A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients With Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC)
Phase: PHASE3
Conditions: Metastatic Renal Cell Carcinoma, Sarcomatoid Renal Cell Carcinoma, Stage II Renal Cell Cancer AJCC v7, Stage III Renal Cell Cancer AJCC v7, Unclassified Renal Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

 
EA8143 
1 
This is an FDA Registration Study 
A Phase 3 RandOmized Study Comparing PERioperative 
Nivolumab vs. Observation in Patients with Renal Cell 
Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
STUDY CHAIR: Mohamad Allaf, M.D. 
STUDY STATISTICIAN: Se Eun Kim, MPH.. 
STUDY CO-CHAIR: David F. McDermott, M.D. 
UROLOGY CO-CHAIR: Viraj Master, M.D. 
TRANSLATIONAL SCIENCE CO-CHAIR: Naomi B. Haas, M.D. 
PATHOLOGY CO-CHAIR: Sabina Signoretti, M.D. 
IMAGING CO-CHAIR: Rajan Gupta, M.D. 
QUALITY OF LIFE AND OUTCOMES CO-CHAIR: David Cella, Ph.D. 
COMMUNITY CO-CHAIR: Suzanne Cole, M.D. 
RENAL SUBCOMMITTEE CHAIR: Naomi B. Haas, M.D. 
GU COMMITTEE CHAIR: Michael Carducci, M.D. 
Version Date:  September 16, 2021 
NCI Update Date:  February 2, 2017 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology  
February 2, 2017 
NRG / NRG Oncology 
 
 
SWOG / SWOG 
 
Addendum #1 – Incorporated Prior to Activation 
CCTG / Canadian Cancer Trials Group 
 
Update #1 – Incorporated Prior to Activation 
 
 
Addendum #2 
NCTN GROUP STUDY CHAMPIONS 
 
Addendum #3 
ALLIANCE: Toni Choueiri, M.D., Bradley 
Leibovich, M.D. 
 
Addendum #4 
Addendum #5 
NRG: M. Dror Michaelson, M.D. 
 
Addendum #6 
SWOG: Brian Shuch M.D., Primo N. Lara Jr., M.D. 
 
Addendum #7 
CCTG: Danny Heng, M.D., Anil Kapoor, M.D. 
 
Addendum #8 
 
 
Addendum #9 
 
 
Addendum #10 
 
Agents 
IND# 
NSC# 
Supply 
Nivolumab 
 
748726 
DCTD, NCI-Supplied 
 
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Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ........................................................................................................ 8 
1.1 
Background ............................................................................................... 8 
1.2 
Rationale ................................................................................................... 9 
1.3 
Safety of Nivolumab ................................................................................ 10 
1.4 
Biomarker Exploration ............................................................................ 12 
1.5 
Quality of Life Component ...................................................................... 12 
1.6 
Dose Justification .................................................................................... 14 
1.7 
Specific Hypothesis and Overarching Goal of the Study ......................... 14 
2. Objectives ......................................................................................................... 16 
2.1 
Primary Objectives .................................................................................. 16 
2.2 
Secondary Objectives .............................................................................. 16 
2.3 
Correlative Objectives ............................................................................. 16 
2.4 
Quality of Life Objective .......................................................................... 16 
2.5 
Other Exploratory Objectives .................................................................. 16 
3. Selection of Patients ......................................................................................... 17 
3.1 
Eligibility Criteria for Randomization ...................................................... 17 
4. Registration and Randomization Procedures ................................................... 23 
4.1 
Randomization ........................................................................................ 29 
4.2 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment34 
4.3 
Additional Registration Training Requirement ....................................... 34 
5. Treatment Plan ................................................................................................. 36 
5.1 
Administration Schedule ......................................................................... 36 
5.2 
Prohibited and/or Restricted Treatments ............................................... 37 
5.3 
Permitted Therapy .................................................................................. 38 
5.4 
Adverse Event Reporting Requirements ................................................. 38 
5.5 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for BMS-
936558 (Nivolumab, MDX-1106, NSC 748726) ....................................... 48 
5.6 
Dose Modifications ................................................................................. 53 
5.7 
Management Algorithms for Immune-related Adverse Events .............. 57 
5.8 
Supportive Care ....................................................................................... 67 
5.9 
Quality of Life Instrument Administration .............................................. 68 
5.10 Duration of Therapy ................................................................................ 71 
5.11 Second Primary Cancers .......................................................................... 72 
5.12 Duration of Follow-up ............................................................................. 72 
6. Measurement of Effect ..................................................................................... 73 
6.1 
Diagnosis of Renal Cell Cancer Recurrence ............................................. 73 
6.2 
Survival .................................................................................................... 73 
6.3 
Time to Recurrence ................................................................................. 74 

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6.4 
Patients with Residual Disease at the time of Surgery or who do not 
undergo nephrectomy ............................................................................ 74 
7. Study Parameters .............................................................................................. 75 
7.1 
Therapeutic Parameters for both arms .................................................. 75 
7.2 
Arm A: Perioperative Nivolumab ............................................................ 75 
7.3 
Arm B: Observation ................................................................................. 80 
7.4 
Biological Specimen Submissions ............................................................ 84 
8. Drug Formulation and Procurement ................................................................. 87 
8.1 
Nivolumab ............................................................................................... 88 
9. Statistical Considerations .................................................................................. 91 
9.1 
Design and Objectives ............................................................................. 91 
9.2 
Endpoints ................................................................................................ 91 
9.3 
Statistical Analysis Plan ........................................................................... 92 
9.4 
Sample Size Considerations .................................................................... 94 
9.5 
Projected Accrual .................................................................................... 96 
9.6 
Randomization Scheme........................................................................... 96 
9.7 
Gender and Ethnicity .............................................................................. 96 
9.8 
Monitoring Procedures and Interim Analyses ........................................ 97 
10. Submission of Biospecimens for Research ..................................................... 101 
10.1 Specimen Collection and Submission Schedule .................................... 101 
10.2 Submissions to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) ........................................................................................ 102 
10.3 Serum Submissions for Pharmacokinetic and Immunogenicity Studies 
(Arm A only) .......................................................................................... 106 
10.4 ECOG-ACRIN Sample Tracking System .................................................. 108 
10.5 Institutional Reimbursements ............................................................... 109 
10.6 Use of Specimens in Research .............................................................. 110 
10.7 Specimen Inventory Submission Guidelines ......................................... 111 
11. Laboratory Research Studies .......................................................................... 112 
11.1 Pharmacokinetic and Immunogenicity Studies (Arm A Mandatory) .... 112 
11.2 Correlation of PD-L1 Tumor Tissue Expression with Outcome ............. 112 
11.3 Additional Potential Laboratory Research Studies. .............................. 114 
11.4 Immunohistochemistry (IHC)/Immunofluorescence (IF) Analysis of RCC 
Tumors .................................................................................................. 115 
11.5 NanoString Discovery of Immune Gene Signatures .............................. 117 
11.6 Tumor Sequencing for Predictive Genes ............................................... 118 
11.7 Characterization of T Cell Receptor Repertoire (TCR) and Change in 
Response to Nivolumab ........................................................................ 119 
11.8 Circulating Cytokine Levels ................................................................... 121 
11.9 T Cell Proliferation Assays to Detect Neoantigen Responses using 
Cryopreserved Lymphocytes ................................................................. 122 
11.10 Lab Data Transfer Guidelines ................................................................ 123 

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12. Bone Metabolism Imaging & Serum Correlative Research Study (Optional) . 124 
12.1 Changes in Bone Metabolism and Density in Response to Nivolumab 
Administration ...................................................................................... 124 
13. Quality of Life (QOL) Studies ........................................................................... 129 
13.1 Statistical Considerations ...................................................................... 129 
13.2 Analysis Plan .......................................................................................... 131 
13.3 PRO-CTCAE ............................................................................................ 131 
13.4 Missing Data .......................................................................................... 132 
14. Electronic Data Capture .................................................................................. 133 
14.1 Records Retention ................................................................................. 133 
15. Patient Consent and Peer Judgment .............................................................. 133 
16. References ...................................................................................................... 133 
Appendix I  Pathology Submission Guidelines ...................................................... 137 
Appendix II  Patient Thank You Letter ................................................................... 142 
Appendix III  CRADA/CTA ....................................................................................... 143 
Appendix IV  ECOG Performance Status ............................................................... 145 
Appendix V  Instructions for Reporting Pregnancies on a Clinical Trial ................ 146 
Appendix VI  EA8143 Collection and Shipping Kit Order Instructions ................... 148 
Appendix VII  EA8143 Biopsy Reimbursement Form ............................................ 149 
Appendix VIII  Methods Of Contraception ............................................................ 150 
Appendix IX  Financial Disclosure Information Form ............................................ 152 
Appendix X  How To Measure Your Waist Circumference2 .................................. 155 
Appendix XI  American Joint Committee on Cancer (AJCC) TNM Staging System for 
Kidney Cancer (7th Edition) ............................................................................ 156 
Appendix XII  EA8143 ICON Site Information/Initial Kit Order Form .................... 157 
Appendix XIII  iSite User Guide for Kit Reordering ................................................ 159 
Appendix XIV  Correlative Studies of the EA8143 Trial ......................................... 161 
 

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STUDY CHAIRS 
Mohamad E. Allaf, M.D. 
John Hopkins University School of Medicine 
600 North Wolfe Street, Pak 223 
Baltimore, MD 21278 
Phone: 410-502-7710 
Email: mallaf@jhmi.edu 
Naomi Haas, MD  
University of Pennsylvania  
Perelman Center for Advanced Medicine 
3400 Civic Center Boulevard 
 10-112 South Tower 
Philadelphia, PA 19104 
Phone: 215-662-7615 
Email: naomi.haas@pennmedicine.upenn.edu 
 
STUDY CHAIR LIAISON (SCL) 
Kathleen Harlacker, RN, BSN 
Lead Clinical Research Nurse, GU Oncology 
University of Pennsylvania Abramson Cancer 
Center 
10th floor South PCAM 
Phone: 215- 662-3510  
Email: 
kathleen.harlacker@pennmedicine.upenn.edu 
 
EA8143 PROSPER EMAIL ALIAS 
Email: EA8143_PROSPER@ecog-acrin.org 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal: 
Regulatory Submission Portal 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory 
tab.)  
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions on 
using the Oncology Patient Enrollment 
Network (OPEN) which can be accessed 
at https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
through Medidata 
Rave. Please see the 
data submission 
section of the protocol 
for further instructions. 
Do not submit study 
data or forms to CTSU 
Data Operations. Do 
not copy the CTSU on 
data submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
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Schema 
Nivolumab 
480mg x 1 
dose2
Stratification Factors
• Clinical T stage
• cT1 or cT2
• cT3 or cT4
• Clinical N stage
• cN0
• cN+
• Clinical Metastatic Stage
• cM0
• cM1
Partial or 
Radical 
Nephrectomy
Nivolumab 480mg 
q4 weeks x 9 doses5
Partial or 
Radical 
Nephrectomy 
followed by 
observation
1. Patients randomized to Arm A must either have RCC confirmed by a standard of care biopsy in 12 months prior to randomization 
or if a biopsy was not already performed, a research biopsy must be performed after randomization to Arm A. RCC confirmation 
by biopsy is required in order to avoid exposing patients to neoadjuvant nivolumab who clearly have benign lesion or another type 
of cancer.
2. The neoadjuvant dose of nivolumab must be administered within 4 weeks (w 28 days) from randomization and prior to partial or 
radical nephrectomy.
3. Nephrectomy required in arm B within 8 weeks after randomization.
4. Nephrectomy required in arm A within  7 and   28 days from neoadjuvant dose.
5. First dose of adjuvant nivolumab should be within 4 to 10 weeks post-nephrectomy or last local treatment. See section 3.1.2 and 
5.1.1.2.2.
Histolology 
confirmation 
required
R
A
N
D
O
M
I
Z
A
T
I
O
N
Histolology 
confirmation not 
required
Arm A1,4
Arm B3
L
O
N
G
-
T
E
R
M
F
O
L
L
O
W
U
P
Accrual Goal = 805 patients
 
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1. 
Introduction 
1.1 
Background 
More than 60,000 patients will be diagnosed with renal cell carcinoma (RCC) in 
2015, and approximately 13,000 people will die from advanced disease.1 With 
the increased use of imaging over the last several decades, the incidence of 
earlier stage and potentially more curable disease is rising. However despite 
nephrectomy, many patients recur and for them, subsequent cure is unlikely. 
Treatment options for advanced disease have significantly improved since 2005 
with seven FDA approved targeted therapies that in sequence can improve 
overall survival (OS) compared to the interferon era. However, these multi-
tyrosine kinase and mTOR inhibitors are generally cytostatic and durable 
complete responses are rare. Given the lack of cure with the available agents in 
the advanced setting, targeting microscopic disease in the perioperative setting is 
rational. 
Despite resection of the primary tumor, approximately 30% of patients with 
localized disease and 65% of patients with nodal involvement relapse.2 Currently 
there is no known effective adjuvant therapy for localized RCC after 
nephrectomy. At least eight trials have shown no benefit to adjuvant interferon- or 
interleukin-2-based therapies, or a CA-IX antibody. Trials are assessing the 
efficacy of the approved multi-targeted tyrosine kinase inhibitors in the adjuvant 
setting including sunitinib, sorafenib, pazopanib, and axitinib (accrual complete: 
S-Trac, SORCE, PROTECT; accrual ongoing: ATLAS) and the mTOR inhibitor 
everolimus (accrual ongoing: S0931, EVEREST). However, the first trial to report 
results, E2805 (ASSURE) revealed no benefit to 1 year of adjuvant sunitinib or 
sorafenib (Haas et al, Lancet, 2016).45 The negative results of ASSURE provide 
even greater impetus to test an effective agent with a different mechanism of 
action in the perioperative setting. 
Programmed Death-1 (PD-1) is a receptor expressed on activated T cells and a 
negative regulator of the immune response. Aberrant expression of PD-L1 by 
RCC tumor cells and tumor-infiltrating lymphocytes (TILs) may impair T cell 
function resulting in impaired host antitumor immunity.3,4 PD-L1 may act by 
inhibiting both the cytokine production and the cytotoxic activity of PD-1+, tumor-
infiltrating CD4+ and CD8+ T cells.5 Higher expression of PD-L1 by tumor cells 
and TILs portends more aggressive pathology and tumor behavior as well as 
poorer survival.3,6-8  
Multiple blocking antibodies against either the PD receptor or its ligands are 
being developed to interrupt this pathway. Nivolumab is a fully human IgG4 
monoclonal antibody against PD-1 which has received FDA approval for 
advanced treatment refractory RCC. 
Multiple phase 1 and 2 studies in patients with treatment refractory RCC revealed 
nivolumab’s potential efficacy.9,10 Its use in RCC was initially explored in two 
phase I refractory solid tumor trials, a phase 1 biomarker study, and a phase 2 
dose ranging study. In the largest phase 1 experience, 34 RCC patients were 
treated with nivolumab at 1 or 10 mg/kg.9,11 Median progression-free survival 
(PFS) was 7.3 months. Nearly 30% of patients experienced an objective 
response with median duration of response being 12.9 months. Another 27% 
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experienced disease stabilization > 24 weeks. Responses were generally rapid 
with a median time to response of 16 weeks. Notably, responses could occur 
after treatment cessation and persist off treatment. Median overall survival was 
encouraging at 22.4 months. These results were especially promising given that 
many of the patients were heavily pre-treated with 71% having had 2 or more 
lines of therapy. 
Given the lack of a dose/toxicity relationship seen in the phase 1 studies, Motzer 
and investigators investigated the effect of dose on PFS in a randomized phase 2 
study of 168 VEGF targeted therapy treatment refractory patients 
(NCT01354431).10 No dose/PFS relationship was found, with median PFS 
ranging from 2.7 to 4.2 months at the 1, 3, and 10mg/kg doses (p=0.9). 
Nivolumab elicited objective responses in 20-22% and disease stabilization in 37-
44%. Median time to achievement of an objective response was 2.8-3.0 months. 
Again the durability of responses was notable with a median duration of response 
of 22.3 months (4.8, NR) in the 10mg/kg arm and not yet reached in the two 
lower dose cohorts. Only 7% of patients required treatment discontinuation for 
drug related toxicity supporting the tolerability of this strategy. Median overall 
survival was favorable at 18.2-25.5 months.  Fatigue was the most frequent 
toxicity (22-35%). No new toxicities were identified with 11% experiencing Grade 
3-4 treatment-related events; none of which were due to pneumonitis. A parallel 
biomarker-focused trial using the same 3 dose levels was executed to explore 
predictors of response and identify mechanisms of resistance. (NCT01358721).12 
The results mirrored the efficacy and toxicity profile of the phase 2 study with an 
overall ORR of 17% (9-23%) and disease stabilization in another 32% in a mix of 
treatment refractory and naïve patients. At 24 weeks, 36% of patients were free 
from progression. 
Recently, the phase 3 randomized study that compared nivolumab to everolimus 
in 821 patients who had VEGFR inhibitor-refractory disease demonstrated an 
overall survival advantage with nivolumab.13 Nivolumab achieved a median OS of 
25 months (95% CI: 21.8-NE) compared to 19.6 months (17.6-23.1) with 
everolimus; HR 0.73 (0.57-0.93, p=0.002). It also elicited a significantly higher 
objective response at 25% vs. 5% (p<0.001). There were 4 complete responses 
with nivolumab (1%) and 2 with everolimus. Median time to response was 3.5 
months (range: 1.4-24.8 mo) and median duration of response was 12 months 
(0-27.6 mo). In the nivolumab responders, 48% had an ongoing response for 12 
months or longer. Median PFS was similar between the two arms at 4.6 vs. 4.4 
months (HR 0.88, p=0.11) highlighting that it may take more time for 
immunotherapy to engage the immune system and elicit tumor shrinkage or 
disease control. Post-hoc analysis of patients who had not progressed or died by 
6 months: median PFS was 15.6 vs. 11.7 mo for everolimus (HR 0.64, 95% CI: 
0.47-0.88). Notably, this is the first agent to demonstrate a clear survival benefit 
in patients with metastatic RCC across patients with MSKCC good, intermediate, 
and poor risk groups. 
1.2 
Rationale 
Transitioning agents that have been previously found to be effective in advanced 
disease to an earlier disease setting is a common pathway for oncology drug 
development, and has been applied to multiple agents in several tumor types. 
This approach is especially relevant for higher risk RCC, where the relapse rate 

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is high and there are no drugs that have been shown to enhance the cure rate 
over surgery alone. 
Nivolumab’s efficacy is thought due to activation of anti-tumor PD-1 expressing T 
cells. Preliminary data from animal models suggest that the anti-tumor CD8 T 
cells that infiltrate tumors after PD-1 blockade may arise in the primary tumor, the 
surrounding microenvironment, and tumor-draining lymph nodes (Charles Drake, 
personal communication).14 If true, nephrectomy may remove the antigen and the 
majority of these effector cells and cytokines that drive PD-1 and PD-L1 
expression resulting in a less potent response to subsequent PD-1 blockade. The 
Campbell Laboratory has shown that RCC patients have elevated levels of 
peripheral circulating PD-1 cells prior to surgery which significant decreases after 
nephrectomy.15 These observations provide our rationale to administer two 
priming doses of nivolumab prior to surgery with the goal of expanding the 
patient's endogenous anti-tumor PD-1 expressing cells. These effector cells can 
then traffic to other distant sites (e.g., spleen, lung, distant lymph nodes), escape 
surgical removal, and go on to potentially eradicate micrometastatic disease. 
Further administration of nivolumab in the adjuvant setting will continue to 
reverse the inhibition of the anti-PD-1 immune cells and potentially kill residual 
microscopic disease. Administration in the setting of lower tumor burden may 
also enhance the efficacy of nivolumab. Recently, Joseph et al observed that 
smaller baseline tumor volume was prognostic for improved survival with the anti-
PD-1 antibody pembrolizumab in melanoma (ASCO 2014, abstract 2015). 
Further, multiple immunosuppressive populations, such as MDSCs and Tregs, 
are likely to be decreased post-nephrectomy resulting in diminished inhibitory 
immune cell populations to counteract nivolumab-activated CD8 effector cells. In 
support of these general principles in RCC, two large phase 3 studies 
demonstrated a survival benefit to adding cytoreductive nephrectomy to 
interferon-a in the metastatic setting.16 
Given the low rates of cure with the available agents once patients have 
evidence of metastatic disease, targeting micro-metastatic disease in the 
perioperative setting where the disease burden is smaller is logical. Using a 
survival-improving agent like nivolumab with a different mechanism of action than 
that of previously tested agents is clearly needed to improve outcomes. As the 
current standard of care after nephrectomy is surveillance, we will compare 
perioperative PD-1 blockade with nivolumab to an observation arm. 
1.3 
Safety of Nivolumab 
As early stage patients are potentially cured with nephrectomy alone and are 
often asymptomatic, it is important that the adjuvant systemic therapy be 
tolerable, safe and directed to an appropriately high-risk population. In the phase 
I trials in refractory solid tumors, nivolumab was quite tolerable, and no maximally 
tolerated dose (MTD) was identified.11,17 Only 5% of patients had to discontinue 
treatment due to an adverse event (AE). AEs were generally low grade and 
reversible. Fatigue, rash, diarrhea, and pruritus were the most frequently 
reported AEs. Grade 3 or 4 treatment-related AEs occurred in 14% of patients 
and 11% were serious AEs (SAEs). No relationship between dose and the 
spectrum, frequency, or severity of treatment-related AEs was observed. “Select” 
treatment-related AEs that were thought likely due to immune or inflammatory 
phenomenon have been reported and generally consisted of skin toxicity (e.g., 

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rash, vitiligo), GI disorders (e.g., diarrhea, colitis, transaminitis), endocrinopathies 
(e.g, hypothyroidism), and pneumonitis. These events have generally been 
reversible with drug discontinuation, hormone replacement, steroids, or 
immunosuppressive agents. While pneumonitis is a concerning toxicity with this 
agent, it is also seen with relatively high incidence of up to 15-39% with the 
mTOR inhibitors.18-21 With enhanced recognition, drug withdrawal, and early use 
of steroids, the incidence of fatal pneumonitis appears to have decreased since 
the initial phase 1 studies.  
In the phase 3 study comparing nivolumab to everolimus, nivolumab again 
proved tolerable and safe in over 400 patients.10 There were fewer treatment 
related AEs that led to treatment discontinuation (8 vs. 13%) and no treatment 
related deaths compared to 2 in the everolimus arm. The most common any 
grade nivolumab treatment-related AEs were fatigue (33%), nausea (14%), 
pruritus (14%), diarrhea (12%), decreased appetite (12%), and rash (10%). 
Grade 3 related events occurred in 18%. Only 1% of patients treated with 
nivolumab had Grade 4 events, which included fatigue (2%), nausea (< 1%), 
diarrhea (1%), decreased appetite (< 1%), rash (< 1%), anemia (2%), dyspnea 
(1%), pneumonitis (1%), and hyperglycemia (1%). More serious autoimmune 
toxicities such as pneumonitis, colitis, and hepatitis are rare and generally 
manageable with early recognition and multidisciplinary care but should be 
monitored. 
Importantly, mean change in quality of life in the nivolumab group increased over 
time, which was significantly different than observed in the everolimus cohort (p< 
0.05). Overall, the toxicity profile of nivolumab compares favorably to the 
approved TKIs and mTOR inhibitors, which could provide patients with a 
tolerability and quality of life advantage. 
Nivolumab has been studied in over 8,600 subjects and is widely approved in 
multiple indications. Extensive details on the safety profile of nivolumab are 
available in the Investigator Brochure, and will not be repeated herein (ref IB). 
Overall, the safety profile of nivolumab monotherapy as well as combination 
therapy is manageable and generally consistent across completed and ongoing 
clinical trials with no MTD reached at any dose tested up to 10 mg/kg. Most AEs 
were low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 
4) AEs. There was no pattern in the incidence, severity, or causality of AEs with 
respect to nivolumab dose level. 
A pattern of immune-related adverse events has been defined, for which 
management algorithms have been developed; these are provided in Section 
5.7. Most high-grade events were manageable with the use of corticosteroids or 
hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms. 
Safety concerns regarding delays to surgery or increased perioperative 
complications must be considered. Across the nivolumab trials in multiple solid 
tumors including a neoadjuvant lung study, there were no reported issues with 
wound healing or increased surgical complications in patients who underwent a 
variety of unplanned surgeries (BMS personal communication). Treatment-
related toxicities can also adversely affect function and quality of life. Nivolumab 
is generally quite well-tolerated, however, fatigue, rash, pruritus and diarrhea can 
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1.4 
Biomarker Exploration 
Currently, there are no predictive biomarkers in RCC that can direct therapy 
selection. The neoadjuvant approach with a pre-therapy biopsy and serial serum 
collection will permit further characterization of the effects of nivolumab’s PD-1 
blockade on tumor tissue, T cell infiltrate, and other measures of the host 
immune response in patients that have pre-treatment biopsies.  
Preoperative renal mass biopsy is increasingly being utilized and has a great 
safety record in contemporary analyses. Recent systematic review by the AHRQ 
reveals a low rate of major complications (< 1%, M. Allaf personal 
communication). A positive biopsy will increase the confidence of diagnosis and 
justifies the potential risks of neoadjuvant treatment in a potentially surgically 
curable patient population. Many institutions already have renal biopsy protocols 
in place where sampling is performed prior to surgery, and the practice is well 
accepted. 
To minimize the risk of exposing patients with other cancers or clearly benign 
conditions to nivolumab and its potential adverse side effects, a biopsy ruling out 
these findings will be required in patients who are randomized to receive 
preoperative nivolumab (Arm A). 
Additionally, the trial will permit further characterization of PD-L1 expression in 
RCC. The use of PD-L1 as a predictive biomarker is an area of active 
investigation requiring validation and development of accurate expression 
assays. As the phase 3 study of nivolumab in treatment-refractory RCC did not 
demonstrate that PD-L1 positivity correlated with overall survival, we will not 
stratify or require PD-L1 positivity for eligibility. We plan an exploratory analysis 
to evaluate whether primary tumor PD-L1 expression and a patient’s immune 
profile correlates with better outcome. If proven, predictive biomarkers could be 
identified that will allow future individualization of treatment and spare patients 
futile toxicity.  
1.5 
Quality of Life Component 
1.5.1 
Background and Rationale for Quality of Life (QOL) Study 
Patients with no evidence of disease following nephrectomy are likely 
to be symptom free, after recovery from surgery. Symptomatic 
nivolumab induced adverse events identified in prior studies include 
fatigue, rash, diarrhea, pruritus, decreased appetite and nausea. An 
assessment of patient-reported symptom burden will aid in 
interpretation of results if a significant improvement in recurrence-free 
survival (RFS) is observed, particularly if the overall survival results 
are equivocal. These analyses will also provide information that can 
guide supportive care strategies if the treatment is found to be 
effective. 
1.5.2 
QOL Study Design 
The approach to studying QOL is guided by a desire to capture 
treatment-related symptoms with fairly frequent assessments during 
the first year, followed by an assessment of what is expected to be 
emerging disease-related symptoms and functional burden at 
recurrence and 1 year post-treatment. Importantly, discontinuing study 
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drug for any reason (toxicity, progression, etc.) should NOT be a 
reason for terminating the QOL assessment. That is, regardless of 
treatment status, and including patients who go on to second-line 
therapy, scheduled assessments should be conducted to avoid bias 
induced by non-ignorable missing data over time. Scheduled 
assessments are noted in Section 5.9. Almost half of the patients are 
expected to have progressed by 5-years post baseline, providing a 
reasonable estimate of the impact of progression on QOL, which can 
in turn help inform the value of prolonging progression, if nivolumab is 
shown to do so. 
1.5.3 
Rationale for Quality of Life Measure Selection 
The QOL assessments will be comprised of three instruments: The 
NCCN/FACT Kidney Symptom Index-19 (NFKSI-19), the PROMIS 
Physical Function 10-item short form (PROMIS PF-10) and a carefully 
selected subset of 9 questions from the PRO-CTCAE pool of items 
measuring patient-reported toxicity. Since this study involves patients 
entering treatment with few or no symptoms of disease, it will provide 
a unique opportunity to identify quality of life concerns attributable to 
treatment with nivolumab, among patients who start therapy without 
disease-related symptoms. In order to examine treatment-related 
symptoms during the first year, we will use selected items from the 
PRO-CTCAE (Basch et al 2014) and the NFKSI-19 (Rothrock et al, 
2013).44,40 The PRO-CTCAE items were selected based upon prior 
reports of the most common side effects of nivolumab. Selection of 
side effects from the PRO-CTCAE was guided by a procedure for 
selecting the more commonly expected side effects, as recommended 
Cella and Wagner (2015).43 Drawing from the more than 100 PRO-
CTCAE items available, we identified 9 questions, covering the 
following adverse events: Fatigue (item 1; 2 questions), decreased 
appetite (item 2; 2 questions), diarrhea (item 4; 1 question), nausea 
(item 5; 2 questions), itch (item 11; 1 question); rash (item 12; 1 
question). In addition, we will use the 19-item NFKSI-19. This index 
provides a score for disease-related symptoms, bother with treatment 
side effects, and function/well-being. In addition to the selected PRO-
CTCAE items, we note that the NFKSI-19 includes assessment of 
musculoskeletal pain (2 items), fatigue (2 items), dyspnea (1 item), 
cough (1 item) and fever (1 item). Similar to the descriptive approach 
proposed with the PRO-CTCAE items, these items can be reported 
individually as to their severity during the perioperative time period for 
nephrectomy on the experimental arm, and compared to the control 
arm, to aid evaluation of the possible additive effects of surgery and 
nivolumab. Finally, as a measure of overall burden of the combination 
of adverse events and disease response over time, we propose to use 
the PROMIS PF-10, which is a 10-item measure of physical function 
that has been validated for use in cancer. The PF-10 is scored on a T 
score metric, with mean=50 and SD=10; differences in the 4-6 point 
range are meaningful to patients (Yost et al).41 
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comparisons, and the PROMIS PF-10 as a secondary evaluation of 
overall impact of disease and treatment upon functioning throughout 
the period of study. The single question on overall side effect bother, 
and the subscale measuring function/well-being, are expected to favor 
the nephrectomy-only arm in the first year. In the second year; 
however, we anticipate an advantage to the nivolumab arm with 
regard to the emergence of disease-related symptoms. Given the 
overlap of symptoms like fatigue as both a toxicity and a symptom of 
disease, attribution of its cause will be aided by noting the timing of 
onset relative to clinical events such as tumor response while on 
treatment, versus disease progression. 
1.6 
Dose Justification 
PPK analyses have shown that the PK of nivolumab is linear with proportional 
exposure over a dose range of 0.1 to 10 mg/kg, and no differences in PK across 
ethnicities and tumor types were observed. Nivolumab clearance and volume of 
distribution were found to increase as the body weight increases, but less than 
the proportional with increasing weight, indicating that mg/kg dosing represents 
an over-adjustment for the effect of body weight on nivolumab PK. 
Nivolumab is safe and well tolerated up to 10 mg/kg Q2W. Adverse events have 
been broadly consistent across tumor types following monotherapy and have not 
demonstrated clear dose-response or exposure-response relationships. 
Additionally, the simulated median and 95th prediction interval of nivolumab 
summary exposures across body weight range (35 - 160 kg) are predicted to be 
maintained below the corresponding observed highest exposure experienced in 
nivolumab ie, 95th percentile following nivolumab 10 mg/kg Q2W from clinical 
study CA209003. Thus, while subjects in the lower body weight ranges would 
have slightly greater exposures than 80 kg subjects, the exposures are predicted 
to be within the range of observed exposures at doses (up to 10 mg/kg Q2W) 
used in the nivolumab clinical program, and are not considered to put subjects at 
increased risk. 
The FDA recently approved nivolumab 480 mg to be given every 4 weeks 
(Q4W), which provides a more convenient dosing regimen for subjects. Based on 
PK modeling and simulations, administration of nivolumab 480 mg is predicted to 
provide Cavgss similar to 240 mg Q2W. While 480 mg Q4W is predicted to 
provide greater (approximately 20%) maximum steady state concentrations and 
lower (approximately 10%) steady state trough concentrations, these exposures 
are predicted to be within the exposure ranges observed at doses up to 10 mg/kg 
Q2W used in the nivolumab clinical program, and are not considered to put 
subjects at increased risk. Similar to the nivolumab 240 mg Q2W dosing 
regimen, the exposures predicted following administration of nivolumab 480 mg 
Q4W, are on the flat part of the exposure-response curves for previously 
investigated tumors, melanoma and NSCLC, and are not predicted to affect 
efficacy. Based on these exposure data, nivolumab 480 mg Q4W is expected to 
have similar efficacy and safety profiles to nivolumab 240 mg Q2W. 
1.7 
Specific Hypothesis and Overarching Goal of the Study 
When given in conjunction with radical or partial nephrectomy, patients who 
receive perioperative nivolumab (Arm A) will have increased recurrence-free 
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survival compared to those who undergo nephrectomy alone (Arm B). Ultimately, 
if proven successful in increasing recurrence-free survival or overall survival, the 
addition of an effective perioperative treatment for RCC would dramatically alter 
our current treatment paradigm from surveillance (+/- 1 year of adjuvant sunitinib 
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2. 
Objectives 
2.1 
Primary Objectives 
2.1.1 
To compare recurrence-free survival (RFS) between patients with 
renal cell carcinoma randomly assigned to perioperative nivolumab in 
conjunction with radical or partial nephrectomy with patients 
randomized to surgery alone. 
2.2 
Secondary Objectives 
2.2.1 
To evaluate for differences in recurrence-free survival associated with 
perioperative nivolumab compared to surgery alone among the subset 
of patients with clear cell histology. 
2.2.2 
To compare the overall survival between the two arms. 
2.2.3 
To describe the safety and tolerability of perioperative nivolumab 
2.3 
Correlative Objectives 
2.3.1 
To correlate the primary tumor’s expression of PD-L1 with outcome. 
2.3.2 
To correlate the expression of PD-L1 on tumor tissue at nephrectomy 
and recurrence with outcome. 
2.3.3 
To archive images for potential central confirmation of recurrence and 
for future correlative work with ACRIN, including markers predicting 
outcome or response. 
2.3.4 
To prospectively collect tumor and biologic specimens (e.g., serum, 
PBMCs) for future correlative studies. 
2.3.5 
To characterize the pharmacokinetics of nivolumab and explore 
exposure response relationships with respect to safety and efficacy. 
2.3.6 
To characterize the immunogenicity of nivolumab. 
2.4 
Quality of Life Objective 
2.4.1 
To evaluate differences in change from baseline in patient-reported 
symptoms and toxicities among patients randomized to treatment with 
nivolumab compared to surgery alone. 
2.5 
Other Exploratory Objectives 
2.5.1 
To explore descriptively the efficacy of treatment with nivolumab in 
patients with non-clear cell (including unclassified) histologies. 
2.5.2 
To characterize the effects of nivolumab on bone metabolism and 
bone density. 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
NOTE: 
Renal Mass Biopsy in Arm A (Histologic proof required). 
To avoid exposing patients to neoadjuvant nivolumab who do not have RCC, 
all patients randomized to Arm A must have histological confirmation of RCC. 
A standard of care diagnostic biopsy must have been completed within 12 
months prior to randomization or the patient must agree to undergo a core 
biopsy if randomized to Arm A. If the biopsy clearly demonstrates a benign 
condition, oncocytoma, or a different type of cancer that is not RCC, the 
patient will come off study. All other outcomes, including results that are 
ambiguous or inconclusive (“non-diagnostic”), will be considered a good faith 
effort and the patient can continue on the study without a repeat biopsy if 
both the patient and treating investigator agree. Important: Patients 
randomized to Arm A must have their histology confirmed at the site level 
prior to receiving the neoadjuvant dose of nivolumab. 
3.1 
Eligibility Criteria for Randomization 
3.1.1 
Patient must have a renal mass consistent with a clinical stage ≥ 
T2Nx RCC or TanyN+ RCC for which radical or partial nephrectomy is 
planned. 
Stage:  T_____ N______ M ______ 
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3.1.2 
Patient must have no clinical or radiological evidence of distant 
metastases (M0) unless the presumed M1 disease is planned to be 
resected/definitively treated (e.g., thermal ablation, stereotactic 
radiation) at the same time or up to 12 weeks after the date of the 
initial procedure such that the patient is considered “no evidence of 
disease” (M1 NED). 
3.1.2.1 
Liver, bone, or brain metastases are not permitted. 
3.1.2.2 
No more than 3 metastases are permitted, and all must be 
able to be removed or definitively treated within 12 weeks 
of the primary tumor resection. 
3.1.3 
If histological confirmation of RCC has not been done within 12 
months prior to randomization, patient must be willing to undergo a 
core biopsy for this purpose if randomized to Arm A. 
NOTE: 
This histologic confirmation can be a (1) standard of care 
diagnostic biopsy or (2) a research biopsy or a planned 
metastasectomy. Tissue must be obtained with results 
available prior to the neoadjuvant dose. 
Patients randomized to Arm A: core tumor biopsy must 
have demonstrated RCC of any histology, including 
sarcomatoid, unclassified, or “unknown histology” (if 
preoperative biopsy was uninformative) with exception 
below for non-diagnostic biopsies. 
If the biopsy performed following randomization clearly 
demonstrates a benign condition, oncocytoma or a 
different type of cancer that is not RCC, the patient is not 
eligible and must come off study.  
A non-diagnostic biopsy is considered a good faith effort 
and does not need to be repeated unless deemed 
clinically necessary by the treating investigator. 
NOTE: 
Refer to Section 10.5 for biopsy reimbursement 
guidelines. 
3.1.4 
Patient must not have any prior systemic or local anti-cancer therapy 
for the current RCC. 
3.1.4.1 
Patient must not have undergone a partial nephrectomy for 
the current RCC. 
3.1.4.2 
Patient must not have had a metastasectomy for the 
current RCC diagnosis unless performed to render patient 
NED (in addition to the planned nephrectomy) within 6 
months prior to the current diagnosis. 
3.1.4.3 
Patient must not have received current or past 
antineoplastic systemic therapies for RCC: i.e., 
chemotherapy, hormonal therapy, immunotherapy, or 
standard or investigational agents for treatment of RCC. 
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3.1.4.4 
Patient must not have received prior treatment with an anti-
PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways. 
NOTE: 
Please see Sections 5.2 and 5.3 for the lists of 
therapies that are prohibited and permitted for 
patients during treatment. 
3.1.5 
Patient must be ≥ 18 years of age. Because no dosing or adverse 
event data are currently available on the use of nivolumab therapy in 
patients < 18 years of age, children are excluded from this study. 
3.1.6 
Patient must have an ECOG Performance Status of 0 or 1 
3.1.7 
Patient must not have a prior history of RCC that was treated with 
curative intent within the past 5 years.  
3.1.7.1 
Patients with a prior RCC that was treated >5 years before, 
are eligible if the current tumor is consistent with a new 
primary in the opinion of the treating investigator. 
3.1.7.2 
Patients with bilateral synchronous RCCs are eligible if 
they can be resected or definitively treated at the same 
time or within a 12 week window from time of initial 
nephrectomy (partial or radical) or procedure and maintain 
adequate residual renal function. The patient is not eligible 
if both kidneys are to be completely removed and 
subsequent hemodialysis will be required. 
• Permitted forms of local therapy for second tumor: 
• Partial or radical nephrectomy 
• If kidney tumor is ≤3cm: thermal ablation (e.g., 
radiofrequency ablation, cryoablation or stereotactic 
radiosurgery) 
3.1.8 
Patient cannot have concurrent malignancies, with the following 
exceptions: 
• Adequately treated basal cell or squamous cell skin cancer  
• In situ cervical cancer 
• A history of superficial Ta urothelial cancer is permitted (as long as 
not currently undergoing treatment) whereas T1 or greater disease 
of any stage is excluded if <3 years from diagnosis. Concurrent 
persistent disease is not permitted. 
• Adequately treated Stage I or II cancer from which the patient is 
currently in complete remission 
• Any other cancer and stage from which the patient has been 
disease-free for at least 3 years prior to the time of randomization 
and as long as they are not receiving any current treatment (e.g. 
adjuvant or maintenance systemic or local therapy). 
• Concurrent low risk prostate cancer on active surveillance. 
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3.1.9 
Patient must not have active known or suspected autoimmune 
disease. The following autoimmune disorders are permitted: patients 
with vitiligo, type I diabetes mellitus, controlled/stable hypo or 
hyperthyroidism due to autoimmune or non-autoimmune conditions 
(hormone replacement is allowed), psoriasis not requiring systemic 
treatment, or other conditions not expected to recur. 
3.1.10 
Patient must not have any ongoing condition requiring systemic 
treatment with either corticosteroids (> 10 mg daily prednisone 
equivalent) or other immunosuppressive medications with the 
exceptions outlined below. Patient must not have received any  
treatment with other immunosuppressive agents within 14 days prior 
to the first dose of study drug with the following exceptions: 
• Topical, ocular, intra-articular, intranasal, inhaled steroids and 
adrenal replacement steroid doses > 10 mg daily prednisone or the 
equivalent are permitted in the absence of active autoimmune 
disease. 
• A brief (less than 3 weeks) course of corticosteroids (any amount) 
for prophylaxis (for example: contrast dye allergy) or for treatment 
of non-autoimmune conditions (for example: nausea, delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted. 
3.1.11 
Patient must not have uncontrolled adrenal insufficiency. 
3.1.12 
Patient must not have known evidence of chronic active liver disease 
or evidence of acute or chronic Hepatitis B Virus (HBV) or Hepatitis C 
(HCV). HBV and HCV testing must be completed within 8 weeks prior 
to randomization (See sections 3.1.22.8 and 3.1.22.9). 
NOTE: 
If the patient has been treated and cured, and the HCV 
RNA is undetectable, the patient is eligible for this study. 
3.1.13 
Patient must not have any serious intercurrent illness, including 
ongoing or active infection requiring parenteral antibiotics. 
3.1.14 
Patient must not have known evidence of HIV infection, since the 
effects of nivolumab on anti-retroviral therapy have not been studied. 
HIV testing is only required if past or current history is suspected. 
3.1.15 
Patient must not have any known medical condition (e.g. a condition 
associated with uncontrolled diarrhea such as ulcerative colitis or 
acute diverticulitis) that, in the investigator’s opinion, would increase 
the risk associated with study participation or interfere with the 
interpretation of safety results. 
3.1.16 
Patient must not have had any major surgery within 28 days prior to 
randomization. 
3.1.17 
Patient must not be currently enrolled in other clinical trials testing a 
therapeutic intervention. 
3.1.18 
Patient must not have any history of severe hypersensitivity to a 
monoclonal antibody. 
3.1.19 
Patient must have the ability to understand and the willingness to sign 
a written informed consent document. 
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3.1.20 
Patients must not be pregnant or breast-feeding, as the effects of 
nivolumab on the developing human fetus or in the nursing infant are 
unknown. 
All patients of childbearing potential must have a blood test or urine 
study within 2 weeks prior to randomization to rule out pregnancy. 
A patient of childbearing potential is defined as anyone, regardless of 
sexual orientation or whether they have undergone tubal ligation, who 
meets the following criteria: 1) has achieved menarche at somepoint 
2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) 
has not been naturally postmenopausal for at least 24 consecutive 
months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
Patient of child bearing potential? ______ (Yes or No)  
Date of blood test or urine study: ___________ 
3.1.21 
Patients must not expect to conceive or father children by using 
accepted and effective method(s) of contraception, as described in 
the Informed Consent Form (ICF) and in Appendix VIII, or by 
abstaining from sexual intercourse for the duration of their 
participation in the study. Patients of childbearing potential must use 
adequate methods to avoid pregnancy for 5 months after the last dose 
of nivolumab. 
3.1.22 
Patient must have the following baseline laboratory values within 8 
weeks prior to randomization: 
3.1.22.1 
White blood cells  2000/uL 
WBC:________ Date of test:______ 
3.1.22.2 
Absolute Neutrophil Count (ANC) ≥ 1,500/mm3  
ANC:________ Date of test:______ 
3.1.22.3 
Platelet Count ≥ 100,000/mm3 
Platelet count:______ Date of test:______ 
3.1.22.4 
Hemoglobin ≥ 9.0g/dL 
Hemoglobin:________ Date of test:______ 
Transfusions permitted. 
3.1.22.5 
Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or 
calculated creatinine clearance (CrCl) ≥ 40mL/min (CrCl= 
Wt (kg) x (140-age)*/72 x Cr. level, *female x 0.85) 
Serum creatinine: ______ Date of test:______ 
ULN:______ 
CrCL:______ Date of test:______ 
3.1.22.6 
Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert 
Syndrome, who can have total bilirubin < 3.0 x ULN) 
Total bilirubin:______ Date of test:______ ULN:______ 
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Patient with Gilbert Syndrome?_______(Yes or No) 
3.1.22.7 
AST and ALT ≤ 2.5 x ULN 
AST:________ Date of test:______ ULN:______ 
ALT:________ Date of test:______ ULN:______ 
3.1.22.8 
Hepatitis B Virus (HBV)* 
Result: ______ Date of test: ________ 
3.1.22.9 
Hepatitis C Virus (HCV)* 
Result: ______ Date of test: ________ 
NOTE*: 
For patients that are positive for Hep B core antibody, 
hepatitis B surface antigen (HBsAg) must be negative. For 
patients that are positive for Hep C antibody, polymerase 
chain reaction (PCR) must be negative. 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
 
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4. 
Registration and Randomization Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
RCR utilizes five person registration types. 
• IVR — MD, DO, or international equivalent; 
• NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and 
certification) 
 
 
 
 
 
HSP/GCP training 
 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN) 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
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In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 
participating organization (i.e., Alliance). Additional information can be found at the 
CTEP website at <https://ctep.cancer.gov/investigatorResources/default.htm>. For 
questions, please contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and 
applied to the RSS in an automated process. Signatory Institutions must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate 
their intent to open the study locally. The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office. In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved 
institutions aligned with the Signatory Institution are participating in the study 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
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Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a PO on the protocol. 
• 
Log on to the CTSU members’ website https://www.ctsu.org using your CTEP-IAM 
username and password 
• 
Click on the Protocols in the upper left of your screen 
• 
Either enter EA8143 in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN name link to expand, then select trial protocol EA8143 
• 
Click on Documents, select the Site Registration and download and complete the 
forms provided. (Note: For sites under the CIRB initiative, IRB data will load 
automatically to the CTSU as described above.) 
Requirements for EA8143 Site Registration: 
• 
EA8143 Protocol Training (please see Section 4.3 for more details). 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website, 
To access the Regulatory Submission Portal log on to the CTSU members’ website. 
Regulatory → Regulatory Submission 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent document 
must be justified in writing by the investigator and approved by the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
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3. Copies of the EA8143 specific regulatory documents, as outlined in the table below, 
are required for site registration. Please submit these documents per the frequency, 
regulatory reference, and instructions outlined in the table below. 
NOTE: 
The above submissions must include the following details: 
• Indicate all sites approved for the protocol under an assurance number. 
OHRP assurance number of reviewing IRB 
Full protocol title and number 
Version Date 
Type of review (full board vs. expedited) 
Date of review. 
Signature of IRB official 
In addition to the annual CTEP Investigator Registration requirements, the following 
study specific documents are required to be submitted to CTSU Regulatory Office via 
the Regulatory Submissions Portal, where they will be entered and tracked in the 
CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab → 
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Document 
Frequency  
Regulatory 
Reference  
Instructions  
Curriculum Vitae (CV) for 
principal investigator and all 
sub-investigators 
participating in the trial 
• Study start–up 
21 CFR 
312.53(2)  
GCP: 4.1.1; 
8.2.10; 8.3.5 
• Label CV with EA8143  
Study Specific Form FDA 
1572 
• Study start-up  
• Any time there is a 
change to any of 
the information 
originally provided  
21 CFR 
312.53(c) 
• Instructions for completing 
form: 
http://www.fda.gov/downloa
ds/aboutfda/reportsmanuals
forms/forms/ucm223432.pdf 
• Blank form: 
https://www.fda.gov/media/
71816/download 
EA8143 Financial 
Disclosure Form** – 
documents Financial 
Interests and Arrangements 
of Clinical Investigators for 
principal investigator and all 
sub-investigators 
participating in the trial and 
listed on the FDA Form 
1572 
• Study start-up  
• Any time there is a 
financial status 
change 
• Any time a new 
investigator is 
added 
21 CFR 
54.4(b)). 
• Blank form in Appendix IX: 
EA8143 Institutional 
Review Board Chairman 
Collection Form 
• Study start-up 
• Any time there is a 
change Chair 
oversight for the  
IRB of Record 
during the course of 
the trial* 
• Any time there is a 
change to the IRB 
of Record during 
the course of the 
trial* 
 
• Not Required from sites 
utilizing the NCI CIRB as 
the IRB of Record for 
EA8143 
• Blank form located on the 
CTSU website at 
www.ctsu.org under ‘Site 
Registration Documents’ for 
EA8143 
* “During the course of the study” refers to the time from the date the clinical investigator enters a patient 
onto the study until the completion of the study. For the purposes of financial disclosure under part 54, 
completion of the study means that all study subjects have been enrolled and follow-up of primary 
endpoint data on all subjects has been completed in accordance with the protocol.  
** The EA8143 Financial Disclosure Form is a required protocol specific regulatory document. This form is 
required independent of the Financial Disclosure Form that is required as part of the CTEP Investigator 
Registration Procedures. 
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Delegation of Task Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the 
DTL application in the Delegation Log section on the CTSU members’ website. The 
Clinical Investigator (CI) is required to review and electronically sign the DTL prior to the 
site receiving an Approved site registration status and enrolling patients to the study. To 
maintain an approved site registration status the CI must re-sign the DTL at least 
annually and when a new version of the DTL is released; and activate new task 
assignments requiring CI sign-off. Any individual at the enrolling site on a participating 
roster may initiate the site DTL. Once the DTL is submitted for CI approval, only the 
designated DTL Administrators or the CI may update the DTL. Instructions on 
completing the DTL are available in the Help Topics button in the DTL application and 
include a Master Task List, which describes DTL task assignments, CI signature, and 
CTEP registration requirements. 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
• 
Go to https://www.ctsu.org Log on to the CTSU members’ website; Click on the 
Regulatory at the top of your screen 
• 
Click on the Site Registration 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol treatment prior to randomization. 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must 
hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
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Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Randomization 
4.1.1 
The following information will be captured at time of randomization: 
4.1.1.1 
Protocol Number 
4.1.1.2 
Investigator Identification 
• 
Institution and affiliate name 
• 
Investigator’s name 
4.1.1.3 
Patient Identification 
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.1.2 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.1.3 
Stratification Factors 
• 
cT1, cT2 or cT3, cT4 
• 
cN0 or cN+ 
• 
cM0 or cM1 
NOTE: 
Only oligometastatic disease is permitted and is defined as 
≤3 metastases (see exclusions in the eligibility criteria) that 
can be resected or treated at the same time of 
nephrectomy or within a 12 week window. 
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4.1.4 
Additional Requirements 
4.1.4.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office - Boston 
RESEARCH BIOPSY: 
The establishment of research 
rates within the institution’s 
financial office must be in place 
prior to the performance of the 
biopsy for confirmation of 
disease if considered non-
standard of care. See Section 
10.5 for guidelines. 
4.1.4.2 
Pathological specimens must be submitted from all 
patients on both arms for central diagnostic review and 
classification and defined and/or undefined laboratory 
research studies as outlined in Section 10.  
4.1.4.3 
Peripheral blood, serum, and plasma are to be submitted 
for defined and/or undefined laboratory research studies 
per patient consent as outlined in Section 10. 
4.1.4.4 
Serum specimens must be submitted for pharmacokinetic 
and immunogenicity studies for Arm A patients only as 
outlined in Section 10. 
4.1.4.5 
Medidata Rave is a clinical data management system 
being used for data collection for this trial/study. Access to 
the trial in Rave is controlled through the CTEP-IAM 
system and role assignments. To access Rave via 
iMedidata, site staff will need to be registered with CTEP 
and have a valid and active CTEP-IAM account; and 
assigned one of the following Rave roles on the relevant 
Lead Protocol Organization (LPO) or Participating 
Organization roster at the enrolling site: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm 
for registration types and documentation required. To the 
hold Rave CRA role or Rave CRA (Lab Admin) role, the 
user must hold a minimum of an AP registration type. To 
hold the Rave Site Investigator role, the individual must be 
registered as an NPIVR or IVR. Associates can hold read-
only roles in Rave. 
If the study has a Delegation of Tasks Log (DTL), 
individuals requiring write access to Rave must also be 
assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
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roster will be sent a study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata 
screen. If an eLearning is required and has not yet been 
taken, the link to the eLearning will appear under the study 
name in iMedidata instead of the Rave EDC link; once the 
successful completion of the eLearning has been 
recorded, access to the study in Rave will be granted, and 
a Rave EDC link will display under the study name. 
Users that have not previously activated their 
iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive 
a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource 
materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by 
e-mail at ctsucontact@westat.com. 
4.1.4.6 
Digital Imaging Data Submission Using TRIAD  
Copies of imaging studies are to be submitted via TRIAD. 
TRIAD submission schedule of CT or MRI scan of chest, 
abdomen and pelvis with IV and +/- oral contrast (until 
recurrence): 
• 
Screening (Baseline) scans 
• 
Year 1: 4.5 and 9 months (approximately weeks 20 and 
40 from randomization) 
• 
Year 2: every 6 months: 15 and 21 months from 
randomization  
• 
Year 3: every 6 months: 27 and 33 months from 
randomization  
• 
Years 4-5: annually: 39 and 51 months from 
randomization  
• 
Any scan/s used to evaluate recurrence 
Outside of the above time points please refer to the study 
parameters table and below for additional submissions into 
TRIAD. 
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• 
Pelvis imaging is only required at baseline and at 
recurrence per protocol. Pelvis imaging outside of 
these time-points should be performed as clinically 
indicated and these images should be uploaded to 
TRIAD.  
• 
CT or MRI scans of chest and abdomen are to be 
performed as clinically indicated in follow-up 6-10 years 
from randomization and these images should be 
uploaded into TRIAD. 
• 
Bone Imaging (when it meets protocol criteria) 
• 
Optional bone mineral density test at baseline and 
week 40 (for patients that consent). Areal bone mineral 
density will be quantified by dual energy X-ray 
absorptiometry (DXA). Note that if patient consented, 
40 week DXA should be completed only if baseline 
DXA completed. Images should be uploaded to TRIAD. 
TRIAD is ACR’s proprietary image exchange application 
that will be used as the sole method of data transfer to the 
ACR Clinical Research Center Core Laboratory for this 
trial. TRIAD can be installed on one or several computers 
of choice within the institutional “firewall” and on the 
institutional network; internet access is required. The 
TRIAD application can then be configured as a DICOM 
destination on either scanner(s) and/or PACS system for 
direct network transfer of study related images into the 
TRIAD directory. When properly configured, the TRIAD 
software de-identifies, encrypts, and performs a lossless 
compression of the images before they are transferred to 
the ACR Imaging Core Laboratory image archive in 
Philadelphia. 
TRIAD Access Requirements: 
• 
Site radiology staff who will submit images through 
TRIAD will need to be registered with the Cancer 
Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management 
(IAM) account, and be registered as an A, AP, NPIVR 
or IVR. Please refer to the CTEP Registration 
Procedures section for instructions on how to request a 
CTEP-IAM account and complete registration in RCR. 
To submit images, site staff must hold the TRIAD Site 
User role on an NCTN or ETCTN roster. Individuals 
requiring a TRIAD Site User role should contact the 
person holding a primary role at the site for their 
affiliated NCTN or ETCTN roster.  
All individuals on the Imaging and Radiation Oncology 
Core provider roster have access to TRIAD, and may 
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submit images for credentialing purposes, or for 
enrollments to which the provider is linked in OPEN. 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with the 
proper user role, he/she will need to have the TRIAD 
application installed on his/her workstation to be able to 
submit images. TRIAD installation documentation can be 
found by following this link 
https://triadinstall.acr.org/triadclient/ 
This process can be done in parallel to obtaining your 
CTEP-IAM account username and password and RCR 
registration. 
If you have any questions regarding this information, 
please send an e-mail to the TRIAD Support mailbox at 
TRIAD-Support@acr.org or 1-703-390-9858. 
4.1.4.7 
Monitoring 
ECOG-ACRIN has contracted with Alpha Oncology, a 
contract research organization (CRO) to conduct on-site 
and remote monitoring activities. The goal of these 
monitoring activities is to provide source document 
verification (SDV). Alpha Oncology will be in contact with 
sites as patients reach the pre-defined milestones for 
initiation of monitoring activities. 
Alpha Oncology will also be conducting data sweeps. The 
goal of these data sweeps is to assist institutions with 
timely data entry and query resolution. Alpha Oncology will 
utilize phone requests and email notifications to request 
entry of outstanding data and/or completion of open 
queries. The objective of these sweeps is to collect data; 
they are not designed as an audit, nor are they intended to 
generate corrections to previously submitted data. 
4.1.5 
Data Quality Portal  
The Data Quality Portal (DQP) provides a central location for site staff 
to manage unanswered queries and form delinquencies, monitor data 
quality and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data 
Management. The Rave Home section displays a table providing 
summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, 
delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and 
have access to the CTSU website. Staff that have Rave study access 
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To learn more about DQP use and access, click on the Help icon 
displayed on the Rave Home, DQP Queries, and DQP Delinquent 
Forms modules. 
NOTE: 
Some Rave protocols may not have delinquent form details 
or reports specified on the DQP. A protocol must have the 
Calendar functionality implemented in Rave by the Lead 
Protocol Organization (LPO) for delinquent form details 
and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
4.2 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the EA8143 Forms Completion Guidelines. 
4.3 
Additional Registration Training Requirement 
ECOG-ACRIN has developed a training course to provide an overview of the 
EA8143 trial to site research staff and investigators. This training includes a 
general protocol overview and information regarding data collection and data 
management. 
Prior to the first patient enrollment at a participating site, one investigator 
must review and complete the EA8143 training course. Patient enrollments 
will be blocked via the OPEN system until this training requirement is 
completed. 
Additionally, ECOG-ACRIN recommends all research staff (CRAs, Data 
Managers, Imaging Staff, Investigators, Pharmacy Staff, etc.) involved in EA8143 
complete the training. 
Investigators and site staff are able to self-enroll in the course by 
accessing the training URL: 
https://coccg813.mindflash.com/PublicCoursePage.aspx?c=1710661420 
Upon completion of the training course continue through to the end of the module 
until you are directed to the electronic copy of your completion certificate. You 
will also receive an email notification at the email address registered with 
Mindflash that the training has been completed. Download and save the 
certificate, as you will need to upload this to the CTSU Regulatory Submission 
Portal, following the process listed below. Please note that only investigators 
need to submit the training completion certificate to the CTSU. Once submitted, 
the training record will be stored in the regulatory database as a person attribute 
and the corresponding site regulatory requirement will be update. 
If you have questions regarding training, please contact the CTSU Regulatory 
Office at 1-866-651-2878 or the ECOG-ACRIN Clinical Education and 
Awareness Team at EAClinEd@ecog-acrin.org. Additional information can be 
accessed on the CTSU: Search EA8143 → Supplemental Documents → 
12Dec2019 post date 
Training Requirement Approval Process: 
1. Complete the required protocol training, using the link provided in the protocol 
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2. Save a copy of the training completion certificate 
3. Submit certificate to the CTSU Regulatory Office: 
3.1. 
Regulatory Submission Portal: https://www.ctsu.org  
3.2. 
Log in to the Members’ area using your CTEP-IAM username and 
password  
3.3. 
Select the Regulatory Tab → Regulatory Submission → Add New 
Submission 
3.4. 
Under the “Documents being submitted are for:” drop-down menu, 
select “Specific Person(s) Only”  
3.5. 
In the “Pick Person(s)” field either select the applicable name(s) using 
the drop-down menu, or type the applicable name(s) into the search 
field to narrow down the choices in the drop-down menu 
3.6. 
Select “Add to Cart” 
3.7. 
Select “Next” 
3.8. 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
5.1.1 
Arm A: Perioperative Nivolumab 
5.1.1.1 
Patients randomized to arm A PRIOR to the Activation 
of Amendment #4 
Prior to the activation of amendment 4, patients were 
treated with 2 neoadjuvant doses (240 mg each dose) prior 
to nephrectomy and up to 9 months of adjuvant therapy 
given every 2 weeks (240 mg each dose) for 3 months (6 
cycles) then every 4 weeks (480 mg each dose) for 6 
months (6 cycles). Patients who are unable to receive their 
second dose of neoadjuvant nivolumab within the protocol 
specified time frame of 14 days (+/-3 days) of the first dose 
were permitted to proceed to surgery as scheduled per the 
protocol and omit the 2nd dose. Nephrectomy was 
required to be performed ≥7 and ≤ 28 days from last 
neoadjuvant dose. 
5.1.1.2 
Patients randomized to arm A AFTER the Activation of 
Amendment #4 
5.1.1.2.1 
Dose and Schedule 
Nivolumab 480mg intravenously, given per 
the following guidance: 
• 
After randomization, the neoadjuvant 
(pre-operative) dose of nivolumab must 
be administered within 4 weeks (within 
28 days) from randomization and prior 
to partial or radical nephrectomy. 
• 
Adjuvant (post-operative) dosing: 9 
doses; 1 dose every 4 weeks for 9 
months. 
5.1.1.2.2 
Timeframes for Perioperative Nivolumab 
Administration 
Nephrectomy required to be performed 
≥7 and ≤ 28 days from neoadjuvant dose. 
NOTE: 
In bilateral RCC or metastectomy 
cases where there is more than 
one nephrectomy or local 
treatment planned, this window 
will pertain to the date of the 
initial local treatment. 
NOTE: 
Nephrectomy can be done at 
any qualified hospital, surgery is 
not required to be performed at 
an ECOG-ACRIN or NCTN 
affiliated center. 
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• 
First dose of adjuvant nivolumab 
should be within 4 to 10 weeks post-
nephrectomy or last local treatment. 
If longer timeframes are needed, it 
should be approved by study chair. No 
delay beyond 15 weeks from last local 
treatment will be permitted. 
NOTE: 
In bilateral RCC or 
metastectomy cases where 
there is more than one 
nephrectomy or local 
treatment planned, this 
window will pertain to the 
date of the last expected 
local treatment. 
• 
While it is not optional, patients who 
were unable to get the neoadjuvant 
dose for unforeseen reasons are still 
eligible for adjuvant dosing if they 
meet the other protocol treatment 
criteria. 
5.1.2 
Arm B: Observation 
Partial or radical nephrectomy followed by observation. 
5.1.2.1 
Timeframes for Nephrectomy 
• 
Should be within 8 weeks after randomization in the 
observation arm (Arm B). 
NOTE:  
In bilateral RCC or metastectomy cases 
where there is more than one nephrectomy 
or local treatment planned, this window will 
pertain to the date of the initial local 
treatment. 
NOTE: 
Nephrectomy can be done at any qualified 
hospital, surgery is not required to be 
performed at an ECOG-ACRIN or NCTN 
affiliated center. 
5.2 
Prohibited and/or Restricted Treatments 
The following medications are prohibited during the treatment phase of the study 
(unless utilized to treat a drug-related adverse event) and encouraged to avoid 
during the follow-up phase prior to recurrence: 
• 
Immunosuppressive agents 
• 
Immunosuppressive doses of systemic corticosteroids (except as stated 
below) 
• 
Any concurrent anti-neoplastic therapy (including, but not limited to 
chemotherapy, hormonal therapy, immunotherapy, radiation therapy, or 
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standard or investigational agents for treatment of RCC) that would affect the 
primary endpoint of this study. 
5.3 
Permitted Therapy 
Subjects are permitted the use of topical, ocular, intra-articular, intranasal and 
inhalational corticosteroids (with minimal systemic absorption). 
Physiologic replacement doses of systemic corticosteroids are permitted even if 
> 10 mg daily prednisone (or equivalent) as long as no active autoimmune 
disease. 
A brief course of corticosteroids for prophylaxis (e.g., for contrast dye allergy) or 
for treatment of non-autoimmune conditions (e.g., nausea, delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted. 
Intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors are 
permitted if used according to the approved ocular indication, such as macular 
degeneration. 
Patients with bilateral synchronous RCCs or resectable M1 disease as detailed in 
the eligibility criteria are permitted to undergo resection or other definitive local 
treatments such as thermal ablation or radiosurgery as long as both procedures 
can be done within a 12 week time frame from the date of initial nephrectomy 
(partial or radical) or procedure (see eligibility). In the unanticipated event that 
both kidneys are completely removed after randomization, and the patient 
requires subsequent hemodialysis, the patient may continue on adjuvant 
nivolumab at the investigator’s discretion. 
5.4 
Adverse Event Reporting Requirements 
NOTE: 
The timeframes for reporting SAEs on this FDA registration trial are 
longer than the standard (all SAEs that occur within 100 days of the 
last dose of investigational treatment or surgery must be reported). 
Please review this section carefully to ensure all reporting 
requirements are met. 
NOTE: 
Starting April 1, 2018, CTEP-AERS reporting will use CTCAE v5. At 
this time, CTCAE v4 should continue to be used for both dose 
modifications and routine adverse event reporting.  
5.4.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents. 
5.4.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent or surgery in humans, 
whether or not considered agent drug or surgery related. 
Therefore, an AE can be ANY unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product or 
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procedure, whether or not considered related to the medicinal 
product or procedure. 
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to protocol 
treatment. 
Unlikely 
The AE is doubtfully related to protocol 
treatment. 
Possible 
The AE may be related to protocol treatment. 
Probable 
The AE is likely related to protocol treatment. 
Definite 
The AE is clearly related to protocol treatment. 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List): An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND. Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports. 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours. 
• 
Exception: Hospitalization for the planned partial or radical 
nephrectomy or any procedure (e.g. thermal ablation, 
radiation) to manage bilateral RCC or metastases will not be 
considered a SAE. 
• 
Life Threatening Adverse Event: Any AE that places the subject 
at immediate risk of death from the AE as it occurred. 
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
Exception: Hospitalization for the planned partial or 
radical nephrectomy or any procedure (e.g. thermal 
ablation, radiation) to manage bilateral RCC or metastases 
will not be considered a SAE. 
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
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• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they 
may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in 
this definition. 
• 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting):  A subset of AEs within the CAEPR that contains list 
of events that are protocol specific exceptions to expedited 
reporting. If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported via CTEP-AERS if the grade being reported exceeds the 
grade listed in the parentheses next to the event. 
5.4.3 
Mechanisms for Adverse Event Reporting 
Routine reporting: Adverse events are reported in a routine manner 
at scheduled times during a trial using the Medidata Rave clinical data 
management system. Please refer to Section 4 of the protocol for 
more information on how to access the Medidata Rave system and 
the EA8143 forms packet for instructions on what, where and when 
adverse events are to be reported routinely. 
Expedited reporting: In addition to routine reporting, certain adverse 
events must be reported in an expedited manner for timelier 
monitoring of patient safety and care. The remainder of this section 
provides information and instructions regarding expedited adverse 
event reporting. 
5.4.4 
Expedited Adverse Event Reporting Procedures 
Adverse events requiring expedited reporting will use CTEP’s Adverse 
Event Reporting System (CTEP-AERS). CTEP’s guidelines for CTEP-
AERS can be found at http://ctep.cancer.gov. 
For this study, a CTEP-AERS report must be submitted electronically 
via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov. so that ECOG-ACRIN, the NCI, and all 
appropriate regulatory agencies will be notified of the event in an 
expeditious manner. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (857-504-2900) 
• 
the NCI (301-897-7497)  
An electronic report MUST be submitted via CTEP-AERS immediately 
upon re-establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI (301-897-7404) the same 
timeframe.  
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CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.4.5 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 100 days of the last 
administration of investigational agent or surgery vs. ≥ 100 days 
after the last administration of investigational agent or surgery) 
• 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol EA8143 and outline the 
specific expedited adverse event reporting requirements for study 
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5.4.6 
Steps to determine if an adverse event is to be reported in an 
expedited manner – Arms A and B  
5.4.6.1 
Guidelines for reporting adverse events OCCURRING 
WHILE ON PROTOCOL TREATMENT AND WITHIN 100 
DAYS of the last administration of the investigational 
agent(s) or surgery. 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the 
table below in Section 5.4.7. 
Yes 
No 
Identify the type and 
grade of the event 
using the CTCAE. 
Determine if the patient 
was hospitalized for  
≥ 24 hours for the event. 
With this information, 
review the chart in Section 
5.4.7 to determine if event 
is reportable via  
CTEP-AERS. 
Refer to Section 5.4.8 to 
determine if the event 
meets the protocol specific 
reporting requirements for 
this study. If so, report the 
event via CTEP-AERS. 
Refer to Section 5.4.8 to determine 
if the event meets the protocol 
specific reporting requirements for 
this study. If so, report the event via 
CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Refer to Section 5.4.8 to determine if the event meets the 
criteria as an exception to reporting on this protocol. If it 
does not, report the event via CTEP-AERS. 
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5.4.6.2 
Guidelines for reporting adverse events OCCURRING 
GREATER THAN 100 DAYS after the last administration 
of the investigational agent(s) or surgery. 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.4.7, OR the 
protocol specific requirements in Section 5.4.8 the 
following events require reporting as follows AND has an 
attribution of possible, probably or definite: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 100 days after 
the last dose of investigational agent or surgery 
with an attribution of possible, probable or 
definite must be reported via CTEP-AERS even 
if the patient is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization. Hospitalization for 
nephrectomy is not considered an adverse event. 
• 
Exception: Hospitalization for the planned partial 
or radical nephrectomy will not be considered a 
SAE. 
• 
Grade 3 adverse events   
5.4.7 
Expedited Reporting Requirements for Arms A and B on protocol 
EA8143 
Investigational Agents: Nivolumab   
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 100 Days of the Last Administration of 
the Investigational Agent/Intervention or Surgery.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 100 days after the last administration 
of investigational agent/intervention or surgery. 
 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. 
Death 
2. 
A life-threatening adverse event  
3. 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours  
4. 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5. 
A congenital anomaly/birth defect.  
6. 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE: Protocol-specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
• 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
• 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1 Serious adverse events that occur more than 100 days after the last administration of investigational 
agent/intervention or surgery and have an attribution of possible, probable, or definite require reporting 
as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 
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5.4.8 
Additional instructions, requirements and exceptions for protocol 
EA8143 
Additional Instructions 
• 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-7497. This will 
need to be discussed on a case-by-case basis. 
• 
Reporting a death on study: A death occurring while on study 
treatment or within 100 days of the last dose of study treatment 
requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be 
provided 
NOTE: 
A death due to progressive disease should be 
reported as a Grade 5 “Disease progression” under 
the System Organ Class (SOC) “General disorder and 
administration site conditions”. Evidence that the 
death was a manifestation of underlying disease (e.g. 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted 
 
EA8143 specific expedited reporting requirements: 
• 
Pregnancies (Arm A requirement only): Pregnancies and 
suspected pregnancies (including a positive or inconclusive 
pregnancy test, regardless of age or disease state) occurring 
while the female patient is on nivolumab, or within 100 days of 
the female patient’s last dose of nivolumab, are considered 
immediately reportable events. The pregnancy, suspected 
pregnancy, or positive/ inconclusive pregnancy test must be 
reported via CTEP-AERS within 24 hours of the Investigator’s 
knowledge. Please refer to Appendix V for detailed instructions 
on how to report the occurrence of a pregnancy as well as the 
outcome of all pregnancies. 
• 
Infusion Reactions: All Grade 3 and 4 infusion reactions that 
meet the definition of SAE must be reported via CTEP-AERS 
according to the timeframes outlined in the AE table in Section 
5.4.7. 
• 
Hospitalization for nephrectomy is NOT considered a serious 
adverse event. However, if the patient’s hospitalization at the 
time of surgery is prolonged due potentially to the effect of 
neoadjuvant nivolumab, this would be considered a reportable 
SAE and must be reported via CTEP-AERS according to the 
timeframes outlined in the AE table in Section 5.4.7. 
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EA8143 specific expedited reporting exceptions: 
For study arm A, the adverse events listed below do not require 
expedited reporting via CTEP-AERS: 
• 
If an AE meets the reporting requirements of the protocol, and it 
is listed on the SPEER, it should ONLY be reported via CTEP-
AERS if the grade being reported exceeds the grade listed in the 
parentheses next to the event. 
5.4.9 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested MUST be submitted to BOTH the NCI and ECOG-ACRIN. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.4.10 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported as 
follows: 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol). Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis on the Adverse Event Form or Late 
Adverse Event Form in the appropriate Treatment Cycle or 
Post Registration folder in Medidata Rave 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
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NOTE: 
When reporting attribution on the AE Form, assess 
the relationship between the secondary malignancy 
and the current protocol treatment ONLY (and NOT 
relationship to any anti-cancer treatment received 
either before or after protocol treatment). 
3. Report the diagnosis via CTEP-AERS at 
http://ctep.cancer.gov. Report under a.) Leukemia 
secondary to oncology chemotherapy, b.) myelodysplastic 
syndrome, or c.) treatment related secondary malignancy 
4. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming 
the diagnosis. 
5. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN via Medidata Rave and submit a copy to 
NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the ECOG-ACRIN 
Second Primary Form. 
 
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5.5 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for BMS-
936558 (Nivolumab, MDX-1106, NSC 748726) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as 
noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 2069 patients. 
Below is the CAEPR for BMS-936558 (Nivolumab, MDX-1106). 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the parentheses 
next to the event in the SPEER. 
Version 2.4, December 2, 20201 
Adverse Events with Possible 
Relationship to Nivolumab 
(CTCAE 5.0 Term) 
[n= 2069] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency3 
 
  
 
Hyperthyroidism3 
 
  
 
Hypophysitis3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision 
  
 
 
Dry eye 
  
 
 
Eye disorders - Other 
(diplopia)3 
  
 
 
Eye disorders - Other (Graves 
ophthalmopathy)3 
  
 
 
Eye disorders - Other (optic 
neuritis retrobulbar)3 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada) 
  
 
Uveitis 
 
  
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Adverse Events with Possible 
Relationship to Nivolumab 
(CTCAE 5.0 Term) 
[n= 2069] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Enterocolitis 
  
 
 
Gastritis 
  
 
 
Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 
2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - 
Other (immune-mediated 
hepatitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5 
  
 
 
Immune system disorders - 
Other (GVHD in the setting of 
allotransplant)3,6 
  
 
 
Immune system disorders - 
Other (sarcoidosis)3 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased3 
 
 Alanine aminotransferase 
increased3 (Gr 3) 
 
Aspartate 
aminotransferase 
increased3 
 
 
Aspartate 
aminotransferase 
increased3 (Gr 3) 
 
Blood bilirubin increased3  
 Blood bilirubin increased3 
(Gr 2) 
 
CD4 lymphocytes 
decreased 
 
 CD4 lymphocyte 
decreased (Gr 4) 
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count 
decreased 
 
 Lymphocyte count 
decreased (Gr 4) 
 
Neutrophil count 
decreased 
 
  
 
Platelet count decreased 
 
  
 
Serum amylase increased  
  

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Adverse Events with Possible 
Relationship to Nivolumab 
(CTCAE 5.0 Term) 
[n= 2069] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus with ketoacidosis)3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - 
Other (demyelination 
myasthenic syndrome) 
  
 
 
Nervous system disorders - 
Other (encephalitis)3 
  
 
 
Nervous system disorders - 
Other (meningoencephalitis) 
  
 
 
Nervous system disorders - 
Other (meningoradiculitis)3 
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome)   
 
 
Peripheral motor neuropathy   
 
 
Peripheral sensory 
neuropathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
 
 
Renal and urinary disorders - 
Other (immune-mediated 
nephritis) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  

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Adverse Events with Possible 
Relationship to Nivolumab 
(CTCAE 5.0 Term) 
[n= 2069] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Pruritus3 
 
 Pruritus3 (Gr 2) 
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 
2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (bullous 
pemphigoid) 
  
 
Skin and subcutaneous 
tissue disorders - Other 
(Sweet's Syndrome)3 
 
  
 
Skin hypopigmentation3 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
3 Nivolumab being a member of class of agents involved in the inhibition of “immune checkpoints”, may 
result in severe and possibly fatal immune-mediated adverse events probably due to T-cell activation 
and proliferation.  This may result in autoimmune disorders that can include (but are not limited to) 
autoimmune hemolytic anemia, acquired anti-factor VIII immune response, autoimmune aseptic 
meningitis, autoimmune hepatitis, autoimmune nephritis, autoimmune neuropathy, autoimmune 
thyroiditis, bullous pemphigoid, exacerbation of Churg-Strauss Syndrome, drug rash with eosinophilia 
systemic symptoms [DRESS] syndrome, facial nerve disorder (facial nerve paralysis), limbic 
encephalitis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, 
endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia 
gravis, polymyositis, and Guillain-Barre syndrome. 
4 Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
5 Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying 
fever and pancytopenia. 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in 
patients receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These complications may 
occur despite intervening therapy between receiving Nivolumab and allo-SCT. 
7 Infusion reactions, including high-grade hypersensitivity reactions which have been observed following 
administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or 
hypotension, or difficulty breathing during and immediately after administration of nivolumab. 
Adverse events reported on Nivolumab trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that Nivolumab caused the adverse 
event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; 
Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema 

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GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; 
Gastrointestinal disorders - Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; 
Malaise; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune 
thrombotic microangiopathy); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper 
respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - 
Other (protein total decreased); Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal 
and connective tissue disorder - Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (Histiocytic 
necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other 
(tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; 
Dyspnea; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain 
of skin; Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other 
(rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
NOTE: 
BMS-936558 (Nivolumab, MDX-1106) in combination with other agents could cause 
an exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with 
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5.6 
Dose Modifications  
All toxicity grades below are described using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. 
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 
website (http://ctep.cancer.gov). 
There are no dose reductions for nivolumab. In the event of toxicities that 
are possibly, probably or definitely related to nivolumab, the drug should 
be held, early evaluation performed and toxicities managed as below.  
Treatments identified in the management algorithms (Section 5.7) and the 
nivolumab prescribing information are recommended unless there are 
specific circumstances in which the treating physicians identifies an 
alternative treatment strategy is necessary 
5.6.1 
Criteria to omit dose of nivolumab 
Doses of nivolumab should be omitted (not delayed) if any of the 
following criteria are met:  
• 
Grade ≥ 1 pneumonitis  
• 
Any Grade ≥ 2 drug-related adverse event, with the exception of: 
• 
Grade 2 fatigue, asthenia, or malaise 
• 
Grade 2 skin/rash event 
• 
Grade 2 diabetes 
• 
Grade 2 – 4 asymptomatic thyroid abnormalities 
• 
Grade ≥ 3 diabetes or other endocrinopathy (with exception of 
asymptomatic thyroid abnormalities)  
• 
Any symptomatic endocrinopathy 
• 
Suspicion of adrenal crisis (e.g., hypotension, early signs of 
shock) 
• 
Any Grade 3 skin drug-related adverse event 
• 
Grade ≥ 2 creatinine rise. 
• 
Barring clinically significant renal toxicity, the first post-
nephrectomy creatinine assessment can be used as the new 
baseline as long as criteria outlined in Section 3.1.22.5 are 
met. 
• 
Grade ≥ 2 AST, ALT, or total bilirubin abnormalities 
• 
Grade 2 = AST or ALT > 3xULN and < 5xULN 
• 
Grade 2 = Total bilirubin > 1.5- 3xULN 
• 
Any Grade 3 drug-related laboratory abnormality (excluding AST, 
ALT or Total Bilirubin which requires discontinuation) with the 
following exceptions: 
• 
Grade 3 lymphopenia does not require dose delay 
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• 
Any Grade ≥ 3 drug-related amylase or lipase abnormalities 
that are not associated with symptoms or clinical 
manifestations of pancreatitis does not require dose delay. 
• 
Grade 3 or 4 elevations that persist after an additional 
cycle should prompt consideration of imaging or other 
evaluation per investigator discretion. 
• 
For CPK elevations, hold if Grade 2 and symptomatic; otherwise 
hold for Grade 3 or greater. 
• 
Any grade encephalitis. 
• 
Any other Grade 4 event with the exception of asymptomatic 
laboratory abnormalities that can be managed by electrolyte or 
hormone treatment, or those noted above such as asymptomatic 
amylase, lipase, and asymptomatic thyroid dysfunction being 
managed by hormone replacement. 
For held doses:  
• 
If the criteria to resume treatment are met within the dosing 
window (Day 1, Week X ± 3 business days), then the dose may be 
given. 
NOTE: 
Per BMS standards, the term “interruption” is reserved 
for interruption of the actual IV infusion during 
administration. The terms omission and interruption 
should not be used synonymously when completing the 
CRF forms. 
Tumor surveillance assessments, QOL questionnaires collection 
and biomarker sampling should continue as per protocol even if 
dose is omitted. 
5.6.2 
Criteria to resume treatment with nivolumab 
Subjects may resume treatment with study drug when the drug-
related AE(s) resolve to Grade  1 or baseline value, with the 
following caveats: 
• 
Can resume with Grade 2 fatigue, asthenia, or malaise 
• 
Subjects who have not experienced a prior Grade 3 drug-related 
skin AE may resume treatment in the presence of Grade 2 skin 
toxicity  
• 
Grade 2 drug-related diarrhea or colitis must have resolved to 
baseline before treatment is resumed and any steroid therapy 
started for prolonged Grade 2 toxicity must be complete. 
• 
Subjects with asymptomatic drug-related endocrinopathies which 
are adequately controlled with only physiologic hormone 
replacement may resume treatment. 
• 
For patients who have been treated with steroids for other 
Grade 2 events, they must have been tapered down to 10mg 
of prednisone or its equivalent and preferably off steroids 
without recurrence of symptoms or new events for 2 weeks 
prior to restarting treatment. 
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• 
Any patient who recurs to Grade 3 during this tapering period 
should discontinue study therapy. 
5.6.2.1 
Timing of restarting nivolumab 
• 
If the criteria to resume treatment are met, the subject 
should restart treatment at the next scheduled 
timepoint per protocol. 
• 
If the treatment is withheld past the window period of 
the next scheduled nivolumab administration in order to 
allow for adequate recovery from the adverse event or 
tapering of immunosuppression, the dosing should 
continue to be withheld until the next scheduled study 
drug administration. 
• 
See criteria in 5.6.3 for considerations pertaining to 
cases where treatment is held > 12 weeks past the 
scheduled dosing 
5.6.3 
Criteria which require permanent discontinuation of nivolumab 
• 
Any Grade 2 drug-related uveitis, 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  
• 
Grade ≥ 2 pneumonitis 
• 
The following Grade ≥ 3 drug related events require immediate 
discontinuation: renal toxicity (including acute kidney injury and 
increased creatinine), hepatitis, bronchospasm, diarrhea, colitis, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, 
myositis, myocarditis, and uveitis. 
• 
Examples (but not limited to) of Grade 3 drug-related neurotoxicity 
requiring discontinuation include: 
• 
Inflammatory CNS event, Guillain-Barre, myasthenia, 
polymyopathy, seizure 
• 
Any other Grade 3 or greater non-skin, drug-related adverse event 
lasting > 7 days or that recurs, with the following exceptions: 
• 
Grade 3 drug-related endocrinopathies such as diabetes or 
thyroid dysfunction adequately controlled with only physiologic 
hormone replacement do not require discontinuation 
• 
Grade 3 drug-related laboratory abnormalities do not require 
treatment discontinuation except: 
• 
Grade 3 drug-related thrombocytopenia or lower grade 
associated with significant bleeding requires 
discontinuation 
• 
Grade ≥ 3 drug-related AST, ALT or total bilirubin requires 
discontinuation 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x 
ULN requires discontinuation 
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• 
For any other Grade 3 events not listed above, at the 
discretion of the investigator, the patient may be allowed to 
be re-treated when the event is resolved and patient is off 
steroids – for the first occurrence. A second similar event 
requires discontinuation of nivolumab. 
• 
Any Grade 4 drug related skin or renal toxicity 
• 
Any Grade 3 or 4 drug related adrenal insufficiency 
• 
Any Grade 3 or 4 drug related cardiac dysfunction 
• 
Any Grade 2 drug related cardiac dysfunction events that do not 
recover to baseline or that reoccur 
• 
Any immune-related toxicity requiring immunosuppressive therapy 
beyond steroids 
• 
Any severe or Grade 3 immune-mediated adverse reaction that 
recurs to Grade ≥ 3 on reintroduction of nivolumab 
• 
Persistent Grade 2 immune-mediated adverse drug reactions that 
do not recover to Grade 1 or resolve within 6 weeks after the last 
dose of study drug (exceptions: rash, fatigue, amylase/lipase 
elevations, thyroid disorders or diabetes) 
• 
Dosing that is withheld > 12 weeks from the last dose with the 
following exceptions: 
• 
Dosing omissions to allow for prolonged steroid tapers to 
manage drug-related adverse events are allowed (provided 
they do not meet other discontinuation criteria above). Prior to 
re-initiating treatment in a subject with a dosing omission 
period lasting > 12 weeks from the last dose, the PI must be 
consulted.  
• 
Dosing omissions > 12 weeks from the last dose that occur for 
non-drug-related reasons may be allowed if approved by the 
PI.  
• 
Any adverse event, laboratory abnormality, or intercurrent illness, 
which in the judgment of the Investigator presents a substantial 
clinical risk to the subject with continued nivolumab dosing. 
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5.6.4 
Management/Next Dose Guidelines for BMS-936558 (Nivolumab) 
Cardiac Toxicities 
Cardiac*  
Management/Next Dose for BMS-936558 
(Nivolumab)  Cardiac Toxicities 
≤ Grade 1  
Hold dose pending evaluation and observation.**  
Evaluate for signs and symptoms of CHF, ischemia, 
arrhythmia or myositis. Obtain history EKG, CK (for 
concomitant myositis), CK-MB. Repeat troponin, CK 
and EKG 2-3 days. If troponin and labs normalize 
may resume therapy. If labs worsen or symptoms 
develop then treat as below. Hold pending 
evaluation  
Grade ≥ 2 with 
suspected myocarditis 
Hold dose.** Admit to hospital. Cardiology consult. 
Rule out MI and other causes of cardiac disease. 
Cardiac Monitoring. Cardiac Echo. Consider cardiac 
MRI and cardiac biopsy. Initiate high dose 
methylprednisolone. If no improvement within 24 
hours, add either infliximab, ATG or tacrolimus. 
Consult algorithm for more details. Resume therapy 
if there is a return to baseline and myocarditis is 
excluded or considered unlikely. 
Grade ≥ 2 with 
confirmed myocarditis   
Off protocol therapy. Admit to CCU (consider 
transfer to nearest Cardiac Transplant Unit). Treat 
as above. Consider high dose methylprednisolone   
Add ATG or tacrolimus if no improvement. Off 
treatment. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated 
according as “other event”   
Note: The optimal treatment regimen for immune mediated myocarditis has 
not been established. Since this toxicity has caused patient deaths, an 
aggressive approach is recommended.   
Treatment with steroids as clinically indicated 
5.7 
Management Algorithms for Immune-related Adverse Events  
• 
The following algorithms contain recommended management guidelines for 
nivolumab immune-related AEs. The criteria in Section 5.6 are mandatory 
and should be followed over the algorithms if discrepant.  
• 
The nivolumab prescribing information can also be used for AEs not detailed 
below and for other suggested steroid or management regimens. For any 
questions where the two may be discrepant or if questions arise, contact the 
Principal Investigator. 
• 
Clarifications regarding steroid use: 
• 
Please note that in some cases the management algorithms recommend 
steroids if symptoms do not resolve in 7 days. However, this 
recommendation is not meant to delay steroid treatment if it is clinically 
indicated sooner. 
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• 
Before starting steroids baseline values should be obtained for cortisol, 
ACTH, TSH, free T4. 
• 
Any patient started on corticosteroids initially who is determined to not 
require steroid treatment for an autoimmune adverse event may resume 
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5.8 
Supportive Care 
• 
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
• 
Bisphosphonates and RANK ligand inhibitors used for osteopenia, 
osteoporosis, and hypercalcemia are permitted. 
• 
Treatment of Nivolumab Related Infusion Reactions  
Since nivolumab contains only human immunoglobulin protein sequences, it 
is unlikely to be immunogenic and induce infusion or hypersensitivity 
reactions. However, if such a reaction were to occur, it might manifest with 
fever, chills, rigors, headache, rash, pruritus, arthralgias, hypotension, 
hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 and 
4 infusion reactions that meet the definition of SAE must be reported via 
CTEP-AERS according to the timeframes outlined in the AE table in Section 
5.4.77. Infusion reactions reported via CTEP-AERS should be graded 
according to NCI CTCAE (Version 5.0) guidelines. 
Treatment recommendations are provided below and may be modified based 
on local treatment standards and guidelines, as appropriate: 
• 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; 
intervention not indicated): 
• 
Study staff (e.g, RN, NP, PA or MD) should remain at bedside and 
monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg IV or PO (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg PO at least 30 minutes 
before additional nivolumab administrations. 
• 
For Grade 2 symptoms: (moderate reaction required therapy or infusion 
interruption but responds promptly to symptomatic treatment (e.g., 
antihistamines, non-steroidal anti-inflammatory drugs, narcotics, 
corticosteroids, bronchodilators, IV fluids); prophylactic medications 
indicated for  24 hours): 
• 
Stop the nivolumab infusion, begin an IV infusion of normal saline, 
and treat the subject with diphenhydramine 50 mg IV or PO (or 
equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg; 
remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart 
the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate 
may be increased to 100% of the original infusion rate. Monitor 
subject closely. If symptoms recur, then no further nivolumab will be 
administered at that visit. 
• 
For future infusions, the following prophylactic premedications are 
recommended: diphenhydramine 50 mg IV or PO (or equivalent) 
and/or acetaminophen/paracetamol 325 to 1000 mg should be 
administered at least 30 minutes before nivolumab infusions. If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or 
equivalent) may be used. 
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• 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not 
rapidly responsive to symptomatic medication and/or brief interruption of 
infusion]; recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates). Grade 4: Life-threatening; pressor or 
ventilator support indicated): 
• 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of 
normal saline and treat the subject as follows: Recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 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 or PO 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 will be 
permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at 
bedside and monitor subject until recovery of the symptoms. 
• 
In case of late-occurring hypersensitivity symptoms (e.g., appearance 
of a localized or generalized pruritus within 1 week after treatment), 
symptomatic treatment may be given (e.g., oral antihistamine or 
corticosteroids). 
5.9 
Quality of Life Instrument Administration 
5.9.1 
Quality of Life Instruments to be administered 
The NCCN/FACT Kidney Symptom Index-19 (NFKSI-19), PROMIS 
PF-10 and PRO-CTCAE items will be administered to patients 
enrolled on EA8143. PRO-CTCAE items will be administered through 
the first year post-baseline, but not thereafter. The NFKSI-19 and 
PROMIS PF-10 will be administered at all scheduled time points. 
5.9.2 
Quality of Life Assessment Schedule 
NOTE: 
All assessments are to be administered PRIOR to 
nivolumab infusion on Arm A. 
Patients will be assessed according to the following schedule: 
Baseline (pre-treatment and pre-nephrectomy) 
• 
Post-randomization, prior to the initiation of protocol therapy (Arm 
A). 
• 
Post-randomization, prior to date of nephrectomy (Arm B) 
Post-baseline assessments 
• 
Pre-nephrectomy (Arm A) but post neoadjuvant dose 
• 
8 weeks post-nephrectomy 
• 
20, 40 and 54 weeks post randomization  
• 
At recurrence 
• 
2 years post randomization 
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5.9.3 
Quality of Life Administration Instructions 
• 
QOL Assessments should be administered at all scheduled 
assessments, regardless of whether the patient recurs or is 
removed from the protocol for any reason. 
NOTE: 
The NFKSI-19, PROMIS, and PRO-CTCAE are 
available in Spanish translations. No other translations 
are available at this time. Sites should not translate their 
own versions of these documents. For the purposes of 
this study when a translated version is not available, 
document this reason in RAVE. For sites, this would not 
be considered a deficiency/ violation at the time of audit, 
as QOLs are not primary or secondary objective. 
• 
The pre-treatment pre-nephrectomy baseline assessments of 
PRO-CTCAE items, PROMIS PF-10, and NFKSI-19 will be 
administered during the patient’s clinic visit post-
randomization, prior to the initiation of protocol therapy (Arm 
A) or nephrectomy (Arm B). Follow-up PRO-CTCAE items, 
PROMIS PF-10, and NFKSI-19 assessments are to be 
completed pre-nephrectomy but post neoadjuvant dose (Arm 
A), 8 weeks post-nephrectomy, 20, 40, and 54 weeks post 
randomization, and at recurrence. PROMIS PF-10, and 
NFKSI-19 assessments will also be administered 2 years post 
randomization. These assessments may not coincide with 
scheduled clinic visits. Patients will be given blank assessment 
forms and asked to complete assessment forms at home at 
these time points. Administration instructions for baseline (pre-
treatment pre-nephrectomy) assessment and post-baseline 
assessments are detailed below. 
• 
Baseline (pre-treatment and pre-nephrectomy) assessment 
• 
Whenever possible, the PRO-CTCAE, PROMIS PF-10, 
and NFKSI-19 assessments should be administered at the 
clinic visit before the patient is seen by the physician, 
before evaluations are performed and before test results 
are shared with the patient. In the event that the 
questionnaires are not administered at the clinic visit, the 
PRO-CTCAE, PROMIS PF-10, and NFKSI-19 data can be 
collected by telephone or mail as backup methods 
provided that PRO-CTCAE, PROMIS PF-10, and NFKSI-
19 data is captured prior to initiation of treatment. For 
patients receiving nivolumab, assessments should be done 
prior to the start of the infusion. 
• 
The CRN/CRA should read the instructions printed on the 
questionnaire to the patient and ensure the patient 
understands the instructions. It is important to assure the 
patient that all material on the questionnaire is confidential 
and will not be shared with the health care team and that it 
will not become part of the medical record. 
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• 
Assistance in reading the questionnaire is permitted if the 
patient is unable to complete the questionnaire on his/her 
own (e.g. difficulty in reading, vision problems). It is 
important not to influence the response of the patient. Note 
why the patient required assistance and the type of 
assistance given on the Assessment Compliance Form. 
• 
Patients should be instructed to answer all the questions 
regardless of whether the symptoms or conditions asked 
about are related to the cancer or cancer treatment. 
Discourage family members from being present during 
questionnaire completion or from influencing the patient’s 
responses. 
• 
Review the questionnaire for completeness before the 
patient leaves. If the patient has marked more than one 
answer per question, ask the patient which answer best 
reflects how they are feeling. If the patient has skipped a 
question or questions, assure that he or she intended to 
leave the question blank. 
• 
If the patient refuses or cannot complete the questionnaire 
at any time point, he or she should be asked to do so at 
the next scheduled QOL assessment time point. 
• 
The patient may decline to complete the QOL 
assessments for any reason. The reason must be 
documented on the Assessment Compliance Form. 
• 
Post-Baseline Assessments (pre-nephrectomy but post 
neoadjuvant dose on Arm A, post-nephrectomy on both Arms, 
at weeks 20, 40, and 54, at 2 years, and at recurrence.) 
• 
Assessments at 20, 40, and 54 weeks should be done 
when patient returns to clinic for scans and labs, prior to 
receiving scan. 
• 
The CRN/CRA should contact the patient by telephone, e-
mail or postal mail 1-3 days prior to the target assessment 
date to remind the patient to complete their assessments. 
If the returned questionnaires are not received at the site, 
a reminder contact phone call should occur no longer than 
5 days following the target completion date. Patients 
should complete the HRQL assessment forms on or as 
close as possible to the target assessment date. If the 
patient misses the target assessment date they can 
complete the assessment as long as they have not started 
the subsequent cycle of protocol therapy. 
• 
The CRN/CRA should confirm that the patient has a 
stamped, addressed envelope to return his/her completed 
QOL assessment forms. The CRN/CRA may offer to 
complete the QOL assessment by telephone. The mode of 
administration (mail, telephone) should be noted on the 
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misplaced the forms, the site can send new blank forms by 
mail, fax or email. 
• 
For telephone administration of QOL assessment, 
encourage the patient to have the written form in front of 
them to read along during the assessment. Read the 
instructions printed on the questionnaires to the patient 
and ensure the patient understands the instructions. If the 
patient is unable to complete the questionnaires on his/her 
own (e.g. difficulty in reading, vision problems) follow-up 
QOL assessments should be conducted by telephone. 
Telephone administration of QOL assessment by the 
CRN/CRA is preferable to having the patient ask a family 
member or someone in the household for assistance with 
completing the forms. It is important not to influence the 
response of the patient. Note why the patient required 
assistance and the type of assistance given on the 
Assessment Compliance Form. 
• 
The CRN/CRA should instruct the patient to record the 
actual date the patient completed the QOL assessment on 
each form, reminding the patient that the date recorded on 
the forms is their target date of assessment completion. It 
is important to assure the patient that all material on the 
questionnaire is confidential and will not be shared with the 
health care team and that it will not become part of the 
medical record. 
• 
Patients should be instructed to answer all the questions 
regardless of whether the symptoms or conditions asked 
about are related to the cancer or cancer treatment. 
Discourage family members from being present during 
questionnaire completion or from influencing the patient’s 
responses. 
5.10 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
EA8143 Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
• 
Pregnancy. 
• 
Patient is found not to have RCC at biopsy or nephrectomy (Off-treatment 
date should be the date of biopsy or surgery, when it is found the patient 
does not have RCC). 
After Amendment #4, patients will not receive more than 1 dose of neoadjuvant 
nivolumab and 9 doses of adjuvant nivolumab (4-week intervals) during the 
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course of the study. If a patient started on trial prior to Amendment #4, they may 
receive more doses given the 2 week treatment intervals, but no more than 2 
doses of neoadjuvant therapy and 9 months of adjuvant therapy. 
Patients will not receive nivolumab at recurrence as part of the study. 
Subsequent therapy at recurrence is at the treating physician’s discretion. 
5.11 
Second Primary Cancers 
Patients who develop second (but not secondary) primary cancers may continue 
protocol treatment at the discretion of their physician as long as they do not 
require systemic therapy for the treatment of that secondary cancer. Surgical 
resection, radiation (with the exception of to the renal bed), and other local 
therapies may be considered. 
5.12 
Duration of Follow-up  
For this protocol, all patients (except those found not to have RCC at biopsy or 
nephrectomy), including those who discontinue protocol therapy early, will be 
followed for response until recurrence, even if non-protocol therapy is initiated 
and for survival for 10 years from the date of randomization. All patients must 
also be followed through completion of all protocol therapy. 
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6. 
Measurement of Effect 
6.1 
Diagnosis of Renal Cell Cancer Recurrence 
The diagnosis of a first renal cell carcinoma recurrence can be made only when 
the clinical and pathology findings meet the criteria acceptable for recurrence as 
defined below. Anything not listed as acceptable should be considered 
unacceptable for evidence of renal cell cancer recurrence and should not be an 
indication to alter protocol therapy if still on therapy at time of possible 
recurrence. Any recurrence of malignant disease should be proven by core 
needle biopsy or resection whenever possible. At the time of tumor recurrence 
the investigator should clearly indicate the site of tumor recurrence and whether 
multiple sites are involved.  
Supporting documentation must be submitted following diagnosis of renal cell 
carcinoma recurrence or second primary cancer. Refer to the EA8143 Forms 
Packet for data to be collected. Copies of the pathology, radiology and, if 
relevant, surgery reports should be uploaded via Medidata Rave. If biopsy 
material is available, a copy of the pathology report should also accompany the 
materials submission to the CBPF. 
The following criteria for recurrence are required. Supporting documentation 
includes a copy of radiology and pathology reports. 
• 
Positive cytology or biopsy  
• 
If biopsy is not possible of a solitary new lung, soft tissue, or visceral lesion 
that is ≥1 cm, confirmation of growth by at least 5mm or appearance of other 
new lesions on subsequent scans at least 4 weeks later. 
• 
If biopsy is not possible of a solitary new lung, soft tissue, or visceral lesion 
that is <1 cm, confirmation of growth to ≥1cm or appearance of new lesions 
on subsequent scans at least 4 weeks later. 
• 
If biopsy is not possible of a lymph node ≥1.5cm in short axis, confirmation of 
growth by at least 5mm or appearance of other new lesions on subsequent 
scans at least 4 weeks later. 
• 
For bone lesions: 
• 
A positive radiographic study such as bone scan with 2 or more new 
lesions that are confirmed with MRI or CT 
• 
For a solitary lesion or equivocal finding on a scan, biopsy is required or 
subsequent scans demonstrating growth or at least one new lesion at 
least 4 weeks later. 
• 
For brain lesion(s), a positive brain CT or MRI is acceptable without a biopsy 
or confirmation. 
NOTE: 
Patients should continue treatment until recurrence has been 
proven per these guidelines. 
6.2 
Survival  
Survival will be measured from the date of randomization. 
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6.3 
Time to Recurrence  
This interval will be measured from the date of randomization to the appearance 
of new lesion(s). Date of recurrence will be backdated to the time the lesion was 
first observed. 
6.4 
Patients with Residual Disease at the time of Surgery or who do not undergo 
nephrectomy 
Patients who are found to have residual local, regional or distant disease at the 
time of surgery or who do not undergo surgery will be included as recurrence 
events using the date of randomization. Patients will not continue on to the 
adjuvant portion of nivolumab if randomized to that arm. The following should be 
done as detailed in the study calendar under “recurrence.” 
• 
History and physical exam 
• 
Waist circumference  
NOTE: 
waist circumference is being collected to investigate the 
relationship of BMI to clinical outcome. 
• 
ECOG performance status  
• 
CT/MRI scan chest abdomen /pelvis with IV +/- oral contrast (if none within 8 
weeks) 
• 
Bone imaging (if none within 8 wks and only if clinically indicated) 
• 
Tumor Biopsy (if nephrectomy specimen not available) 
• 
EKG if clinically indicated 
 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters for both arms  
1. Baseline imaging should be done ≤ 8 weeks prior to randomization. 
2. Eligibility and baseline laboratories outlined in Sections 3, 7.2, and 1.1 should be done and resulted ≤ 8 weeks 
before randomization. 
7.2 
Arm A: Perioperative Nivolumab 
Therapeutic Parameters Table 
Procedures 
Baseline2 
Day 1, 
Neoadjuvant 
Cycle(s)1,8 
Pre-
Surgery Surgery 
Day 1, 
Adjuvant 
Cycles1,8 
Month 4.5 
(Week 
20)1 
Month 9 
(Week 
40)1 
Within 6 Weeks 
after Final 
Treatment 
Follow-
up1,11 
Recurrence 
History and Physical 
examination 
X 
X 
 
 
X 
 
 
X 
  X15 
X 
Waist Circumference13 
X 
 
 
 
 
 
 
 
 
X 
Medication review 
X 
X 
 
X 
X 
 
 
X 
 
X 
ECOG performance status 
X 
X 
 
 
X 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital signs (including BP, HR, 
temperature) and weight 
X 
X 
 
 
X 
 
 
X 
 
 
HCV, HBV3 
X 
 
 
 
 
 
 
 
 
 
Laboratory parameters4 
X 
X 
 X 
 
X 
 
 
X 
X 
 
Toxicity assessment 
X 
X 
 
X 
X 
 
 
X 
X 
 
CT or MRI scan of chest, 
abdomen and pelvis with IV and 
+/- oral contrast5 
X 
 
 
 
 
X 
X 
 
 X5 
X 
Bone imaging (bone scan or 
PET/CT) 
X6 
 
 
 
 
 
 
 
 
 X6 
OPTIONAL Bone imaging (dual 
energy x-ray absorptiometry)16 
X 
 
 
 
 
 
X 
 
 
 
Tumor Biopsy 
  X12 
 
 
 
 
 
 
 
 
X17 
Partial or radical nephrectomy9 
 
 
 
X 
 
 
 
 
 
 
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Therapeutic Parameters Table 
Procedures 
Baseline2 
Day 1, 
Neoadjuvant 
Cycle(s)1,8 
Pre-
Surgery Surgery 
Day 1, 
Adjuvant 
Cycles1,8 
Month 4.5 
(Week 
20)1 
Month 9 
(Week 
40)1 
Within 6 Weeks 
after Final 
Treatment 
Follow-
up1,11 
Recurrence 
Pregnancy Testing7 
X 
 X7 
 
 
 X7 
 
 
 
 
 
Nivolumab administration8 
 
X 
 
 
X 
 
 
 
 
 
QOL 
 X10 
Survival 
 
 
 
 
 
 
 
 
X 
 
EKG, echocardiogram 
 X14 
1. Cycles are 4 weeks long (28 days). Dosing window is +/-3 business days. Months 4.5 (Week 20), 9 (Week 40), and all follow-up time-points are 
to be calculated as weeks/months from the date of randomization. 
• 
Prior to Amendment 4, there will be 2 neoadjuvant cycles (doses) and up to 12 adjuvant cycles (doses) 
• 
After Amendment 4, there will be only 1 neoadjuvant cycle (dose) and up to 9 adjuvant cycles (doses) 
2. Eligibility parameters must be done and resulted within 8 weeks prior to randomization. Biopsy results must be available prior to neoadjuvant 
nivolumab dose. Hepatitis test results must be available prior to randomization. Baseline QOL will be administered per Footnote 10. 
3. Patients will require HBV and HCV testing utilizing local consent procedures for this collection. Results must be available prior to randomization. 
For patients that are positive for Hep B core antibody, hepatitis B surface antigen (HBsAg) should be negative. For patients that are positive for 
Hep C antibody, polymerase chain reaction (PCR) should be negative. These tests could be repeated later during the course of the study if 
clinically indicated. 
4. On site (Local) Laboratories include: 
• 
Baseline labs within 8 weeks prior to randomization: CBC (wbc with differential, hemoglobin and platelet count), CMP (Na, K, Cl, CO2 or 
HCO3, BUN, creatinine, glucose), LDH, liver function tests (AST, ALT, total bilirubin, alkaline phosphatase), serum calcium, albumin, total 
protein; cortisol, TSH, free T4 (only required if TSH is abnormal), amylase, lipase, PT/INR, PTT* 
• 
*PTT is only required for patients on heparin. 
• 
Every on-study visit after randomization (within 72 hours before dose) and within 6 weeks after final treatment: CBC (wbc with 
differential, hemoglobin and platelet count), CMP (Na, K, Cl, CO2 or HCO3, BUN, creatinine, glucose), LDH*, liver function tests (AST, ALT, 
total bilirubin, alkaline phosphatase), serum calcium, albumin, total protein. 
• 
*LDH is only required at imaging time-points during on-study time-points. 
• 
CBC and CMP labs must be reviewed prior to treatment on Day 1 of each cycle. If other labs are drawn, they need to be reviewed when 
resulted but do not need to hold dosing for their result. 
• 
Amylase and lipase are to be performed only as clinically indicated. 
• 
PT/INR and PTT are to be performed only as clinically indicated.  
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• 
Cycle 1 Day 1 (neoadjuvant dose), Cycle 2 Day 1 (first adjuvant dose), Cycle 5 Day 1 (fourth adjuvant dose), Cycle 8 Day 1 (seventh 
adjuvant dose) (within 72 hours before dose): TSH, free T4 (only required if TSH is abnormal) 
• 
Pre-surgery labs (after the neoadjuvant dose of nivolumab but within 5 business days prior to surgery): CBC with diff, CMP (Na, K, 
Cl, CO2 or HCO3, BUN, creatinine, glucose), TSH, free T4 (only required if TSH is abnormal), PT/INR, PTT*, cortisol** 
• 
*PTT is to be performed for patients on heparin. 
• 
**Cortisol is to be performed as clinically indicated. 
• 
Follow-up11 Labs: LDH*, CMP**, CBC*** 
• 
*LDH is to be performed at follow-up time-points prior to year 6, then as clinically indicated during year 6-10 follow-up visits. 
• 
**CMP is to be performed at follow-up time-points prior to year 6, then as clinically indicated during year 6-10 follow-up visits. 
• 
***CBC is to be performed as clinically indicated. 
• 
Laboratory windows: if treatment is delayed, they must be repeated within the noted window 
• 
On-therapy visits: within 72 hours prior to nivolumab dose 
• 
Pre-surgical labs: within 5 business days before surgery 
• 
Follow-up11 labs (the first follow-up visit should be within 6 weeks after the final dose of nivolumab.  Long- term follow-up labs +/-35 days 
of protocol dictated date). 
5. IV contrast is required unless contraindicated. The use of oral contrast is optional. Scan schedule should remain the same even if doses have 
been omitted. Scans can be obtained +/- 7 business days, with the exception of baseline scans, which must be done within 8 weeks prior to 
randomization. 
Scan schedule: (Until recurrence) 
Year 1: 4.5 and 9 months (approximately weeks 20 and 40 from randomization) 
Year 2: q 6 months: 15 and 21 months from randomization 
Year 3: q 6 months: 27 and 33 months from randomization 
Years 4-5: annually: 39 and 51 months from randomization 
NOTE: Pelvis imaging is only required at baseline and at recurrence per protocol. Pelvis imaging outside of these time-points should be 
performed as clinically indicated.  Images should be uploaded into TRIAD. For images demonstrating recurrence or progression, scans 
should be uploaded to the “Recurrent/progression” time point. 
NOTE: CT or MRI scans of chest and abdomen are to be performed as clinically indicated in follow-up 6-10 years from randomization. Images 
should be uploaded into TRIAD. 
Digital copies of all imaging studies are to be submitted via upload to TRIAD™ per Section 4.1.4.6. If you have any technical questions, please 
send an e-mail to the TRIAD Support mailbox at TRIAD-Support@acr.org. If you have questions related to what imaging is to be submitted and 
under what time point you can email EA8143@acr.org. 
6. Bone imaging (e.g. bone scan or PET/CT) is only required if elevated alkaline phosphatase or if clinician believes it is warranted due to bone 
pain/symptoms. Images should be uploaded into TRIAD under “unscheduled”. 
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7. Beta HCG pregnancy testing can be done by blood or urine and is required only for patients of childbearing potential. Pregnancy testing is to be 
done within 2 weeks prior to randomization. Pregnancy testing is to be done within 24 hours prior to the first dose of nivolumab. Pregnancy 
testing by blood or urine must also be performed at least every 4 weeks while on nivolumab therapy but the dose that day does not need to be 
held prior to result. 
8. Nivolumab administration: 
• 
Neoadjuvant dose: nivolumab must be administered within 28 days after randomization. 
• 
Nivolumab x 1 dose intravenously within 7-28 days prior to partial or radical nephrectomy 
• 
Adjuvant dosing: The first dose of nivolumab in adjuvant setting must be within 4-10 weeks of the last resection or local treatment 
• 
Nivolumab every 4 weeks intravenously post partial or radical nephrectomy 
• 
Doses must be given within +/- 3 business day window (holidays and weekends are exempted). Otherwise they should be omitted. Patient 
should stay on schedule as dictated by the study calendar as if omitted dose was received. 
NOTE: Please refer to Section 5.1.1.1 for the administration schedule of perioperative nivolumab for patients enrolled prior to the activation of 
Amendment #4. 
9. Nephrectomy (partial or radical, or initial local treatment of metastatic disease) must be done between 7-28 days after neoadjuvant dose of 
nivolumab. 
10. Please refer to Section 5.9 for detailed instructions on the administration of the QOL forms. 
11. Patients will be followed for 10 years past their date of randomization. Once the patient is in long-term follow-up after 6 weeks post treatment 
visit, except those found not to have RCC at biopsy or nephrectomy, these procedures/assessments must be performed every 3 months for 
patients < 2 years from randomization; every 6 months for patients 2-5 years from randomization; and every 12 months for patients 6-10 years 
from randomization. Please note that survival information may be obtained by any means allowable by site’s IRB (e.g., can be obtained by 
phone call if this is allowed by IRB).  There are no specific requirements for follow-up if patient is >10 years from study entry. At the time of 
important analyses, additional updates to survival status may be requested. Continue to follow footnote 5 and 6 for additional CT or MRI scan of 
chest, abdomen, and pelvis with IV +/- oral contrast time-points. Continue to follow footnote 15 for History and Physical Examination guidelines. 
Follow Section 4.1.4.6 in relation to imaging for follow-up. 
• 
These procedures are not required after a patient has demonstrated recurrent disease per Section 6; however, submission of forms per the 
forms submission schedule is still mandatory. Telephone confirmation of survival post-recurrence is sufficient. QOL measures are required 
post-recurrence at time-points per Section 5.9 and footnote 10. Continue to follow footnote 5 for CT or MRI scan of chest, abdomen and 
pelvis time-points. 
12. Core needle biopsy for histology confirmation of RCC is mandatory for patients randomized to Arm A with results available prior to the 
neoadjuvant dose. If patient has had biopsy (core or other type) within twelve (12) months prior to randomization that confirms RCC, they do not 
need to undergo a repeat biopsy. Non-diagnostic biopsies are considered a good faith effort and patients do not need to repeat biopsy unless 
deemed clinically necessary by treating physician. If the biopsy performed following randomization clearly demonstrates a benign condition, 
oncocytoma or a different type of cancer that is not RCC, the patient is not eligible and must come off study. 
13. Please refer to Appendix X for instructions regarding how to measure waist circumference. This parameter is to be completed at baseline and at 
recurrence or off-study. 
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14. EKG and echocardiograms should be conducted as clinically indicated per the investigator’s discretion for any patients with a history of CHF or 
at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs. For patients with evidence of CHF, MI, cardiomyopathy, 
or myocarditis, further cardiac evaluation, lab tests and cardiology consultations, including EKG, CPK, troponin, and echocardiogram, should be 
conducted as clinically indicated. 
15. History and physical examinations are to be conducted every 3 months if less than 2 years from randomization, every 6 months if 2-5 years from 
randomization, then every 12 months during year during 6-10 years post- randomization. Physical examinations are conducted as clinically 
indicated once the patient reaches year 6. 
16. Optional test: Areal bone mineral density will be quantified by dual energy X-ray absorptiometry (DXA) at the spine, hip, femoral neck and distal 
1/3 radius in research participants receiving nivolumab as well as observation arm at baseline and week 40. Note that if patient consented, 40 
week DXA should be completed only if baseline DXA completed. Images should be uploaded to TRIAD. 
17. Any recurrence of malignant disease should be proven by core needle biopsy or resection whenever possible. If there is evidence of recurrence 
see Section 6.1 for guidelines. 
 
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7.3 
Arm B: Observation 
Therapeutic Parameters Table 
Procedures 
Baseline1 
Pre-
surgery Surgery 
Within 6 
Weeks 
after 
Surgery 
Week 
1213, 14 
Week 
1513, 14 
Month 4.5 
(Week 20) 
13, 14 
Week 
3013, 14 
Month 9 
(Week 
4013, 14) 
Week 5413, 
14 
Follow-
up9, 13 Recurrence 
History and Physical 
examination 
X 
 
 
X 
 
 
 
 
 
 
  X14 
X 
Waist Circumference10 
X 
 
 
 
 
 
 
 
 
 
 
X 
Medication review 
X 
 
 
X 
 
 
 
 
 
 
 
X 
ECOG performance 
status 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs including 
BP, HR, temperature, 
weight 
X 
 
 
X 
 
 
 
 
 
 
 
 
HCV, HBV3 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
parameters2 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Toxicity assessment 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
Telephone call for 
symptom 
assessment12 
 
 
 
 
 
X 
 
X 
 
 
 
 
CT or MRI scan of 
chest, abdomen and 
pelvis with IV and +/- 
oral contrast4 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
Bone Imaging (bone 
scan or PET/CT) 
 X5 
 
 
 
 
 
 
 
 
 
 
 X5 
OPTIONAL Bone 
imaging (dual energy 
x-ray absorptiometry)16 
X 
 
 
 
 
 
 
 
X 
 
 
 
Tumor Biopsy 
  X15 
 
 
 
 
 
 
 
 
 
 
X17 
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Therapeutic Parameters Table 
Procedures 
Baseline1 
Pre-
surgery Surgery 
Within 6 
Weeks 
after 
Surgery 
Week 
1213, 14 
Week 
1513, 14 
Month 4.5 
(Week 20) 
13, 14 
Week 
3013, 14 
Month 9 
(Week 
4013, 14) 
Week 5413, 
14 
Follow-
up9, 13 Recurrence 
Partial or radical 
nephrectomy7 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Testing6 
X 
 
 
 
 
 
 
 
 
 
 
 
QOL 
X8 
Survival 
 
 
 
 
 
 
 
 
 
 
X 
 
EKG, echocardiogram 
X11 
1. Eligibility parameters must be done within ≤ 8 weeks prior to randomization. Baseline QOL will be administered per Footnote 8. 
2. On site (Local) laboratories at baseline, pre-surgery, 6 weeks after surgery and from date of randomization 12, 20, 40, 54 weeks include (+/-7 
business days of planned visit): 
• 
Baseline labs: CBC (wbc with differential, hemoglobin and platelet count), Chemistries (Na, K, Cl, CO2 or HCO3, BUN, creatinine, glucose), 
LDH, Liver function tests (AST, ALT, total bilirubin, alkaline phosphatase), serum calcium, albumin, total protein; cortisol, TSH, free T4 (only 
required if TSH is abnormal), amylase, lipase, PT/INR, PTT* 
• 
*PTT is to be performed for patients on heparin. 
• 
Pre-surgery labs: CBC with diff, CMP (Na, K, Cl, CO2 or HCO3, BUN, creatinine, glucose), TSH*, free T4 (only required if TSH is 
abnormal), PT/INR, PTT**, cortisol***. The preoperative labs should be done within 5 business days prior to surgery. Baseline labs can be 
used if they meet this 5 day window. 
• 
*TSH is to be performed as clinically indicated. 
• 
**PTT is to be performed for patients on heparin. 
• 
***Cortisol is to be performed as clinically indicated. 
• 
Within 6 weeks after surgery, and from the date of randomization: weeks 12, 20, 40, 54: CBC (wbc with differential, hemoglobin and 
platelet count), Chemistries (Na, K, Cl, CO2 or HCO3, BUN, creatinine, glucose), LDH*, Liver function tests (AST, ALT, total bilirubin, 
alkaline phosphatase), serum calcium, albumin, total protein. TSH**, free T4 (only required if TSH is abnormal), amylase***, lipase***.  
• 
*LDH is only required at imaging time-points 
• 
**TSH is to be performed as clinically indicated. 
• 
***Amylase and lipase are to be performed as clinically indicated. 
• 
If the “Within 6 Weeks after Surgery” and “Week 12” time-points overlap, then one lab blood draw is sufficient to cover both. 
• 
Follow-up9 labs [(after 54 weeks): +/-35 days of protocol dictated date]: LDH*, CMP**, CBC*** 
• 
*LDH is to be performed at follow-up time-points prior to year 6, then only as clinically indicated during year 6-10 follow-up visits. 
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• 
**CMP is to be performed at follow-up time-points prior to year 6, then only as clinically indicated during year 6-10 follow-up visits. 
• 
***CBC is to be performed only as clinically indicated. 
3. Patients will require HBV and HCV testing utilizing local consent procedures for this collection. Results must be available prior to randomization. 
For patients that are positive for Hep B core antibody, hepatitis B surface antigen (HBsAg) should be negative. For patients that are positive for 
Hep C antibody, polymerase chain reaction (PCR) should be negative. These tests could be repeated later during the course of the study if 
clinically indicated. 
4. IV contrast is required unless contraindicated. The use of oral contrast is optional. Scans can be obtained +/- 7 business days, with the 
exception of baseline scans, which must be done within 8 weeks prior to randomization. 
Scan schedule: (Until recurrence) 
Year 1: 4.5 and 9 months (approximately weeks 20 and 40 post- randomization) 
Year 2: q 6 months: 15 and 21 months from randomization 
Year 3: q 6 months: 27 and 33 months from randomization 
Years 4-5: annually: 39 and 51 months from randomization 
NOTE: Pelvis imaging is only required at baseline randomization at recurrence per protocol. Pelvis imaging outside of these time-points should 
be performed as clinically indicated. Any imaging performed should be uploaded into TRIAD. Recurrent imaging should be uploaded 
under “unscheduled visit.” For images demonstrating recurrence or progression, scans should be uploaded to the 
“Recurrent/progression” time point. 
NOTE: CT or MRI scans of chest and abdomen are to be performed as clinically indicated in follow-up 6-10 years post-randomization. Images 
should be uploaded into TRIAD. 
Digital copies of all imaging studies are to be submitted via upload to TRIAD™ per Section 4.1.4.6. If you have any technical questions, please 
send an e-mail to the TRIAD Support mailbox at TRIAD-Support@acr.org. If you have questions related to what imaging is to be submitted and 
under what time point you can email EA8143@acr.org 
5. Bone imaging (e.g. bone scan or PET/CT) is only required if elevated alkaline phosphatase (if >ULN local range) or if clinician believes it is 
warranted due to bone pain/symptoms and all images should be uploaded into TRIAD under “unscheduled.” 
6. Beta HCG pregnancy testing by blood or urine is required for patients of childbearing potential. Pregnancy testing is to be done within 2 weeks 
prior to randomization. 
7. Nephrectomy (partial or radical) or initial local treatment of metastasis must be done within 8 weeks after randomization. 
8. Please refer to Section 5.9 for detailed instructions on the administration of the QOL forms. 
9.  Patients will be followed for 10 years past their date of randomization. Once the patient is in long-term follow-up, which is defined as after week 
54 (post randomization), these procedures/assessments must be performed every 3 months for patients < 2 years from randomization; every 6 
months for patients 2-5 years from randomization; and every 12 months for patients 6-10 years from randomization. Please note that survival 
information may be obtained by any means allowable by site’s IRB (i.e., can be obtained by phone call if this is allowed by IRB). There are no 
specific requirements for follow-up if patient is >10 years from study entry. At the time of important analyses, additional updates to survival status 
may be requested. Continue to follow footnote 4 for additional CT or MRI scan of chest, abdomen, and pelvis with IV +/- oral contrast time-
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points. Continue to follow footnote 14 for History and Physical Examination requirements. Follow Section 4.1.4.6 in relation to imaging for follow-
up. 
• 
These procedures are not required after a patient has demonstrated recurrent disease per Section 6; however, submission of forms per the 
forms submission schedule is still mandatory. Telephone confirmation of survival post-recurrence is sufficient. QOL measures are required 
post-recurrence at time-points per Section 5.9 and Footnote 8. Continue to follow footnote 4 for CT or MRI scan of chest, abdomen and 
pelvis time-points. 
• 
These procedures are not required for the patients who are found to not have RCC at biopsy or nephrectomy. 
10. Please refer to Appendix X for instructions regarding how to measure waist circumference. This parameter is to be completed at baseline, and at 
recurrence or off-study. 
11. EKG and echocardiograms should be conducted as clinically indicated for any patients with a history of CHF or at risk because of underlying 
cardiovascular disease or exposure to cardiotoxic drugs. For patients with evidence of CHF, MI, cardiomyopathy, or myocarditis, further cardiac 
evaluation, lab tests and cardiology consultations, including EKG, CPK, troponin, and echocardiogram, should be conducted as clinically 
indicated. 
12. Telephone assessments can be done +/- 7 business days from scheduled time-point. 
13. Week 12, Week 15, Month 4.5 (Week 20), Week 30, Month 9 (Week 40), Week 54, and all additional follow-up time-points are to be calculated 
as weeks/months from the date of randomization. 
14. History and physical examinations are to be conducted every 3 months if less than 2 years from randomization, every 6 months if 2-5 years from 
randomization, then every 12 months during 6-10 years post- randomization. Physical exams are to be conducted as clinically indicated once the 
patient reaches year 6. 
15. Baseline core needle biopsy is encouraged but not mandatory for patients who have not had a biopsy (core or other type) within twelve (12) 
months prior to randomization that confirms RCC. 
16. Optional test: Areal bone mineral density will be quantified by dual energy X-ray absorptiometry (DXA) at the spine, hip, femoral neck and distal 
1/3 radius in research participants receiving nivolumab as well as observation arm at baseline and week 40. Note that if patient consented, 40 
week DXA should be completed only if baseline DXA completed images should be uploaded to TRIAD. 
17. Any recurrence of malignant disease should be proven by core needle biopsy or resection whenever possible. See guidelines section 6.1. 
Submission of biopsy is strongly encouraged but not mandatory. 
 
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7.4 
Biological Specimen Submissions 
Specimens are to be submitted as outlined in Section 10. 
All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). 
Biological Materials 
Prior to Start of 
Treatment 
Prior to 
Nephrectomy9 
Nephrectomy 
Month 9 (Week 
40 Post 
Randomization) 
Recurrence 
Submit to: 
MANDATORY for Central Diagnostic Review and Defined Laboratory Research Studies: 
Diagnostic Primary 
Tumor Tissue 
X8 (Arm A required and 
Arm B if collected) 
 
X (Both Arms)12 
 
 
CBPF 
From patients who answer “Yes” to “I agree to have my samples collected and I agree that my samples and related information may be used for 
laboratory studies.” 
Tumor Tissue2 
 
 
X (Both Arms) 
 
X (Both Arms) 
CBPF 
Serum (two 8.5mL 
SST red top tubes)1 
X (Arm A Only) 
X (Both Arms) 
 
X (Both Arms) 
X (Both Arms) 
From patients who answer “Yes” to “I agree to provide additional specimens for research.” 
Tumor Tissue11 
X (Both Arms) 
 
 
 
 
CBPF 
Peripheral Blood 
(ten 10mL green 
top heparin tubes)1 
X (Arm A Only) 
X (Both Arms) 
 
X (Both Arms) 
X (Both Arms) 
Plasma (two 10mL 
EDTA purple top 
tubes)1 
X (Arm A Only) 
X (Both Arms) 
 
X (Both Arms) 
X (Both Arms) 
 
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Biological Materials 
Cycle 1, Day 
1 (pre-
dose)4, 
Cycle 2, 
Day 1 (pre-
dose)4 
Cycle 2, Day 
1 (EOI-nivo)5 
Cycle 3, Day 
1 (pre-dose)4 
Cycle 5, Day 
1 (pre-dose)4
Cycle 5, 
Day 1 
(EOI-nivo)5 
Cycle 7, 
Day 1 (pre-
dose) 4 
Cycle 7, 
Day 1 
(EOI-nivo)5 
First 2 
Follow-
Up Visits7 
MANDATORY (Arm A 
Only) for 
Pharmacokinetic and 
Immunogenicity Studies: 
Serum SST vacutainer 
tubes)3,6, 10 
1 – 8.5mL 
SST 
1 – 8.5mL 
SST 
1 – 4mL SST 
1 – 8.5mL 
SST 
1 – 8.5mL 
SST 
1 – 4mL 
SST 
1 – 8.5mL 
SST 
1 – 4mL 
SST 
1 – 
8.5mL 
SST 
CBPF = Central Biorepository and Pathology Facility 
1. Kits are being provided for the collection and shipment of the blood specimens. See Appendix VI for instructions. Kit orders will on average be 
delivered within three (3) business days from the time the order is placed. 
2. Additional surgical FFPE primary tumor and normal tissue blocks, and recurrence FFPE primary tumor tissue blocks, if available, are requested 
from consenting patients who answer “Yes” to “I agree to have my samples collected and I agree that my samples and related information may 
be used for laboratory studies.” 
3. If patient discontinues study drug treatment during the sampling period, they will move to sampling at the follow-up visits. 
4. All pre-dose blood specimens should be collected prior to the start of nivolumab infusion (anytime within 24 hours prior to first dose). 
5. EOI-nivo = End of Nivolumab Infusion. These serum specimens should be collected prior to stopping the nivolumab infusion (preferably within 2 
minutes prior to end of infusion but within 15 minutes of the end of infusion). If the infusion takes longer than expected, the collection at the end 
of infusion should be adjusted accordingly. 
6. Kits are being provided for the collection and shipment of the serum specimens for the pharmacokinetic and immunogenicity studies. See 
Section 10.3 for instructions. 
7. First (1st) follow-up visit approximately six (6) weeks post discontinuation of nivolumab. Second (2nd) follow-up visit approximately three months 
from first follow-up visit. Note that specimens should be collected even if the visit is delayed. 
8. In patients randomized to Arm A, diagnosis of RCC must be confirmed by core biopsy after randomization unless the patient had a prior biopsy 
confirming RCC within twelve (12) months prior to randomization in order to avoid exposing patients to neoadjuvant nivolumab who clearly have 
a benign lesion or another type of cancer. A non-diagnostic biopsy is considered good faith effort and patient may proceed with treatment at 
investigator and site discretion. Pre-surgery biopsy tumor tissue (primary tissue is preferred if metastasis is also present) and related pathology 
reports must be submitted for central diagnostic review and defined laboratory research studies within one (1) month following randomization or 
collection as outlined in Section 10. Patients randomized to Arm B are encouraged, but not required, to have a core biopsy after randomization if 
they have not had a biopsy within twelve (12) months of randomization that confirms diagnosis of RCC. Biopsy tumor tissue (primary tissue is 
preferred if metastasis is also present) and related pathology reports must be submitted if collected for central diagnostic review and defined 
laboratory research studies within one (1) month following randomization or collection as outlined in Section 10. 
9. For Arm B patients- serum, peripheral blood, and plasma are to be collected Prior to Nephrectomy. For Arm A patients- serum, peripheral blood 
and plasma are to be collected after Cycle one (1) but Prior to Nephrectomy. 
10. Patients on treatment prior to amendment #4 should follow new PK schedule. 
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11. Additional representative formalin-fixed paraffin embedded (FFPE) primary tumor tissue blocks from pre-trial diagnostic biopsy is requested from 
patients who answer “Yes” to “I agree to provide additional specimens for research.” 
12. Surgical FFPE primary tumor tissue blocks must be submitted from patients on BOTH ARMS A and B for central diagnostic review along with 
related pathology reports within one (1) month following collection. 
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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
NCI -supplied agents may be requested by eligible participating investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead participating 
investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status. For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time. Refer to the 
PMB’s website for specific policies and guidelines related to agent management. 
NCI Supplied Agent(s) – General Information 
NOTE: 
Under no circumstances can commercially supplied nivolumab (OPDIVO) be 
used or substituted for the NCI-supplied nivolumab. 
NOTE 
Sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must 
return the study drug to the PMB using the NCI Return Agent Form available on the NCI 
home page (http://ctep.cancer.gov) or by calling the PMB at 240-276-6575.  
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all 
drugs received from the PMB using the NCI Investigational Agent Accountability Record 
available on the NCI home page (http://ctep.cancer.gov) or by calling the PMB at 240-
276-6575.  
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
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• 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov  
• 
PMB email: PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application. Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account 
status, a “current” password and active person registration status. Questions about IB 
access may be directed to the PMB IB Coordinator via email. 
8.1 
Nivolumab  
8.1.1 
Amino Acid Sequence: 
4 polypeptide chains, which include 2 identical heavy chains with 440 
amino acids and 2 identical light chains. 
8.1.2 
Other Names: 
BMS-936558, MDX1106 
8.1.3 
Classification: 
Anti-PD-1MAb 
8.1.4 
M.W.: 
146,221 Daltons 
8.1.5 
Mode of Action:  
Nivolumab targets the programmed death–1 (PD-1, cluster of 
differentiation 279 [CD279]) cell surface membrane receptor. PD-1 is 
a negative regulatory receptor expressed by activated T and B 
lymphocytes. Binding of PD-1 to its ligands, programmed death–
ligand 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Nivolumab inhibits the binding of PD-1 to PD-
L1 and PD-L2. Inhibition of the interaction between PD-1 and its 
ligands promotes immune responses and antigen-specific T-cell 
responses to both foreign antigens as well as self-antigens. 
8.1.6 
Description: 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow 
liquid; light (few) particulates may be present. The drug product is a 
sterile, nonpyrogenic, single-use, isotonic aqueous solution 
formulated in sodium citrate dihydrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), polysorbate 80 
(Tween® 80), and water for injection. Dilute solutions of hydrochloric 
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acid and/or sodium hydroxide may be used for pH adjustment (pH 
5.5-6.5). 
8.1.7 
How Supplied: 
Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg 
vials (10 mg/mL) with a 0.7mL overfill. It is supplied in 10 mL type I 
flint glass vials, with fluoropolymer film-laminated rubber stoppers and 
aluminum seals. 
8.1.8 
Preparation: 
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted 
with 0.9% Sodium Chloride Injection, USP or 5% Dextrose. When the 
dose is based on patient weight (i.e., mg/kg), nivolumab injection can 
be infused undiluted or diluted to protein concentrations as low as 
0.35 mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg 
flat dose), nivolumab injection can be infused undiluted or diluted so 
as not to exceed a total infusion volume of 160 mL. For patients 
weighing less than 40 kilograms (kg), the total volume of infusion must 
not exceed 4 mL per kg of patient weight. During drug product 
preparation and handling, vigorous mixing or shaking is to be avoided. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or 
polyolefin containers and infusion sets, and glass bottles. 
8.1.9 
Storage: 
Vials of Nivolumab injection must be stored at 2°- 8°C (36°- 46°F) and 
protected from light and freezing. The unopened vials can be stored at 
room temperature (up to 25°C, 77°F) and room light for up to 48 
hours. 
If a storage temperature excursion is identified, promptly return 
Nivolumab to 2°C-8°C and quarantine the supplies. Provide a detailed 
report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
8.1.10 
Stability: 
Shelf-life surveillance of the intact vials is ongoing. 
The administration of undiluted and diluted solutions of Nivolumab 
must be completed within 24 hours of preparation. If not used 
immediately, the infusion solution may be stored up to 24 hours in a 
refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the 
total 24 hours can be at room temperature (up to 25°C, 77°F) and 
room light. The maximum 8-hour period under room temperature and 
room light conditions includes the product administration period. 
CAUTION: 
The single-use dosage form contains no antibacterial 
preservative or bacteriostatic agent. Therefore, it is 
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8.1.11 
Route of Administration  
Intravenous infusion over 30 minutes +/- 5 minutes. Do not administer 
as an IV push or bolus injection. 
8.1.12 
Method of Administration 
Administer through a 0.2 micron to 1.2 micron pore size, low-protein 
binding (polyethersulfone membrane) in-line filter. 
8.1.13 
Potential Drug Interactions: 
The indirect drug-drug interaction potential of nivolumab was 
assessed using systemic cytokine modulation data for cytokines 
known to modulate CYP enzymes. There were no meaningful 
changes in cytokines known to have indirect effects on CYP enzymes 
across all dose levels of nivolumab. This lack of cytokine modulation 
suggests that nivolumab has no or low potential for modulating CYP 
enzymes, thereby indicating a low risk of therapeutic protein-drug 
interaction. 
8.1.14 
Patient Care Implications: 
Patients of childbearing potential receiving nivolumab must continue 
contraception for a period of 5 months after the last dose of nivolumab.  
8.1.15 
Side Effects  
See Section 5.5 for the Comprehensive Adverse Event and Potential 
Risks (CAEPR) list. 
8.1.16 
References  
LexiComp (2014), AHFS (2014) 
 
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9. 
Statistical Considerations 
9.1 
Design and Objectives 
This study is a randomized comparison of neoadjuvant and adjuvant nivolumab 
given perioperatively to surgery alone. 
9.1.1 
Primary objective 
To compare recurrence-free survival (RFS) between patients with 
renal cell carcinoma randomly assigned to perioperative nivolumab in 
conjunction with radical or partial nephrectomy with patients 
randomized to surgery alone. 
9.1.2 
Major secondary objectives 
• 
To evaluate for differences in recurrence-free survival associated 
with perioperative nivolumab compared to surgery alone among 
the subset of patients with clear cell histology 
• 
To compare the overall survival between the two arms 
• 
To describe the safety and tolerability of the two arms 
9.1.3 
Correlative objectives 
• 
To correlate the primary tumor’s expression of PD-L1 with 
outcome 
• 
To correlate the expression of PD-L1 on tumor tissue at 
recurrence with outcome 
• 
To archive images for central confirmation of recurrence and for 
future correlative work with ACRIN, including markers predicting 
outcome or response. 
• 
To prospectively collect tumor and biologic specimens (e.g., 
serum, PBMCs) for future correlative studies. 
• 
To characterize the pharmacokinetics of nivolumab and explore 
exposure response relationships with respect to safety and 
efficacy. 
• 
To characterize the immunogenicity of nivolumab. 
9.1.4 
Quality of Life objective 
• 
To evaluate differences in change from baseline in patient-
reported symptoms and toxicities among patients treated with 
nivolumab compared to surgery alone. 
9.1.5 
Other exploratory objectives 
• 
To explore descriptively the efficacy of treatment with nivolumab in 
patients with non-clear cell (including unclassified) histologies. 
9.2 
Endpoints 
9.2.1 
Primary Endpoint 
The primary endpoint is recurrence-free survival (RFS).  RFS is 
defined as the time from randomization to disease recurrence or 
death from any cause. Patients who do not undergo surgery or whose 
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surgery does not render them disease-free or who have other 
evidence of disease after surgery will be included in the RFS analysis 
as events on Day 1. Patients without recurrence will be censored at 
the date of last disease evaluation. Patients are expected to 
discontinue protocol therapy and receive standard of care treatment 
(e.g., targeted therapy) or other clinical trial at the time residual 
disease is discovered. Patients who develop second primary cancers 
(but not secondary cancers thought due to nivolumab if on that arm) 
may continue protocol treatment at the discretion of their physician as 
long as they do not require systemic therapy for the treatment of that 
secondary cancer. Surgical resection, radiation (with the exception of 
to the renal bed), and other local therapies may be considered. 
Whether or not they remain on treatment, they must continue to be 
followed according to the schedule in the protocol to evaluate for 
recurrence of their renal cell cancer. 
9.2.2 
Secondary endpoints 
9.2.2.1 
Overall survival, defined as time from randomization to 
death from any cause. Patients who have not died will be 
censored at date of last contact. 
9.2.2.2 
RFS among patients with clear cell cancer 
9.3 
Statistical Analysis Plan 
A hierarchical testing plan will be used to evaluate the primary and major 
secondary endpoints. First RFS as defined above will be assessed among all 
randomized patients using a one-sided 2.5% test. If that test is significant, then 
the second test comparing RFS in the subset of clear cell histology will be 
performed at a one-sided 2.5% level. If both the first two tests are significant, 
then OS will be compared among all randomized patients using a one-sided 
2.5% test. Finally, if the first 3 tests are significant, then OS will be compared in 
the clear cell subset, again at the one-sided 2.5% level. Details of the tests are 
given in the following subsections. If any comparison in the hierarchical 
sequence is not significant, the subsequent comparisons will still be performed, 
but will be regarded as exploratory. 
9.3.1 
Primary Endpoint 
The primary endpoint of RFS will be assessed among all randomized 
patients with RCC using a stratified log rank test, with nominal one-
sided Type I error of 2.5%. The Type I error will be adjusted for interim 
analyses as described below.  
 Patients who are confirmed to not have RCC histology via biopsy or 
nephrectomy will be excluded from the primary analysis. The local site 
pathologist’s determination will be used for the primary analysis. In the 
case of contradictory biopsy and nephrectomy results the 
nephrectomy histology will be used to determine inclusion. If the 
nephrectomy histology is poorly differentiated and the biopsy result 
can define the histology, then the biopsy result will be used. In the 
event that a patient does not have histology determination either by 
biopsy or nephrectomy, the case will be counted as unclassified RCC 
in the primary analysis. Blinded central review of histology will also be 
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performed. The rates of agreement will be reported, and a sensitivity 
analysis based on central review results will be performed. 
The removal of the biopsy requirement in Arm B introduces potential 
for bias in the identification of non-RCC patients between arms as 
patients may be randomized prior to pathologic diagnosis. Thus the 
rate of nephrectomy submission on Arm B will be closely monitored. 
Additional monitoring will occur to ensure an acceptable rate of non-
diagnostic biopsies on Arm A (see Section 9.8.5). 
The primary RFS endpoint definition here includes patients who do 
not have surgery or who have residual disease after surgery as 
events on day 1 (this is not a standard definition of ‘RFS’, since these 
patients have not been rendered free of disease). The potential 
impact of these early events on the results will be assessed by a 
sensitivity analysis where follow-up is censored on day 1 for these 
patients, instead of counting them as RFS events. Separate analyses 
will be done 1) censoring the patients who do not have surgery, 2) 
censoring the patients who have residual disease after surgery, and 
3) censoring both groups. 
Since this is not a placebo-controlled trial and the endpoint of RFS 
could also be subject to evaluation time bias,24 several approaches 
will be employed to assess the robustness of the outcome. Every 
effort will be made to assure that patients undergo scans at scheduled 
time points, with scan intervals consistent between arms. Scans at 
baseline and progression will be archived for potential blinded future 
review. A sensitivity analysis will be done in which the dates of 
progression events detected at non-scan visits are carried forward in 
time to the next scheduled scan time. Another sensitivity analysis will 
compare the proportion of patients alive and recurrence-free at the 
27-month post-randomization scan between the arms. 
9.3.2 
Secondary Endpoints 
9.3.2.1 
RFS among patients with clear cell histology 
When 253 RFS events have been observed among 
patients with predominantly clear cell histology, the 
stratified logrank test will be used to evaluate the endpoint 
of RFS. We assume that 85% of patients will have clear 
cell histology and that the 5-year RFS among these 
patients is 55.8%, as for the general population.  There will 
be adequate power (82%) to detect the same treatment 
difference in this subset as in the full population, using a 
one-sided stratified log rank test with Type I error of 2.5%. 
The proportion of patients with clear cell histology will be 
monitored as the study is accruing to ensure balance 
between arms. Additionally, the proportion of patients 
randomized to each arm who do not have RCC will be 
monitored throughout. Patients proven to not have RCC 
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A sensitivity analysis of RFS among patients with 
recurrence documented by biopsy or cytology will be 
conducted. 
9.3.2.2 
Overall survival (OS) 
Patients randomized to placebo on ASSURE had 5-year 
overall survival of 78.7%. Adequate power (80%) will exist 
to detect a 33% reduction in the survival hazard rate, 
among patients randomized to nivolumab. Power for this 
comparison using a one-sided 2.5% stratified log rank test 
will be available when 196 deaths have occurred, which is 
expected to be about 9 years after the start of the study.  
At the time of the primary survival analysis, an analysis of 
disease-specific survival will be conducted. 
9.3.2.3 
Other Secondary Analyses 
Adverse events will be described separately for patients 
treated on each arm to evaluate safety and tolerability. 
• 
Analysis of Patient-Reported Outcomes 
Please see Section 12. 
• 
Analyses of Correlative and exploratory Endpoints 
Please see Section 11. 
9.4 
Sample Size Considerations 
The primary endpoint, as defined above, is recurrence-free survival (RFS). 
Although this endpoint will primarily be tested in the entire cohort, the study is 
designed to have adequate power to detect differences in RFS associated with 
treatment among the subset of patients with clear cell histology. The primary 
analysis population will include all patients with RCC as randomized. Patients 
who do not undergo surgery for any reason or whose primary tumor resection 
does not render them free of disease (e.g., residual tumor, positive margins) will 
be included in the RFS analysis as events on Day 1. Patients will be stratified on 
clinical stage (T2 vs. >T2), clinical nodal status (negative vs. positive), and 
clinical metastatic status (M0 or oligo M1). 
Estimates of RFS among the eligible pool of patients for this study are based on 
ASSURE, the recently completed adjuvant study of sunitinib, sorafenib, or 
placebo. Patients randomized to placebo following curative resection had a 5-
year DFS of 55.8%. The study is designed to demonstrate a 14.4% absolute 
improvement in 5-year RFS among patients disease-free post nephrectomy 
treated with nivolumab to 70.2%. We assume that the distribution is exponential 
with a constant failure (hazard) rate and that accrual is uniform following a brief 
start-up interval at study activation. We further assume that 10% of patients will 
either not undergo nephrectomy or will not be disease-free following 
nephrectomy; these patients will be included in the RFS analysis as events at 
Day 1 (“not NED” events). This rate is assumed to be the same on both arms, 
and the deleterious effect is assumed to be proportional in this subset. We also 
assume that, among the 90% of patients with adequate nephrectomy randomized 
to nivolumab,10% of patients will discontinue treatment early; the statistical effect 
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of early discontinuation will make the patient similar to patients on the 
observation arm--an effect similar to crossing over to observation. The 5-year 
RFS rates were weighted using proportions shown in the following table. After 
these adjustments, the effective 5-year RFS rates on the observation and 
nivolumab arms will be 50.2% and 61.9%, respectively. 
Arm 
Cohort 
Proportion 
Estimated 5-
year RFS 
Adjusted 5-year 
RFS 
Nivolumab 
Inadequate / no 
nephrectomy 
10% 
0 (all events on 
Day 1) 
61.884% 
 
Adequate 
nephrectomy, 
discontinue 
treatment early 
9% 
55.8% (null rate) 
 
Adequate 
nephrectomy and 
treatment 
81% 
70.2% 
Observation 
Inadequate or no 
nephrectomy 
10% 
0 (all events on 
Day 1) 
50.2% 
 
Adequate 
nephrectomy 
90% 
55.8% 
We plan a 1:1 randomization and accrual of 264 patients per year (22 per month) 
for 2.9 years, with 2.6 additional years of follow-up. This represents a total of 766 
RCC patients of all histologies; 383 randomized to each arm. Assuming interim 
analyses as described below and using a stratified log-rank test with one-sided 
Type I error of 2.5%, there will be approximately 84.2% power to detect the 
stated reduction in risk. 
The protocol had defined full information to be 285 RFS events, including “not-
NED” events. In August 2020, after monitoring of the rate of not-NED events had 
occurred, it was observed that the proportion of patients with these events was a 
random quantity that might differ from the assumed rate in the final data. Since 
the “not-NED” events will be included in the analysis but are not expected to 
contribute to the power, this could affect the power of the final comparison. Under 
the assumptions above, 76 of the 285 events were expected to be not-NED 
events in the final analysis. The expected number of follow-up RFS events 
(recurrences and deaths) for full power was 209. Simulations showed that even if 
the proportion of subjects with not-NED events is as high as 15%, an analysis 
with 209 follow-up events would still give > 80% power, while an analysis with 
285 total events would not. It was therefore decided to change the definition of 
information time to be based on the number of follow-up events only, and full 
information will now exist when 209 “follow-up” RFS events have been observed. 
The total number of events (counting both follow-up and not-NED events) for full 
information will also be capped at 325, under the assumption that at most 15% of 
the cases would have not-NED events. The not-NED events will still be included 
in the primary analyses. 
Without a required pre-randomization biopsy, some patients may enroll who have 
benign lesions or other non-RCC cancers. We assume that this group will 
comprise no more than 5% of enrolled patients. These patients will be removed 
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from the study and the total accrual goal will be 805 total patients for a target of 
766 RCC patients. 
9.5 
Projected Accrual 
The total expected accrual is 805 patients, at a projected rate of 22 patients per 
month. 
ECOG-ACRIN’s most recent adjuvant renal trial, E2805, accrued 1943 patients in 
52 months, an overall average rate of 37 patients per month. S0931, the adjuvant 
everolimus study in RCC, has accrued all of its target 1170 patients, with an 
average rate of 22 patients per month. There is significant and wide interest in 
the experimental agent, nivolumab, so we expect equivalent accrual rates once 
sites are activated. 
9.6 
Randomization Scheme 
Randomization will be done using permuted blocks within stratum, where strata 
are defined as follows: 
Clinical T Stage (clinical T1 or T2 vs. greater than clinical T2) 
Clinical Nodal Status (cN0 vs. cN+) 
Clinical Metastatic Status (cM0 or cM1): definition of permitted oligometastatic 
M1 disease detailed in eligibility criteria. 
9.7 
Gender and Ethnicity 
Based on previous data from E2805, the anticipated accrual in subgroups by 
gender and race is: 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska Native 
1 
3 
0 
0 
4 
Asian 
3 
14 
0 
0 
17 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
18 
19 
0 
0 
37 
White 
228 
478 
11 
30 
747 
More Than One Race 
0 
0 
0 
0 
0 
Total 
250 
514 
11 
30 
805 
The accrual targets in individual cells are not large enough for definitive 
treatment comparisons to be made within these subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup accrual 
targets. 
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9.8 
Monitoring Procedures and Interim Analyses 
9.8.1 
DSMC 
The ECOG-ACRIN Data Safety Monitoring Committee will review 
accumulating safety data at each semiannual meeting starting with 
the first enrollment and continuing through release of the study for 
analysis. 
This study will be monitored by the ECOG-ACRIN Data Safety 
Monitoring Committee (DSMC). The DSMC meets twice each year. 
For each meeting, all monitored studies are reviewed for safety and 
progress toward completion. When appropriate, the DSMC will also 
review interim analyses of outcome data. Copies of the toxicity reports 
prepared for the DSMC meetings are included in the study reports 
prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while 
only pooled or blinded data will be made public). These group meeting 
reports are made available to the local investigators, who may provide 
them to their IRBs. Only the study statistician and the DSMC 
members will have access to interim analyses of outcome data. Prior 
to completion of this study, any use of outcome data will require 
approval of the DSMC. Any DSMC recommendations for changes to 
this study will be circulated to the local investigators in the form of 
addenda to this protocol document. A complete copy of the ECOG-
ACRIN DSMC Policy can be obtained from the ECOG-ACRIN 
Operations Office. 
9.8.2 
Interim Analysis for Harm and Inefficacy 
The study will be monitored for harm and inefficacy with early 
stopping rules. At 25% information, the DSMC may consider 
recommending that the study stop for harm if the lower bound of a 
95% confidence interval on the hazard ratio (nivolumab/observation) 
is above 1.0. The inefficacy monitoring approach, starting at 44% 
information, is described by Freidlin et al.24,39 The study will be 
stopped if there is not at least a small trend in favor of the alternative 
hypothesis starting at this time. The inefficacy analysis will be done at 
each subsequent semi-annual meeting of the ECOG ACRIN Data 
Safety Monitoring Committee (DSMC) if there has been at least a 
10% increment in the information. The DSMC will also monitor for any 
unusual harm/inefficacy signals in the non-clear cell subgroup. 
9.8.3 
Interim Analyses for Efficacy 
The protocol had planned interim efficacy analyses beginning at 34% 
of the planned full information and continuing every 6 months after 
that. In Fall 2020, it was decided to drop the early efficacy analyses, 
since mature follow-up would be needed to adequately interpret the 
effects of treatment. Interim efficacy analysis schedule was therefore 
switched to plan analyses at only 65% and 85% of full information. To 
correspond to the semiannual ECOG-ACRIN DSMC meeting 
schedule, the analyses will be performed for the first meeting where 
this amount of information is available. Significance levels at each 
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analysis will be determined from the O’Brien-Fleming error spending 
rate function using the actual information times.   
The error spending plan is summarized in the following table. 
Because interim analyses are timed to coincide with meetings of the 
DSMC, the exact boundary value and its associated nominal 
significance will be based on the number of events at the time of the 
analysis. 
Analysis 
Information 
Proportion 
Follow-up 
Events 
Upper 
Boundary 
Nominal 
Significance 
1 
0.65 
136 
2.55 
0.005 
2 
0.85 
178 
2.21 
0.013 
3 
1.00 
209 
2.05 
0.020 
9.8.4 
Rates of Incomplete Resection and Treatment Discontinuation 
At each semiannual meeting of the DSMC, the rates of incomplete 
resection and treatment discontinuation will be reviewed. Specifically, 
the following will be reviewed: 
• 
Proportion of patients on each arm with residual local disease or 
metastatic disease post-surgery 
• 
Proportion of patients on each arm discontinuing treatment or 
observation immediately post-nephrectomy 
• 
Proportion of patients not undergoing nephrectomy 
• 
Proportion of patients with no cancer or cancer other than RCC at 
biopsy or nephrectomy. 
If at any interim analysis time as described above the lower bound of 
a 90% confidence interval on any of these rates is greater than 10%, 
the DSMC may recommend that the study’s design be reviewed for 
continued feasibility. Any potential changes to the design (for 
example, increasing the study size to compensate for these patients) 
would occur prior to the first interim efficacy analysis. 
9.8.5 
Rates of Nephrectomy Specimen Submission and Non-Diagnostic 
Biopsy 
The lack of diagnostic biopsy requirement on Arm B creates a 
potential for imbalance between arms with respect to removal of non-
RCC patients. Therefore, after 100 patients are enrolled on Arm B the 
rate of nephrectomy submission will be reported to CTEP. For every 
subsequent 100 patients enrolled to this arm, if the submission rate is 
below 95% the DSMC will be alerted and a corrective plan of action 
presented. 
An analogous rule will apply to the rate of indeterminate biopsies on 
Arm A. 
9.8.6 
Adherence to Scan Schedule 
Since the study is not placebo-controlled, it is possible that anxiety 
about possible recurrence could lead to more frequent scans on the 
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observation arm. To assess the study’s robustness against potential 
observation time bias arising from inconsistencies in scan intervals 
between the two arms, the following sensitivity analyses will be 
considered. If the results of these analyses are consistent with those 
of the primary analysis, there will be more confidence that the results 
are not affected by observation time bias. 
2-year RFS Proportion 
An analysis of the proportion of patients alive and free of recurrence 
two years post-randomization will be conducted.  Patients who are 
alive and have at least one scan on or after the 27-month scan (the 
closest scheduled scan to 2 years) will be considered event free; all 
other patients will be included as events. An appropriate stratified test 
will be used to compare the proportions. For example, if the 
assumption of a common odds ratio across strata can be supported, a 
Mantel Henszel test will be used.  Otherwise a more conservative test, 
such as a stratified Fisher’s exact test, may be necessary. 
Carry Forward Unscheduled Scans 
Another sensitivity analysis will establish windows around the 
protocol-specified scan time points (+/- 1 week). For scans done 
outside the acceptable window on which recurrence is detected, the 
date of recurrence will be carried forward to the next scheduled scan 
date. Then the stratified log-rank test will be used to compare RFS 
between arms. 
9.8.7 
Accrual Monitoring 
Accrual will be monitored using NCI’s Phase III Accrual guidelines. 
Specifically, if accrual is not occurring at 20% of the target rate by 
quarter 5, the study team may need to consider redesigning the study. 
If it is not accruing at 50% of the target rate by quarter 8, it may need 
to be closed. 
9.8.8 
Safety Monitoring 
9.8.8.1 
Surgical Complications 
After the first 50 patients have been followed for 4 weeks 
post-surgery on both arms, an interim analysis of surgical 
complication rates will be conducted. 
Based on previous data from E2805, 14% is the expected 
rate of surgical complications in the absence of an effect of 
neoadjuvant nivolumab. A true complication rate of 28% 
among the first 50 patients on an arm would be 
unacceptable. This trial will undergo a review if 
complications are reported for 9 or more patients among 
the first 50 patients on either arm. Potential outcomes of 
the review could be to modify the study, suspend accrual 
for further investigation, add a second review, continue as 
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9.8.8.2 
Semiannual Reports 
Comprehensive analyses of interim toxicity data are 
routinely performed at least twice yearly. These reports are 
posted on the CTSU website and on the ECOG-ACRIN 
members website to be available to local institutions. 
9.8.8.3 
Monthly Toxicity Monitoring 
Serious adverse events reported using the CTEP-AERS 
system will be monitored using ECOG-ACRIN’s standard 
monthly toxicity monitoring process. A study is flagged for 
monitoring if an arm of the protocol has a previously 
uncirculated Grade 5 event, 2 previous reports in the past 
month containing a Grade 3 or higher event, or 6 reports in 
the past 6 months containing a Grade 3 or higher event.  
The toxicity monitoring team, consisting of the study chair, 
statistician, and an independent reviewer, will assess the 
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10. 
Submission of Biospecimens for Research 
If procured, primary tumor tissue from diagnostic biopsies and surgical tumor tissue 
from both arms must be submitted for central diagnostic review and defined laboratory 
research studies. Additional tumor tissue from the diagnostic core biopsy, surgery and 
recurrence, if available, are to be submitted per patient consent. Peripheral blood is to 
be submitted from consenting patients for defined and undefined laboratory research 
studies. Serum must be submitted for pharmacokinetic and immunogenicity studies as 
defined in Section 10.3 for Arm A patients only. 
It is required that all specimens submitted on this trial be entered and tracked using the 
ECOG-ACRIN Sample Tracking System (see Section 10.4). An STS shipping manifest 
form is to be included with every submission. 
All specimens must be labeled clearly with the ECOG-ACRIN protocol number 
(EA8143), ECOG-ACRIN patient sequence number, patient’s initials, date and time of 
specimen collection, time point and specimen type. 
10.1 
Specimen Collection and Submission Schedule 
Specimens are to be submitted as follows: 
• 
MANDATORY (Arm A): Pre-surgery biopsy tumor tissue (primary tumor 
tissue is preferred if metastasis is also present) must be submitted within one 
(1) month following randomization or collection if submitting blocks or within 
one (1) week of sectioning fresh slides. 
NOTE:  
Patients randomized to Arm B are encouraged, but not required, 
to have a core biopsy after randomization if they have not had a 
biopsy within twelve (12) months of randomization that confirms 
diagnosis of RCC. 
• 
MANDATORY (Both Arms): Surgical tumor tissue must be submitted within 
one (1) month of collection if submitting blocks or within one (1) week of 
sectioning fresh slides. 
• 
OPTIONAL (Both Arms): Additional diagnostic core needle biopsy, 
nephrectomy tumor and normal tissue, and recurrence core needle biopsy or 
resection tissue, if available, should be submitted within one (1) month of 
collection if submitting blocks or within one (1) week of sectioning fresh slides 
per patient consent. See Section 10.2.1. 
• 
OPTIONAL (Both Arms): Peripheral blood specimens are to be submitted per 
patient consent as outlined in Section 10.2.2. Blood specimens are to be 
collected at the following time points for each tube type: 
• 
Prior to Start of Treatment, Arm A Only 
• 
Prior to Nephrectomy, Both Arms (For Arm B patients, collect Prior to 
Nephrectomy. For Arm A patients, collect after Cycle one (1) but Prior to 
Nephrectomy). 
• 
Week 40 Post Randomization, Both Arms 
• 
Recurrence, Both Arms 
• 
MANDATORY (Arm A): Serum specimens must be submitted for 
pharmacokinetic and immunogenicity studies from Arm A patients as outlined 
in Section 10.3. Serum specimens must be collected at the following time 
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points (specimens collected at EOI-nivo time points are only for PK studies, 
and are not part of immunogenicity studies): 
• 
Cycle 1, Day 1, Prior to Start of Nivolumab Infusion 
• 
Cycle 2, Day 1, Prior to Start of Nivolumab Infusion 
• 
Cycle 2, Day 1, EOI-nivo: End of Nivolumab Infusion 
• 
Cycle 3, Day 1, Prior to Start of Nivolumab Infusion 
• 
Cycle 5, Day 1, Prior to Start of Nivolumab Infusion 
• 
Cycle 5, Day 1, EOI-nivo: End of Nivolumab Infusion 
• 
Cycle 7, Day 1, Prior to Start of Nivolumab Infusion  
• 
Cycle 7, Day 1, EOI-nivo: End of Nivolumab Infusion 
• 
First follow-up visit, approximately six (6) weeks post discontinuation of 
nivolumab 
• 
Second follow-up visit, approximately three (3) months from first follow-up 
visit. Note that follow-up specimens should be collected even if the visit is 
delayed. 
NOTE: 
All pre-dose serum specimens should be collected prior to the start of 
nivolumab infusion (anytime within 24 hours prior to first dose). 
NOTE: 
EOI-nivo = End of Nivolumab Infusion. These serum specimens 
should be collected prior to stopping the nivolumab infusion 
(preferably within 2 minutes prior to end of infusion but within 15 
minutes of the end of infusion is acceptable). If the infusion takes 
longer than expected, the collection at the end of infusion should be 
adjusted accordingly. 
10.2 
Submissions to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF) 
If you have any questions concerning specimen collection and shipment, please 
contact the ECOG-ACRIN CBPF at (844) 744-2420. 
10.2.1 
Pathology Submissions 
Representative formalin-fixed paraffin embedded (FFPE) tumor tissue 
blocks from pre-trial diagnostic pathology materials must be submitted 
for central diagnostic review and defined laboratory research studies. 
Arm A Biopsy: Image guided percutaneous core needle biopsy of 
primary tumors (or metastasis) will be performed prior to starting 
treatment. Primary tumor is preferred over metastasis. Six non-
fragmented biopsy cores should be obtained. One biopsy core will be 
sent to surgical pathology for standard of care histological analysis by 
the local pathologist and the five (5) other biopsy cores will be 
retained for research purposes. These cores will be placed in 
specimen containers and paraffin embedded. Of note, the paraffin 
embedded research cores will not be utilized until a histological 
diagnosis is reached. In the event that a histological diagnosis cannot 
be reached with the dedicated diagnostic tissue core, one or more of 
these research cores will be released to pathology for analysis. 
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NOTE: 
Patients randomized to Arm B are encouraged, but not 
required, to have a core biopsy after randomization if they 
have not had a biopsy within twelve (12) months of 
randomization that confirms diagnosis of RCC. 
Submitting pathologist and clinical research associate may refer to 
Appendix I which outlines the Pathology Submission Guidelines. 
ICON (who is distributing the PK kits) is also providing zipper lock 
bags and specimen ID/barcode accession labels and tissue 
requisition forms for the baseline tissue submissions. Place blocks 
and/or slides in the zipper lock bags. 
The pathology specimens and reports are to be labeled with the 
institutional Pathology ID# and ICON specimen ID/barcode/accession 
label on the zipper lock bags provided as well as the information 
above. 
Required Materials 
Forms: Must be submitted with all pathology submissions. 
• 
STS generated shipping manifest form 
• 
Copy of the institutional diagnostic and surgical pathology report 
• 
Immunological study reports, if available 
• 
ICON Tissue Requisition Form (baseline only) 
Tumor Tissue Submissions:  
• 
MANDATORY (Arm A): Representative formalin-fixed paraffin 
embedded FFPE blocks from any pre-trial diagnostic primary or 
metastatic tumor tissue biopsy (primary tumor tissue is preferred if 
metastasis is also present). 
• 
MANDATORY (Both Arms): Representative formalin-fixed paraffin 
embedded FFPE primary tumor blocks from surgical tumor tissue 
biopsy 
• 
MANDATORY (Both Arms): Representative H&E slides from 
diagnostic and surgical tumor tissue blocks 
• 
From consenting patients (both arms) who answer “Yes” to “I 
agree to provide additional specimens for research”: Additional 
representative formalin-fixed paraffin embedded (FFPE) primary 
tumor tissue blocks from diagnostic biopsy 
• 
From consenting patients (both arms) who answer “Yes” to “I 
agree to have my samples collected and I agree that my samples 
and related information may be used for laboratory studies”: 
Additional surgical FFPE primary tumor and normal tissue blocks 
• 
From consenting patients (both arms) who answer “Yes” to “I 
agree to have my samples collected and I agree that my samples 
and related information may be used for laboratory studies”: 
Recurrence FFPE primary tumor tissue blocks (if available). 
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• 
Leftover tumor tissue (both arms) will be stored from patients who 
answer “Yes” to “My samples and related information may be kept 
in a bio-bank for use in future health research.” 
NOTE: 
In order to address heterogeneity in expression of 
candidate biomarkers (including PD-L1) (Callea et al., 
Cancer Immunol Res 2015), for nephrectomy specimens, 
tumor tissue blocks containing predominant and highest 
Fuhrman grade areas should be selected. A block 
containing tissue from uninvolved kidney cortex should 
also be selected. 
NOTE: 
During central diagnostic review, ECOG-ACRIN CBPF 
may request additional or alternative pathology materials 
selected by the review team to complete tumor tissue 
submission requirements. 
NOTE: 
If blocks are unavailable for submission, cores and fresh 
cut slides are to be submitted. All cores and slides must be 
adequately labeled, with slides numbered sequentially in 
the order cut. Alternative submission requirements for each 
selected block: 
• 
One (1) H&E slide from each source block, and 
• 
Fresh Cut Slides: Twenty (20) 4 µm unstained, 
positively charged, air-dried plus slides from the 
thickest part of the tumor (Superfrost Plus 
recommended). After cutting, the slides should be kept 
refrigerated (2-5°C) until shipment. 
• 
One (1) or more core punches (minimum of 4mm 
diameter). If core punch tool is unavailable, request 
core punch kit from the ECOG-ACRIN CBPF (844) 
744-2420. Adequately label every slide and core 
submitted. 
If these criteria cannot be met, please contact the ECOG-ACRIN 
CBPF (eacbpf@mdanderson.org) to obtain alternative submission 
requirements. 
10.2.2 
Blood Submissions 
Blood is to be collected at the time points in Section 10.1 per patient 
consent for defined and/or undefined laboratory research studies. 
Kits for the collection and shipment of the blood specimens are 
ordered on-line from Cenetron Central Laboratories. Instructions are 
provided in Appendix VI. Questions regarding kits can be directed to 
projectmanagement@cenetron.com or call the Cenetron Clinical 
Trials Group at (512) 439-2000. Kits must be ordered after the patient 
has been randomized to the trial and will generally arrive within three 
(3) business days from when the order was placed. 
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10.2.2.1 
Specimen Preparation Guidelines 
SST Red Top Tubes  
• 
Draw two (2) 8.5mL SST tubes of blood at each time 
point. Invert each tube gently five times.   
• 
Allow to clot at room temperature for 20 minutes  
• 
Centrifuge 15 minutes or longer at 1000-1500g 
(approximately 3000 rpm)   
• 
Remove serum and aliquot into eight (8) cryovials 
• 
Place in -70°C freezer and ship overnight on dry ice or 
batch for subsequent shipping. If a -70°C freezer is not 
available, store blood at -20°C until shipped. If dry ice 
is not available, please contact the ECOG-ACRIN 
CBPF at (844) 744-2420 for shipping alternatives. 
Green Top Heparin Tubes 
• 
Draw ten (10) 10mL green top heparin tubes of blood 
at each time point.  
• 
Package and ship the day of collection at ambient 
temperature (no wet or dry ice and no cool packs) on 
the day of collection. 
Purple Top EDTA Tubes 
• 
Draw two (2) 10mL EDTA tubes of blood at each time 
point. Invert each tube gently 8-10 times.  
• 
Within 20 minutes of collection, centrifuge 15 minutes 
or longer at 1000-1500g (approximately 3000 rpm) 
NOTE: 
20 minutes is preferred, but collection can 
be done within 2 hours. 
• 
Aliquot plasma into eight (8) cryovials 
• 
Replace the stopper on the EDTA tube containing the 
cells 
• 
Place plasma and residual cells in -70°C freezer and 
ship overnight on dry ice or batch for subsequent 
shipping. If a -70°C freezer is not available, store blood 
at -20°C until shipped. If dry ice is not available, please 
contact the ECOG-ACRIN CBPF at (844) 744-2420 for 
shipping alternatives. 
10.2.3 
Shipping Procedures 
Tissue blocks are to be shipped at ambient temperature within one (1) 
month following randomization or collection. 
Fresh cut tissue slides must be shipped overnight within one (1) week 
of sectioning on refrigerated gel packs. 
Ship serum, plasma, and remaining cells frozen on dry ice. 
The green top heparin tubes must be shipped the same day they are 
drawn because they must be processed the day after collection. Ship 
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the green top heparin tubes at ambient temperature (no wet or dry ice 
and no cool packs). 
Ship Monday-Thursday via overnight courier using the CBPF’s FedEx 
Priority overnight account using the FedEx online ship manager. 
Ship pathology materials, peripheral blood, serum, plasma, and 
residual cells to: 
MD Anderson Cancer Center CBPF 
Mike Balco 
2130 West Holcombe Boulevard, LSP9.4227 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
Access to the FedEx shipping account for shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained 
by logging onto fedex.com with an account issued by the ECOG-
ACRIN CBPF. For security reasons, the account number will no 
longer be given out in protocols, over the phone, or via email. If your 
site needs to have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org 
An STS shipping manifest form and ICON Tissue Requisition Form 
(baseline only) must be generated and shipped with all specimen 
submissions.  
10.3 
Serum Submissions for Pharmacokinetic and Immunogenicity Studies (Arm A 
only) 
Serum specimens must be submitted at all time points outlined in Section 10.1. 
Collection and shipping kits are available. Each kit will contain the materials 
(vacutainers, Micronic transport tubes, labels, shippers, requisition forms, air 
bills) for the collection and submission of the serum. 
Please email Appendix XII “EA8143 ICON Site Information/Initial Kit Order Form” 
in order to obtain three (3) starter kits and the Laboratory Instruction Manual. 
Please note ICON requires fifteen to twenty (15-20) business days to process 
this form and ship out the initial kits. To reorder kits sites must register with ‘iSite’, 
ICON Central Laboratories Secure Website Portal. Please see instructions 
outlined in Appendix XIII. Kit reorder shipments usually take about seven (7) to 
ten (10) business days. Updated Laboratory Instruction Manuals can also be 
obtained via iSite. 
Questions regarding kits can be directed to ICON toll-free at (877) 797-4422 or 
LabSiteHelp@iconplc.com. Please reference protocol number: CA209-531 
(EA8143) when contacting ICON. 
Do not mix contents from one kit with another. 
• 
Blood specimens will be collected by direct venipuncture or through an 
indwelling catheter. If catheter is used for blood collection, then approximately 
one (1) mL of blood should be withdrawn initially and discarded. Only saline 
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is permitted to keep catheters patent. If blood are obtained through heparin 
lock, sufficient blood (~1mL) must be withdrawn to remove the heparin 
solution. Blood specimens should not be collected from the same line as an 
infusion. Specifically, if the compound is infused through an IV line, the 
contralateral arm should be used to collect the blood specimens. If central 
line is used for dosing, then direct venipuncture in either arm would be 
appropriate. When the drug is infused through multi-lumen catheter, the 
alternate lumen should not be used for sampling due to the risk of drug 
contamination. 
• 
Draw SST vacutainer tubes of blood at each time point as outlined in the 
Section 7.4 table. 
• 
To ensure sufficient blood volume for the required tests is obtained, fill SST 
tubes until vacuum is exhausted and blood ceases to flow. 
• 
Immediately after collection, gently invert each blood specimen five (5) times 
for complete mixing and allow blood to clot for 30-45 minutes at room 
temperature (tube standing upright). 
• 
Centrifuge specimens at room temperature for 10 minutes (swing out) or 15 
minutes (fixed) 1100-1300 x g until clot and serum are well separated. 
• 
Aliquot according to the following: 
• 
Transfer all serum from the 4mL gold top SST collection tubes into one 
(1) appropriately labeled, screw capped, polypropylene Micronic transport 
tubes. 
• 
Transfer serum equally from the 8.5mL red/gray top SST collection tube 
into two (2) appropriately labeled, screw capped, polypropylene Micronic 
transport tubes. 
NOTE: 
Write the ECOG-ACRIN five-digit patient sequence on each 
bar code label before collecting specimens. 
NOTE: 
Aliquoted serum specimens must be kept in cryoblock (4-6C) 
or in chipped wet ice at all times until stored in -20C or colder 
freezer. 
• 
Store the serum specimens immediately (within two (2) hours of collection) at 
-20°C or colder (-70°C freezer preferred) to ensure stability of the serum 
specimens until they are batch shipped overnight on dry ice via FedEx to 
ICON using the shipping supplies and mailer provided in the kit. 
• 
Serum should be batch shipped monthly. Serum from multiple patients may 
be shipped together, but must be in separate biohazard bags with absorbent 
material. 
• 
Ship serum Monday-Thursday only, do not ship on the day before a weekend 
or holiday. 
• 
Serum must be submitted in pre-labeled bar-coded tubes with the appropriate 
completed laboratory requisition form containing the matching barcode. No 
unlabeled serum specimens are to be shipped. 
• 
Complete all required information on the requisition forms or processing of 
the serum may be delayed. Place the requisition form on the outside of the 
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For the Requisition Form: 
• 
Place ‘Requisition’ bar code label on each copy of the requisition form 
• 
Subject ID Number is the ECOG-ACRIN assigned EA8143 patient number 
The laboratory is open to receive shipments Monday through Friday. 
NOTE: 
Supplies leftover from used kits should be discarded. 
Please refer to the Laboratory Instruction Manual for details on the Specimen 
Collection, Processing, and Shipping Guidelines. 
If you have any questions concerning serum specimen collection and shipment 
please refer to the contact information provided in the Laboratory Instruction 
Manual. 
An STS Shipping Manifest Form must be submitted with every shipment. 
The exact date and time (to the minute – start and stop time, and duration of 
infusion must be noted) of nivolumab administration and of serum specimen 
collection must be entered into the ECOG-ACRIN Sample Tracking System 
(STS) and be provided with the documentation submitted with the serum. 
10.4 
ECOG-ACRIN Sample Tracking System  
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN STS. The software will allow the use of either 1) an 
ECOG-ACRIN user-name and password previously assigned (for those already 
using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html 
Please take a moment to familiarize yourself with the software prior to using the 
system. 
An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Study Specific Notes 
The exact date and time (to the minute – start and stop time, and duration of 
infusion) of nivolumab administration and of serum specimen collection must be 
entered into the ECOG-ACRIN Sample Tracking System and provided with the 
documentation submitted with the serum. 
Generic Specimen Submission Form (#2981v3) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. 
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Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.5 
Institutional Reimbursements 
10.5.1 
Arm A Biopsy Reimbursements 
Core biopsies performed following randomization to confirm RCC, are 
reimbursable at the research rate of $3,000 per biopsy, one biopsy 
per patient. Biopsies that were billed to insurance are not eligible for 
reimbursement. Biopsies obtained prior to randomization are not 
eligible for reimbursement. However, if the patient had a biopsy more 
than twelve (12) months from time of randomization, then they are 
eligible for a repeat biopsy that is eligible for reimbursement. 
All sites are eligible for the reimbursement for applicable biopsies 
regardless of cooperative group. The site must set up the mechanism 
for the ‘billing’ of these biopsies. ECOG-ACRIN recommends billing 
the cooperative group Principal Investigator (PI) of the site. Contact 
your coordinating group’s operations office and ask to whom this 
account should be named. 
Please note that the completed EA8143 Biopsy Reimbursement Form 
(Appendix VII) and supporting documentation (if requested) MUST be 
submitted in order to receive the reimbursement. 
Prior to recruiting patients to the biopsy portion, the following 
conditions must be met: 
a. 
The research rate of $3,000 per biopsy is deemed acceptable by 
the IRB or central research office. Costs above $3,000 are not to 
be billed to the patient or patient’s insurance. 
b. 
The research rate is reported to the institution’s financial office 
and an account established in the institution’s cooperative group 
principal investigator’s name. 
Supporting documentation for the biopsies may be requested prior to 
the release of any funds. Expenses for biopsies will be paid only to 
participating institutions, not to any other persons or entities, at the 
stated research rate of $3,000 per biopsy. 
NOTE: 
Reimbursements are not applicable for biopsies billed to 
patients or their insurance companies. 
Distribution of the reimbursements requires: 
• 
Submission and receipt of the biopsies via the ECOG-ACRIN 
Sample Tracking System (STS) 
• 
Receipt of EA8143 Biopsy Reimbursement Form (Appendix VII) to 
the ECOG-ACRIN Operations Office - Boston. 
• 
Supporting documentation indicating performance of biopsy was 
not billed to insurance. 
Reimbursements will be paid from the ECOG-ACRIN Operations 
Office to the ECOG-ACRIN Principal Investigator (PI) of the 
submitting ECOG-ACRIN institution. 
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10.5.2 
Pharmacokinetic Reimbursements 
To offset research-related costs associated with the collection and 
submission of the serum specimens at the time points outlined above 
in Section 10.1, institutions are eligible to receive reimbursements. 
Please see the Funding Sheet for further details. Serum specimens 
must be collected and submitted to trigger payment. Receipt of the 
serum specimens will be verified prior to the release of funds. 
NOTE: 
Neither patients nor their insurance companies are to be 
billed for the collection or submission of the 
pharmacokinetic serum specimens. 
Distribution of the reimbursements requires: 
• 
Submission of the required pharmacokinetic serum specimens 
using the ECOG-ACRIN Sample Tracking System (STS) [Refer to 
Section 10.4 for STS requirements] 
• 
Receipt and verification of the serum specimens by ICON 
Laboratory Services. 
10.6 
Use of Specimens in Research 
Pathological materials will be distributed to investigators for central diagnostic 
review and defined laboratory research studies. Serum specimens will be 
distributed to investigators for defined laboratory research studies. 
Specimens from patients who consented to allow their specimens to be used for 
future undefined ECOG-ACRIN approved research studies will be retained in an 
ECOG-ACRIN designated central repository. 
For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility.  
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Tissue processing may include, but not limited to, 
extraction of DNA and RNA and construction of tissue microarrays (TMAs). DNA, 
RNA, serum, and plasma (if appropriate) will be isolated from the submitted 
peripheral blood specimens. 
Any residual blocks will be available for purposes of individual patient 
management on specific written request per submission of the ‘Specimen Return 
Request for Patient Care or Legal Issue’ form to the ECOG-ACRIN Central 
Biorepository and Pathology Facility. 
Residuals/derivatives from the serum specimens submitted for the 
pharmacokinetic and immunogenicity studies will not be retained for future 
research studies. 
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. Pathology 
materials may be retained for documentation purposes or returned to the site. All 
other specimens will be destroyed per guidelines of the respective repository. 
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10.7 
Specimen Inventory Submission Guidelines  
Inventories of all specimens submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory.  
Inventories of specimens forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
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11. 
Laboratory Research Studies 
11.1 
Pharmacokinetic and Immunogenicity Studies (Arm A Mandatory) 
This study evaluates the effect of nivolumab in patients in the adjuvant setting 
with localized renal cell carcinoma undergoing nephrectomy and affords the 
opportunity to assess the long term pharmacokinetics and immunogenicity of 
nivolumab. 
The pharmacokinetic analysis will be used to describe the pharmacokinetics of 
nivolumab in patients and to assess the effects of patient factors on the 
nivolumab pharmacokinetics. Serum specimens from the following time points 
will be used for this pharmacokinetic analysis: Cycle 1 Day 1 (pre-dose), Cycle 2, 
Day 1 (pre-dose and EOI-nivo), Cycle 3 Day 1 (pre-dose), Cycle 5 Day 1 (pre-
dose and EOI-novi), Cycle 7 Day 1 (pre-dose and EOI-nivo), and First 2 Follow-
Up Visits. 
Serum concentration analyses for nivolumab will be performed by validated bio-
analytical methods for nivolumab. 
The immunogenicity specimen is a serum specimen collected to assess the 
presence of anti-drug antibodies to nivolumab. If ADA +, the samples would be 
assessed for Nab as well. This is a specimen collected in tandem with the PK 
specimen, at pre-dose on the indicated study days. Along with specimens to 
quantitate drug concentrations, given nivolumab is a Mab, specimens are 
included to assess incidence of immunogenicity. Serum specimens from the 
following time points will be used for this immunogenicity analysis: Cycle 1 Day 
(pre-dose), Cycle 2 Day 1 (pre-dose), Cycle 3 Day 1 (pre-dose), Cycle 5 Day 1 
(pre-dose), Cycle 7 Day 1 (pre-dose), and First 2 Follow-Up Visits. 
11.2 
Correlation of PD-L1 Tumor Tissue Expression with Outcome 
In the metastatic setting, primary tumor expression of PD-L1 portends prognosis 
and may correlate with a higher chance of response to nivolumab but does not 
ensure response.8,9 In the phase 3 study, PD-L1 positivity did not predict higher 
overall survival with nivolumab. (Motzer, 2015 #1861). Conversely, patients with 
PD-L1 negative tumors can still achieve response. This could be due to the 
dynamic nature of the marker, intratumoral heterogeneity, or differences in PD-L1 
expression between the primary tumor and metastases. We will further 
characterize the association of the PD-L1 positivity of the tumor and tumor-
immune infiltrating cells at the time of pretreatment biopsy, nephrectomy, and at 
recurrence with outcomes as exploratory aims with the goal of identifying better 
selection criteria for this strategy. 
Immunohistochemical (IHC) analysis for PD-L1 will be performed on formalin-
fixed, paraffin-embedded tumor tissue specimens using: the BMS assay, Dako 
PD-L1 28-8 IHC assay, which uses the Dako PD-L1 antibody will be performed 
on archival or newly obtained tissue. (Cogswell JP Cancer immunotherapy. 
http://www.freepatentsonline.com/). 
11.2.1 
Statistical Considerations 
An independent pathologist who is blinded to the outcomes will score 
the percentage of cells exhibiting cell-surface staining for PD-L1. PD-
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L1 positivity will be defined per specimen by a 5% expression 
threshold.22,23 Additional analyses will assess the 1% and 10% 
threshold levels. We will also capture information with respect to the 
relative abundance and location (peritumoral/intratumoral) of immune 
cell (macrophage and lymphocyte) PD-L1 staining. To be eligible for 
analyses, the section must have at least 100 tumor cells. We will test 
the hypothesis that patients whose tumors have a higher expression 
of PD-L1 have improved RFS on nivolumab (i.e., we will test the 
expression-by-treatment interaction using a proportional hazards 
model). 
We assume that viable tissue from nephrectomy specimens will be 
available for 80% of patients, and that 30% of patients have tumors 
that express PD-L1. We further assume that the proportion of patients 
with tissue from each of the two treatment arms is equal, so the 
overall observed hazard ratio will be a mixture of that expected for the 
experimental and observation arms. There will be 80% power to 
detect a hazard ratio of about 1.63 comparing DFS between patients 
with high and low PD-L1 if those who express PD-L1 have better 
outcome. 
Additionally, among patients with biopsy specimens available, we will 
evaluate for differences in PD-L1 expression and immune cell infiltrate 
levels between biopsy and nephrectomy specimens. If there are no 
differences between biopsy and surgery levels in the observation arm 
but we observe differences in the neoadjuvant nivolumab arm, the 
effect will be attributable to the neoadjuvant administration and not to 
differences due to the nature of the specimens (biopsy vs surgery). 
McNemar’s Test will be used to explore categorical changes within 
each treatment group, although changes are only expected in treated 
patients. The following table shows the sample size that would be 
required and the change that would be detectable with adequate 
power given a range of proportions positive for PD-L1 in the biopsy 
specimen. We assume about half of patients will have paired biopsy 
and tumor specimens with viable material (maximum 190 per arm). 
There are no published data about the direction of change, so power 
and sample sizes are shown for both increases and decreases. A 
50% relative change in proportions would be considered clinically 
meaningful (e.g., from 30% positive pre-treatment to 45% positive 
post-treatment). Differences detectable with 190 patients per group 
are also shown in the table below. 
% Positive pre-
treatment (biopsy) 
% Positive post-
treatment (nephrectomy) 
Power 
Required 
sample size 
30% 
45% 
83% 
190 
 
15% 
93% 
190 
40% 
20% 
92% 
125 
 
60% 
90% 
140 
 
24% 
90% 
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% Positive pre-
treatment (biopsy) 
% Positive post-
treatment (nephrectomy) 
Power 
Required 
sample size 
 
57% 
90% 
190 
50% 
25% 
89% 
75 
 
75% 
89% 
75 
 
33% 
91% 
190 
 
67% 
91% 
190 
60% 
30% 
91% 
65 
 
90% 
90% 
47 
 
43% 
90% 
190 
 
76% 
90% 
190 
11.2.2 
Specimen Submission 
Tumor tissue specimens obtained at the time of the pre-surgical 
biopsy, nephrectomy, and biopsy at recurrence (if available) will be 
used in this analysis. 
11.3 
Additional Potential Laboratory Research Studies. 
When sufficient information is available from the parent study a full correlative 
science proposal or amended protocol document detailing the scientific 
hypotheses, research plans, and assay methods for use of the bio-specimens, 
and a formal statistical analysis plan with adequate power justification will be 
submitted to and reviewed by CTEP. 
Results of these studies are for the purposes of the trial only and will not be 
returned to the site or reported to the patient. 
List of studies in order of priority: 
Tissue: 
1. Immunohistochemistry (IHC)/immunofluorescence (IF) analysis of RCC 
tumors 
(A) 
Multiplex IF assays to be done at Dr. Signoretti’s laboratory at Brigham 
and Women’s Hospital using two established panels 
2. NanoString discovery of immune gene signatures (RNA specimens) 
3. Tumor sequencing for predictive genes: Whole exome/transcriptome 
sequencing. Alternatively, based on the field at the time of analysis, genome 
or targeted sequencing of panels of genes may be performed. 
4. T cell receptor repertoire characterization 
Blood: 
1. T cell proliferation assays to detect neoantigen responses using 
cryopreserved lymphocytes 
2. T cell receptor repertoire characterization 
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3. Circulating Cytokine Levels 
11.4 
Immunohistochemistry (IHC)/Immunofluorescence (IF) Analysis of RCC Tumors 
RCC is characterized by complex interactions between the host immune 
response and a variety of immunosuppressive pathways operative in the tumor 
microenvironment.26 Despite getting to the tumor, effector lymphocytes may 
encounter regulatory cells in the tumor microenvironment that can functionally 
inactivate their potential anti-cancer activities.26 PD-L1 expressed by the tumor 
cell can inhibit the proliferation, cytokine production and cytotoxic activity of anti-
tumor PD-1+, CD4+ and CD8+ T cells.4 Its expression on tumor cells and tumor-
infiltrating lymphocytes (TILs) may impair host T cell anti-tumor function. Baseline 
and on-treatment levels of helper and cytotoxic T lymphocyte infiltrate will be 
characterized. Tissue for biomarker analysis will be harvested at baseline from 
the primary tumor (biopsy), at nephrectomy (primary tumor and when available, 
any resected lymph nodes), and at recurrence. Normal kidney or nodal tissue will 
also be sampled concurrently. IHC will be used to quantify PD-L1 and PD-L2 
expression on tumor cells as well as on infiltrating immune cells. Multiplex IF 
assays will be utilized to characterize the immune infiltrate. These assays will 
quantify CD8+ T cells, Tregs (FoxP3+ CD4+ cells), and total CD4 T cells (in both 
normal and tumor tissue). Co-expression of multiple immune checkpoint 
molecules (e.g. PD1, TIM3, LAG-3. VISTA, B7-H3) on tumor infiltrating immune 
cells will be also assessed by multiplex IF. 
Staining levels expressed as percent positivity will be summarized using 
descriptive statistics. Staining levels expressed as scores will be tabulated 
categorically. Changes over time will be portrayed graphically by arm. 
Correlations between baseline immune infiltrate, changes after nivolumab, and 
efficacy outcomes will be explored. 
11.4.1 
General IHC Methods 
All immunohistochemical staining will be performed utilizing the DAKO 
automated stainer. 5µm-thick paraffin-embedded tissue sections will 
be dewaxed, soaked in alcohol, and after microwave treatment in 
antigen unmasking solution for 10 minutes, incubated in 3% hydrogen 
peroxide for 15 minutes to inactivate endogenous peroxidase. 
Sections will then be incubated with the appropriate primary antibody 
and detection will be performed using the DAKO EnVision™+ System 
according to the manufacturer’s instructions.  
Immunohistochemically stained slides will be evaluated by a 
Pathologist. Scoring will be performed according to the staining 
intensity and the percentage of positive cells. This analysis will be 
performed at the DF/HCC Renal Cancer Program Pathology Core at 
Brigham and Women’s Hospital under the direction of Dr. Sabina 
Signoretti. 
11.4.2 
Correlation of PD-L1 Tumor Tissue Expression with Outcome 
Immunohistochemical (IHC) analysis for PD-L1 will be performed on 
formalin-fixed, paraffin-embedded tumor tissue specimens using two 
multiplex IF assays to be done at Dr. Signoretti’s laboratory at 
Brigham and Women’s Hospital: Tumor infiltrating activated cytolytic 
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CD8-positive T cell will be investigated by four-color IF using validated 
CD8, Ki67, Granzyme-A, and Perforin-1 antibodies. Co-expression of 
immune checkpoint molecules on immune cell subsets (CD8-positive 
or CD68-positive or DC-Lamp-positive) will be investigated by 
multiplex IF using validated antibodies against CD8, CD68, DC-Lamp, 
PD-L1, PD-L2, PD-1, TIM-3, LAG-3, VISTA and B7-H3. Tumor 
infiltrating Tregs will be quantified by IF using anti-CD4 and anti-
FOXP3 antibodies. 
Image acquisition will be performed using the Mantra platform (Perkin 
Elmer). Positive cells will be quantified using the Inform software 
program (Perkin Elmer). Results of image analysis will be validated 
visually by Dr. Signoretti. 
11.4.3 
Statistical Considerations 
An independent pathologist who is blinded to the outcomes will score 
the percentage of cells exhibiting cell-surface staining for PD-L1. PD-
L1 positivity will be defined per specimen by a 5% expression 
threshold.22,23 Additional analyses will assess the 1% and 10% 
threshold levels. We will also capture information with respect to the 
relative abundance and location (peritumoral/intratumoral) of immune 
cell (macrophage and lymphocyte) PD-L1 staining. To be eligible for 
analyses, the section must have at least 100 tumor cells. We will test 
the hypothesis that patients whose tumors have a higher expression 
of PD-L1 have improved RFS on nivolumab (i.e., we will test the 
expression-by-treatment interaction using a proportional hazards 
model). 
We assume that viable tissue from nephrectomy specimens will be 
available for 80% of patients, and that 30% of patients have tumors 
that express PD-L1. We further assume that the proportion of patients 
with tissue from each of the two treatment arms is equal, so the 
overall observed hazard ratio will be a mixture of that expected for the 
experimental and observation arms. There will be 80% power to 
detect a hazard ratio of about 1.63 comparing DFS between patients 
with high and low PD-L1 if those who express PD-L1 have better 
outcome. 
Additionally, among patients with biopsy specimens available, we will 
evaluate for differences in PD-L1 expression and immune cell infiltrate 
levels between biopsy and nephrectomy specimens. If there are no 
differences between biopsy and surgery levels in the observation arm 
but we observe differences in the neoadjuvant nivolumab arm, the 
effect will be attributable to the neoadjuvant administration and not to 
differences due to the nature of the specimens (biopsy vs surgery). 
McNemar’s Test will be used to explore categorical changes within 
each treatment group, although changes are only expected in treated 
patients. The following table shows the sample size that would be 
required and the change that would be detectable with adequate 
power given a range of proportions positive for PD-L1 in the biopsy 
specimen. We assume about half of patients will have paired biopsy 

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and tumor specimens with viable material (maximum 190 per arm). 
There are no published data about the direction of change, so power 
and sample sizes are shown for both increases and decreases. A 
50% relative change in proportions would be considered clinically 
meaningful (e.g., from 30% positive pre-treatment to 45% positive 
post-treatment). Differences detectable with 190 patients per group 
are also shown in the table below. 
% Positive pre-
treatment (biopsy) 
% Positive post-
treatment (nephrectomy) 
Power 
Required 
sample size 
30% 
45% 
83% 
190 
 
15% 
93% 
190 
40% 
20% 
92% 
125 
 
60% 
90% 
140 
 
24% 
90% 
190 
 
57% 
90% 
190 
50% 
25% 
89% 
75 
 
75% 
89% 
75 
 
33% 
91% 
190 
 
67% 
91% 
190 
60% 
30% 
91% 
65 
 
90% 
90% 
47 
 
43% 
90% 
190 
 
76% 
90% 
190 
11.4.4 
Specimen Submission 
Tumor tissue specimens obtained at the time of the pre-surgical 
biopsy, nephrectomy, and biopsy at recurrence will be used in this 
analysis. No additional specimens are requested. 
11.5 
NanoString Discovery of Immune Gene Signatures 
RNA samples from archived FFPE tissue can often be low quality. Platforms that 
permit multiplex analysis of limited amounts of RNA such as the NanoString 
Technologies nCounter platform may be more efficient than traditional RT-PCR 
techniques. NanoString uses a fluorescent barcode technology to measure up to 
800 targets per sample. The goal of these exploratory analyses will be to define 
signatures that correlate with an increased CD8 infiltrate post-nivolumab 
treatment, as well as signatures that correlate with a lack of infiltrate – i.e. a non-
response signature. Novel transcripts discovered via NanoString will be verified 
and quantified at the protein level via IHC as described above. 
Methods: Using sections identified by the study pathologist (Sabina Signoretti), 
total RNA will be isolated using Ambion RecoverAll Total Nucleic Acid Isolation 
Kit for FFPE Tissues (Applied Biosystems, Waltham, MA). RNA expression will 
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(NanoString Technologies, Seattle, WA) by counts. NanoString nCounter 
expression data will be analyzed using the “edgeR” and “limma” R/Bioconductor 
packages as follows: Each sample will first be rescaled using the “relative log 
expression” method proposed by Anders and Huber. Count data will then be 
transformed to log2-counts per million, the mean-variance relationship estimated, 
and the appropriate observational-level weights computed as described by Law 
et al (26). Finally, differential gene expression between therapy response groups 
will be analyzed using mixed effects linear modeling by robust regression, 
controlling for technical replication (27) and applying an empirical Bayes 
approach for moderating gene-wise variances (28). We will also perform Analysis 
of Functional Annotation (29) to identify relevant biological processes and 
signaling pathways associated with a therapy response ( defined as CD8 T Cell 
infiltration quantified via IHC as above). Since the NanoString platform to be used 
in this study contains only immunological genes, we will apply a non-competitive 
method based on rotation gene set testing for linear models (30). Gene lists used 
in this analysis were retrieved from the Broad Institute Molecular Signature 
Database (MSigDB) (31). The Benjamini and Hochberg method will be used to 
control for multiple testing (32). The NanoString analyses will be performed in the 
Johns Hopkins University high-throughput genetics core, under the direction of 
Dr. Charles Drake, with bioinformatics analyses directed by Dr. Luigi Marchioni. 
11.5.1 
Specimen Submission 
Tumor tissue specimens obtained at the time of the pre-surgical 
biopsy, nephrectomy, and biopsy at recurrence (if available) will be 
used in this analysis.  
11.6 
Tumor Sequencing for Predictive Genes 
11.6.1 
Whole Exome/Transcriptome Sequencing 
Whole exome and transcriptome sequencing of the patient’s RCC 
tissue specimens and matched germline samples may enable 
identification of predictive markers of resistance and clinical benefit 
that can lead to future personalization of therapy with this 
perioperative strategy or identify potential resistance mechanisms that 
may make this approach futile and suggest future combinatorial 
strategies. Several genes have been identified to be prognostic when 
mutated in RCC such as BAP1 and SEDT2.  
11.6.2 
Whole exome sequencing is a cancer genomic assay that can detect 
somatic mutations, copy number variations and structural variants in 
tumor DNA in all of the coding regions of the genome, and can be 
done from fresh, frozen or formalin-fixed paraffin-embedded samples 
(Van Allen, et al Nature Medicine 2014). Whole exome sequencing 
surveys exonic DNA sequences of all ~20,000 cancer genes. To be 
eligible for DNA isolation, tissue must contain at least 20% tumor 
nuclei. The DNA is then analyzed by massively parallel sequencing 
using a solution-phase Illumina hybrid capture kit and an Illumina 
HiSeq 2500 sequencer at the Broad Institute using established 
methodology. In parallel, capture based whole transcriptome 
sequencing, which can be performed from either frozen or formalin-
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tumor samples to determine gene expression quantification through 
orthogonal methods, as well as identify fusion products and 
alternative splicing events. Dr. Eliezer Van Allen at DF/HCC will lead 
this substudy. 
Alternative sequencing methods such as genomic and targeted 
panels of genes may also be utilized depending on the field at the 
time. 
11.6.3 
Specimen Submission 
Tumor tissue specimens obtained at the time of the pre-surgical 
biopsy, nephrectomy, and biopsy at recurrence (if available) will be 
used in this analysis. 
11.7 
Characterization of T Cell Receptor Repertoire (TCR) and Change in Response 
to Nivolumab 
The diversity of the T cell receptor repertoire is critical to the anti-tumor 
immune response and to combating tumor escape. Subsequent changes in a 
patient’s T cell receptor (TCR-β) repertoire over time and in response to 
therapy likely have significant influence on survival. Early work has unveiled 
intriguing observations into the impact of TCRs on clinical outcomes. For 
example, a prospective T cell monitoring study revealed that baseline high 
frequency of CTLA-4+, PD-1+, or non-naive T cells was associated with 
improved clinical outcomes with the CTLA-4 antibody, ipilimumab when given in 
combination with the GVAX vaccine in patients with castration-resistant prostate 
cancer (CRPC).1 In another study of patients with CRPC and melanoma, 
Fong and colleagues found significant increases in the size and diversity of the 
TCR-β repertoire after treatment with ipilimumab.2 While the degree of 
change in TCR clonotype abundance did not necessarily correlate with 
improved outcomes, the patients who maintained a high frequency of TCR-β 
clonotypes during treatment had greater overall survival. Interestingly, the 
clones that expanded the most in response to treatment were non-naïve T 
cells suggesting that responders have an existing pre-primed T cell 
armamentarium that converts to an effector response during treatment. Another 
study of melanoma patients treated with the PD-1 antibody pembrolizumab 
observed that responders tended to have a more clonal TCR repertoire at 
baseline, which then expanded as much as 10 times more than those patients 
who progressed in response to therapy.3 In RCC, Choueiri et al demonstrated 
that TCR clonality in blood and tumor may be associated with survival in a cohort 
of patients with metastatic RCC treated with single agent nivolumab suggesting 
that TCR rearrangement could be an important factor when evaluating response 
(Choueiri ASCO 2015). 
Next generation sequencing (NGS) can detect millions of uniquely rearranged 
TCR-β clonotypes using primers that can recognize the variable (V), diversity 
(D), joining (J), and constant gene segments.2 A clonotype represents a distinct 
VDJ readout. NGS platforms can monitor how these unique TCR-β sequences 
transform over time and in response to therapies that may modulate the 
immune response.2  
Differences in baseline TCR diversity and abundance may impact response to 
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repertoire. Using peripheral blood mononuclear cells and tumor tissue samples, 
we will characterize the TCR repertoire serially at baseline, after nivolumab (in 
arm A), and at the time of recurrence to assess for changes over time and in 
response to therapy. We will evaluate for any associations between clonality and 
risk of recurrence and survival. 
The Adaptive platform is one of the most advanced high output sequencing 
technologies for sequencing TCRs and will be used to assess the effect of 
nivolumab on the T cell repertoire in peripheral blood. 
The following is a condensed version o f  the methodology, which will be 
performed to evaluate TCR clonotype abundance.2 
(1) Cryopreserved PBMCs from baseline, serially, and at the time of recurrence 
will be thawed. To amplify and sequence the TCR-β repertoire, RNA will 
be isolated using AllPrep DNA/RNA mini and/or micro kits (Qiagen).2 Life 
Technology Vilo kits will be used to reverse transcribe the RNA to 
complementary DNA (cDNA). Locus-specific primer sets for TCR-β will be 
used to amplify the cDNA.2 
(2) To identify and enumerate the different clonotypes, the reads will be 
mapped to V and J seqments. A clonotype will be defined as identical 
sequences of the mapped readouts. Frequency, a.k.a., clone abundance, will 
be assessed by dividing the number of samples with the same clonotype 
by the total number of reads sampled. 
11.7.1 
Statistical Analysis: 
(1)  Absolute T cell clonotype abundance will be determined by 
assessing the number of unique clonotypes identified. High 
frequency will be defined as the number of unique TCR 
clonotypes >10-3 similar to that used by Cha et al.2 The data will 
be summarized descriptively and graphically. 
(2) To measure the degree of repertoire change from diagnosis to 
on therapy or to time of recurrence, we will use Morisita’s 
distance as utilized by Cha and colleagues.2 Morisita’s 
distance ranges from 0-1. Zero indicates minimal change in 
TCR repertoire size (number of unique clonotypes) and 1 
indicates maximal change after treatment. For example, in the 
Cha study, median travel distance for untreated patients was 
0.039 vs. 0.197 for the ipilimumab treated patients (p=0.005, 
Mann-Whitney).2 This finding suggested that CTLA-4 blockade 
elicited significant changes (either increases or decreases) in 
clonotype abundance consistent with increased turnover of the 
TCR repertoire. This method is useful as it is not as vulnerable to 
sample size fluctuations.2 
(3) To evaluate TCR diversity, change in repertoire size per patient 
will be used. We will identify the top 25% of unique clonotypes by 
sorting for clone frequency. Fold change after recurrence will be 
measured and plotted on a logarithmic scale. 
(4) Working with a computational biologist, the DESeq R package will 
be employed to identify which patients had significant changes in 
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whether the changes were due more to clonotype loss or 
gain.2,9 This established DESeq algorithm has been modified to 
adjust for normal variation in the repertoire. 
11.8 
Circulating Cytokine Levels 
Serum levels of circulating pro- and anti-inflammatory cytokines such as TNF-
alpha, IL-8, IL-1 and IL-6 will be quantified in all patients at baseline, time of 
nephrectomy, and ~3-4 months after nephrectomy on nivolumab or surveillance, 
and at recurrence. The list of cytokines to be explored will be curated based on 
the NanoString results and other relevant results at the time of analysis, but in 
general will utilize the luminex multiplexed platform (Austin TX). Briefly, this 
platform uses internal standards and a spline-fit curve method to accurately 
quantify panels of 17-35 cytokines from replicates of 25 microliters of patient 
sera. This analysis will be performed at the DF/HCC under the direction of Dr. 
Rupal Bhatt in the DF/HCC Immune Monitoring Core.  
11.8.1 
Statistical Analysis: 
The following questions will be considered: 
Among patients randomized to perioperative nivolumab: 
• 
Do cytokine levels change in response to neoadjuvant nivolumab? 
• 
Changes between randomization and pre-nephrectomy, 
assuming paired samples available for 90% of patients 
randomized to nivolumab (345 pts).   
• 
Do cytokine levels change in response to adjuvant nivolumab? 
• 
Changes between pre-nephrectomy and 36 weeks, assuming 
paired samples similarly available 
• 
Do cytokine levels change in response to any nivolumab? 
• 
Changes between randomization and 36 weeks 
• 
Is there an association between changes in cytokine levels and 
clinical outcome among patients treated with nivolumab or 
placebo? 
As an example of power that will exist for the above analyses of the 
magnitude of change, we consider a preliminary analysis of IL-8, 
which was measured at baseline and 4 weeks among 59 patients 
treated with sorafenib on ASSURE. Mean levels among 59 patients 
measured at baseline and 4 weeks were 4.19 and 4.70 respectively, 
with standard errors of 0.32 and 0.41. We estimate that 90% of 
patients randomized to nivolumab will have paired serum samples 
available for this analysis.   
Assuming a standard deviation of 3.15, there will be 83% power using 
a two-sided Wilcoxon rank sum test with 5% Type I error. 
Cutpoints that best distinguish patients with robust CD8 infiltration at 
randomization from those without a robust infiltration will be estimated 
using recursive partitioning. If the number of available samples 
permits, patients will be randomly divided into test and validation 
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exploratory analysis without internal validation is assumed in the 
following sample size estimates. 
Once the study is completed, we will perform additional analyses to 
explore associations between cytokine levels and clinical outcome. 
For these studies, we estimate that 90% of patients will have blood 
samples at both baseline (randomization) and 3 months 
(approximately 345 patients per arm). At full information, we estimate 
that between 90 and 124 disease recurrences or deaths will have 
occurred among these patients on a given arm, depending on the 
efficacy of treatment. Within each arm, there will be 80% power to 
detect a hazard ratio of 1.67 to 1.84 using a two-sided log-rank test 
with two-sided Type I error of 5%, assuming percent change is split at 
the median.  
If changes are observed, then among all patients: 
• 
Are there differences in the magnitude of change between 
patients randomized to nivolumab and those randomized to 
observation? 
• 
Is there an interaction between treatment and cytokine change 
with respect to clinical outcome? 
Differences in RFS between patients with and without robust CD8 
infiltration will be explored. A Cox proportional hazards model will be 
used to test the interaction between treatment and cytokine changes.  
These analyses are exploratory in nature.   
11.8.2 
Specimen Submission 
Specimens from the SST tubes will be used in this analysis. 
11.9 
T Cell Proliferation Assays to Detect Neoantigen Responses using 
Cryopreserved Lymphocytes 
These studies will be performed as previously described (Sheikh, 2012). Briefly, 
mutation associated neo-antigens (MANA) will be predicted using the PDGx 
platform. For each patient, 4-8 peptides with optimal MHC binding that patient’s 
HLA-A alleles will be synthesized under GMP conditions. T cell proliferation to 
neoantigens will be assayed using a standard tritiated thymidine (3H-thymidine) 
incorporation assay. The degree of proliferation will be expressed as a 
stimulation index (SI), defined as 3H-thymidine incorporation in the presence of 
antigen divided by 3H-thymidine incorporation with media alone. For these 
studies, proliferation to the CEF (CMV, EBV, Flu) pool will be used as a positive 
control. Control, i.e. irrelevant peptides will be used as a negative control. It 
should be noted that we are well aware that alternative, more complex methods 
are available to measure antigen-specific T cell responses, including Elispot, 
Fluroispot, CFSE dilution and multiplexed tetramer staining. For the purposes of 
this study, however, we plan to initially conduct screening studies with standard, 
robust H3 proliferation assays. If interesting T cell reactivity is noted, we will 
follow-up with additional studies to further characterize the nature of the MANA 
response, those additional studies will utilize flow cytometry with intracellular 
staining to determine whether the MANA response is productive, i.e. whether it is 
characterized by secretion of effector cytokines like IFN-γ, TNF-α and IL-2. 
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These studies are exploratory, and descriptive summary statistics will be utilized, 
as above focusing on CD8 infiltrate “responders” versus “non-responders”, i.e. 
patients without a significant post-treatment infiltrate at the time of surgery. 
11.9.1 
Specimen Submission 
Specimens from the cryopreserved lymphocytes will be used in this 
analysis. 
11.10 Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secure data transfer to the ECOG-ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
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12. 
Bone Metabolism Imaging & Serum Correlative Research Study (Optional) 
For patients that consent to take part in the optional imaging research study, all dual 
energy X-ray absorptiometry (DXA) bone scans are to be submitted via TRIAD as 
outlined in Section 4.1.4.6.  
12.1 
Changes in Bone Metabolism and Density in Response to Nivolumab 
Administration 
The skeletal toxicities of immune therapy (IT) are unknown. Bone loss and occult 
fracture may be unrecognized sequelae of IT threatening long-term cancer 
survival. Skeletal failure is associated with substantial morbidity and mortality but 
can be prevented with current osteoporosis drugs; therefore, it is critical to 
understand the adverse effects of IT on bone metabolism and the mechanisms 
by which unfavorable bone remodeling states may occur. Checkpoint inhibitors 
activate host T-cells, unleashing an anti-tumor immune response. There is 
preliminary data to indicate that IT accelerates skeletal deterioration.  Pro-
inflammatory states and immune reconstitution have established, adverse effects 
on the skeleton. Increased levels of cytokines including IL-6 and TNF-α in 
rheumatoid arthritis and postmenopausal osteoporosis drive bone-resorbing 
osteoclastogenesis while simultaneously stunting bone-building osteoblast 
maturation. These same cytokines are implicated in IT’s anti-tumor effects, but 
with unknown skeletal sequelae. In HIV, antiretroviral initiation fosters T-cell 
secretion of Receptor Activator of Nuclear Factor-κB Ligand (RANK-L) and 
reduced osteoprotegerin (OPG), leading to bone loss and increased fracture risk.   
Checkpoint inhibition also mobilizes and reconstitutes the immune system, 
though the skeletal aftermath is unclear. 
This correlative study will test the hypotheses that 1) PD-1 blockade with 
consequent T-cell activation used for the treatment of RCC has adverse 
downstream effects on bone metabolism and density, 2a) systemic inflammatory 
and bone regulatory markers will change following checkpoint inhibition, and 2b) 
that these changes will be related to unfavorable alterations in skeletal 
metabolism. 
To test these hypotheses, serum bone turnover and inflammatory markers, bone 
density data will be measured in participants treated and untreated with 
nivolumab to investigate the following objectives: 
To characterize the effect of nivolumab on measures of bone remodeling. We will 
follow participants and quantify baseline and post-treatment bone parameters to 
include the following: A) serum C-telopeptides (CTX, bone resorption) and B) 
procollagen type 1 N-terminal propeptide (P1NP, bone formation). 
To characterize the effect of nivolumab on measures of bone density. We will 
follow participants and quantify baseline and post-treatment bone parameters to 
include the following: A) areal bone density using dual energy X-ray 
absorptiometry and B) volumetric bone density using quantitative computed 
tomography (derived from CT scans obtained from screening and surveillance 
visits). 
To investigate inflammatory and immunogenic mechanisms by which T-cell 
activation with nivolumab administration mediates changes in parameters of 
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bone remodeling and density in patients with RCC. We will quantify baseline and 
post-treatment serum levels of 1) circulating pro- and anti-inflammatory cytokines 
including TNF-α, INF-gamma, IL-1 and IL-6, and 2) circulating RANK-L and OPG 
in all participants.  Serum findings will be correlated with changes in parameters 
of bone strength and metabolism. 
12.1.1 
Study Procedures 
The capacity of a bone to resist fracture is determined by bone 
remodeling and quantity. We have hypothesized that IT leads to 
deficiencies in these parameters of bone metabolism and strength. 
Serum markers of bone formation and resorption help quantify bone 
remodeling. Clinically, bone quantity is measured using dual energy 
X-ray absorptiometry (DXA) which provides areal bone mineral 
density (aBMD) parameters.  Quantitative CT scan (QCT) provides 
volumetric bone mineral density (vBMD) Derangement to any 
component of skeletal homeostasis – quantity, quality or remodeling – 
will compromise bone strength and increase fracture risk. To 
characterize the effect of nivolumab on measures of bone remodeling 
and density, serum studies and bone density measurements will be 
collected on study participants, outlined below. 
12.1.2 
Serum Markers of Bone Metabolism 
At baseline, prior to nephrectomy and 40-weeks post-randomization, 
parameters of osteoclast-mediated bone resorption (C-telopeptides, 
CTX) and osteoblast-mediated bone formation (Procollagen 1 N-
terminal peptide, P1NP) will be measured using serologic assays on 
serum collected from all research participants who consented to 
optional research receiving nivolumab as well as controls as a part of 
the existing parent study protocol. CTX (Serum Crosslaps ELISA; CV: 
2.3%; Nordic Bioscience A/S, Herlev, Denmark) and P1NP (Elecsys 
2010 Immunoassay System; CV: 6.5%; Orion Diagnostica UniQ P1NP 
RIA, Espoo, Finland) will be measured from archived serum (section 
10.2.2) and then analyzed in batches at the JHU Advanced Chemistry 
Laboratory. 
12.1.2.1 
Statistical Analysis 
We will determine if nivolumab therapy is associated with 
changes in bone turnover marker levels (CTX and P1NP) 
at 40 weeks post-randomization. The dependent variables 
are CTX and P1NP levels at 40 weeks post-randomization 
using serologic assays on serum collected from all 
consenting research participants. The primary outcome 
measure will be percent change from baseline to peak 
biomarker serum level (continuous). The independent 
variable is receipt of nivolumab for individuals undergoing 
nephrectomy. Initially, we will use multivariable linear or 
nonlinear regression (depending on the distribution of each 
bone turnover biomarker) to test whether nivolumab 
therapy prior to nephrectomy is associated with the percent 
change in CTX and P1NP levels from baseline to 
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maximum levels post-nephrectomy. However, since the 
bone turnover biomarker levels assessed over time from 
the same subject are likely to be correlated, we will also 
pursue a more efficient, albeit complicated analysis that 
will utilize all the bone turnover biomarker data collected 
over time in one model to assess whether nivolumab 
therapy is associated with the outcome longitudinal profiles 
of each bone turnover biomarker. Subgroup analyses will 
be performed for 1) sex; 2) age, 3) turnover state at 
baseline, 4) tumor response. Secondary outcomes of 
interest include modeling both the mean change in CTX 
and P1NP from baseline to 40 weeks post-randomization, 
as well as the mean change in CTX and P1NP from 
surgery to 40 weeks post-randomization. We will also 
explore the relationship of vitamin D, calcium, renal 
function and parathyroid hormone with possible changes in 
bone remodeling over time through correlation analyses, 
as well as, potential role as either a mediating or 
moderating in the association between nivolumab and 
biomarkers. Power calculation: Change in CTX and P1NP 
levels from baseline to max. Based upon study population 
of 766 patients (383 receiving nivolumab therapy and 383 
not receiving nivolumab therapy) with analyzable data 
while assuming 5% attrition in each group, we will have 
80% power to detect a small effect size (Cohen’s f2) of 
0.02 for CTX and P1NP based upon an F test from a 
mutivariable linear regression analyses conservatively 
assuming adjustment for 6 covariates (in addition to time 
and time x treatment interaction terms) with an alpha of 
0.05 (two-sided). Power calculations were based on the 
effect size, as there is no preliminary data in this patient 
population. 
12.1.3 
Measures of Areal and Volumetric Bone Density 
At baseline and 40-weeks post- randomization, aBMD at the spine, 
hip, femoral neck and distal 1/3 radius will be quantified using DXA 
using standard imaging protocols in research participants receiving 
nivolumab (n>50) as well as controls (n>50). There is no restriction on 
center participation. At baseline and 40-weeks post-nephrectomy, 
vBMD of the spine (non-contrast scans) and hip (with or without 
contrast) will be quantified using screening and surveillance CT 
imaging collected per parent study protocol in research participants at 
all participating sites. Parameters of vBMD will be calculated on CT 
scans collected under the existing protocol (opportunistic use) with 
validated software (MindWays, Austin, TX). 
NOTE: 
If a patient consented to participate in this sub-study, the 
40 week DXA should be completed only if the baseline 
DXA completed. 
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12.1.3.1 
Statistical Analysis 
We will determine if nivolumab therapy is associated with 
change in aBMD or vBMD at 40 weeks post-
randomization. The dependent variable is aBMD or vBMD. 
The independent variable is receipt of neoadjuvant 
nivolumab therapy in patients undergoing nephrectomy. 
We will determine the effect of neoadjuvant nivolumab 
therapy on changes in BMD measurements using 
multivariable linear or nonlinear (depending on the 
distribution of each bone quantity biomarker) regression. 
Subgroup analyses will be performed, as above. Power 
calculation: Change in BMD measurements from baseline 
to 40 weeks post-randomization. A sample of 50 patients 
(25 receiving neoadjuvant nivolumab therapy and 25 not 
receiving neoadjuvant nivolumab therapy) with available 
BMD measurements at both baseline and 40 weeks post 
randomization will permit, at 80% power and an alpha of 
0.05 (two-sided), the detection of a clinically significant 
large effect size (Cohen’s f2) of 0.35 from multivariable 
linear regression models conservatively assuming 
adjustment for 4 covariates. 
12.1.4 
Serum Measures of Circulating Cytokine Levels and Additional 
Regulators of Bone Metabolism 
Serum levels of cytokines known to both stimulate and inhibit 
osteoclastic and osteoblastic activity will be quantified in serum 
collected from all participants who answer “yes” to additional research 
conducted on serum collections (see 10.2.2). Cytokines such as IFN-
γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10 and TNF-α will be quantified 
in all patients at baseline, prior to nephrectomy, and at 40-weeks post 
randomization. The list of cytokines to be explored will be curated 
based on the NanoString results and other relevant results by 
correlatives at the time of analysis, but will utilize the Luminex 
Multiplex platform (Invitrogen /ThermoFischer Scientific, Austin, TX).  
This analysis will be performed in collaboration with Dr. Rupal Bhatt 
(Dana Farber / Harvard Cancer Center Immune Monitoring Core). 
Additional Regulators of Bone Metabolism: At baseline, prior to 
nephrectomy, and 40-weeks post-randomization, OPG and RANK-L 
(Alpco Diagnostics, Salem, NH) as well as TGF-B (R&D Systems, 
Minneapolis) will be measured using serologic assays on serum 
collected from all consenting research participants receiving 
nivolumab as well as controls as a part of the existing protocol. Serum 
will be frozen at -80C and then analyzed in batches at the JHU 
Advanced Chemistry Laboratory. 
12.1.4.1 
Statistical Analysis 
We will determine if higher levels of pro and anti-
inflammatory cytokines and circulating RANK-L/OPG are 
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measured at multiple time points with primary and 
secondary measures defined in Aim 1.  The independent 
variables will T-cell secreted regulators of bone 
metabolism (Table 1). The data for this hypothesis have a 
nested structure (i.e., repeated measurement of cytokines, 
RANK-L and OPG levels and nivolumab derived 
inflammation over time (level one) within patients (level 
two).  Our outcome is at the time level (level one). Multiple 
correlation analyses will be performed between the 
inflammatory markers and other continuous independent 
measures using Pearson correlation including exploratory 
stratified analyses by group assignment.  In unadjusted 
and adjusted multilevel linear or nonlinear (depending on 
the distribution of each biomarker) regression, we will test 
whether nivolumab derived inflammation measures at each 
time point predict the current or using a temporal lag, the 
next time points measure of a biomarker. We will 
determine the effect of pro and anti-inflammatory cytokines 
on elevations in the biomarkers using generalized 
estimating equations (GEE) to adjust for the correlation 
within a subject of multiple measures of a biomarker over 
time. Subgroup analyses will be performed, as above.  
Power calculation: Enrollment of approximately 600 
patients, 80% power and an alpha of 0.05 (two-sided) will 
permit the detection of at least a 0.12 correlation between 
indicators of nivolumab derived inflammation and 
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13. 
Quality of Life (QOL) Studies 
13.1 
Statistical Considerations 
The primary objective is to evaluate differences in change from baseline in 
patient-reported outcomes and toxicities among patients randomized to treatment 
with nivolumab compared to surgery alone.  Within this objective are several 
specific questions of interest: 
1. How do quality of life and symptom/toxicity burden change following a short 
course of neoadjuvant nivolumab? 
2. How does quality of life change from pre- to post-nephrectomy? 
3. Are there differences in the change in quality of life and symptom burden 
following nephrectomy between patients randomized to nivolumab and those 
randomized to surgery alone? 
4. Is there a difference in the change in quality of life over time between arms at 
40 weeks (in the midst of treatment in patients on arm A)? 
5. Is there a difference in the pattern of change in quality of life over time 
between arms after the end of treatment (up to 2 years)? 
6. Is there a difference in the pattern of change in quality of life over time from 
baseline to recurrence? 
The overarching goal is to characterize the impact of nivolumab on symptoms 
and quality of life. Therefore, question 4 above is of primary interest and will drive 
the sample size. The primary analysis will have 3 dimensions. Overall Type I 
error of 5% will be split among the 3 dimensions described below. 
The QOL component of the study will be mandatory, and target accrual of 320 
patients is planned in order to have adequate power to detect an effect size of 
0.5 for the primary analysis, which consistent with a clinically meaningful change. 
As the target accrual approaches, the consent form will be amended to remove 
reference to the QOL component. 
13.1.1 
Symptoms - Items from NFKSI-19 
Although it was originally developed and validated to assess disease-
related symptoms in patients with advanced kidney cancer, this 
instrument will also be useful to capture many of the most common 
side effects associated with nivolumab. Six of the 8 symptoms 
occurring among patients enrolled in the nivolumab arm of the 
Checkmate trial (existing reference 13) at rates of 5% or greater are 
captured on the NFKSI-19: fatigue, nausea, diarrhea, decreased 
appetite, cough, and dyspnea. These, along with pain, weakness, and 
fever, will form the symptom assessment instrument for the study. 
The null hypothesis is that there is no difference in the change from 
baseline to week 40 in this symptom score. The alternative hypothesis 
is that the change in symptom burden differs among patients 
randomized to observation. This hypothesis will be tested using a two-
sided Wilcoxon rank sum test with Type I error of 3%. As shown in the 
table, there will be 90% power to detect an effect size of about 0.45 if 
adherence at 40 weeks is 80%, and an effect size of about 0.5 if 
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adherence is 65%. Estimates of 40-week adherence are projected 
based on ASSURE, which demonstrated that 85% of enrolled patients 
had quality of life information available at 22 weeks. Estimates of 
variability for the FKSI-19 have been previously published40; we 
assume similar variability on the selected subset of items. 
Standard 
Deviation 
Correlation 
Standard 
Deviation of 
Change 
Difference between Nivolumab 
and Observation arms in mean 
change score between 
randomization and Week 40 
65% 
Adherence 
(104 per arm) 
80% 
Adherence 
(128 per arm) 
9.0 
0.4 
9.86 
4.93 
4.44 
 
0.6 
8.05 
4.02 
3.62 
10.5 
0.4 
11.50 
5.75 
5.18 
 
0.6 
9.39 
4.70 
4.23 
12.0 
0.4 
13.15 
6.57 
5.92 
 
0.6 
10.73 
5.37 
4.83 
13.5 
0.4 
14.79 
7.39 
6.65 
 
0.6 
12.07 
6.04 
5.43 
13.1.2 
Bother from side effects of treatment 
At 40 weeks, in the midst of nivolumab treatment on Arm A, we will 
compare the proportions of patients who respond to the NFKSI-19 
item with “somewhat”, “quite a bit”, or “very much” between the two 
arms. The null hypothesis is that the rates will be the same. The 
alternative is that the rates will be higher among patients receiving 
nivolumab. Using Fisher’s exact test with 1-sided Type I error of 0.005 
(0.5%), there will be good power (90% to 95%) to detect a 20% 
difference in proportions (for example, 25% on the nivolumab arm and 
5% on the observation arm), assuming adherence is between 65% 
and 80%. 
13.1.3 
Quality of Life:  Change in PROMIS-physical function 
The null hypothesis is that there will be no difference between arms in 
the change in physical function as assessed by the PROMIS 
instrument from baseline to 40 weeks. The alternative is that there is a 
difference. This is a two-sided hypothesis, since it is unknown whether 
the freedom from treatment-related interference on the observation 
arm will be outweighed by declines in function related to disease 
recurrence. Minimally important differences (MIDs) have been 
estimated for the PROMIS Physical Function instrument in advanced-
stage cancer patients41, and are 4.0 – 6.0 points, corresponding to 
effect sizes between 0.45 and 0.67. This hypothesis will be tested 
using a two-sided Wilcoxon rank sum test with Type I error of 1%. 
There will be 82 to 99% power to detect an effect size in this range if 
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13.2 
Analysis Plan 
The primary QOL analysis can be done once all patients have submitted 40-
week quality of life forms, expected to be about 3 years after activation assuming 
accrual occurs as planned. At this time, analyses of questions 1 through 4 above 
can be conducted. Quality of life data are expected to be fully mature when all 
patients have been followed for 2 years, which is expected to be 4.9 years after 
study activation. 
Instruments will be scored using standard procedures. Instrument scores (and 
subscale scores as appropriate) will be prorated by multiplying the sum of the 
scale by the number of items in the scale, then dividing by the number of items 
actually answered. When there are missing data, prorating in this way is 
acceptable as long as more than 50% of items are answered. 
The distribution of scores on all instruments and subscales will be estimated at 
each time point and reported using standard tabular and graphic analyses.  The 
impact of missing data will be characterized. 
In addition to the analyses described above, changes in NFKSI-19 and PROMIS 
Physical Function scores from baseline to pre-nephrectomy among patients 
randomized to neoadjuvant nivolumab will be explored using a Wilcoxon signed 
rank test. The response proportions to the item, “I am bothered by side effects of 
treatment” will also be reported. Similarly, changes from pre-nephrectomy to 8 
weeks post-nephrectomy will be analyzed using this test. Differences in scores 
post-nephrectomy between the arms will be described and tested using a 
Wilcoxon rank-sum test. 
There is at least 80% power to detect a clinically meaningful ½-standard 
deviation change in each of these analyses, assuming 2-sided Type I error of 
5%. 
Total and subscale scores on NFKSI-19 at the time of recurrence will be 
described in order to characterize patient-perceived symptoms experienced at 
the time of scan-detected recurrence. 
Differences in the pattern of change over time in NFKSI-19 and PROMIS 
Physical Function scores will be examined using mixed effects models. A 
significant time-by-treatment interaction from the model would indicate such a 
difference. The model will include stratification factors and could include baseline 
scores if they are found to be different at baseline.   
The above secondary analyses will be done using two-sided tests with Type I 
error of 5%. 
13.3 
PRO-CTCAE 
PRO-CTCAE items related to toxicities associated with nivolumab administration 
have been systematically chosen for collection, based on frequencies and 
severity observed on the Checkmate study in advanced renal cell cancer (13). 
These include fatigue, nausea, itch, diarrhea, decreased appetite, and rash. 
These items will be captured at baseline, pre-nephrectomy (Arm A), 8 weeks 
post-nephrectomy, week 20, week 40, and week 54, which are the times at which 
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will describe the severity, interference, and (as appropriate) frequency rates, 
along with response rates at each time point. 
13.4 
Missing Data 
Describing quality of life is challenging in the presence of missing data. Such 
missingness can occur at several levels and due to a variety of causes. Patients 
may not complete all items on an instrument. As previously indicated, we will 
score instruments if patients complete at least half of the items.  Instrument 
administration can be omitted at a given time point if patients do not come to the 
clinic for scheduled visits, or if there is not time during a visit to administer QOL 
instruments. We have provided contingency instructions in the protocol for 
mailing in QOL forms if these circumstances occur. We have scheduled the 
PRO-CTCAE assessments to occur in alignment with physician-assessed AEs, 
during clinic visits. At each timepoint, if QOL is not completed as planned, sites 
are asked to provide the reason that QOL was not done. These forms are 
completed with a very high compliance rate (> 95%), so reasons can be 
examined and acted on where possible. Reasons for missing data will be 
reported as part of the analysis. 
This study is a registration study, and as such will include an on-site monitoring 
plan as well as telephone sweeps for outstanding data. These can be used to 
prospectively alert sites to upcoming QOL timepoints for patients. 
Nonetheless, missing data may occur. This may increase over time, possibly 
among patients who have had disease recurrence. It cannot be assumed to be 
missing completely at random (MCAR) or even missing at random (MAR), since 
patients who recur or die are likely to have higher rates of missing data. We are 
extremely interested in the symptom burden attributable to disease recurrence, 
however, and the later time points are essential to explore. To address this, we 
will use a model-based method proposed by Schluchter42, jointly modeling the 
distribution of RFS and QOL with a multivariate normal model. The model will 
compare the area under the quality of life curves for the two arms, taking into 
account the missing data. 
 

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14. 
Electronic Data Capture 
Please refer to the EA8143 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol and patient specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application. 
Reports are due January 31, April 30, July 31, and October 31. Instructions for 
submitting the data using the CDUS can be found on the CTEP website 
(http://ctep.cancer.gov/reporting/cdus.html). 
Imaging studies are to be submitted via TRIAD (Section 4.1.4.6) 
14.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being 
studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office – Boston prior to destroying 
any source documents. 
15. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
16. 
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Clinicians 2015; 65(1): 5-29. 
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Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. 
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Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell 
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Latchman YE, Liang SC, Wu Y, et al. PD-L1-deficient mice show that PD-L1 on T 
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Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and Activity of Anti-PD-L1 
Antibody in Patients with Advanced Cancer. N Engl J Med 2012. 
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Krambeck AE, Dong H, Thompson RH, et al. Survivin and b7-h1 are collaborative 
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Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating 
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McDermott DF, Drake CG, Sznol M, et al. Survival, Durable Response, and Long-
Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma 
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10. 
Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for Metastatic Renal Cell 
Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol 2015; 33(13): 
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Topalian SL, Hodi FS, Brahmer JR, et al. Safety, Activity, and Immune Correlates 
of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012. 
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Choueiri TK FM, Escudier BJ, Kim JJ, Kluger HM, Stadler WM, Perez-Gracia JM,  
McNeel DG, Curti BD, Harrison MR, Plimack ER, Appleman LJ, Fong L, Drake CG, 
Cohen LJ, Srivastava S, Jure-Kunkel M, Hong Q, Kurland JF, Sznol M;. 
Immunomodulatory activity of nivolumab in previously treated and untreated 
metastatic renal cell carcinoma (mRCC): Biomarker-based results from a 
randomized clinical trial. J Clin Oncol 32:5s, 2014 (suppl; abstr 5012). 
13. 
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in 
Advanced Renal-Cell Carcinoma. The New England Journal of Medicine 2015; 
373(19): 1803-13. 
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Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and 
PD-1 synergistically regulate T-cell function to promote tumoral immune escape. 
Cancer Research 2012; 72(4): 917-27. 
15. 
Macfarlane AWt, Jillab M, Plimack ER, et al. PD-1 Expression on Peripheral Blood 
Cells Increases with Stage in Renal Cell Carcinoma Patients and Is Rapidly 
Reduced after Surgical Tumor Resection. Cancer Immunology Research 2014; 
2(4): 320-31. 
16. 
Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. 
Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined 
analysis. J Urol 2004; 171(3): 1071-6. 
17. 
Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-
programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, 
pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28(19): 3167-
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18. 
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for 
advanced renal-cell carcinoma. N Engl J Med 2007; 356(22): 2271-81. 

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19. 
Maroto JP, Hudes G, Dutcher JP, et al. Drug-related pneumonitis in patients with 
advanced renal cell carcinoma treated with temsirolimus. J Clin Oncol 2011; 
29(13): 1750-6. 
20. 
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal 
cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. 
Lancet 2008; 372(9637): 449-56. 
21. 
White DA, Camus P, Endo M, et al. Noninfectious pneumonitis after everolimus 
therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 2010; 
182(3): 396-403. 
22. 
Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal 
tumors: an analysis of pathological features related to tumor size. J Urol 2003; 
170(6 Pt 1): 2217-20. 
23. 
Pierorazio PM, Hyams ES, Mullins JK, Allaf ME. Active surveillance for small renal 
masses. Reviews in Urology 2012; 14(1-2): 13-9. 
24. 
Freidlin B, Korn EL, Hunsberger S, Gray R, Saxman S, Zujewski JA. Proposal for 
the use of progression-free survival in unblinded randomized trials. J Clin 
Oncol2007; 25(15): 2122-6. 
25. 
Webster WS, Lohse CM, Thompson RH, et al. Mononuclear cell infiltration in clear-
cell renal cell carcinoma independently predicts patient survival. Cancer 2006; 
107(1): 46-53. 
26. 
Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response 
with B7-h1 expression in human melanocytic lesions supports an adaptive 
resistance mechanism of immune escape. Sci Transl Med 2012; 4(127): 127ra37. 
27. 
Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with 
poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer 
Res 2006; 66(7): 3381-5. 
28. 
Law CW, Chen Y, Shi W, Smyth GK. Voom: precision weights unlock linear model 
analysis tools for RNA-seq read counts. Genome Biol 2014; 15(2): R29. 
29. 
Smyth GK, Michaud J, Scott HS. Use of within-array replicate spots for assessing 
differential expression in microarray experiments. Bioinformatics 2005; 21(9): 
2067-75. 
30. 
Smyth G. Linear models and empirical Bayes methods for assessing differential 
expression in microarray experiments. 2004. Statistical Applications in Genetics 
and Molecular Biology; 3. 
31. 
Kortenhorst MS, Wissing MD, Rodriguez R, et al. Analysis of the genomic 
response of human prostate cancer cells to histone deacetylase inhibitors. 
Epigenetics 2013; 8(9): 907-20. 
32. 
Wu D, Lim E, Vaillant F, Asselin-Labat M-L, Visvader JE, Smyth GK. ROAST: 
rotation gene set tests for complex microarray experiments. Bioinformatics 2010; 
26(17): 2176-82. 
33. 
Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a 
knowledge-based approach for interpreting genome-wide expression profiles. 
Proceedings of the National Academy of Sciences of the United States of America 
2005; 102(43): 15545-50. 

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34. 
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and 
powerful approach to multiple testing. Journal of the Royal Statistical Society 
Series B (Methodological) 1995: 289-300. 
35. 
Santegoets SJ, Stam AG, Lougheed SM, et al. T cell profiling reveals high 
CD4+CTLA-4 + T cell frequency as dominant predictor for survival after prostate 
GVAX/ipilimumab treatment. Cancer Immunology, Immunotherapy : CII 2013; 
62(2): 245-56. 
36. 
Cha E, Klinger M, Hou Y, et al. Improved survival with T cell clonotype stability 
after anti-CTLA-4 treatment in cancer patients. Science Translational Medicine 
2014; 6(238): 238ra70. 
37. 
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by 
inhibiting adaptive immune resistance. Nature 2014; 515(7528): 568-71. 
38. 
Anders S, Huber W. Differential expression analysis for sequence count data. 
Genome Biology 2010; 11(10): R106. 
39. 
Freidlin B, Korn EL, Gray R, A general inefficacy interim monitoring rule for 
randomized clinical trials, Clinical Trials 2010; 7: 197-208. 
40. 
Rothrock NE, Jensen SE, Beaumont JL, et al.  Development and initial validation 
of the NCCN/FACT Symptom Index for advanced kidney cancer.  Value in Health 
2013; 16: 789-796. 
41. 
Yost KJ, Eton DT, Garcia SE, Cella D.  Minimally important differences were 
estimated for six Patient-Reported Outcomes Measurement Information System-
Cancer scales in advanced cancer patients.  J Clin Epidemiol 2011; 64: 507-516. 
42. 
Schluchter MD.  Methods for the analysis of informatively censored longitudinal 
data.  Stat Med 1992; 11: 1861-1870. 
43. 
Cella D, Wagner L, Re-personalizing precision medicine: Is there a role for patient-
reported outcomes? J Commun Support Oncol 2015; 13(7): 275-277. 
44. 
Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer 
Institute’s Patient Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events (PRO_CTCAE). J Natl Cancer Inst 2014; 106. 
45. 
Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, 
non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805); a double-blind, 
placebo-controlled, randomized, phase 3 trial. Lancet 2016. Doi 10.1016/50140-
6736(16) 00559-6. 

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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
Rev. Add4 
Rev. Add8 

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Guidelines for Submission of Pathology Materials 
The following pathology materials are to be submitted within one (1) month of randomization 
or collection or within one (1) week of sectioning fresh slides:  
1. Pathology Submissions: 
• 
MANDATORY (Arm A): Representative formalin-fixed paraffin embedded FFPE blocks 
from any diagnostic primary or metastatic tumor tissue biopsy (primary tumor tissue is 
preferred if metastasis is also present). 
• 
Arm A Biopsy: Image guided percutaneous core needle biopsy of primary tumors 
(or metastasis) will be performed prior to starting treatment. Primary tumor is 
preferred over metastasis. Six non-fragmented biopsy cores should be obtained. 
One biopsy core will be sent to surgical pathology for standard of care histological 
analysis by the local pathologist and the five (5) other biopsy cores will be retained 
for research purposes. These cores will be placed in specimen containers and 
paraffin embedded. Of note, the paraffin embedded research cores will not be 
utilized until a histological diagnosis is reached. If in the event that a histological 
diagnosis cannot be reached with the dedicated diagnostic tissue core, one or 
more of these research cores will be released to pathology for analysis 
NOTE: 
Patients randomized to Arm B are encouraged, but not required, to have 
a core biopsy after randomization for patients who have not had a biopsy 
within twelve (12) months prior to randomization that confirms RCC. 
• MANDATORY (Both Arms): Representative formalin-fixed paraffin embedded FFPE 
blocks from surgical tumor tissue must be submitted within one (1) month of 
collection. 
• 
MANDATORY (Both Arms): Representative H&E slides from diagnostic and surgical 
tumor tissue blocks 
• 
OPTIONAL (Both Arms): Additional representative formalin-fixed paraffin-embedded 
(FFPE) primary tumor tissue blocks from diagnostic core needle biopsy, surgical FFPE 
primary tumor and normal tissue blocks, and recurrence or resection FFPE primary 
tumor tissue blocks (if available) 
NOTE: If blocks are unavailable for submission, cores and fresh cut slides are to be 
submitted. All cores and slides must be adequately labeled, with slides numbered 
sequentially in the order cut. Alternative submission requirements: 
• 
One (1) H&E slide from each source block, and  
• 
Twenty (20) 4 µm unstained, positively charged air-dried plus slides from the 
thickest part of the tumor (Superfrost Plus recommended). After cutting, the 
slides should be kept refrigerated (2-5°C) until shipment. Fresh slides must 
be shipped overnight within one (1) week of sectioning on refrigerated gel 
packs. 
• 
One (1) or more core punches (minimum of 4mm diameter). If core punch 
tool is unavailable, request core punch kit from the ECOG-ACRIN CBPF 
(844) 744-2420 
If these criteria cannot be met, please contact the ECOG-ACRIN CBPF 
(eacbpf@mdanderson.org) to obtain alternative submission requirements. 
2. Forms and Reports: 
NOTE: Adequate patient identifying information must be included with every submission. 
It is strongly recommended that full patient names be provided. The information 

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will be used only to identify patient materials and will help to expedite any 
required communications with the institution (including site pathologists). 
ICON (who is distributing the PK kits) is also providing zipper lock bags and specimen 
ID/barcode accession labels and tissue requisition forms for the baseline tissue 
submissions. Place blocks and/or slides in the zipper lock bags. 
The pathology specimens are to be labeled with the institutional Pathology ID# and ICON 
sample ID/barcode/accession label on the zipper lock bags provided. 
The following items are to be included with the pathology materials: 
• 
Institutional Diagnostic and Surgical Pathology Reports 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981) [If STS is unavailable] 
• 
Sample Tracking System (STS) Shipping Manifest Form  
• 
Immunological study reports, if available 
• 
ICON Tissue Requisition Form (baseline only) 
3. Mail pathology materials to: 
MD Anderson Cancer Center CBPF 
Mike Balco 
2130 West Holcombe Boulevard, LSP9.4227 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions, contact the pathology 
coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility by 
telephone: (844) 744-2420 or email: eacbpf@mdanderson.org 
Rev. Add10 

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MEMORANDUM 
TO:  
______________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
_______________________ 
SUBJECT: 
Submission of Pathology Materials for EA8143: A Randomized Phase III Study 
Comparing Perioperative Nivolumab vs. Observation in Patients with Unfavorable 
Localized Renal Cell Carcinoma Undergoing Nephrectomy 
 
A patient has been entered onto an ECOG-ACRIN protocol by 
______________________________ (ECOG-ACRIN Investigator). This protocol requires the 
submission of pathology materials for central diagnostic review and defined and/or undefined 
laboratory research studies. 
Please return the surgical pathology report(s), the slides and/or blocks and any other required 
materials to the Clinical Research Associate (CRA). The CRA will forward all required pathology 
materials to the ECOG-ACRIN Central Biorepository and Pathology Facility. 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility for undefined future research studies. Paraffin blocks will 
be returned upon written request for purposes of patient management. 
If you have any questions regarding this request, please contact the ECOG-ACRIN Central 
Biorepository and Pathology Facility at Tel: (844) 744-2420, Fax: (713) 563-6506 or Email 
eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: ________________________________________  
Address: _______________________________________  
Phone: ________________________________________  
Thank you. 
 

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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 

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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality and comprehensive care. My research staff and 
I will maintain very close contact with you. This will allow me to provide you with the best 
care while learning as much as possible to help you and other patients with kidney 
cancer. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix III 
 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all 
Clinical Data and Results and Raw Data will be collected , used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 

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4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s 
confidential and proprietary data, in addition to Collaborator(s)’s intellectual property rights, 
are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also 
be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/ proprietary information. 
 

ECOG-ACRIN 
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Version Date: September 16, 2021 
 
NCI Update Date: February 2, 2017 
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Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 

ECOG-ACRIN 
EA8143 
Cancer Research Group 
Version Date: September 16, 2021 
 
NCI Update Date: February 2, 2017 
146 
A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix V 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy 
test regardless of age or disease state) of a female patient while she is on nivolumab, or 
within 100 days of the female patient’s last dose of nivolumab must be reported in an 
expeditious manner. The outcome of the pregnancy and neonatal status must also be 
reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be 
reported via CTEP’s Adverse Event Reporting System (CTEP-AERs) 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy 
test need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, 
followed by a complete expedited CTEP-AERs report within 5 calendar days of the initial 24-
hour report. 
What other information do I need in order to complete the CTEP-AERs report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium 
and perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) 
“Pregnancy, puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a Grade 3 event.   
• 
The start date of the pregnancy should be reported as the calculated date of conception.   
• 
The potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” section of 
the CTEP-AERs report.  
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status via CTEP-AERs.  
• 
The decision on whether an individual female patient can continue protocol treatment will 
be made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office – Boston.  Please contact the ECOG-ACRIN Operations Office – 
Boston to ask for a conference call to be set up with the appropriate individuals.   
• 
It is recommended the female patient be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling.  
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How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERs 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  
However, if the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-
AERs report should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the CTEP 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed 
on a case by case basis.   
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
It must be reported via CTEP-AERs as a Grade 4 “Pregnancy loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A pregnancy loss should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A newborn death occurring during the first 28 
days after birth” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention.  However, for this protocol, any neonatal death that 
occurs within 28 days of birth, without regard to causality, must be reported via CTEP-AERs 
AND any infant death after 28 days that is suspected of being related to the in utero 
exposure to nivolumab must also be reported via CTEP-AERs. 
It must be reported via CTEP-AERs as Grade 4 “Death neonatal” under the System Organ 
Class (SOC) “General disorder and administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERs reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any 
additional medical information to CTEP (301-897-7404). This form is available on CTEP's 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReport
Form.pdf) 

ECOG-ACRIN 
EA8143 
Cancer Research Group 
Version Date: September 16, 2021 
 
NCI Update Date: February 2, 2017 
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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix VI 
 
EA8143 Collection and Shipping Kit Order Instructions 
Specimen Collection/Shipping Kits are being provided by CENETRON CENTRAL 
LABORATORIES and are to be ordered ONLINE. 
Starter kits are not available. Kit requests are to be made AFTER patient randomization. 
Questions regarding kits can be directed to projectmanagement@cenetron.com or call the 
Cenetron clinical trials group at (512) 439-2000.  
Ordering Process: 
• 
At time of patient randomization, provide the contact for kit ordering in OPEN. 
• 
Following randomization of the patient to the trial, go to the website www.cenetron.com 
and click on the ‘Order Kits’ button at the top right. It is recommended that kits be 
ordered same day as patient randomization. 
• 
The order form is not study specific and can be used for any study. Complete the 
online form as follows: 
o Sponsor (REQUIRED): ECOG-ACRIN 
o Contact Name (REQUIRED): Name of the site kit contact. Should match the name 
of the individual provided in OPEN as the kit contact 
o Protocol Number (REQUIRED): EA8143 
o Phone Number (REQUIRED): Phone number of the kit contact. Please ensure 
that this is a number that can be reached from an external caller 
o Site Number (REQUIRED): Institution NCI Site ID 
o FAX Number: Fax number of the kit contact 
o Investigator: Last name of the kit contact is adequate 
o Email (REQUIRED): Email of the site kit contact. Must be entered twice to confirm 
o Date Supplies Needed (REQUIRED): Add three (3) business days or more to 
order date.  (Reminder that weekends and holidays must also be considered in this 
timeline) 
o KIT NAME (REQUIRED): EA8143 Collection Kit 
o Quantity: 1 
o 
Comments: Provide EA8143 Patient Case ID# and full shipping address 
• 
‘Patient Case ID =’ ##### 
• 
Ship Kit to name of the individual to whom the kit is being shipped. (May be 
different than the kit contact provided above) 
• 
Full street address, town, state and zip code 
o Answer the security question 
Please complete this form correctly, including the valid ECOG-ACRIN patient case 
number and complete shipping address. If information is missing the kit processing 
will be delayed. 
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Version Date: September 16, 2021 
 
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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix VII 
 
EA8143 Biopsy Reimbursement Form 
This form is to be used to request reimbursements for the performance and submission of the non-SOC 
biopsies as outlined in Section 10. Reimbursements are NOT applicable for biopsies performed as part of 
standard of care, and thus billed to patients or their insurance. 
If you have questions about the reimbursement 
process, please contact the EA funding team at 
ea.fundingsheet@jimmy.harvard.edu.   
Please fax the completed form to the  
ECOG-ACRIN Translational Science Team (TST),  
FAX: (617) 589-0914 
 
Payee Address 
 
 Payee/W-9 Name: 
      
 
 
Payee Tax ID #: 
      
Attention To: 
      
 
 
 
Institution CTEP ID: 
      
Street Address: 
      
 
Name of Investigator: 
      
 City, State, Zip: 
      
 
NCI Investigator ID #: 
      
 Any Requested Reference on 
Payment (i.e. Invoice #): 
      
 
 
ECOG-ACRIN 
Case ID 
Time Point 
Date of 
Service 
Service Performed  Amount Requested  
#1 
      
Following randomization, 
prior to start of protocol 
therapy 
      
      
$ 3000.00 
#2 
      
      
      
$ 3000.00 
#3 
      
      
      
$ 3000.00 
 
I confirm that these patients are registered to the protocol referenced above, the patient numbers and 
procedure dates are correct, and the biopsies were performed for the purposes of the trial only, following 
randomization of the patient to the lowest step of the trial, and that the biopsy was NOT standard of care 
and was NOT billed to insurance or the patient 
Signature: ___________________________________________________ Date: _________ 
 
If there are problems with this invoice, please contact:  
 
Name 
 
Phone 
 
Fax 
 
Email 
 
      
      
      
      
 
ECOG-Operations Office Use Only:      TST Reviewer: ____________________  Date: _____________ 
Patient 
#1 
#2 
#3 
Date of Randomization 
 
 
 
Registering Institution 
 
 
 
Data in STS indicates “Not billed to insurance” 
 
 
 
Performed after randomization, prior to start of therapy. 
 
 
 
Specimen indicated as received by the receiving laboratory in STS 
 
 
 
Approved 
 
 
 
 
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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix VIII 
 
Methods Of Contraception 
At a minimum, patients must agree to use one highly effective OR one less effective method of 
contraception as listed below: 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. Patients of child bearing potential and partners of male subjects, who are of childbearing 
potential, are expected to use one of the highly effective methods of contraception listed below. 
Male patients must inform their partners who are of childbearing potential of the contraceptive 
requirements of the protocol and are expected to adhere to using contraception with their partner. 
Contraception methods are as follows: 
1. Progestogen only hormonal contraception associated with inhibition of ovulation. 
2. Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) 
such as Mirena. 
3. Nonhormonal IUDs, such as ParaGard 
4. Bilateral tubal occlusion 
5. Vasectomised partner with documented azoospermia 90 days after procedure 
• 
Vasectomised partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant of childbearing potential and that the 
vasectomised partner has received medical assessment of the surgical success. 
6. Intrauterine hormone-releasing system (IUS) 
7. Complete abstinence 
• 
Complete abstinence is defined as the complete avoidance of heterosexual intercourse. 
(refer to Glossary of Terms) 
• 
Complete abstinence is an acceptable form of contraception for all study drugs and must 
be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days). 
• 
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
• 
Patients who choose complete abstinence must continue to have pregnancy tests, as 
specified in Section 7 
• 
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the patient chooses to forego complete abstinence. 
• 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
8. Diaphragm with spermicide 
9. Cervical cap with spermicide 
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10. Vaginal sponge with spermicide 
11. Male or female condom with or without spermicide* 
12. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action. 
* A male and a female condom must not be used together. 
UNACCEPTABLE METHODS OF CONTRACEPTION 
13. Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
14. Withdrawal (coitus interruptus) 
15. Spermicide only 
16. Lactation amenorrhea method (LAM) 
 

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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix IX 
 
Financial Disclosure Information Form 
The following items are included in Appendix IX: 
1. EA8143 Financial Disclosure Information Form 

ECOG-ACRIN 
EA8143 
Cancer Research Group 
Version Date: September 16, 2021 
 
NCI Update Date: February 2, 2017 
153 
EA8143 FINANCIAL DISCLOSURE INFORMATION FORM 
Name: 
Investigator 
Sub Investigator 
Independent Assessor 
IRC Member 
Other (specify): 
NOTE: Name and Role must match the information on Form FDA 1572 or Site Information Sheet (SIS) and Curriculum Vitae (CV), as applicable. 
Protocol Number: 
EA8143 - CA209 
Site Number: 
 
 
Please answer each of the questions below BY CHECKING THE APPROPRIATE BOX. 
If you check YES to any question you MUST provide details of the disclosable information. 
Please note that if there is any discrepancy between the financial disclosure information reported on this form (or updated versions of it)  
and internal financial records, an explanation will be required. 
Do you, your spouse, or your dependent children participate in any financial arrangement with Bristol-Myers Squibb and/or Ono Pharmaceutical 
Co., LTD whereby the value of the compensation could be influenced by the outcome of the study (i.e. could be higher for a favorable outcome 
than for an unfavorable outcome)? If yes, please describe: 
YES
 NO
 
 
This could be compensation that is explicitly greater for a favorable result, compensation in the form of an equity interest in BMS and/or Ono or compensation tied 
to sales of the product, such as a royalty interest. [21 CRF 54.2 (a)] 
During the time you are conducting the study and for one (1) year following completion of the study, will you, your spouse or dependent children 
or your institution (to the extent used to support your activities), receive any significant payments of other sorts from Bristol-Myers Squibb 
and/or Ono Pharmaceutical Co., LTD that exceed $25,000 USD (exclusive of the costs of conducting the clinical study or other clinical studies)? 
If yes, please provide the USD amount and the nature of the payments: 
YES
 NO
 
 
Such payments might be a grant to you or your institution to fund ongoing research, compensation in the form of equipment, retainers for ongoing consultation, 
or honoraria. 
[21 CFR 54.2 (f)] 
Do you, your spouse or dependent children, hold any proprietary interest (property or other financial interest) in the product? If yes, please 
describe: 
YES
 NO
 
 
Proprietary interest would include, but not be limited to, a patent, trademark, copyright or licensing agreement [21 CRF 54.2 (c)] 
Do you, your spouse or dependent children, hold any significant equity interest in Bristol-Myers Squibb and/or Ono Pharmaceutical Co., LTD  
(any ownership interest [stock], stock options or other financial interest) that exceeds $50,000 USD? If yes, please provide the USD amount 
and the nature of the equity interest below: 
YES
 NO
 
 
Equity interest includes any options, puts, calls, straddles and other privileges in addition to an equity ownership position in BMS and/or Ono. This does not 
include ownership interest, stock options or other financial interests over which you have no direct control or input as to the quantities or amounts, e.g., a 401k, 
IRA, Mutual Fund. 
[21 CRF 54.2 (b)] 
 
 
 

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Version Date: September 16, 2021 
 
NCI Update Date: February 2, 2017 
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In accordance with U.S. Code of Federal Regulations (21 CFR Part 54), I declare that the information provided on this form is, to the best of my 
knowledge and belief, true, correct and complete. 
Furthermore, if my financial interests and arrangements, or those of my spouse and dependent children, change from the information provided above 
during the course of the study or within one year following completion of the study as per site closure letter, I will promptly notify Bristol-Myers 
Squibb. 
SIGNATURE & DATE 
 
 
 
DAY 
MONTH 
YEAR 
 

ECOG-ACRIN 
EA8143 
Cancer Research Group 
Version Date: September 16, 2021 
 
NCI Update Date: February 2, 2017 
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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix X 
 
How To Measure Your Waist Circumference2 
 

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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix XI 
 
American Joint Committee on Cancer (AJCC) TNM Staging System for Kidney Cancer (7th 
Edition) 
 
Primary tumors (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
T1 
Tumor ≤ 7 cm in greatest dimension, limited to the kidney 
T1a 
Tumor ≤ 4 cm in greatest dimension, limited to the kidney 
T1b 
Tumor > 4 cm but ≤ 7 cm in greatest dimension, limited to the kidney 
T2 
Tumor > 7 cm in greatest dimension, limited to the kidney 
T2a 
Tumor > 7 cm but ≤10 cm in greatest dimension, limited to the kidney 
T2b 
Tumor > 10 cm, limited to the kidney 
T3 
Tumor extends into major veins or perinephric tissues but not into the 
ipsilateral adrenal gland and not beyond the Gerota fascia 
T3a 
Tumor grossly extends into the renal vein or its segmental (muscle-containing) 
branches, or tumor invades perirenal and/or renal sinus fat but not beyond the 
Gerota fascia 
T3b 
Tumor grossly extends into the vena cava below the diaphragm 
T3c 
Tumor grossly extends into the vena cava above the diaphragm or invades the 
wall of the vena cava 
T4 
Tumor invades beyond the Gerota fascia (including contiguous extension into 
the ipsilateral adrenal gland) 
Regional lymph node (N) 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in regional lymph node(s) 
Distant metastasis (M) 
M0 
No distant metastasis 
M1 
Distant metastasis 
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Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix XII 
 
EA8143 ICON Site Information/Initial Kit Order Form 
Please complete this form for the initial shipment of three (3) kits and the Laboratory Instruction 
Manual. ICON requires fifteen to twenty (15-20) days to process this form and ship out the initial 
kits. Please complete and email to EA8143_initial_ICON_kit@ecog-acrin.org as soon as possible. 
Questions regarding kits can be directed to ICON toll-free at (877) 797-4422 or 
LabSiteHelp@iconplc.com. Please reference protocol number: CA209-531 (EA8143) when 
contacting ICON. 
To reorder kits sites must register with iSite, ICON Central Laboratories Secure Website Portal. 
See Appendix XIII for instructions. Kit reorder shipments usually take about seven (7) to ten (10) 
business days. 
Please write using block letters. 
STUDY COORDINATOR LAST NAME 
 
STUDY COORDINATOR FIRST NAME 
 
STUDY COORDINATOR TELEPHONE NUMBER 
 
STUDY COORDINATOR FAX NUMBER 
 
CELL PHONE NUMBER/PAGER NUMBER 
 
EMAIL ADDRESS 
 
PROVIDE ADDRESS WHERE KITS ARE TO BE SHIPPED BELOW 
INSTITUTION 
 
DEPARTMENT 
 
BUILDING/FLOOR/ ROOM*  
 
STREET 
 
CITY/STATE/POSTAL CODE/COUNTRY 
 
ADDRESS WHERE LABORATORY 
SPECIMENS ARE COLLECTED 
 
INSTITUTION NCI CTEP ID# 
 
INVESTIGATOR NCI CTEP ID# 
 
INVESTIGATOR LAST NAME 
 
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INVESTIGATOR FIRST NAME 
 
STREET ADDRESS 
 
CITY/STATE/POSTAL CODE/COUNTRY 
 
INVESTIGATOR TELEPHONE NUMBER 
 
INVESTIGATOR FAX NUMBER 
 
INVESTIGATOR EMAIL ADDRESS 
 
* Mandatory information for hospital, clinic or large sites. 

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A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in 
Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix XIII 
 
iSite User Guide for Kit Reordering 
Getting Started 
To ensure security, only email addresses on file with ICON Central Laboratories are able to 
register with iSite. You must submit the EA8143 ICON Site Information/Initial Kit Order Form 
before you can create an account in iSite. If you are unsure of the email address that ICON has 
for your site please contact ICON toll-free at (877) 797-4422 or LabSiteHelp@iconplc.com. 
Please reference protocol number: CA209-531 (EA8143) when contacting ICON.  
Creating an Account in iSite 
Step 1. To register, visit https://isite.iconplc.com 
Step 2. Click Create Account. The Registration screen displays. 
Step 3. Enter the Email Address that is on file with ICON Central Laboratories. Click Submit. 
Registration screen will display automated message advising of email being sent to 
complete the registration process. 
Step 4. From your email account, open the message from iSite Support. Click the link. The ‘Create 
a New Account’ screen will display. 
Step 5. Select your Name*, enter in a Password**, Confirm password and accept the Terms 
and conditions. Click Register. The ‘Select Study’ screen displays. 
*NOTE: 
If more than one name displays, this indicates our database has the email address 
entered associated to each contact listed. Choose the name you want associated with 
iSite. 
**NOTE: Follow the instructions on the Registration screen of iSite for password requirements. 
Log In 
Step 1. Go to https://isite.iconplc.com 
Step 2. Enter Email Address used to create the account and Password. 
Step 3. Click Log In. The ‘Select Study’ screen displays 
IMPORTANT: 
After three unsuccessful attempts, your account will be locked. You will need to 
click the Forgot password link to change your password. 
Selecting a Study 
Step 1. From the Home screen, in the To Start section, select the applicable Study from the drop 
down list. 
NOTE: 
Only active studies that you are participating in are listed in the drop down menu. If 
you are only participating in one study, it will automatically be selected for you. 
To order kits select the tab at the top of the screen for Supplies and Kit Ordering and then 
select your site. 
Changing Your Password 
If you need to change your password, you may do so directly from iSite. 
Step 1. From the menu bar, click MY ACCOUNT. The ‘My Account’ screen displays. 
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Step 2. Click Change Password. The ‘Change Password’ screen displays. 
Step 3. Enter your Current password, New password and Confirm new password. Click 
Change Password. When entered correctly, “Congratulations! Your password has been 
changed successfully” will display. 
NOTE: 
Follow the instructions on the Change Password screen for password requirements. 
Logging Out of iSite 
Step 1. From any tabbed window, click Log Out. The window displays “You have successfully 
logged out. 
 

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Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) 
Appendix XIV 
 
Correlative Studies of the EA8143 Trial 
 
Title of Study:   
 
Correlative Studies of the EA8143 Trial 
Principal Investigator: 
Sabina Signoretti, MD 
Co-Investigators: 
 
Mohamad Allaf, MD  
       
 
 
 
Naomi Haas, MD 
       
 
 
 
David McDermott, MD 
       
 
 
 
Toni Choueiri, MD 
       
 
 
 
Rupal Bhatt, MD 
Primary Statistician:   
Se Eun Kim, MS 
Abstract: 
PROSPER RCC (EA8143, NCT03055013) is a Phase III, randomized trial that investigates the 
impact of perioperative nivolumab compared with observation on recurrence-free survival (RFS) in 
patients with high-risk Renal Cell Carcinoma (RCC) undergoing radical or partial nephrectomy. On 
April 8th, 2021, it was announced that treatment with pembrolizumab led to improvement in 
disease-free survival in patients with RCC following nephrectomy, meeting the primary endpoint of 
the phase 3 KEYNOTE-564 trial. These findings raise cautious optimism that the PROSPER trial 
will also meet its primary endpoint, demonstrating that anti-PD-1 therapy is also effective, and 
perhaps even more so, when administered perioperatively in patients with high-risk RCC. 
While immune-checkpoint inhibitors are approved for patients with stage 3 resected melanoma, 
their use has been limited by their toxicity. Therefore, the development of biomarkers that can 
identify the subset of patients with RCC who are most likely to experience disease recurrence 
after surgery and benefit from neoadjuvant/adjuvant therapy is warranted. Here we plan to 
validate biomarkers for RCC that we have already developed in different settings and have been 
published in high impact journals. 
Intratumor immune infiltration and expression of immune checkpoint molecules (e.g., PD-L1) are 
associated with poor prognosis in localized clear RCC (ccRCC) but improved clinical outcome to 
anti-PD-1/PD-L1 therapy in metastatic ccRCC. We have recently identified tissue-based immune 
biomarkers (including T cell immunophenotypes, gene expression signatures and endogenous 
retroviruses) associated with response or resistance to nivolumab therapy in metastatic ccRCC. 
We hypothesize that immune biomarkers levels assessed in tumor tissue specimens from the 
PROSPER trial are associated with disease recurrence in patients not receiving nivolumab 
therapy (control arm). We expect that the immune biomarkers will be predictive of clinical 
outcome to perioperative nivolumab relative to control (especially if the trial meets its primary 
endpoint). 
Recently, our group has developed robust plasma-based assays for circulating biomarkers (i.e., 
cell-free methylated DNA and kidney injury molecule-1 (KIM-1)) that allow the detection of RCC in 
various clinical settings. We hypothesize that biomarker levels in post-nephrectomy plasma 
samples from the PROSPER trial are associated with disease recurrence in the entire trial 
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cohort. We are also interested in exploring whether biomarker levels in pre-treatment plasma 
specimens can predict clinical outcomes. 
Finally, we anticipate that the comparison of tumor intrinsic and tumor extrinsic features in 
paired pre- and post-treatment (i.e., nephrectomy) tissue specimens will provide novel 
insights into immune cell populations and/or signaling pathways that mediate response or 
resistance to PD-1 blockade. 
These hypotheses will be tested by performing multiplex immunofluorescence, RNA 
(transcriptome) sequencing and whole-exome sequencing on tissue specimens; a microbead-
based assay (for KIM-1) and an assay for detection of cell-free methylated DNA sequencing on 
blood specimens. Please note that all these correlative analyses (with the exception of the 
detection of cell-free methylated DNA, which is a newer method) are identical to those 
embedded in the clinical trial protocol (Section 11.3). Of note, the proposed studies will not 
exhaust the collected materials. 
As the field is moving forward quickly, it would be critical to start correlative studies before the 
results of the trial are reported to be maximally impactful as correlative science. If the trial 
meets its primary endpoint, the timely identification of predictive biomarkers for perioperative 
nivolumab in high-risk RCC would ensure the optimal utilization of this regimen in the clinic. 
However, even if the trial fails to meet its endpoints, the proposed studies are likely to identify 
prognostic (and possibly predictive) biomarkers as well as potential therapeutic targets for 
localized high risk RCC that could inform the design of future clinical investigations. 
Specific Aims: Objectives and Hypotheses 
a. Objectives: The main goal of this proposal is to develop tissue- and blood-based 
biomarkers that guide optimal treatment of patients with high-risk localized RCC. 
b. Hypotheses: 
1. 
TISSUE-BASED BIOMARKERS: On the basis of current knowledge of RCC biology 
and our preliminary data (see below), we hypothesize that tissue-based immune 
biomarkers identified in the metastatic setting also predict clinical outcome in high-risk 
RCC. More specifically, we hypothesize that biomarker levels assessed in pre- and/or 
post-treatment tumor tissue specimens from the PROSPER trial (a) are associated 
with disease recurrence in patients not receiving nivolumab therapy (control arm); (b) 
predict clinical outcome to perioperative nivolumab relative to control, especially if the 
trial meets its primary endpoint. 
If, as anticipated, multiple biomarkers are found to predict clinical outcome in 
high risk RCC, in future efforts we will assess whether a combination of these 
biomarkers can improve the risk stratification, with the final goal of developing an 
integrated model for prediction of RFS using a biomarker panel. 
The specific hypotheses that we will test in this proposal are listed below: 
(i) High levels of mildly exhausted CD8+ tumor infiltrating cells (determined by 
multiplex immunofluorescence) combined with tumor cell PD-L1 expression 
(Pignon et al. Clin Cancer Res 2019; Ficial et al, Clin Cancer Res 2021) are (a) 
associated with worse RFS in patients not receiving nivolumab therapy (control 
arm) and (b) predictive for benefit of perioperative nivolumab relative to control, 
especially if the trial meets its primary endpoint. Therefore, this biomarker could be 
useful to identify patients that are likely to relapse after nephrectomy and benefit 
from perioperative nivolumab. 

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(ii) A molecular RCC subtype characterized by high expression of T-effector and 
cell proliferation related genes (determined by RNAseq) (cluster #4 in Motzer et 
al, Cancer Cell 2020) is (a) associated with worse RFS in patients not receiving 
nivolumab therapy (control arm), and (b) predictive for benefit of perioperative 
nivolumab relative to control, especially if the trial meets its primary endpoint. 
Therefore, this biomarker could be useful to identify patients that are likely to 
relapse after nephrectomy and benefit from perioperative nivolumab. 
(iii) Expression of human endogenous retroviruses (hERVs) (determined by 
RNAseq) (Ficial et al, Clin Cancer Res 2021) is (a) associated with worse RFS in 
patients not receiving nivolumab therapy (control arm) and (b) predictive for benefit 
of perioperative nivolumab relative to control, especially if the trial meets its primary 
endpoint. Therefore, this biomarker could be useful to identify patients that are 
likely to relapse after nephrectomy and benefit from perioperative nivolumab. 
(iv) Mutations in SETD2 and potentially other genomic alterations (determined by 
whole exome sequencing) (McDermott et al, J Clin Oncol 2020) (a) are associated 
with worse RFS in patients not receiving nivolumab therapy (control arm), and (b) 
might be predictive for benefit of perioperative nivolumab relative to control, 
especially if the trial meets its primary endpoint. Therefore, this biomarker could be 
useful to identify patients that are likely to relapse after nephrectomy and benefit 
from perioperative nivolumab. 
(v) High levels of a gene signature of interaction between terminally exhausted 
CD8 cells and tumor associated macrophages (determined by RNAseq) (Braun 
et al, Cancer Cell 2021) is (a) associated with worse RFS in both study arms 
(regardless of the outcome of the trial), and (b) predictive for lack of benefit of 
perioperative nivolumab relative to control, especially if the trial meets its primary 
endpoint. Therefore, this biomarker could be useful to identify patients that are 
likely to relapse after nephrectomy but don’t benefit from perioperative nivolumab, 
and thus need other therapeutic approaches and/or intensified monitoring. 
(vi) Exploratory hypothesis: High levels of intratumoral PD-1+ regulatory T cells 
(determined by multiplex immunofluorescence) are (a) associated with worse RFS 
in both study arms (regardless of the outcome of the trial) and (b) predictive for 
lack of benefit of perioperative nivolumab relative to control, especially if the trial 
meets its primary endpoint. Therefore, this biomarker might be useful to identify 
patients that are likely to relapse after nephrectomy but don’t benefit from 
perioperative nivolumab, and thus need other therapeutic approaches and/or 
intensified monitoring. 
(vii) Exploratory hypothesis: Comparison of tumor intrinsic and tumor extrinsic 
features in paired pre- and post-treatment (i.e., nephrectomy) tissue specimens will 
provide novel insights into immune cell populations and/or signaling pathways that 
mediate response or resistance to PD-1 blockade.  This work will include analyses 
of data obtained from genomic, transcriptomic, multiplex IF and histopathologic 
(from H&E-stained slides) studies. 
2. 
BLOOD-BASED BIOMARKERS: We developed robust plasma-based assays for 
circulating biomarkers (i.e., cell-free methylated DNA and kidney injury molecule-1 
(KIM-1)) that allow the detection of RCC in various clinical settings. We hypothesize 
that biomarker levels measured in post-nephrectomy plasma specimens collected at 
week 40 within the PROSPER trial are associated with disease recurrence in the entire 
clinical trial cohort, regardless of the outcome of the trial. 

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We are also interested in exploring whether biomarker levels in pre-treatment plasma 
specimens can predict clinical outcomes. 
The specific hypotheses that we will test in this proposal are listed below: 
(i) Kidney injury molecule-1 (KIM-1) levels (Xu et al, Clin Cancer Res 2021) 
measured in post-nephrectomy plasma specimens are associated with disease 
recurrence in both study arms. Therefore, this non-invasive biomarker could be 
useful to identify patients that are likely to relapse after nephrectomy (with or 
without perioperative treatment). 
(ii) Detection of cell-free methylated DNA (Nuzzo et al, Nat Med 2020) in post-
nephrectomy plasma specimens are associated with disease recurrence in both 
study arms. Therefore, this non-invasive biomarker could be useful to identify 
patients that are likely to relapse after nephrectomy (with or without perioperative 
treatment). 
(iii) Exploratory hypothesis: KIM-1 levels in pre-treatment plasma sps can predict 
clinical outcomes after nephrectomy.  
Background and Significance 
Bio-specimens Being Requested: 
Currently, pretreatment tissue specimens have been collected from 335 patients and 
nephrectomy specimens have been collected from 401 patients. Pre-nephrectomy plasma 
specimens have been collected from 391 patients and post-nephrectomy plasma specimens have 
been collected from 179 patients. Specimen collection is still ongoing, and we anticipate that we 
will be able to collect specimens from all the patients who have provided consent for use of 
specimens for research (n=670). 
From the nephrectomy specimen, we request ten (10) 4μm unstained slides from a representative 
tissue block and access to all available H&E slides/digital images (once pathology review is 
complete)  
From the pretreatment biopsy specimen, we request fifteen (15) 4μm unstained slides and access 
to all available H&E slides/digital images (once pathology review is complete).  
We have a specific interest in identifying biomarkers that can identify the subset of patients with 
RCC who are most likely to experience disease recurrence after surgery and can benefit from 
neoadjuvant anti-PD-1 therapy.  The PROSPER trial is the only clinical trial investigating the 
efficacy of perioperative PD-1 blockade in high risk RCC. 
From the post-nephrectomy specimen (week 40), we request one 10mL EDTA purple top tube. 
From the pre-nephrectomy specimen, we request one 10mL EDTA purple top tube. 
Preliminary Data and Study Justification:  
TISSUE-BASED BIOMARKERS 
We have used a multi-faceted approach to identify predictors of response and resistance to anti-
PD-1 monotherapy in patients with metastatic RCC. These preliminary data constitute the basis 
for the development of biomarkers for nivolumab in patients with localized kidney cancer 
undergoing nephrectomy. 
 

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1. Candidate biomarkers of response to anti-PD-1 therapy 
(i) High levels of mildly exhausted CD8+ tumor infiltrating cells combined with tumor cell 
PD-L1 expression are associated with improved clinical outcomes to anti-PD-1 
monotherapy in metastatic RCC. Results from preclinical studies have demonstrated that CD8+ 
PD-1+ cells that do not express additional inhibitory receptors, are less dysfunctional than CD8+ 
PD-1+ cells expressing multiple inhibitory receptors (e.g., CD8+PD-1+TIM-3+ cells are more 
dysfunctional than CD8+PD-1+TIM-3- cells (1, 2) Therefore, mildly dysfunctional CD8+ tumor 
infiltrating lymphocytes (TILs) may be more effectively re-invigorated by anti-PD-1 therapy. In line 
with these data, using tumor 
specimens from CheckMate 
010 trial, we have shown that 
high levels of CD8+ TILs 
expressing PD-1 but not the 
inhibitory receptors TIM-3 and 
LAG-3 (hereafter referred to 
as IF Biomarker) are 
associated with response to 
anti-PD-1 therapy in 
ccRCC.(8) Moreover, we 
have also shown that the 
combination of the IF 
biomarker with tumor cell 
PD-L1 expression identifies 
three subgroups of patients 
with different clinical 
outcomes (see Pignon et al. 
Clin Cancer Res 2019 for 
details) (3).  
Subsequently, we have validated these findings in the randomized CheckMate 025 trial. At an 
optimized cut-off, nivolumab-treated patients   with high IF biomarker (24/116, 21%) had higher 
overall response rate (ORR) (46% vs. 20%, P=0.01) and longer median PFS (9.6 vs. 3.7 months, 
P=0.03) than those with low IF biomarker (4).  
In models considering a biomarker-by-treatment interaction term for both PFS and OS were 
significant (2-sided P=0.02 and 0.08, respectively, significance threshold set at 0.15 for the 
interaction term) (4). When combined 
with expression levels of the IF 
biomarker, TC PD-L1 expression of ≥1% 
further separated clinical outcomes 
(ORR and PFS) for those treated with 
nivolumab, but not for those treated with 
everolimus (Figure 1 and Table 1) (see 
Ficial et al. Clin Cancer Res 2021 for 
details) (4). 
Overall, these results obtained from two 
independent cohorts indicate that 
combining CD8+ cell immunophenotyping 
with TC PD-L1 status is effective in 
identifying subsets of  
Marker Combination 
n 
Nivolumab  
(n=111) 
ORR 
PD-L1 High / IF Biomarker High  
12 50% 
PD-L1 Low / IF Biomarker High  
90 22% 
PD-L1 Low / IF Biomarker Low  
9 
11% 
Trend test 1-sided P-value 
0.027 
Table 1. ORR per tumor cell PD-L1 (cutoff ≥1%) and log density of 
CD8+PD-1+TIM-3-LAG-3-TIC levels (high vs. low) in the nivolumab arm 
of the CM-025 trial. 
Figure 
1. 
Stratification 
of 
PFS 
by 
tumor 
cell 
PD-L1 
expression 
and
immunophenotype of infiltrating T cells in CheckMate 025 trial. In the nivolumab arm
(left) but not in the everolimus arm (right), patients with high expression of PD-1
(without TIM-3 and LAG-3) on T cells and high expression PD-L1 on tumor cells (TC)
(green line) were the most likely to benefit from nivolumab; those with high 
expression of PD-1 (without TIM-3 and LAG-3) on T cells in absence of TC PD-L1
expression (red line) had an intermediate response; and those with neither high T 
cell PD-1 expression (without TIM-3 and LAG-3) nor TC PD-L1 expression (black line)
had an overall poor response. 

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Everolimus                                   Nivolumab 
CM-025 PFS 
Better 
with 
Nivolumab 
Better 
with 
Everolimus 
      PFS HR 
 
patients with high likelihood of experiencing durable responses to anti-PD-1 therapy in previously 
treated patients with metastatic RCC. 
(ii) A molecular RCC subtype characterized by high expression of T-effector and cell 
proliferation related genes is associated with improved clinical outcomes to anti-PD-1 
monotherapy in metastatic RCC. A biomarker analysis was recently conducted on specimens 
from patients enrolled in the IMmotion151 clinical trial that compared the efficacy of atezolizumab 
(a PD-L1 ICI) plus bevacizumab (anti-VEGF), versus sunitinib in the first-line setting in advanced 
ccRCC. 
The investigators (including Dr. 
McDermott) identified several 
molecular RCC subtypes and 
provided evidence that these molecular subgroups 
associate with differential clinical outcomes on 
atezolizumab plus bevacizumab versus sunitinib 
(5). Of note, atezolizumab + bevacizumab 
significantly improved clinical benefit in tumors with 
high T-effector and/or cell-cycle gene signatures, 
relative to sunitinib (see Motzer et al Cancer Cell 
2020 for details) (5). To assess whether this 
molecular classification could be useful to also 
predict outcome to anti-PD-1 monotherapy, we 
recently applied the IMmotion 151 signatures to the 
patient specimens from the Checkmate 025 trial.  In 
line with IMmotion 151 results, we observed that 
patients in cluster 4 (T effector/proliferative) 
benefited more from nivolumab compared to 
everolimus (HR 2.82, 95% CI 1.15-6.93) (Figure 2).  
In terms of ORR, there was a strong trend toward 
better response in nivolumab treated patients 
compared to everolimus treated patients in cluster 4 (33.3% versus 0%; p = 0.07). This trend was 
confirmed when CR (complete response)/PR (partial response) were compared to progressive 
disease only (62.5% vs 0, p=0.04).
Figure 2. Association between transcriptomic clusters 
and clinical outcomes to nivolumab or everolimus
(CheckMate-025 trial). 

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Figure 3. Kaplan-Meier curves for PFS per ERVE4 status (positive is red line, negative 
is black line) at the optimized cut-off (Youden’s Index approach) in the nivolumab (left 
panel) and everolimus (right panel) arms (CheckMate-025 trial). 
 
Figure 4. Immune-related gene signature 
scores upregulated in ERVE4-positive 
(orange) and ERVE4-negative (purple) 
tumors. Dotted lines indicate FDR q-
value of 0.25 (light) and 0.05 (dark). 
(iii) Expression of human endogenous retroviruses (hERVs) is associated with improved 
clinical outcomes to anti-PD-1 monotherapy in metastatic RCC. There is some evidence that 
expression of hERVs correlates with high levels of immune infiltration, increased cytolytic activity 
and immune checkpoint expression in ccRCC (6-8). hERV expression has also been shown to 
correlate with response to 
immune checkpoint inhibitor 
(ICI) therapy in small patient 
cohorts (6,7). Of note, it has 
been demonstrated that 
HERV-E/ERVE4 
(henceforth referred to as 
ERVE4)-derived epitopes 
can elicit a tumor-restricted 
CD8+ T cell-mediated 
immune response (7, 9, 10). 
Based on the published 
literature, we conducted our 
own discovery analyses using specimens obtained from 
patients treated with the anti-PD-1 antibody nivolumab 
and non-ICI (everolimus, control) as part of the 
CheckMate 025 trial(29). We performed RT-pPCR on 
formalin-fixed paraffin-embedded (FFPE) pre-treatment 
tumors to assess ERVE4 mRNA levels in 224 patients 
(nivolumab=112; everolimus=112). ERVE4 expression 
as a continuous measure was associated with PFS in 
the nivolumab arm (HR=0.42, P=0.020). At the 
optimized cutoff (Youden’s Index), nivolumab-treated 
patients expressing ERVE4 had a significantly longer 
PFS (5.3 vs 3.6 months, P=0.017) than patients not 
expressing ERVE4. In the everolimus arm, ERVE4 
status was not associated with clinical outcomes (Figure 
3). We also demonstrated that immune-related gene signature scores including Tumor 
Inflammation Score (TIS), IMmotion150_Teff, Cytolytic Activity, and JAVELIN were upregulated in 
ERVE4-positive tumors (FDR q < 0.25) (Figure 4) (see Ficial et al. Clin Cancer Res 2021 for 
details) (4). 
Our team has now optimized a computational pipeline for quantification of hERV expression at a 
transcriptome-wide level using RNA-seq, which we validated using qPCR measurements of 
individual hERV transcripts (see Braun et al. Nat Med 2020 for details) (11).    
(iv) Mutations in SETD2 tend to be associated with improved clinical outcomes to anti-PD-1 
monotherapy in metastatic RCC.  The impact of genetic alterations on predicting clinical benefit 
from anti-PD-1 therapy was recently assessed in tumor specimens obtained from the clinical trial 
KEYNOTE-427 (led by David McDermott), which investigated the safety and efficacy of first-line 
pembrolizumab monotherapy in patients with metastatic RCC. We found a trend toward an 
association between mutations in SETD2 and higher ORR (44% (95% CI 25-66) in mutant cases 
versus 24% (95% CI 15-37) in non-mutant cases) (12). Of note, SETD2 mutations are clinically 
associated with worse kidney cancer specific survival in localized RCC. The impact of SETD2 
NIVOLUMAB 
EVEROLIMUS 

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Figure 5. T-distributed stochastic neighbor
embedding (tSNE) plot of single-cell RNA-seq
data obtained from clear cell RCC cases 
showing sub-clustering of T cells with major
groups of T cell populations labeled. 
mutations in predicting responses to anti-PD-1 therapy needs to be further investigated in larger 
patient cohorts. 
2. Candidate biomarkers of resistance to anti PD-1 monotherapy 
(v) Terminally exhausted CD8+ TILs are associated 
with resistance to anti-PD-1 monotherapy in 
metastatic RCC.  As mentioned above, the expression of 
multiple inhibitory receptors on CD8+ cells identifies highly 
dysfunctional, terminally exhausted T cells that might fail 
to be re-activated by PD-1 blockade alone.(30, 31) 
Recently, we performed additional analyses of 
CheckMate 025 data aimed at directly interrogating 
whether, among tumors harboring a CD8+ infiltrate, a high 
proportion of terminally exhausted TILs correlated with 
lack of response to anti-PD-1 therapy. Our analysis 
revealed that high percentage of CD8+ PD-1+ TILs 
expressing TIM-3 was associated with poorer response to 
nivolumab monotherapy. Using a cut-off that maximizes 
sensitivity and specificity for ORR, we observed that ORR 
to nivolumab was 14% in the group of patients presenting 
with a high percentage of terminally exhausted CD8+ PD-
1+ TIM-3+ TILs, compared to 35% in the group patients 
presenting with a low percentage of terminally exhausted CD8+ PD-1+ TIM-3+ TILs (P=0.009).  
(vi) Intratumoral myeloid infiltration is associated with resistance to anti-PD-1/PD-L1 to 
therapy in metastatic RCC. An analysis led by David McDermott was conducted using 
specimens obtained from participants of the IMmotion150 clinical trial that compared the efficacy 
of atezolizumab monotherapy atezolizumab combined with bevacizumab, or sunitinib in the first-
line setting in advanced ccRCC. RNA-seq data were utilized to assess whether levels of T cell 
effector function/IFN response (T-eff signature) or myeloid cell-associated gene activity (myeloid 
signature) might be predictive of treatment benefit. Tumors that were found to have high T-eff 
gene signature and high myeloid signature (T-effhighMyeloidhigh) showed significantly shorter PFS 
on atezolizumab monotherapy versus those with T-effhighMyeloidlow tumors (13). More recently, the 
effect of gene signatures was also investigated in tumor specimens obtained from the clinical trial 
KEYNOTE-427 (also led by David McDermott) testing the efficacy of pembrolizumab 
monotherapy for patients with metastatic RCC in the first-line setting (including both ccRCC and 
non-ccRCC). By analyzing bulk tumor RNA-seq data from 78 ccRCC, they found that a myeloid 
signature (MDSC signature) was inversely associated with response (12). Overall, these data 
support the hypothesis that intratumoral myeloid infiltration mediates resistance to first-line PD-
1/PD-L1 monotherapy in RCC. 

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Figure 6. Schema of inhibitory interactions 
between terminally exhausted T cells and M2-like 
macrophages. 
Figure 7. TCGA tumors with a high
terminal 
exhaustion/TAM 
interaction 
signature (>median) (green line) have
worse OS. 
(vii) A dysfunction circuit between terminally 
exhausted T cells and tumor associated 
macrophages (TAMs) is associated with poor 
outcome to anti-PD-1 monotherapy in metastatic 
RCC. Because myeloid cells play a crucial role in the 
tumor microenvironment and seem to contribute to 
anti-PD1 treatment resistance, we sought to evaluate 
individual myeloid subsets in tumor and adjacent 
(normal) tissues. For that, we relied on single-cell 
transcriptomic profiling of immune cells in ccRCC and 
adjacent normal tissue from 13 patients at various 
clinical stages to evaluate how infiltrating immune 
cells change with advancing disease (Figure 5). Our 
preliminary 
analyses revealed 
increased CD8+ T 
cell exhaustion (P=2.210-16) and a higher proportion of 
immunosuppressive M2-like macrophages in advanced 
disease. Through computational inference of cell-cell 
interactions, we further identified both known and novel 
inhibitory interactions between terminally exhausted CD8+ T 
cells and TAMs that are enriched in metastatic disease. 
(Figure 6). This terminal CD8+ exhaustion and TAM 
interaction “signature” was enriched in advanced disease 
stages (P=8.210-08). Furthermore, in an external dataset 
(TCGA KIRC cohort), high expression of this signature was 
significantly associated with worse OS across all disease 
stages (P=2.510-04, Figure 7). This finding was validated in 
an additional external cohort of metastatic ccRCC patients treated with PD-1 blockade, where 
high expression of the terminal exhaustion/TAMs interaction gene signature was also associated 
with worse OS (P=0.043). These data were recently published in Cancer Cell (14).  
(viii) Intratumoral PD-1+ regulatory T cells might mediate resistance to anti-PD-1 
monotherapy. Beyond terminally exhausted T cells and myeloid cells, regulatory T (Treg) cells 
have also been linked to resistance to anti-PD-1 monotherapy. It has long been recognized that 
Treg cells can promote tumor development and progression by suppressing antitumor immunity. 
A study led by Arlene Sharpe (collaborator), focusing on PD-1 function in Treg cells, recently 
demonstrated that PD-1-deficient Treg cells exhibit an enhanced immunosuppressive function 
both in vitro and in vivo, indicating that PD-1 inhibits Treg cell activation and suppressive capacity 
(15). It is therefore conceivable that the efficacy of anti-PD-1 therapy might be limited by the 
activation of the highly immunosuppressive PD-1+ Treg cells in the tumor microenvironment. This 
hypothesis is further supported by an independent study from other investigators showing that 
PD-1 blockade enhances PD-1+ Treg cell-mediated suppressive function via activation of the TCR 
and CD28 signals, and that PD-1+ Treg cells activated by PD-1 blockade are involved in 
resistance to anti-PD-1 therapies (16).  
BLOOD-BASED BIOMARKERS 
We developed robust plasma-based assays for circulating biomarkers (i.e. cell-free methylated 
DNA and kidney injury molecule-1 (KIM-1)) that allow the detection of RCC in various clinical 
settings. It would now be important to assess whether biomarker levels measured in post-

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nephrectomy plasma specimens can predict disease recurrence in the neoadjuvant setting by 
analyzing specimens from the EA8143 trial. 
(i) Plasma KIM-1 is associated with recurrence risk after nephrectomy for localized Renal 
Cell Carcinoma in the ASSURE trial. There is currently no blood-based biomarker for renal cell 
carcinoma (RCC) onset or prognosis. We have identified kidney injury molecule-1 (KIM-1) / T cell 
immunoglobulin mucin domain-1 (TIM-1) as a potential RCC biomarker that is elevated in the 
plasma of RCC patients. KIM-1 is a transmembrane protein with known functions in immune 
regulation and kidney injury. Our work shows that KIM-1 levels correlate with clinical outcome in 
patients with metastatic RCC and that KIM-1 levels decrease after nephrectomy. We have also 
previously shown that plasma KIM-1 can be detected up to 5 years prior to RCC diagnosis.  
Despite recent advances in the treatment of metastatic RCC including targeted therapies and 
immune checkpoint therapies, there remain key unmet needs in RCC management: Can we 
identify a high-risk patient population who may be most likely to benefit from adjuvant therapy 
after nephrectomy for localized disease?   We recently showed that plasma KIM-1 is a prognostic 
biomarker in patients with localized RCC after nephrectomy. The ECOG-ACRIN E2805 
(ASSURE) trial evaluated adjuvant sunitinib, sorafenib, or placebo in resected high-risk RCC. 
KIM-1 levels were measured from banked plasma at trial enrollment 4-12 weeks post-
nephrectomy (17). Lognormal accelerated failure time (AFT) models were used to test for 
association between KIM-1 and disease-free survival (DFS) as well as overall survival (OS). 
Plasma from 418 patients was analyzed. Higher post-nephrectomy KIM-1 was associated with 
worse DFS across all study arms after adjustment for Fuhrman grade, T-stage, N-stage, and 
tumor histology (survival time ratio 0.56 for 75th vs 25th percentile of KIM-1, 95% CI 0.42-0.73, p < 
0.001). The association between KIM-1 and DFS was stronger among patients with pathologic 
nodal involvement (p-value for interaction 0.0086). The addition of post-nephrectomy KIM-1 
improved the concordance of clinical prognostic models (SSIGN concordance 0.57 vs 0.43, p = 
0.05; UISS concordance 0.60 vs 0.40, p = 0.0005). Higher post-nephrectomy KIM-1 was also 
associated with worse overall survival (OS) after multivariable adjustment (survival time ratio 0.71 
for 75th vs 25th percentile of KIM-1, 95% CI 0.56-0.91, p < 0.001).   
Thus, post-nephrectomy plasma KIM-1 is associated with DFS and OS in RCC, and may be a 
biomarker for microscopic residual disease.  It will be important to validate these findings in other 
cohorts.  We will assess KIM-1 in the EA8143 cohort to support the hypothesis that post 
nephrectomy KIM-1 could stratify patients most likely to benefit from neoadjuvant therapy.   
(ii) Cell-free methylated DNA immunoprecipitation and high-throughput sequencing 
(cfMeDIP–seq) is a highly sensitive assay capable of detecting early-stage RCC. Identifying 
tumor-specific alterations in cell-free DNA (cfDNA) presents a powerful opportunity to potentially 
reduce morbidity and mortality through early and accurate cancer detection. Cell-free methylated 
DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a novel method for 
plasma cfDNA methylation profiling, demonstrated to be highly sensitive for detecting and 
classifying several tumor types, performing equally well in patients with localized and metastatic 
disease (18,19). Additional benefits include low DNA input (≤ 10 ng) and balance of genome 
coverage, resolution, and cost. We performed the first independent validation of cfMeDIP-seq for 
1) cancer detection using plasma cfDNA, reporting an AUROC of 0.99 for accurate classification 
of patients with stage I-IV RCC versus cancer-free controls, and 2) the first application of 
cfMeDIP-seq on urine cfDNA for cancer detection, reporting an AUROC of 0.86 for accurate 
classification of patients with RCC versus cancer-free controls (20).  
The excellent performance of this epigenetic approach to detect RCC-specific alterations in 
cfDNA may reflect underlying tumor biology. Molecular characterization of RCC tumors in TCGA 
identified 289 genes with aberrant DNA methylation compared to only 19 recurrently mutated 
genes (21). Consistent with this observation, we achieved significantly higher detection rates 
using cfMeDIP-seq than assays to detect somatically acquired DNA mutations: less than 80% in 

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patients with metastatic RCC (22,23). Further, these studies did not account for false positive 
results from clonal hematopoiesis. We performed a comparative analysis of cfMeDIP-seq versus 
massively parallel sequencing of cfDNA to detect tumor-specific genetic alterations in 34 patients 
with metastatic RCC (24). Clonal hematopoiesis was detected in 28% of specimens (consistent 
with published reports) (25), while tumor variants were detected in only 21% of specimens. In 
contrast, cfMeDIP-seq achieved 100% sensitivity at 88% specificity. The preponderance of data 
demonstrating superior sensitivity of cfMeDIP-seq for detecting RCC across all stages, and in 
comparison to other approaches, highlights the promise of this assay. 
We have performed the first independent validation of cfMeDIP-seq for detection of RCC and the 
first application of cfMeDIP-seq on urine cfDNA for cancer detection. We performed cfMeDIP-seq 
on 148 specimens: N=99 stage I-IV RCC cases, N=21 stage IV urothelial bladder cancer (UBC) 
cases, and N=28 cancer-free controls. Notably, 33.3% of plasma specimens and 66.7% of urine 
specimens were collected from patients with TNM stage I/II disease. 
cfMeDIP-seq accurately classifies plasma cfDNA RCC cases from cancer-free controls and other 
cancer types: The top 300 DMRs cleanly partitioned plasma RCC and control specimens (Figure 
8a). 67/69 (97.1%) of RCC specimens were assigned a higher median methylation score than all 
control specimens (Figure 8b), culminating in a mean AUROC of 0.99 (Figure 8c). There was no 
statistical association between RCC stage (p=0.09) or histology (p=0.38) with methylation score 
(see Nuzzo et al, Nat Med 2020 for details) (20).  
 
cfMeDIP-seq differentiates between patients with and without recurrence 
post-nephrectomy: We subsequently generated preliminary data 
evaluating the performance of cfMeDIP-seq in patients with localized 
RCC who had undergone nephrectomy with post-operative restaging 
imaging negative for metastases. We selected plasma collected following 
nephrectomy from patients with high-risk localized disease who either 
recurred within 6 months (early recurrence) or who did not recur after 
long-term follow-up. We performed cfMeDIP-seq on these 16 specimens 
and plotted a principal component (PC) analysis based on the cfDNA 
methylation profiles (Figure 9). Although the analysis is influenced by 
two “outlier” specimens, the PCA plot clearly shows that patients with 
early recurrence clustered separately from patients with no recurrence in 
PC3. The two outlier specimens were a result of technical issues and 
would be excluded from subsequent analysis due to not passing quality 
control metrics. This data supports that cfDNA methylation profiling using 
cfMeDIP-seq is discriminating between patients at high risk of recurrence following nephrectomy 
for localized RCC versus those who are likely cured. We plan to further test this hypothesis by 
analyzing specimens from patients enrolled in the EA8143 trial. 
Figure 9. PCA plot showing 
that 
patients 
with 
early 
recurrence 
clustered
separately 
from 
patients 
with no recurrence in PC3. 

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Research Design and Methods 
All laboratory methods listed here are identical to those embedded in the clinical 
trial protocol (Section 11.3), with the exception of the detection of cell-free 
methylated DNA, which is a newer methodology.   
Appendix containing the relevant publications from our group that are cited below can be   
downloaded using the link below: 
https://www.dropbox.com/s/e6fhgfsv6jzsi2x/appendix_relevant_publications.pdf?dl=0The 
Methods that will be utilized for tissue-based analyses include:  
1) Multiplex immunofluorescence for measurement of intratumoral CD8+ PD-1+ TIM-3- 
LAG-3- lymphocytes, described in detail in Pignon et al, Clin Cancer Res 2019 and 
Ficial et al, Clin Cancer Res 2021 (see Appendix). 
2) RNA (transcriptome) sequencing for assessment the transcriptomic clusters (i.e., 
molecular RCC subtypes), described in detail in Motzer et al, Cancer Cell 2020 (see 
Appendix). 
3) RNA (transcriptome) sequencing for the measurement of ERV levels, described in 
detail in and Braun et al, Nat Med 2020 (see Appendix). 
4) Whole-exome sequencing for assessment of SETD2 mutations and other genomic 
alterations described in detail in Braun et al, Nat Med 2020 (see Appendix). 
5) RNA (transcriptome) sequencing for the assessment of a gene signature of interaction 
between terminally exhausted CD8 cells and tumor associated macrophages, 
described in detail in Braun et al, Cancer Cell 2021 (see Appendix). 
The Methods that will be utilized for blood-based analyses include:  
1) A microbead-based assay for the measurement of KIM-1 levels in plasma, described 
in Xu et al, Clin Cancer Res 2021 (see Appendix). 
2) Cell-free methylated DNA immunoprecipitation and high-throughput sequencing 
(cfMeDIP-seq), described in detail in Nuzzo et al, Nat Med 2020 (see Appendix). 
Statistical Considerations 
a. Endpoints: 
The primary endpoint will be recurrence-free survival, defined as time from randomization 
to recurrence or death from any cause. Patients who have not recurred or died will be 
censored at the date of last evaluation. All patients that were eligible for primary clinical 
analysis will be eligible for the correlative study. Also, those that either did not undergo 
nephrectomy or are not disease-free after nephrectomy will be included in the correlative 
analysis and will be considered as having event at Day 1 just like the primary clinical 
analysis. 
b. Statistical Analysis Plan for Addressing the Primary Objectives: 
Tissue and plasma-based hypotheses are listed above. Tissue-based hypotheses #1-4 
focus on the association of the particular biomarker with RFS among the control arm 
patients only since these hypotheses stay valid regardless of the primary endpoint results. 
Tissue-based hypothesis #5 and plasma-based hypotheses focus on both the treatment 
and the control arms, because the hypothesis holds regardless of the treatment they 
receive. We have taken a more conservative approach, where the power calculations for 
each of the aims are clinically relevant regardless of the outcome of the trial, since the 
primary outcome is unknown.  

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To assess the tissue-based hypotheses, log-rank test will be used to test the differences in 
RFS between biomarker groups. For plasma-based hypothesis #1, analysis methods used 
in Xu study (Xu et al, Clin Cancer Res 2021) will be replicated: KIM-1 levels will be divided 
into quartiles and will be compared to the other quartiles in terms of RFS. Univariable, PH 
Cox model and AFT model will be used to evaluate the associations between KIM-1 and 
clinical outcomes and the power statement is based on the PH Cox model. Lastly, for 
plasma-based hypothesis #2, basic descriptive statistics will be reported, such as the 
sensitivity and the specificity of cfDNA detection in RCC recurrence.  
c. Statistical Justification for Sample Size 
Sample Size Estimate: 670 baseline and nephrectomy/post-nephrectomy specimens. 
However, a sample size of 536 was used for power calculation assuming that 80% of 
patients will have specimens available for analysis. 
Rationale for the Sample Size Estimate: 670 patients have consented for use of 
specimens for research. Assuming 80% of the 670 participants’ specimens will be 
available, our total sample size for power calculation is assumed to be 536. The 
prevalence for each biomarker of interest are based on past studies. Expected 5-year RFS 
rates in each biomarker group was estimated using the prevalence of the biomarker and 
the assumed 5-year RFS rates in both treatment arms of EA8143.  
Tissue-based Aims: 
(i) High levels of mildly exhausted CD8+ tumor infiltrating cells combined with tumor 
cell PD-L1 expression: According to studies lead by Pignon and Ficial, about 11% of 
the RCC patients had both high PD-L1 and high CD8+PD-1+TIM-3-LAG-3- TIC 
expressions. As a result, 5-year RFS rates in high PD-L1 & high CD8+PD-1+TIM-3-LAG-
3- TIC is assumed to be 30%, with about 25% increase in 5-year RFS for those not in 
that group. Since only the control group is of interest, with 268 patients’ specimens 
available, there will be 77.7% power to detect a hazard ratio of 2.01 or higher with a 
two-sided type I error rate of 5% using log-rank test. Full information will occur at 109 
events. 
 
PD-L1 high & 
CD8+PD-1+TIM-3-LAG-3- 
TIC high 
Other 
Prevalence 
11% 
89% 
5-yr RFS 
30% 
55% 
Sample Size 
29 
239 
HR 
2.01 
Power 
77.7% 

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(ii) A molecular RCC subtype characterized by high expression of T-effector and cell 
proliferation related genes: According to the Rini study, about 14% of the RCC 
patients were included in the T-effector/proliferative cluster. With 268 patients’ 
specimens, there will be about 84.9% power to detect a difference between 5-year RFS 
rates of 30% in T-effector/proliferative cluster and 55% in other group, corresponding to 
a hazard ratio of 2.01 or higher with a two-sided type I error rate of 5% using log-rank 
test. Full information will occur at 111 events. 
 
T-effector/proliferative 
cluster 
Other 
Prevalence 
14% 
86% 
5-yr RFS 
30% 
55% 
Sample Size 
38 
230 
HR 
2.01 
Power 
84.9% 
(iii) Expression of human endogenous retroviruses (hERVs): According to the Ficial 
study, hERV4700-ENV was expressed in 40% of RCC patients. With 268 patients’ 
available specimens, there will be about 86.4% power to detect a difference between 5-
year RFS rates of 40% in those that express hERVs and 60% that don’t, corresponding 
to hazard ratio of 1.79 or higher with a two-sided type I error rate of 5% using log-rank 
test. Full information will occur at 110 events. 
 
Express 
hERVs 
Other 
Prevalence 
40% 
60% 
5-yr RFS 
40% 
60% 
Sample 
Size 
107 
161 
HR 
1.79 
Power 
86.4% 
(iv) Mutations in SETD2: According to preliminary studies, there are SETD2 mutations in 
about 25% of the RCC patients. Assuming that 268 patients’ specimens are available, 
there will be 80.9% power to detect a difference between 5-year RFS of 35% for those 
with SETD2 mutation vs. 55% for others, which leads to hazard ratio of 1.76 or higher 
with two-sided type I error rate of 5% using log-rank test. Full information will occur at 
114 events. 
 
SETD2 
mutation 
Other 
Prevalence 
25% 
75% 
5-yr RFS 
35% 
55% 
Sample Size 
67 
201 
HR 
1.76 
Power 
80.9% 

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(v) High levels of a gene signature of interaction between terminally exhausted CD8 
cells and tumor associated macrophages: Braun study utilized the median as the 
cutoff of gene signature, so we assumed that about 50% of patients express high levels 
of a gene signature of interaction between terminally exhausted CD8 cells and tumor 
associated macrophages. Since both the treatment and the control arms are of interest 
for this aim, assuming that 536 of the patients’ specimens are available, there will be 
90.1% power to detect a difference in 5-year RFS of 50% for those expressing high 
gene signatures vs. 65% for those that don’t, corresponding to hazard ratio of 1.61 or 
higher with two-sided type I error rate of 5% using log-rank test. Full information will 
occur at 193 events. 
 
High gene signature of interaction 
between terminally exhausted CD8 
call and tumor associated 
macrophages 
Other 
Prevalence 
50% 
50% 
5-yr RFS 
50% 
65% 
Sample Size 
268 
268 
HR 
1.61 
Power 
90.1% 
Blood-based Aims: 
(i) Kidney injury molecule-1 (KIM-1) levels: The main goal of this aim is to replicate 
the analysis that the Xu study conducted. In Xu study, the 5-year DFS was about 
50% in KIM-1 levels greater than median and those that had KIM-1 level greater than 
median value had a 5-year DFS of about 65%, hence those rates were also used as 
our 5-year RFS rate assumptions. Since both the treatment and the control arms are 
of interest, assuming that 536 of the patients’ specimens will be available, there will 
be about 90.1% power to detect the difference between those with KIM-1 levels less 
than median and greater than it. Full information will occur at 193 events. Similarly, 
5-year RFS of 45% was used for those in 1st quartile KIM-1 level versus 60% for 
those that have higher than 1st quartile KIM-1 level, and with the same sample size, 
there will be about 83.5% power to detect the difference in these two groups. Full 
information will occur at 199 events. Two-sided type I error rate of 5% was used and 
log-rank test will be utilized for both comparisons. Comparisons for those that are in 
other quartiles will also be assessed against others. 
 
KIM-1 level less than 
median 
KIM-1 level greater 
than median 
Prevalence 
50% 
50% 
5-yr RFS 
50% 
65% 
Sample Size 
268 
268 
HR 
1.61 
Power 
90.1% 
 

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1st quartile KIM-1 
level patients 
Other 
Prevalence 
25% 
75% 
5-yr RFS 
45% 
60% 
Sample Size 
134 
402 
HR 
1.56 
Power 
83.5% 
(ii) Detection of cell-free methylated DNA: Cell-free methylated DNA 
immunoprecipitation and high-throughput sequencing (cfMeDIP–seq) is a highly 
sensitive assay capable of detecting early-stage RCC, cfDNA demonstrated a 
sensitivity of 100% and specificity of 88%. However, to be more realistic, 97% was 
assumed as the sensitivity, since in Nuzzo study, 67 of 69 RCC specimens were 
assigned a higher median methylation score than all control specimens. Also, with 
the assumption that about 56% (average between 50.2% 5-year RFS for control arm 
and 61.9% 5-year RFS for treatment arm) of the patients will be recurrence-free at 5 
years, we consequently assumed that 44% will have a recurrence at 5 years. On top 
of that, prevalence of 44% is assumed since only those that have a recurrence are 
known to have cfDNA detected. The confidence intervals for sensitivity and 
specificity assuming binomial distribution can be found in the table below. 
cfDNA detection 
Recurrence 
Yes 
No 
Yes 
229 
36 
No 
7 
264 
 
 
Estimate 
Two-sided 
95% Confidence 
Interval 
Sensitivity 
0.97 
(0.94,0.99) 
Specificity 
0.88 
(0.84,0.91) 
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