles, corresponding 
with radiology imaging. If off treatment collection is within 2 weeks of prior collection, 
research samples do not need to be collected. 
 
9.3 
Tissue Studies 
Tissue will be collected to assess the immunomodulatory properties of nivolumab in 
combination with ipilimumab as determined immunohistochemistry assessment of 
immunologic parameters including, but not limited to, T cell subset markers (CD4, CD8, 
FoxP3, LAG3), cytokines/chemokines (IFN, TNF), immune regulation (PD-L2, CTLA-4), and 
tumor infiltrating lymphocytes (TILs). Additionally, mutation profiling of molecular 
mechanisms of response and resistance will be analyzed via whole exome sequencing and 
RNA sequencing. 
 
Mutational profiling of molecular mechanisms of response and resistance will be analyzed via 
whole exome or whole genome sequencing and via RNA-sequencing. If fresh tissue is 
available, the specimen will be collected, as stated in this protocol and according to institutional 
guidelines, and put on ice to be transported to the processing laboratory. A portion of fresh 
tissue will be dissociated into a single cell suspension and frozen for future studies, including 
single cell transcriptome studies and cell line creation. 
 
9.3.1 Archival tumor specimens 
Archival tissue is MANDATORY if available. The archival specimen must contain adequate 
viable tumor tissue and be overall representative of the whole tumor (i.e. containing 
predominant and highest Fuhrman grade areas). Formalin-fixed paraffin-embedded tumor 
tissue blocks are preferred and should contain tumor areas that measure at least 1 cm square in 
aggregate. 
Alternatively, a minimum of 30 unstained 4-micron-thick sections (on charged slides) can be 
provided. The unstained slides should be coated with paraffin. Surgical specimens are 
preferred with order of preference being 1) nephrectomy specimens and 2) metastatectomy 
specimens. If surgical specimens are not available, core-needle biopsy specimens are 
acceptable. Fine-needle aspiration, brushings, cell pellet from pleural effusion, bone marrow 
aspirate/biopsy are not acceptable. 
 
9.3.2 Fresh Tumor Specimens 
MANDATORY tumor biopsies will be performed on all subjects prior to treatment, and 
OPTIONAL tumor biopsies will be performed on subjects at the time of disease progression 
and for patients in arm A at time of disease progression after discontinuation of nivolumab. 

   
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For patients enrolled on the Single Cell Sequencing Cohort the biopsy schedule will be as 
follows: 
Arm A: 
Mandatory biopsy at baseline 
Optional biopsy at time of response following discontinuation of nivolumab 
Mandatory biopsy at final treatment discontinuation/off study 
 
Arm B: 
Mandatory biopsy at baseline 
Mandatory biopsy at final treatment discontinuation/off study 
 
Progression biopsies are strongly recommended in patients who demonstrate a response to 
therapy and subsequently progress. Biopsies will be obtained in a manner that minimizes risk 
and will be taken only if there is no intervening condition (e.g., thrombocytopenia or 
neutropenia) that, in the opinion of the site investigator, increases the likelihood of procedural 
complications to an unacceptable level. 
 
Biopsies should be performed per institutional standards and/or operator preference. Blood 
samples will be drawn within 2 weeks of the biopsy to document an acceptable coagulation 
profile (INR ≤ 1.5, PTT ≤ 60, platelets > 50,000). Aspirin and NSAIDS should be 
discontinued 5 days prior to the biopsy. 
 
Preferred biopsy sites include: lymph nodes, peripheral based liver lesions, exophytic soft 
tissue components associated with bone lesions, subcutaneous nodules, pleural-based lesions, 
and kidney lesions. 
 
In the case that a patient will be undergoing a cytoreductive nephrectomy, metastatectomy, or 
biopsy within 12 months of enrolling on the study with no intervening systemic therapy from 
the time of surgery to study enrollment, fresh tissue obtained from the surgical specimen may 
be used to replace the mandatory baseline fresh tumor biopsy. 
 
9.4 
Radiology Imaging Studies 
Images of all radiologic assessments at baseline, on study, and at treatment discontinuation with 
corresponding imaging reports for non-DFCI patients need to be placed on a CD and sent to the 
DFCI for eventual central review of exploratory imaging response assessment by irRC. Images 
and reports should be sent on all patients once they discontinue study treatment. Please ensure 
that patient data is de-identified and patient study ID is referenced on all materials as detailed in 
the lab manual. Reference the Laboratory Manual for additional information.    
 
9.5 
Storage of Biospecimens 
Samples will be processed for correlative studies and remaining specimens will be stored 
for future use to include assessment of biological and molecular predictive and prognostic 
biomarkers. 
 
9.6 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s study number assigned at the time 

   
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of registration to the trial. Any material issued to collaborating researchers will be anonymized 
and only identified by the subject’s study number. 
 
10. 
CRITERIA FOR DISEASE EVALUATION 
Subjects should be re-evaluated for response every 2 cycles. Response and progression will 
be evaluated in this study using the new international criteria proposed by the RECIST 
guideline (version 1.1).33 Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in 
the RECIST criteria. 
 
10.1 
Definitions 
Evaluable for Target Disease response.  Only those subjects who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for target disease response. These subjects will have 
their response classified according to the definitions stated below. (Note: Subjects who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.)  
 
Evaluable Non-Target Disease Response. Subjects who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-
target disease. The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions. 
 
10.2 
Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray or ≥10 
mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). NOTE: Tumor lesions that are 
situated in a previously irradiated area are not considered measurable. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses 
(not followed by CT or MRI), and cystic lesions are all considered non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 

   
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‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same participant, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum. The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up. 
 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool. All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
 
When possible, the same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. Imaging-
based evaluation is preferred to evaluation by clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using 
calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size of a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 

   
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resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner 
should be used and the image acquisition protocol should be followed as closely as possible 
to prior scans. Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
10.3 
Response Criteria 
 
10.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression). For subjects who demonstrate PD at the first on-
treatment imaging assessment, subjects will be allowed to remain on study until confirmatory 
imaging at the next imaging assessment at the discretion of the treating investigator if it 
appears that the subjects is clinically benefiting from treatment. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
If a target lesion is biopsied at screening, this lesion must be followed as non-target lesion after 
the biopsy unless it is the patient’s only target lesion. If there is only one target lesion, it should 
be followed as a target lesion regardless. 
 
10.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 

   
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progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. For subjects who demonstrate PD at the first on-treatment imaging 
assessment, subjects will be allowed to remain on study until confirmatory imaging at the 
next imaging assessment at the discretion of the treating investigator if it appears that the 
subjects is clinically benefiting from treatment. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
For patients who continue on treatment past progression (past the confirmatory scans), 
see section 6.7 for details on what constitutes subsequent progression and 
discontinuation rules. 
 
10.3.3 Evaluation of New Lesions 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor 
(for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions). 
However, a lesion identified on a follow-up scan in an anatomical location that was not 
scanned at baseline is considered new and will indicate PD. If a new lesion is equivocal 
(because of small size etc.), follow-up evaluation will clarify if it truly represents new 
disease and if PD is confirmed, progression should be declared using the date of the initial 
scan on which the lesion was discovered. 
 
10.3.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The subject's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
Table 2: For Subjects with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 

   
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Any 
PD*** 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
Any 
Yes 
PD 
 
 
 
 
Table 3. For Subjects with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 ‘Non-CR/non-PD’ is preferred over ‘SD’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised 
 
10.4 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Subjects without events reported are censored at the last disease 
evaluation). 
 
Duration of overall CR: The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is objectively 
documented, or death due to any cause. Subjects without events reported are censored at the 
last disease evaluation. 
 
Duration of SD: SD is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
 
10.5 
Immune-Related Response Criteria (irRC) 
The sum of the products of the two largest perpendicular diameters of lesions (SPD; 5 lesions 
per organ, up to 10 visceral lesions) at tumor assessment using the immune related response 
criteria (irRC) for progressive disease incorporates the contribution of new measurable 
lesions (up to 5 new lesions per organ: 10 new visceral lesions).34 Each net Percentage 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
NOTE: Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 

   
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Change in Tumor Burden per assessment using irRC criteria accounts for the size and growth 
kinetics of both old and new lesions as they appear. 
 
10.5.1 Definition of Index Lesions Response Using irRC 
irComplete Response (irCR): Complete disappearance of all target lesions in two 
consecutive observations not less than 4 weeks apart. This category encompasses 
exactly the same subjects as “CR” by the mWHO criteria. 
• irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum 
of the products of the two largest perpendicular diameters of all target and all new 
measurable lesions in two consecutive observations not less than 4 weeks apart. 
(i.e., Percentage Change in Tumor Burden). Note: the appearance of new 
measurable lesions is factored into the overall tumor burden, but does not 
automatically qualify as progressive disease until the SPD increases by > 25% when 
compared to SPD at nadir. 
• irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence 
of progressive disease. 
• irProgressive Disease (irPD): At least 25% increase in the percentage change in tumor 
burden (i.e., taking SPD of all target lesions and any new lesions) when compared to 
SPD at nadir, in two consecutive observations at least 4 weeks apart, in the absence of 
rapid clinical deterioration. 
 
10.5.2 Definition of Non-Index Lesions Response Using irRC 
• irComplete Response (irCR): Complete disappearance of all non-index lesions. 
This category encompasses exactly the same subjects as “CR” by the mWHO 
criteria. 
• irPartial Response (irPR): Non-index lesion(s) are not considered in the definition of 
PR; this term does not apply. 
• irStable Disease (irSD): Does not meet the criteria for irCR or irPD. 
• irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does 
not constitute progressive disease unless/until the Percentage Change in Tumor 
Burden increases by 25% (i.e., the SPD at nadir of the target lesions increases by the 
required amount). 
 
10.5.3 Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However, their 
contribution to total tumor burden is included in the SPD which in turn feeds into the 
irRC criteria for tumor response. Therefore, new non-measurable lesions will not 
discontinue any subject from the study. 
 
10.5.4 Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
• Immune-Related Complete Response (irCR): Complete disappearance of all tumor 
lesions (index and non-index together with no new measurable/unmeasurable lesions) 
for at least 4 weeks from the date of documentation of complete response. 
• Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD 

   
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baseline. At each subsequent tumor assessment, the SPD of the two largest 
perpendicular diameters of all index lesions and of new measurable lesions are added 
together to provide the Immune Response Sum of Product Diameters (irSPD). A 
decrease, relative to baseline of the irSPD compared to the previous SPD baseline, of 
50% or greater is considered an immune Partial Response (irPR). 
Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease. 
• Immune-Related Progressive Disease (irPD): It is recommended to confirm PD by 
serial imaging. Any of the following will constitute progressive disease: 
o At least 25% increase in the SPD of all target lesions over nadir SPD 
calculated for the index lesions, in two consecutive observations at least 4 
wk apart, if clinically permissible*. 
o At least a 25% increase in the SPD of all index lesions and new 
measurable lesions (irSPD) over the nadir SPD calculated for the target 
lesions, in two consecutive observations at least 4 wk apart, if clinically 
permissible*. 
 
Table 4. Immune-Related Response Criteria Definitions 
Target 
Lesion 
Definition 
Non-Target 
Lesion 
Definition 
New 
Measurable 
Lesions 
New  
Unmeasurable 
Lesions 
Percent Change 
in Tumor 
Burden 
(including 
measurable 
new lesions 
when present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR* 
Partial 
Response 
Any 
Any 
Any 
≥-50% 
irPR* 
<-50% to 
<+25% 
irSD* 
>+25% 
irPD* 
Stable 
Disease 
Any 
Any 
Any 
<-50% to 
<+25% 
irSD* 
>+25% 
irPD* 
Progressive 
Disease 
Any 
Any 
Any 
≥+25% 
irPD* 
* In two consecutive observations at least 4 weeks apart, if clinically permissible* 
 
10.5.5 Immune-Related Best Overall Response Using irRC (irBOR) 
irBOR is the best confirmed irRC overall response over the study as a whole, recorded 
between the date of first dose until the last tumor assessment before subsequent therapy 
(except for local palliative radiotherapy for painful bone lesions) for the individual subject in 
the study. For the assessment of irBOR, all available assessments per subject are considered. 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a 
second (confirmatory) evaluation meeting the criteria for response and performed no less than 

   
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4 weeks after the criteria for response are first met. 
 
10.6 
Response Review 
Tumors will be assessed for response and progression by RECIST version 1.1 by 
central radiology review. 
 
11. 
DRUG INFORMATION 
 
11.1 
Nivolumab 
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and 
its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has a 
calculated molecular mass of 146 kDa. 
 
Bristol-Myers Squibb (BMS) will supply nivolumab. Ordering of nivolumab will take place 
through BMS. Each participating institution will receive its own supply of drug. 
 
11.1.1  Pharmacokinetics (PK) 
 
Nivolumab as a single agent: A pooled analysis dataset from a comprehensive population 
pharmacokinetics analysis dataset consisting of covariate data from 3203 patients with 
melanoma (n = 875), RCC (n = 695), non-small cell lung cancer (n = 896), squamous cell 
carcinoma of the head and neck (n = 172), classical Hodgkin’s Lymphoma (n = 256), and 
urothelial carcinoma (n = 308) was used to simulate exposures from nivolumab clinical trials. 
Using a previously established population pharmacokinetics model across multiple tumor 
types, nivolumab exposure was predicted for 480 mg every 4 weeks and 3 mg/kg every 2 
weeks dose schedules. 
 
The time-averaged concentration over the first 28 days for nivolumab 480 mg every 4 weeks 
was 27% higher compared to nivolumab 3 mg/kg every 2 weeks. The time-averaged 
concentration at steady-state was similar between these two dosing schedules.  
 
To analyze exposure-response safety, a pooled safety dataset from nivolumab clinical trials 
containing 2560 patients with melanoma (n = 481), RCC (n= 604), squamous non-small cell 
lung cancer (n = 293), non-squamous non-small cell lung cancer (n = 354), squamous cell  
carcinoma of the head and neck (n = 172), classical Hodgkin’s Lymphoma (n = 253), and 
urothelial carcinoma (n = 308), who received nivolumab 1 to 10 mg/kg every 2 weeks or 0.3 
to 10 mg/kg every 3 weeks were used. Logistic regression models were used to describe the 
relationships between nivolumab exposure and the risk of AEs (AEs leading to 
discontinuation or death, AEs > Grade 3, immune mediated AEs > Grade 2). Cavgd28 was 
the designated exposure measure for exposure-response safety analysis. Exposure (Cmax) 
produced by nivolumab 480 mg every 4 weeks was lower than that produced by 10 mg/kg 
every 2 weeks, which has been shown to have a favorable safety and tolerability profile. The 
predicted risk of experiencing AEs leading to discontinuation or death was similar between 
the 480 mg every 4 weeks and 3 mg/kg every 2 weeks dosing schedules across the tumor 
types.  
 

   
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To analyze exposure-response efficacy, individual datasets from nivolumab clinical trials of 
patients with melanoma (n = 364), RCC (n = 604), squamous non-small cell lung cancer (n = 
293), and non-squamous non-small cell lung cancer (n = 354), who received nivolumab 1 
to10 mg/kg every 2 weeks or 0.3 to 10 mg/kg every 3 weeks were used. OS was assessed by 
Cox Proportional Hazards and objective response by logistic regression. The predicted OS 
for the 480 mg every 4 week dose was similar to the 3 mg/kg every 2 week dose in the four 
indications. In predicted probabilities of achieving response, there were no differences 
between the 480 mg every 4 week dose and 3 mg/kg every 2 week dose, consistent with 
previously established flat exposure-efficacy relationships.  
 
Nivolumab in combination with ipilimumab: The geometric mean (%CV) CL, Vss, and 
terminal half-life of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days 
(94.3%), respectively. When administered in combination, the CL of nivolumab was increased 
by 24%, whereas there was no effect on the clearance of ipilimumab. When administered in 
combination, the clearance of nivolumab increased by 42% in the presence of anti-nivolumab 
antibodies. 
There was no effect of anti-ipilimumab antibodies on the clearance of ipilimumab. 
 
Specific Populations: Based on a population PK analysis, the clearance of nivolumab 
increased with increasing body weight supporting a weight-based dose. The population PK 
analysis suggested that the following factors had no clinically important effect on the 
clearance of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1 expression, 
tumor type, tumor size, renal impairment, and mild hepatic impairment. 
 
Renal Impairment: The effect of renal impairment on the clearance of nivolumab was 
evaluated by a population PK analysis in subjects with mild (eGFR 60 to 89 mL/min/1.73 m2; 
n=313), moderate (eGFR 30 to 59 mL/min/1.73 m 2; n=140), or severe (eGFR 15 to 29 
mL/min/1.73 m 2; n=3) renal impairment. No clinically important differences in the clearance 
of nivolumab were found between subjects with renal impairment and subjects with normal 
renal function. 
 
Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was 
evaluated by population PK analyses in subjects with mild hepatic impairment (total 
bilirubin ≤ ULN and AST > ULN or total bilirubin < 1-1.5 x ULN and any AST; n=92). No 
clinically important differences in the clearance of nivolumab were found between subjects 
with mild hepatic impairment and subjects with normal hepatic function. Nivolumab has not 
been studied in subjects with moderate (total bilirubin > 1.5-3 x ULN and any AST) or 
severe hepatic impairment (total bilirubin > 3 x ULN and any AST). 
 
11.1.2 Preparation 
Nivolumab is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale 
yellow liquid that may contain light (few) particles. Nivolumab injection for IV infusion is 
supplied in single-use vials. Each mL of Nivolumab solution contains nivolumab 10 mg, 
mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 
mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain 
hydrochloric acid and/or sodium hydroxide to adjust pH to 6. 

   
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Injection: 100 mg/10 mL (10 mg/mL) solution in a single-use vial. 
 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard 
the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other 
than a few translucent-to-white, proteinaceous particles. Do not shake the vial. 
 
Withdraw the required volume of nivolumab and transfer into an intravenous container. 
Dilute nivolumab with either 0.9% Sodium Chloride solution or 5% Dextrose solution 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 
nivolumab. 
 
11.1.3 Storage and Stability 
The product does not contain a preservative. Store nivolumab under refrigeration at 2°C to 
8°C (36°F-46°F). Protect nivolumab from light by storing in the original package until time 
of use. Do not freeze or shake. 
 
After preparation of infusion, store the nivolumab infusion either: 
• at room temperature for no more than 8 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 to 46°F) for no more than 24 hours from the 
time of infusion preparation. 
• Do not freeze. 
 
11.1.4 Administration 
Administer the infusion over approximately30-minutes  through an IV line containing a 
sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 
micrometer). 
 
Do not coadminister other drugs through the same intravenous line. Flush the 
intravenous line at end of infusion. When administered in combination with 
ipilimumab, infuse nivolumab first followed by ipilimumab on the same day. Use 
separate infusion bags and filters for each infusion. 
 
11.1.5 Handling and Disposal 
Accountability for investigational product is the responsibility of the investigator. The 
research pharmacy will maintain a careful record of the inventory and disposition of the 
agent using the NCI Drug Accountability Record Form (DARF) or another comparable drug 
accountability form. 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves 
and the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 

   
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Drug should be destroyed at the site, after the investigator approves the drug destruction policy 
at the site. Drug will not be returned to BMS. Destruction will be documented in the Drug 
Accountability Record Form. 
 
11.1.6 Compatibility 
No incompatibilities between the nivolumab and ipilimumab have been observed. When both 
study drugs are to be administered on the same day, separate infusion bags and filters must be 
used for each infusion. Nivolumab is to be administered first. The nivolumab infusion must 
be promptly followed by a saline flush to clear the line of nivolumab before starting the 
ipilimumab infusion. The second infusion will always be ipilimumab, and will start at least 30 
minutes after completion of the nivolumab infusion. 
 
Ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose 
solution. Nivolumab may be diluted in 0.9% Sodium Chloride Solution. 
11.1.7 Adverse Events 
Based on data from phase II and III studies in RCC, nivolumab monotherapy has an 
acceptable safety profile. Based on data from phase III study of nivolumab versus 
everolimus in RCC, treatment-related AEs of any grade occurred in 319 of the 406 subjects 
(79%) treated with nivolumab. The most common treatment-related AEs among subjects 
who received nivolumab were fatigue (134 subjects, 33%), nausea (57 subjects, 14%), and 
pruritus (57 subjects, 14%). 
Grade 3 or 4 treatment-related AEs occurred in 76 of the 406 subjects (19%) treated with 
nivolumab. The most common grade 3 or grade 4 event was fatigue (10 subjects, 2%) with 
nivolumab. Treatment-related AEs leading to treatment discontinuation occurred in 31 of the 
406 subjects (8%) treated with nivolumab. No deaths from study-drug toxic effects were 
reported in the nivolumab group. Please refer to the most current IB and package insert for a 
comprehensive list of AEs. 
 
11.2 
Ipilimumab 
Ipilimumab is a recombinant, human monoclonal antibody that binds to the CTLA-4. 
Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 
kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. 
 
Bristol-Myers Squibb (BMS) will supply ipilimumab. Ordering of ipilimumab will take place 
through BMS. 
 
11.2.1 Pharmacokinetics (PK): 
 
Ipilimumab as a single agent: The pharmacokinetics of ipilimumab was studied in 499 
subjects with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg 
administered once every 3 weeks for four doses. Peak concentration (Cmax), trough 
concentration (Cmin), and area under the curve (AUC) of ipilimumab were found to be dose 
proportional within the dose range examined. Upon repeated dosing of ipilimumab 

   
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administered every 3 weeks, ipilimumab clearance was found to be time invariant, and 
minimal systemic accumulation was observed as evident by an accumulation index of 1.5-fold 
or less. Ipilimumab steady-state concentration was reached by the third dose. The following 
mean (percent coefficient of variation) parameters were generated through population PK 
analysis: terminal half-life of 14.7 days (30.1%); systemic clearance (CL) of 15.3 mL/h 
(38.5%); and volume of distribution at steady-state (Vss) of 7.21 L (10.5%). The mean (±SD) 
ipilimumab Cmin achieved at steady-state with the 3-mg/kg regimen was 21.8 mcg/mL 
(±11.2). 
 
Nivolumab in combination with ipilimumab: The geometric mean (%CV) CL, Vss, and 
terminal half-life of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days 
(94.3%), respectively. When administered in combination, the CL of nivolumab was increased 
by 24%, whereas there was no effect on the clearance of ipilimumab. When administered in 
combination, the clearance of nivolumab increased by 42% in the presence of anti-nivolumab 
antibodies. 
There was no effect of anti-ipilimumab antibodies on the clearance of ipilimumab. 
 
Specific Populations: Cross-study analyses were performed on data from subjects with a 
variety of conditions, including 420 subjects with melanoma who received single or multiple 
infusions of ipilimumab at doses of 0.3, 3, or 10 mg/kg. The effects of various covariates on 
ipilimumab PKs were assessed in population pharmacokinetic analyses. 
 
Ipilimumab CL increased with increasing body weight; however, no dose adjustment of 
Ipilimumab is required for body weight after administration on a mg/kg basis. The following 
factors had no clinically meaningful effect on the CL of ipilimumab: age (range 26 to 86 
years), gender, concomitant use of budesonide, performance status, HLA-A2*0201 status, 
positive anti- ipilimumab antibody status, prior use of systemic anticancer therapy, or 
baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined as there 
were insufficient numbers of subjects in non-Caucasian ethnic groups. 
Renal Impairment: Creatinine clearance at baseline did not have a clinically important effect 
on ipilimumab pharmacokinetics in subjects with calculated creatinine clearance values of 29 
mL/min or greater. 
 
Hepatic Impairment: Baseline AST, total bilirubin, and ALT levels did not have a 
clinically important effect on ipilimumab pharmacokinetics in subjects with various 
degrees of hepatic impairment. 
 
11.2.2 Preparation 
Ipilimumab is a sterile, preservative-free, clear to slightly opalescent, colorless to pale 
yellow solution for intravenous infusion, which may contain a small amount of visible 
translucent-to- white, amorphous ipilimumab particulates. It is supplied in single-use vials 
of 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive 
ingredients: diethylene triamine penta acetic acid (DTPA) (0.04 mg), mannitol (10 mg), 
polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride 
(3.15 mg), and Water for Injection, USP at a pH of 7. 200 mg/40 mL (5 mg/mL). Do not 
shake product. 

   
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Inspect parenteral drug products visually for particulate matter and discoloration prior to 
administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution 
may have pale yellow color), or there is foreign particulate matter other than translucent-to 
white, amorphous particles. 
 
Preparation of Solution: 
• Allow the vials to stand at room temperature for approximately 5 minutes prior 
to preparation of infusion. 
• Withdraw the required volume of ipilimumab and transfer into an intravenous bag. 
• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to 
prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 
mg/mL. Mix diluted solution by gentle inversion. 
• Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 
36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). 
• Discard partially used vials or empty vials of ipilimumab. 
 
11.2.3 Storage and Stability 
Store ipilimumab under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect 
vials from light. 
 
11.2.4 Administration 
Do not mix ipilimumab with, or administer as an infusion with, other medicinal products. 
 
Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 0.5% 
Dextrose Injection, USP after each dose. 
 
Administer diluted solution approximately 30 miuntes through an intravenous line 
containing a sterile, non-pyrogenic, low-protein-binding in-line filter. 
 
11.2.5 Handling and Disposal 
Accountability for investigational product is the responsibility of the investigator. The 
research pharmacy will maintain a careful record of the inventory and disposition of the 
agent using the NCI Drug Accountability Record Form (DARF) or another comparable drug 
accountability form. 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves 
and the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
 
Drug should be destroyed at the site, after the investigator approves the drug destruction policy 
at the site. Drug will not be returned to BMS. Destruction will be documented in the Drug 
Accountability Record Form. 
 
11.2.6 Compatibility 
No incompatibilities between the nivolumab and ipilimumab have been observed. When both 
study drugs are to be administered on the same day, separate infusion bags and filters must be 

   
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used for each infusion. Nivolumab is to be administered first. The nivolumab infusion must 
be promptly followed by a saline flush to clear the line of nivolumab before starting the 
ipilimumab infusion. The second infusion will always be ipilimumab, and will start at least 30 
minutes after completion of the nivolumab infusion. 
 
Ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose 
solution. Nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% 
Dextrose solution. 

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Table 5. Summary of Safety with Nivolumab in Combination with Ipilimumab in RCC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12. 
ADVERSE EVENTS 
Adverse event (AE) monitoring and reporting is a routine part of every 
clinical trial. The following list of reported and/or potential AEs (Section 
12.1) and the characteristics of an observed AE (Section 12.2) will 
determine whether the event requires expedited reporting in addition to 
routine reporting. 

 
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12.1 
Adverse Event List for Nivolumab 
 
Based on data from the Phase I study, nivolumab in combination with ipilimumab has an 
acceptable safety profile in RCC. In summary, AEs were reported in 97.7% of subjects treated 
with nivolumab in combination with ipilimumab. The most frequently reported drug-related AEs 
in subjects treated with 3-mg/kg nivolumab + 1-mg/kg ipilimumab included fatigue (11 subjects, 
52.4%), rash (8 subjects, 38.1%), diarrhea (6 subjects, 28.6%), and pruritus (6 subjects, 28.6%); 
the majority were Grade 1-2. The most frequently reported drug-related AEs in subjects treated 
with 1-mg/kg nivolumab + 3-mg/kg ipilimumab included fatigue (16 subjects, 69.6%); nausea, 
ALT increased, AST increased (9 subjects each, 39.1%); and diarrhea (8 subjects, 34.8%). The 
majority were Grade 1-2. The majority of deaths were due to disease progression. No drug- 
related deaths have been reported to date. See Table 5. Please refer to the most current IB for a 
comprehensive list of AEs. 
 
12.2 
Adverse Event Characteristics 
AE term (AE description) and grade: The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
AE reporting.  All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
sitehttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
• For expedited reporting purposes only: 
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol- 
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
12.3 
DF/HCC and BMS Expedited Adverse Event Reporting 
 
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment 
on the local institutional SAE form. All SAEs that occur following the subject’s written consent 
to participate in the study through 30 days of discontinuation of dosing must be reported to BMS 
Worldwide Safety using the MedWatch Form 3500A, which can be accessed at 
http://www.accessdata.fda.gov/scripts/medwatch/. The BMS protocol ID number must be 
included on the MedWatch Form. SAEs, whether related or not related to study drug, and 
pregnancies must be reported to BMS within 24 hours. SAEs must be recorded on BMS or an 
approved form; pregnancies must be reported on a Pregnancy Surveillance Form. 

 
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SAE Email Address: 
 
SAE Facsimile Number:  
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS (or designee) 
using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization. 
 
The Sponsor will reconcile the clinical database SAE cases transmitted from BMS Global 
Pharmacovigilance (GPV&E) on an quarterly basis. BMS GPV&E will email, upon request 
from the Investigator, the GPV&E reconciliation report. Requests for reconciliation should be 
sent to 
. The data elements listed on the GPV&E reconciliation 
report will be used for case identification purposes. If the Investigator determines a case was 
not transmitted to BMS GPV&E, the case should be sent immediately to BMS. 
 
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the 
DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 with a 
possible, probable or definite attribution, grade 4 toxicities, and grade 5 (death) regardless of 
study phase or attribution. 
 
12.3.1 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE 
form should be forwarded to the Overall PI within the timeframes detailed in the table below. 
  
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events. 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE Expected 
or Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
Not required 
5 calendar days 
5 calendar days# 
5 calendar days 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last intervention, 
the AE should be reported within 1 business day of learning of the event. 

 
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12.3.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
• Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
12.3.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency  
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 
12.4 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
12.5 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 

 
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12.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests. 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences 
of potential DILIs, meeting the defined criteria, must be reported as SAEs. 
 
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE. 
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
12.7 
Pregnancy 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant). 
 
The investigator must immediately notify 
 of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 

 
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Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form (provided upon request from BMS). 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must sign an informed consent form for disclosure of this 
information. 
 
 
13. 
STATISTICAL METHODS 
 
13.1 
Study Design 
The study uses a single arm phase II design. Originally the study planned to enroll a total of 58 
subjects into the two treatment Arms A and B. The design details are stated in Section 2.7. 
 
Single Cell Sequencing Cohort: The study was amended to enroll an additional cohort of 25 
patients to allow for single cell molecular transcriptomic assessment. These additional 25 
patients will undergo the following biopsy schedule: 
Arm A: 
Mandatory biopsy at baseline 
Optional biopsy at time of response following discontinuation of nivolumab 
Mandatory biopsy at final treatment disconuation/off study 
 
Arm B: 
Mandatory biopsy at baseline 
Mandatory biopsy at final treatment disconuation/off study 
 
 
The cohort addition increases the overall enrollment to 83 subjects in the trial. 
 
No stratification factors are used in enrolling subjects. 
 
13.2 
Endpoints 
 
13.2.1 Definition of Primary Endpoint 
 
• The number and proportion of subjects remaining on PR or CR at 1 year since nivolumab 
discontinuation (Arm A) and the number and proportion of subjects achieving PR or CR 
upon the addition of ipilimumab to nivolumab (Arm B). 
 
• The response status of PR or CR will be assessed according to RECIST criteria v1.1. 
 
 
13.2.2 Definition of Secondary Endpoints 
 
• Progression-free survival (PFS): defined as the time from nivolumab discontinuation 
(Arm A) or from ipilimumab initiation (Arm B) until documented progression by 

 
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RESIST criteria or death from any cause, censored at date last known progression-free 
for those who are alive and have not progressed. 
 
• Overall Survival (OS): defined as the time from nivolumab discontinuation (Arm A) or 
from ipilimumab initiation (Arm B) until death from any cause, censored at date last 
known alive or at the time of last assessment of follow-up. 
 
• Salvage therapy-free interval: defined as time from nivolumab discontinuation (arm A) to 
the receipt of re-starting nivolumab. 
 
• Immune related objective response rate defined according to immune-related Responses 
Criteria (irRC) and detailed in section 10.5. 
• Safety and tolerability according to NCI CTCAE v4. 
 
13.2.3 Definition of Correlative Endpoints 
 
Marker assessments: 
 
• Tumor expression for PD-L1 expression in baseline (prior to primary nivolumab) biopsy 
tissue, and progression biopsy specimens will be analyzed in all evaluable samples. 
 
• WES, RNAseq, and IHC assessment of immunologic parameters including Tumor- 
infiltrating lymphocytes (TILs), T cell markers (CD4, CD8, FoxP3, LAG3), 
cytokines/chemokines (IFN, TNF), immune regulation (PD-L1, PD-L2, CTLA-4) will be 
evaluated in fresh tumor specimens obtained prior to initial nivolumab in order to assess 
the mechanisms of responses to nivolumab, with the focus on subjects with a durable 
response (confirmed PR/CR) to the nivolumab assessed during the 1st year since the 
discontinuation of the primary nivolumab start (Arm A) 
 
• Mechanisms of intrinsic and acquired resistance to nivolumab (alone, Arm A) and with 
ipilimumab (Arm B) in fresh tumor specimens obtained at time of radiographic 
progression by WES, RNAseq, and IHC assessment of immunologic parameters 
including T cell subset markers (CD4, CD8, FoxP3, LAG3), cytokines/chemokines (IFN, 
TNF), immune regulation (PD-L1, PD-L2, CTLA-4), and TILs 
 
• cfDNA and CTC evaluated as baseline, on treatment, and at progression. 
• Single cell molecular profile according to baseline and metastasis biopsy specimens 
 
13.3 
Sample Size and Accrual  
Arm A: It’s estimated that 23 subjects of confirmed PR or CR responses after initial nivolumab 
monotherapy will be enrolled (about 29% of total 80 subjects, accounting for 4% lost to follow-
up from the overall enrollment of N=83). There is no prior data for this treatment strategy and 
the main purpose is to generate hypothesis and the assumptions were considered to be clinically 
meaningful from investigators perspectives. We assume that 1-year remission (continued 
CR/PR) rate of 10% is not acceptable and a true PR or CR rate of 35% or higher will be 
considered acceptable for the treatment strategy of nivolumab discontinuation. A single-arm 
design is employed with 23 eligible subjects entered. If 5 or more of the 23 subjects continue 
CR or PR at 1 year off nivolumab (observed rate of 22%), we will conclude that the treatment 
strategy warrants further study. The probability of concluding that the treatment strategy 

 
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effective is 7% if the true PR or CR rate is 10% and is >94% if the true PR or CR rate is 35% or 
higher. 
 
Arm B: Approximately 57 subjects with PD or confirmed SD after initial nivolumab 
monotherapy will be available for the analysis. From historical data, the rates of PR/CR are 
25%, SD 40%, PD 35% in patients treated with nivolumab. We assume that a PR/CR rate of 
20% would be considered promising in this population who do not respond to nivolumab alone. 
The study uses Simon’s optimal two-stage design (Simon Controlled Clinical Trials 1989) to 
allow for early termination if evidence suggests that the addition of ipilimumab is inactive. 20 
subjects will be enrolled in the first stage. If 1 or fewer PR/CR are observed, the enrollment of 
ipilimumab addition will be stopped. If 2 or more PR/CR are observed, then an additional 37 
subjects will be enrolled for a total of 57 evaluable patients.  The regimen will be declared 
worthy of further study if 6 or more PR/CR are observed. These decision rules result in 73% 
probability of stopping early (at the end of first stage) if the regimen is inactive. The design 
yields a 92% probability (statistical power) of declaring the regimen active given a true PR/CR 
rate of 20% or 4.7% probability (targeted type I error rate of 0.05) of declaring the regimen 
active given a true PR/CR rate of 5% or less. 
 
A total accrual goal is 83 subjects. Subjects will continue study therapies till disease 
progressions, withdraw or adverse events. Additional 2-year follow-up after the end of 
treatments (EOT) is planned. The primary study analysis is expected to be at 2 years; 6 
months for accrual, and 18 months from enrollment for last subject. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
+ 
2 
= 
4 
Not Hispanic or Latino 
24 
+ 
55 
= 
79 
Ethnic Category: Total of all subjects 
26 
+ 
57 
= 
83 
Racial Category 
American Indian or Alaskan Native 
2 
+ 
3 
= 
5 
Asian 
2 
+ 
5 
= 
7 
Black or African American 
2 
+ 
6 
= 
8 

 
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Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
20 
+ 
39 
= 
59 
Racial Category: Total of all subjects 
26 
+ 
53 
= 
83 
 
 
13.4 
Analysis Datasets 
 
Population 
Definition 
 
Enrolled 
All subjects who meet the eligibility criteria 
and are registered onto the study. 
 
Evaluable/Analysis 
All subjects who receive at least one dose of trial 
drug or die before any evaluation. 
 
Safety 
All subjects with at least one dose of nivolumab 
or ipilimumab contribute data to the safety 
analysis. 
 
 
Population 
Definition 
Treated 
This will comprise all subjects who have been 
exposed to the planned course of treatment to any 
extent. 
 
 
13.5 
Assessment of Safety 
Adverse event reports are to be submitted within 28 days of each clinic visit. All relevant adverse 
events will be reviewed by the DSMC for up to 4 times each year or more frequently if requested 
by the DSMC. 
 
Arm A: As part of the early safety monitoring to make sure that discontinuation of nivolumab is 
not detrimental for subjects with initial confirmed PR/CR, futility assessments will be 
implemented after 9 (~39%) of the 23 subjects have image assessment (8 +/- 7 days) since 
discontinuing nivolumab: an estimate of PD rate with a two-sided binomial CI will be 
constructed. If 5 or more of the first 9 subjects experience PD (i.e, to have a lower bound of the 
CI ≥ 25%), then the enrollment of arm A may be suspended. The following table gives the 
operating characteristics of the early futility stopping; if the true unknown probability of PD rate 
is 60% or higher, the probability of observing 5 or more subjects with PD will be greater than 
48% at the time of the first subsequent image assessment after discontinuing nivolumab. 
 
13.6 
Operating Characteristics of Early Futility Stopping 
 
True-unknown PD rate 
(%) 
Probability of observing 5 or more PD among 9 subjects 
30 
0.03 
40 
0.1 
50 
0.25 
60 
0.48 
70 
0.73 
 

 
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For subjects who re-start nivolumab due disease progression, given there is no prior data for this 
treatment strategy, and the expected number of subjects to re-start nivolumab maybe small, the 
study team will monitor the non-response rate carefully. Similar futility analysis may take place 
at the subsequent image assessment to assess the risk of subjects no longer respond to nivolumab 
and decide if the strategy is not safe for subjects. The exact criteria will be determined as deemed 
clinically relevant. 
 
Arm B: The safety review will be concurrent with the first efficacy review of PR/CR that is 
specified by the Simon two-stage design. Review of these safety data will be conducted by the 
study team and an independent DFCI Data and Safety Monitoring Committee (DSMC). Based on 
the review, the DSMC may advise that the study regimen be suspended for additional review. 
After this initial safety assessment, toxicity and adverse event data will be evaluated as part of 
the recurrent trial review by the DSMC. 

 
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13.7 
Efficacy Analysis 
 
13.7.1 Primary Efficacy Analysis 
Tumor assessment will be performed every 8 weeks. At the time of each restaging, subjects will 
be classified as achieving complete response (CR), partial response (PR), stable disease (SD), 
progressive disease (PD), or non-evaluable for response according to RECIST (Version 1.1) 
criteria. 
 
Arm A: The proportion of subjects with sustained/continued PR or CR during the 1 year since 
the nivolumab discontinuation will be presented with a two-sided 90% CI using exact binominal 
method. Based on a sample size of 23 subjects, the confidence interval will be no wider than 
0.37. For a targeted 35% PR or CR rate, the estimated PR or CR rate precision (width of two 
sided 90%CI) would be 0.35. 
 
Arm B: The proportion of subjects with PR or CR during the 1-year from the date of first dose of 
ipilimumab will be presented with a two-sided 90% confidence interval calculated using the 
method of Atkinson and Brown, corresponding to the two-stage design. 
 
13.7.2 Secondary Analysis 
 
PFS and OS: The progression-free survival (PFS), and overall survival (OS) will each be 
summarized using the product-limit method of Kaplan-Meier. Median times for each endpoint 
will be presented with two-sided 90% confidence intervals estimated using log(-log(survival)) 
methodology. Kaplan-Meier estimates of PFS at 6 or 12 months may also be presented with two- 
sided 90% confidence intervals. 
 
Salvage Therapy-Free Interval: The proportion of subjects re-start nivolumab since 
nivolumab discontinuation (arm A) during 1-year will be estimated with two-sided 90% 
confidence intervals.  In addition, the reasons for re-starting nivolumab (Arm A) will be 
tabulated. 
 
Subset analysis of study endpoints will be explored according to IMDC* risk group (favorable, 
intermediate, versus poor risk); prior systemic treatment for RCC (yes versus no); first line 
versus second line targeted therapy; histology (clear cell versus non-clear cell RCC subtypes; 
sarcomatoid components present versus absent) 
 
*IMDC risk factors include ECOG < 1, time from original diagnosis to treatment less than one 
year, hemoglobin less than the lower limit of normal, and serum calcium, neutrophil count, or 
platelet count greater than the upper limit of normal 
 
Immune Related Objective Response Rate: The proportion of subjects with immune ORR will 
be presented with two-sided 90% confidence interval estimated using exact binomial methods. 
 
Safety and Tolerability: All adverse events recorded during the trial will be summarized for the 
safety population. The incidence of events that are new or worsening from the time of first dose 
of treatment will be summarized according to system organ class and/or preferred term, severity 
(based on CTCAE version 4), type of adverse event, and relation to study treatment. 

 
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The worst grade will be used if any toxicity event is reported multiple times on the same 
participant. All adverse events resulting in discontinuation, and/or dosing interruption, and/or 
treatment delay will also be summarized. 
 
Given the potential multiple treatment sequences, the incidence of events (grade 3+) will be 
summarized according to treatment arms as well as the type of therapies they are on at the time 
of events. 
 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by primary system organ class, and type of adverse event. 
 
13.7.3 Exploratory Efficacy Analyses 
All expected samples (n=80 presuming approximately 5% unevaluable rate) will be used for the 
exploratory analysis. The sample size justifications are based on assessing the association of TILs 
and response status. 
 
Tumor Infiltrating Lymphocytes (TILs): The relationship between tumor-infiltrating 
lymphocytes (TILs) and study outcomes will be explored according to pre-nivolumab TIL 
percentages (use the mandatory biopsy specimen). It is hypothesized that higher levels of 
lymphocytic infiltration will be associated with better outcomes. 
 
Arm A: With an expected samples of N=23, TILs will be descriptively summarized according to 
response status assessed during the first year after nivolumab discontinuation. An estimated 
difference of TIL score between the response groups will be summarized with 90% conference 
interval. 
 
Arm B: To examine responses according to levels of TILs, the expected samples of N=57 will be 
divided retrospectively according to response status (response (PR/CR) or non-response 
(assessed via serial image assessments after ipilimumab addition to nivolumab). Pre-treatment 
percentages of stromal infiltrating lymphocytes will be summarized descriptively for the two 
response groups and compared using Wilcoxon rank-sum tests. Assume a targeted PR/CR rate of 
20% (our primary study alternative hypothesis), if there are 11 responses (20% of 57 subjects) 
and 46 non-responses, a Wilcoxon rank-sum test with a two-sided, 10% type I error will have 
93% power to detect a difference in pre-treatment TILs that is 1.06 times the common standard 
deviation. 
 
Kaplan-Meier estimates will be used to visualize the relationship between the PFS or OS and 
median of the distribution of intratumoral or stromal percentages (TILs) or disease phenotype 
defined by TILs (≥ 50% versus TILs < 50%) in pre-treatment/baseline samples TILs. Medians of 
the time-to-event endpoints will be calculated with two-sided 90% CIs according to the disease 
phenotype groups. 
 
Changes in TILs between pre-treatment and disease progression/treatment discontinuation will 
be calculated (post-pre) for patient with available biopsy samples at both timepoints and 
summarized descriptively. 

 
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PD-L1 Expression: 
 
The association between pre-treatment PD-L1 expression and outcomes will be explored. 
The PD-L1 expression will be evaluated by IHC in both tumor cell membrane and tumor- 
infiltrating mononuclear cells (TIMC). It is hypothesized that higher expression levels of PD-L1 
will be associated with poor outcomes, due to the fact that up-regulation of PD-L1 may allow 
cancers to evade the immune system. 
 
To examine responses according to PD-L1 expression, the evaluable samples will be divided 
retrospectively according to study objective response or non-response. Pre-nivolumab treatment 
PD-L1 expression will be summarized descriptively for the two response groups. 
 
For the samples from arm A: with the expected small sample (n=23), the analysis will be 
descriptive. Specifically, the proportion of patients remaining on PR or CR at 1 year since 
nivolumab according to pre-treatment PD-L1 positivity (PD-L1>5%) will be summarized with 
two-sided 90% exact, binomial confidence intervals. 
 
For the samples from arm B: in order to assess the association of PD-L1 positivity (PD-L1+) 
with objective response (i.e., achieving PR or CR upon the addition of ipilimumab to 
nivolumab), based on a targeted ORR of 20% for this portion of study, which corresponds to 
have groups of non-responders (n=46) vs responders (n=11) respectively, and assuming an 
overall expected PD-L1+ of 50%-60% in TIMC, the following table provides the statistical 
power using a fisher’s test to detect the PD-L1+ difference between the two response groups, 
with a one-side type I error of 0.05. Note, only large differences in % of PD-L1 positivity (51% 
in non- responder vs. 4% in responders) could be detected with at least 80% power. 
 
Non-responders (N=46) 
Responders (N=11) 
% PD-L1 + in TIMC 
% PD-L1 + in TIMC 
Statistical Power 
(Fisher’s exact test) 
50 
5 
91 
60 
11 
91 
70 
17 
93 
 
In addition, the proportion of patients with objective response i.e., achieving PR or CR upon the 
addition of ipilimumab to nivolumab according to pre-treatment PD-L1+ will be summarized 
with two-sided 90% exact, binomial confidence intervals. Visualization of the relationship 
between baseline PD-L1 expression and the distributions of PFS or OS will employ 
Kaplan-Meier estimates stratified by PD-L1+. Medians of the time-to-event endpoints of PFS 
and OS may be shown with two-sided 90% confidence intervals. 
 
 Single Cell Sequencing: 
The 25 paired samples collected at DFCI and selected sites will undergo the molecular 
profiles (transcriptome) assessments. The molecular profiles will be descriptively 
summarized for the paired samples. The exploratory analysis to assess the correlations of 
single cell molecular profiles with the clinical outcome may be performed. 
  
 
 
 

 
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14. 
DATA REPORTING/REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 12 
(Adverse Events). 
 
14.1 
Data Reporting 
 
14.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study. 
 
14.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
 
14.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
 
14.3 
Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan. The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix D. 
 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier. A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 

 
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14.4 
Data Quality Oversight Activities 
Validation of data will be completed on a continual basis throughout the life cycle of the study. 
A summary report (QC Report) of these checks together with any queries resulting from manual 
review of the eCRFs will be generated for each site and transmitted to the site and the site 
monitor. Corrections will be made by the study site personnel. 
 
There will be at least one routine visit per site per year for sites that have accrued. Additional for 
cause visits may occur as necessary. Source documents will be reviewed for verification of 
agreement with data entered into InForm.  It is important for the site investigator and their 
relevant personnel to be available for a sufficient amount of time during the monitoring visits or 
audit, if applicable. The site investigator and institution guarantee access to source documents by 
the sponsor/investigator or its designee. 
 
14.5 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion. Information posted will allow subjects to identify potentially appropriate trials for 
their disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and study site contact information. 
 
15. 
DATA HANDLING AND RECORD KEEPING 
 
15.1 
Data Management 
The Dana-Farber Cancer Clinical Trials Office will provide Project Management and Monitoring 
services for this trial. Data will be collected through the web based clinical research platform, 
InForm, a system compliant with Good Clinical Practices and Federal Rules and Regulations 
created by the Clinical Trials Research Informatics Office (CTRIO). All data will be collected 
and entered into InForm by study site personnel from participating institutions. 
 
Before trial completion, it is permissable to report data on a subset of patients regarding safety, 
specific cohorts that complete accrual and mature earlier than the overall trial, or results from 
cohorts that were added mainly for correlatives purposes such as the single cell sequencing 
cohort. 
 
15.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in InForm and correlative results will be 
captured in spreadsheets or other secure database(s). If procedures on the study calendar are 
performed for standard of care, at minimum, that data will be captured in the source document. 
Select standard of care data will also be captured in InForm, according to study-specific 
objectives. 
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator. 
 
15.3 
Record Retention 

 
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To enable evaluations and/or audits from Health Authorities, the site investigator agrees to keep 
records, including the identity of all subjects (sufficient information to link records; e.g., hospital 
records), all original signed informed consent forms, copies of all source documents, and detailed 
records of drug disposition. All source documents are to remain in the subject’s file and retained 
by the site investigator in compliance with the site contract. No records will be destroyed until 
the sponsor/investigator confirms destruction is permitted. 
 
15.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel. 
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, BMS, IRB, or government agencies, like the FDA, may inspect 
their medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. If the results of the study are published, the subject’s identity will remain 
confidential. 
 
16. 
PUBLICATION PLAN 
The data will be collected by the investigators and analyzed by the co-principal investigators and 
the statistical team at DFCI. It is anticipated that the results will be made public within 12 
months of the end of data collection. A report is planned to be published in a peer-reviewed 
journal, however initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. 
in consultation with 
. 
 as well as outside investigators will decide on the authorship orders for 
abstracts and manuscripts from the trial. 

 
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18. 
APPENDICES 
 
A. Performance Status Criteria 
 
B. Information on Possible Drug Interactions 
 
C. Management Algorithms for Immune-Mediated Adverse Events 
 
D. Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 

 
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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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20. 
APPENDIX B: INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
Nivolumab and ipilimumab interact with many drugs that affect your immune system.  Because 
of this, it is very important to tell your study doctors about all of your medicine before you start 
this study. It is also very important to tell them if you stop taking any regular medicine, or if you 
start taking a new medicine while you take part in this study.  When you talk about your 
medicine with your study doctor, include medicine you buy without a prescription at the drug 
store (over-the-counter remedy), or herbal supplements such as St. John’s wort. 
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
These are the things that you and they need to know: 
 
Nivolumab and ipilimumab interact with many drugs that affect your immune system. 
• These specifically include corticosteroid agents and other medications that can affect the 
immune system. 
• Please be very careful! Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye. They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list. Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction. 
 
Other medicines can be a problem with your study drugs. 
• You should check with your doctor or pharmacist whenever you need to use an over-the- 
counter medicine or herbal supplement. 
• Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.  Your study doctor’s name is: 
 
  
 and he or she can be contacted at 
 
 

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21. 
APPENDIX C: MANAGEMENT ALGORITHMS FOR IMMUNE-MEDIATED ADVERSE EVENTS 
 
Recommended Management of Immune-mediated AEs.  Will not be considered deviations/violations if not followed exactly. 
 

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22. 
APPENDIX D: DANA-FARBER/HARVARD CANCER CENTER MULTI- 
CENTER DATA AND SAFETY MONITORING PLANTABLE OF CONTENTS 
1. 
INTRODUCTION. ..................................................................................................... 83 
1.1 
Purpose 
83 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
83 
2. 
GENERAL ROLES AND RESPONSIBILITIES ....................................................84 
2.1 
DF/HCC Sponsor 
84 
2.2 
Coordinating Center 
85 
2.3 
Participating Institution 
85 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ................ 86 
3.1 
Protocol Distribution 
86 
3.2 
Protocol Revisions and Closures 
86 
3.3 
Informed Consent Requirements 
86 
3.4 
IRB Documentation 
87 
3.5 
IRB Re-Approval 
87 
3.6 
Participant Confidentiality and Authorization Statement 
87 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
88 
3.8 
DF/HCC Protocol Case Number 
89 
3.9 
Safety Assessments and Toxicity Monitoring 
90 
3.10 
Data Management 
91 
4. 
REQUISITIONING INVESTIGATIONAL DRUG ............................................... 91 
5. 
MONITORING: QUALITY CONTROL ................................................................ 91 
5.1 
Ongoing Monitoring of Protocol Compliance 
91 
5.2 
Monitoring Reports 
92 
5.3 
Accrual Monitoring 
92 
6. 
AUDITING: QUALITY ASSURANCE ................................................................... 92 
6.1 
DF/HCC Internal Audits   
92 
 
6.2 
Audit Notifications 
 93 
6.3 
Audit Reports      
93 
6.4 
 Participating Institution Performance 
93 

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1. 
INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC that 
will be participating in the research protocol. 
 
1.1 
Purpose 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures. 
 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol: A research protocol in which one or more outside institutions 
are collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates. 
 
Lead Institution: One of the Dana-Farber/Harvard Cancer Center consortium members (Dana- 
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital 
(BWH)) responsible for the coordination, development, submission, and approval of a protocol 
as well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines 
(CTEP, Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.). 
The Lead Institution is typically the home of the DF/HCC Sponsor. 
 
DF/HCC Sponsor: The person sponsoring the submitted Multi-Center protocol. Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for initiation, 
management and conduct of the protocol at all research locations. In applicable protocols, the 
DF/HCC Sponsor will serve as the single liaison with any regulatory agencies (i.e. FDA, OHRP, 
etc.). The DF/HCC Sponsor has ultimate authority over the protocol and is responsible for the 
conduct of the study at DF/HCC and all Participating Institutions. In most cases the DF/HCC 
Sponsor is the same person as the DF/HCC Overall Principal Investigator; however, both roles 
can be filled by two different people. 
 
Participating Institution: An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator. 
The Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority 
and responsibility for the overall conduct of the study. 
 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order 
that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as 
specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. 

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DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high- 
quality standards are used for data collection and the ongoing management of clinical trials, 
auditing, and data and safety monitoring. ODQ also coordinates quality assurance efforts related 
to multi-center clinical research. 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within DF/HCC 
responsible for providing a comprehensive data management platform for managing clinical trial 
data. 
 
2. 
GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities: 
 
2.1 
DF/HCC Sponsor 
The DF/HCC Sponsor, 
will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to: 
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments. 
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol. 
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and 
throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language. 
• Monitor progress and overall conduct of the study at all Participating Institutions. 
• Require all DFCI and Participating Institution Institutional Review Boards’ (IRB), 
DF/HCC and other applicable (i.e. FDA) reporting requirements are met. 
• Review data and maintain timely submission of data for study analysis. 
• Act as the single liaison with FDA. 
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the DF/HCC Sponsor and as approved by BMS. 
• Identify and qualify Participating Institutions and obtain accrual projections prior to 
extending the protocol to that site. 

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• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements. 
2.2 
Coordinating Center 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development. 
• Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS). 
• Maintain FDA correspondence, as applicable. 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review and submission to the DFCI IRB, as necessary. 
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the 
DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with. 
• Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring 
• Maintain Regulatory documents of all Participating Institutions which includes but is 
not limited to the following: local IRB approvals/notifications from all Participating 
Institutions, confirmation of Federal Wide Assurances (FWAs) for all sites, all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites 
• Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc.) and maintain documentation all relevant communications. 
 
2.3 
Participating Institution 
Each Participating Institution is expected to comply with all applicable federal regulations, the 
protocol and HIPAA requirements. 
 
The general responsibilities for each Participating Institution may include but are not limited to: 
• Document the delegation of research specific activities to study personnel. 
• Review registration materials for eligibility and register participants from 
Participating Institutions 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per institutional requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial 
as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research 
related activities. 

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• Submit Serious Adverse Event (SAE) reports to IRB per local requirements and to the 
Coordinating Center, in accordance with protocol requirements. 
• Submit protocol deviations and violations to IRB per local requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated drugs 
per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with DFCI ODQ auditors at 
the conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring queries 
or audit findings. 
 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol. 
 
3.1 
Protocol Distribution 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions. 
 
3.2 
Protocol Revisions and Closures 
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its 
IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc. Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately. In addition, the Coordinating 
Center, will update the Participating Institutions on an ongoing basis about protocol 
accrual data so that they will be aware of imminent protocol closures. 
 
3.3 
Informed Consent Requirements 
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible. This document will be provided separately to each 
Participating Institution. 

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Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior 
to submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB for all consent versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that only 
attending physicians obtain informed consent and re-consent to interventional trials (i.e. drug 
and/or device trials). 
 
3.4 
IRB Documentation 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB. 
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB. 
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
3.5 
IRB Re-Approval 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
3.6 
Participant Confidentiality and Authorization Statement 
In 1996, congress passed the first federal law covering the privacy of health information known 
as the Health Insurance Portability and Accountability Act (HIPAA). Any information, related to 
the physical or mental health of an individual is called Protected Health Information (PHI). 
HIPAA outlines how and under what circumstances PHI can be used or disclosed. 
 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an authorization statement. This authorization statement 
may or may not be separate from the informed consent document.  The Coordinating Center, 
with the approval from the DFCI IRB will provide a consent template, with information 
regarding authorization for the use and disclosure of protected health information. 
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its 
trials. However, because of the nature of these trials, certain protected health information must 
be collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, 
rather than limited data sets with data use agreements. 
 
DF/HCC Multi-Center Protocol Confidentiality 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be 
de-identified. It is recommended that the assigned unique subject number (as described below) 

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be used for all participant specific documents. Participant initials may be included or retained for 
cross verification of identification. 
 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
  
• Informed consent must be obtained from subjects before they can be screened. A 
patient will be considered “in screening” when he/she has signed the IRB approved 
Informed Consent Form. 
• Each patient screened must be documented on the Potential Patient/Pre‐Screening 
Log or equivalent site form/software.  The Potential Patient Log/Pre‐Screening Log 
is to aid in fulfilling the ICH requirement of maintaining a confidential list of patient 
names. It should be stored in the site study files. 
• Eligibility Criteria Worksheet is provided as a tool for registration. 
• Once the investigator verifies the patient is eligible, the lead site (DFCI) will 
formally register the patient in the DF/HCC Clinical Trial Management System 
(CTMS) and enter the On Study Date. The sequence number used at screening will 
remain the same for the remainder of the study to identify the enrolled patient. 
• Subjects must be registered prior to starting protocol therapy and begin therapy 
within five business days of the lead site (DFCI) entering the On Study Date into the 
DF/HCC Clinical Trial Management System (CTMS). 
 
Participant Registration and Randomization 
All subjects must be registered by the lead site (DFCI) through the DF/HCC Clinical Trial 
Management System (CTMS) in accordance with section 5 of the protocol. A subject is 
considered registered when an “On Study” date is entered into OnCore. 
• To register a participant, the following documents should be completed by the 
Participating Institution and maintained in the Participating Institutions’ records: 
o Signed informed consent document 
o HIPAA authorization form (if separate from the informed consent document) 
o Other appropriate forms (See Section 5 of the Protocol) 
 
The Coordinating Center will review the submitted documents in order to verify 
eligibility and consent. To complete the registration process, the Coordinating Center 
will: 
• Register the participant on the study with the DF/HCC Clinical Trial Management 
System (CTMS). 
• Upon receiving confirmation of registration, the Coordinating Center will inform the 
Participating Institution and provide the study specific participant case number, and, 
if applicable, assigned treatment and/or dose level 
 
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered. 
 
Registration can only occur during normal business hours, Monday through Friday from 8:00 AM 
to 5:00 PM Eastern Standard Time. 

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Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or 
other protocol-specific interventions. Treatment and other protocol-specific interventions may 
not be initiated until the Participating Institution receives confirmation of the participant’s 
registration from the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must be notified 
of any violations to this policy 
 
Eligibility Exceptions 
 
 No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be 
permitted. All Participating Institutions are required to fully comply with this requirement. 
 
3.8 
DF/HCC Protocol Case Number 
At the time of registration, Coordinating Center requires the following identifiers for all subjects: 
initials, date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique sequence number. 
Participating Institutions should submit all de-identified subsequent communication and 
documents to the Coordinating Center, using this sequence number to identify the subject. 
 
Protocol Deviations, Exceptions, and Violations 
Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB. 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for 
reporting to their local IRB. 
 
Definitions 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g. enrollment 
of a participant who does not meet all inclusion/exclusion criteria. 
 
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB prior 
to its initiation or implementation. 
 
Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol deviations occurring at their 

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site. The DF/HCC Sponsor will also be responsible for ensuring that all protocol deviations are 
promptly reported per DFCI IRB guidelines. 
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. 
The Participating Institution must submit the deviation request to the Coordinating Center who 
will then submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation 
is submitted to the Participating Institution IRB, per institutional policy. A copy of the 
Participating Institution’s IRB report and determination will be forwarded to the Coordinating 
Center within 10 business days after the original submission. The deviation may not be 
implemented without all required approvals. 
 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of violations. 
 
Coordinating Center: Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. 
Subsequently, the Participating Institution’s IRB violation/deviation report will be submitted to 
the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will forward all violation 
reports to CTEP via an internal DF/HCC process, as applicable. 
 
3.9 
Safety Assessments and Toxicity Monitoring 
The study teams at all participating institutions are responsible for protecting the safety, rights 
and well-being of study participants. Recording and reporting of adverse events that occur during 
the course of a study help ensure the continuing safety of study participants. 
 
All participants receiving investigational agents and/or other protocol mandated treatment will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported to the DF/HCC 
Sponsor within 1 business days of becoming aware of the event. 
 
Additional safety assessments and toxicity monitoring is outlined in the protocol. 
 
Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed 
in protocol Section 12. 
 
Participating Institutions must report the SAEs to the Coordinating Center according to the 
protocol. 
 
The Coordinating Center will maintain documentation of all Participating Institution Adverse 
Event reports and be responsible for communicating to all participating investigators, any 
observations reportable under the protocol requirements. Participating Institutions will review 
and submit to their IRB according to their institutional policies and procedures 

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Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports 
are distributed to the Participating Institutions. Participating Institutions will review and submit 
to their IRB according to their institutional policies and procedures. 
 
3.10 
Data Management 
Data will be handled and recorded in accordance with Section 15 of the protocol. 
 
Data Forms Review 
Data submissions are monitored for timeliness and completeness of submission. If study forms 
are received with missing or questionable data, the submitting institution will receive a written or 
electronic query from the DF/HCC Office of Data Quality, Coordinating Center, or designee. 
 
Responses to all queries should be completed and submitted within 14 calendar days. 
 
Responses may be returned on the written query or on an amended paper case report form, or in 
the case of electronic queries, within the electronic data capture (eDC) system. In the case of a 
written query for data submitted on a paper case report form, the query must be attached to the 
specific data being re-submitted in response. 
 
If study forms are not submitted on schedule, the Participating Institution will periodically receive 
a Missing Form Report from the Coordinating Center noting the missing forms. 
 
4. 
REQUISITIONING INVESTIGATIONAL DRUG 
For the Nivolumumab and Ipilimumab, the site will order drug from Bristol-Myers Squibb 
(BMS). Drug will be supplied in boxes. Outside sites will receive their own supply of drug. 
• Once site has IRB approval, the Coordinating Center will send initial drug request 
Form to Bristol-Myers Squibb (BMS) for shipment. 
• Initial orders will be on site no later than three weeks from request date. 
• Resupply orders will be on site no later than one week from request date. 
• Fill out Bristol-Myers Squibb (BMS) Drug Request Form and email as needed (NO 
AUTOMATIC REFILLS) 
 
The ordering of investigational agent is specified in the protocol Section 11.1. 
 
5. 
MONITORING: QUALITY CONTROL 
The quality control process for a clinical trial requires verification of protocol compliance and 
data accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, 
provides quality control oversight for the protocol. 
 
5.1 
Ongoing Monitoring of Protocol Compliance 
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institutions may also be subject to on-site 
monitoring conducted by the Coordinating Center. 

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DFCI will implement ongoing monitoring activities to ensure that Participating Institutions are 
complying with regulatory and protocol requirements, data quality, and participant safety. 
Monitoring will occur during protocol performance and through study completion. Additional 
monitoring practices may include but are not limited to; source verification, review and analysis 
of the following: eligibility requirements, informed consent procedures, adverse events and all 
associated documentation, study drug administration/treatment, regulatory files, protocol 
departures, pharmacy records, response assessments, and data management. 
 
Participating institutions will be required to participate in monthly Coordinating Center initiated 
teleconferences. 
 
Remote Monitoring 
Data will be monitored remotely throughout the study both manually and electronically. Data 
will be assessed for completeness and correctness by DFCI monitoring staff. A Missing Forms 
Report (MFR) will be run on a regular basis, and queries will be issued based on the results to 
site personnel.  Site personnel will make all corrections and/or notations as appropriate. 
 
On-Site Monitoring will occur per section 14.4 of the protocol. 
 
5.2 
Monitoring Reports 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. 
 
5.3 
Accrual Monitoring 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting their 
accrual expectations may be subject to termination. 
 
6. 
AUDITING: QUALITY ASSURANCE 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards and 
procedures were followed. Auditing is the systematic and independent examination of all trial 
related activities and documents. Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per 
the protocol, Standard Operating Procedures (SOPs), and the Code of Federal Regulations 
(CFR). 
 
6.1 
DF/HCC Internal Audits 
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2 day period. If 
violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited. 

DF/HCC Protocol #: 17-064 
                            Protocol Version Date:07January2020 
 
99 
 
6.2 
Audit Notifications 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this 
protocol. All institutions will forward a copy of final audit and/or re-audit reports and corrective 
action plans (if applicable) to the Coordinating Center, within 12 weeks after the audit date. 
 
6.3 
Audit Reports 
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan to the 
DFCI IRB as applicable. 
 
6.4 
Participating Institution Performance 
 
The DF/HCC Sponsor, and DFCI IRB, is charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
and accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be recommended for a six-month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered by 
the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB 
may terminate a site’s participation if it is determined that a site is not fulfilling its 
responsibilities as described above.