Clinical trial NCT03065179
Conditions: Kidney Cancer Metastatic Kidney Cancer Kidney Cancer, Stage IV
Sponsor: University of Texas Southwestern Medical Center
Start date: 2017-03-01; Completion date: 2020-11-17
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multi-institution, single-arm phase II study to determine the safety and efficacy of SBRT (up to 2 metastatic sites preferentially lung, mediastinum or bone in combination of nivolumab and ipilimumab in patients with metastatic renal cell carcinoma(with a clear-cell component and at least 1 measurable metastatic lesion that is not being irradiated).

Detailed description:
The study is planned based on a two-stage design that allows early termination for lack of efficacy. A safety run-in phase will be included comprising the first 6 patients at minimum to ensure that the combination of nivolumab plus ipilimumab and SBRT is safe. Then, the investigators will determine whether the combination of nivolumab plus ipilimumab and SBRT yields a clinically compelling antitumor activity measured as objective response rate (ORR), and evaluate other endpoints including Thrombotic thrombocytopenic purpura (TTP), duration of response (DOR), progression free survival (PFS), overall survival (OS) and local control of irradiated sites.

There is no previous experience with SBRT used concurrently with nivolumab and ipilimumab in this study population. Therefore, to ensure that the combination is safe, the first six patients will be treated and observed for toxicity for 6 weeks after radiation before continuing with further accrual. Therefore, six patients will be enrolled at the proposed dose of nivolumab and ipilimumab in combination with SBRT. If 4 out of the first 6 patients experience Grade 3/4 toxicity or a lower grade toxicity requiring immune suppressive therapy during the safety run-in observation period (defined as the first 4-cycles, 12 weeks), enrollment will cease and the study will be halted until further safety analysis of the combination regimen can be performed. If less than 4 out of the first 6 patients experience Grade 3/4 toxicities or require steroids, the investigators will proceed with additional accrual with this regimen.

Arms: arm 1: Induction Dual Immune Checkpoint Inhibition with nivolumab and ipilimumab plus SBRT to 1-2 metastatic sites, followed by nivolumab monotherapy
Interventions: intervention 1: Nivolumab/Ipilimumab intervention 2: SBRT
Intervention descriptions: intervention 1: IV immunotherapy intervention 2: SBRT will be delivered in conjunction with immunotherapy

Protocol documents:
Prot_SAP_000.pdf: 
Official title: A Phase II trial of Stereotactic Body Radiation Therapy In 
combination with nivolumab plus ipilimumab in patients with Metastatic Renal 
Cell Cancer 
 
NCT number: NCT03065179 
Document date: version 2.0 Date June 27, 2016  
 


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A PHASE II TRIAL OF STEREOTACTIC BODY RADIATION THERAPY 
IN COMBINATION WITH NIVOLUMAB PLUS IPILIMUMAB IN PATIENTS 
WITH METASTATIC RENAL CELL CANCER 
UT Southwestern Medical Center 
Johns Hopkins Protocol #: J15233, IRB00086834 
BMS Protocol #: CA209-444 
IND Number: IND 129041 
IND Sponsor-Investigator: Hans J. Hammers, MD, PhD 
 
Lead Site Principal Investigator:  
Hans J. Hammers, MD, PhD. 
UT Southwestern Medical Center 
Simmons Comprehensive Cancer Center 
5323 Harry Hines Blvd.  
Dallas, TX 75390 
Phone: 214-645-7445 
Fax: 214-645-5915 
Email: Hans.Hammers@utsouthwestern.edu 
 
Study Sites: 
• 
UT Southwestern Medical Center 
Simmons Comprehensive Cancer Center  
(Site-PI: Hans Hammers, M.D., Ph.D.) 
 
• 
Johns Hopkins University  
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins  SKCCC 
 
 
 
(Site-PI: Michael Carducci, M.D.) 
 
Co-Investigator/Protocol Authors: 
Hans Hammers, M.D., Ph.D. 
Danny Song, M.D. 
Rosa Nadal M.D. 
 
Biostatistician:  
 
 
Chul Ahn, PhD.  
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator: 
 
 
 Renee Davis, RN                                            
 
 
Email: Renee.Davis@utsouthwestern.edu                                            
 
 
Phone: 214-645-8787 
 
 
 
 
 
 
Protocol version  2.0  Date  June 27, 2016  


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   3.0 Date  June 20, 2017 
 
 
   4.0 Date  January 22, 2018 
 
 
   5.0 Date  May 11, 2018 
 
 
   6.0 Date  March 1, 2019 
 
 
   7.0 Date Sept. 30, 2019 
 
CONFIDENTIALITY STATEMENT 
The information of this document is provided to you as an investigator, potential investigator, consultant, or contractor, for review 
by you, your staff, and the appropriate Institutional Review Board or Ethics Committee. By accepting this document, you agree 
that the information contained herein will not be disclosed to others without written authorization from the lead site/sponsor, 
except to the extent necessary to initiate the study or conduct study-related activities. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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INVESTIGATOR’S APPROVAL OF PROTOCOL 
Title: A Phase II, Single Arm Trial, Combining Nivolumab Plus Ipilimumab with Stereotactic Body 
Radiation Therapy in Patients with Metastatic Renal Cell Cancer 
 
Principal investigator Signature:        
_____________________________________ 
Principal Investigator Print:              
_____________________________________ 
Date:  
 
          
              ______________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SYNOPSIS 


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Protocol Title: A Phase II, Single Arm Trial, Combining Nivolumab Plus Ipilimumab with 
Stereotactic Body Radiation Therapy in Patients with Metastatic Renal Cell Cancer 
 
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment 
with Investigational Product(s):  
For Nivolumab and Ipilimumab:  
- 
There will be an induction period (12 WEEKS) consisting of up to 4 doses of 
nivolumab plus ipilimumab given every 3 weeks x4 as tolerated, followed by 
maintenance dosing with nivolumab. A treatment cycle during maintenance is 
defined as 6 weeks 
- 
Nivolumab will be administered IV over 60 minutes at 3 mg/kg combined with 
ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 
doses followed by nivolumab administered IV over 60 minutes at 480 mg  every 4 
weeks up to 2 years 
For Stereotactic Body Radiation Therapy (SBRT):  
- 
5 fractions of 10 Gy per fraction depending on organ site will be delivered within 
the first 3 weeks after the initiation of nivolumab and ipilimumab (SBRT is 
preferred to be delivered in the first 2 weeks) 
 
Study Phase: This is single-arm Phase II study in subjects with naïve or pre-treated mRCC 
 
Research Hypothesis: Nivolumab plus ipilimumab and SBRT can be given safely in 
combination and improves the clinical outcomes (with respect to nivolumab plus ipilimumab 
alone) in subjects with mRCC 
 
Objective(s):  
Primary Endpoints 
- 
To assess the overall safety and tolerability of nivolumab plus ipilimumab in 
combination with SBRT in subjects with mRCC.  
- 
To estimate the objective response rate (ORR) of this regimen and compare it to 
the reported data on the antitumor activity with the combination of nivolumab with 
ipilimumab in subjects with mRCC. 


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Secondary Endpoints: 
 
Clinical Endpoints 
- 
To evaluate time to progression (TTP) [defined as time between date of registration 
and date of documented progression] and duration of response (DOR) [defined as 
the time between the date of first response and the date of disease progression or 
death, whichever occurs first.]. 
- 
To evaluate progression free survival (PFS) and overall survival (OS) 
- 
To evaluate the local control of irradiated lesion 
 
 
Exploratory Correlative studies:  
- 
To evaluate potential immune related biomarkers of nivolumab plus ipilimumab in 
combination with SBRT in subjects with mRCC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Contents 
1 
INTRODUCTION AND STUDY RATIONALE ...................................................................................... 11 
1.1 Renal Cell Carcinoma (RCC): Background and Standard Treatments  ........................................ 11 
1.2 Nivolumab in Renal Cell Carcinoma  ........................................................................................... 13 
1.3 Ipilimumab in Renal Cell Carcinoma  .......................................................................................... 13 
1.4Nivolumab Combined with Ipilimumab in Renal Cell Carcinoma  ............................................... 14 
1.5 Stereotactic Body Radiation Therapy in Renal Cell Carcinoma ................................................... 16 
1.6 Rationale to Support Trial Design ............................................................................................... 17 
1.7 Dosing for the Nivolumab Combination with Ipilimumab  ......................................................... 19 
1.8 Dosing for the Stereotactic Body Radiation Therapy .................................................................. 19 
1.9Overall Risk/Benefit Assessment  ................................................................................................ 19 
INVESTIGATIONAL PLAN and PATIENT SELECTION ............................................................................... 20 
2.1 Study Design ................................................................................................................................ 20 
Safety Run-in phase ...................................................................................................................... 20 
Efficacy phase: .............................................................................................................................. 20 
2.2 Duration of Study  ....................................................................................................................... 21 
2.3 Study Population  ........................................................................................................................ 21 
2.3..1  
Inclusion Criteria  .......................................................................................................... 21 
2.3.2 Exclusion Criteria:  ................................................................................................................ 22 
2.3.3. Age and Reproductive Status  ............................................................................................. 24 
2.4 Follow-up Visits  .......................................................................................................................... 25 
2.5 Survival Follow-up  ...................................................................................................................... 25 
2.6 Subsequent therapy .................................................................................................................... 26 
2.7 Concomitant Treatments ............................................................................................................ 26 
2.7.1 Prohibited and/or Restricted Treatments............................................................................ 26 
2.7.2 Other Restrictions and Precautions  .................................................................................... 26 
2.7.3 Permitted Therapy  .............................................................................................................. 26 
2.8 Discontinuation of Subjects following any Treatment with Study Drug  .................................... 27 
2.9 Post Study Drug Study Follow up  ............................................................................................... 27 
2.9.1 Withdrawal of Consent  ....................................................................................................... 28 
2.9.2 Lost to Follow-Up  ................................................................................................................ 28 
TREATMENT PLAN/THERAPEUTIC INTERVENTION ............................................................................... 29 


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3.1 Treatment Plan ........................................................................................................................... 29 
3.1.1 Study Drug ............................................................................................................................ 29 
3.1.2 Investigational Products ....................................................................................................... 30 
3.1.3 Non-investigational Product ................................................................................................ 30 
3.1.4 Storage and Dispensing ........................................................................................................ 30 
3.2 Timing of Dose for Each Subject and Duration of Therapy ......................................................... 31 
3.3 Stereotactic Body Radiation Therapy ......................................................................................... 32 
3.3.2 
Simulation procedure.................................................................................................... 33 
3.4 Intervention Plan ........................................................................................................................ 37 
3.4.1 Antiemetic Premedications and Supportive Care Medications  .......................................... 37 
3.4.2 Bisphosphonates .................................................................................................................. 37 
3.4.3 Dose Delay Criteria for Nivolumab and Ipilimumab  ........................................................... 37 
3.4.4 Dose Modifications for Nivolumab and Ipilimumab ............................................................ 39 
3.4.5 Criteria to Resume Treatment on Nivolumab and Ipilimumab  ........................................... 39 
3.4.6 Discontinuation Criteria for Nivolumab and Ipilimumab ..................................................... 39 
3.4.7 Treatment of Nivolumab or Ipilimumab-Related Infusion Reactions  ................................. 41 
3.5 Treatment Beyond Disease Progression  .................................................................................... 42 
3.6 Treatment Compliance ............................................................................................................... 43 
3.7 Destruction and Return of Study Drug  ....................................................................................... 43 
3.7.1 Destruction of Study Drug  ................................................................................................... 43 
3.7.2 Return of Study Drug  ........................................................................................................... 44 
3.8 Immunotherapy Adverse Event Management ........................................................................... 44 
3.9 Adverse events associated with Stereotactic Body Radiation Therapy (SBRT): ......................... 44 
4 ............................................................................................................................................................ 45 
STUDY ASSESSMENTS AND PROCEDURES............................................................................................. 45 
4.1 Flow Chart/Time and Events Schedule ....................................................................................... 45 
4.2 Initial Registration ....................................................................................................................... 47 
4.3 Study Calendar ............................................................................................................................ 49 
4.4 Safety Assessments / Considerations  ........................................................................................ 52 
4.5 Imaging Assessment for the Study  ............................................................................................. 54 
4.5.1 CT/MRI ................................................................................................................................. 54 
4.5.2 MRI/CT Brain  ....................................................................................................................... 55 


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4.6 Efficacy Assessments................................................................................................................... 55 
4.6.1  Baseline Assessments ......................................................................................................... 55 
4.6.2 Response Criteria  ................................................................................................................ 55 
4.6.3 Therapeutic Response  ......................................................................................................... 55 
4.6.4 Evaluation of Target lesions  ................................................................................................ 56 
4.6.5 Special Notes on the Assessment of Target Lesions  ........................................................... 57 
4.6.6 Evaluation of Non-Target Lesions  ....................................................................................... 58 
4.6.7. Special Notes on Assessment of Progression of Non-Target Disease  ................................ 59 
4.6.8 New Lesions  ........................................................................................................................ 60 
4.6.9 Evaluating best overall response  ........................................................................................ 60 
4.6.10 Confirmation Scans ............................................................................................................ 61 
4.7 Correlatives Studies  ................................................................................................................... 61 
4.7.1 Samples Collection and Banking .......................................................................................... 63 
5 ............................................................................................................................................................ 63 
ADVERSE EVENTS .................................................................................................................................. 63 
5.1 Definition and Grade  .................................................................................................................. 64 
5.2 Unanticipated Problems: ....................................................................................................... 66 
5.3 Reporting..................................................................................................................................... 66 
5.3.1  Unanticipated problems ..................................................................................................... 67 
5.3.2  SAE  ...................................................................................................................................... 68 
5.4  Steps to Determine If an Adverse Event Requires Expedited Reporting ................................... 69 
5.5 Other Events of Special Interest that require Expedited Reporting ........................................... 70 
5.6 Nonserious Adverse Event Collection and Reporting ................................................................. 70 
5.7 Handling of Expedited Safety Reports ........................................................................................ 70 
5.8 Reporting: ................................................................................................................................... 71 
5.9 Nonserious Adverse Event .......................................................................................................... 71 
5.10 Laboratory Test Abnormalities ................................................................................................. 72 
5.11 Pregnancy .................................................................................................................................. 72 
5.12 Overdose ................................................................................................................................... 72 
5.13 Other Safety Considerations ..................................................................................................... 73 
5.14 Seven Calendar-Day Telephone or Fax Report: ........................................................................ 73 
5.15 15 Calendar-Day Written Report: ............................................................................................. 73 


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6 ............................................................................................................................................................ 75 
ETHICAL CONSIDERATIONS ................................................................................................................... 75 
6.1 Good Clinical Practice ................................................................................................................. 75 
6.2 Institutional Review Board/Independent Ethics Committee  ..................................................... 76 
6.3 Informed Consent  ...................................................................................................................... 76 
6.4 Multicenter Guidelines ............................................................................................................... 77 
6.5 Coordinating Center Responsibilities (UTSW) ............................................................................. 78 
6.6 Participating Sites Responsibilities.............................................................................................. 78 
6.6.1 Follow the protocol as written and conduct the study within the guidelines of Good 
Clinical Practice  ............................................................................................................................ 78 
6.6.2 .............................................................................................................................................. 78 
Required Documentation (for multi-site studies) ......................................................................... 78 
7 Data Management, Monitoring/Auditing and Reporting Requirements .......................................... 79 
8 STUDY MANAGEMENT ....................................................................................................................... 80 
8.1 Adherence to the Protocol .......................................................................................................... 80 
8.2 Emergency Modifications ........................................................................................................... 80 
8.3 Other Protocol Deviations/Violations ......................................................................................... 81 
8.4  Amendments to the Protocol..................................................................................................... 81 
8.5 Case Report Form Submission .................................................................................................... 82 
8.5.1 Case Report Forms ............................................................................................................... 82 
8.5.2 Case Report Form Completion ............................................................................................. 82 
9 Statistical Considerations ................................................................................................................... 83 
9.1 Study Design ................................................................................................................................ 83 
9.2 Safety Run-in Phase .................................................................................................................... 83 
9.3  Justification for the Sample Size ................................................................................................ 83 
9.4 Statistical Analyses of Primary Endpoint .................................................................................... 85 
9.5 Statistical Analyses of Secondary Endpoints ............................................................................... 85 
10 Record Retention ............................................................................................................................. 86 
11 Obligations of Investigators ............................................................................................................. 87 
12 REFERENCES ..................................................................................................................................... 88 
13 APPENDIX 1          INTERNATIONAL METASTATIC RCC DATABASE CONSORTIUM (IMDC) 
PROGNOSTIC CRITERIA ......................................................................................................................... 91 
14 APPENDIX 2   MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY AGENTS .......................... 92 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 INTRODUCTION AND STUDY RATIONALE  
 1.1 Renal Cell Carcinoma (RCC): Background and Standard 
Treatments  
Renal cell carcinoma accounts for ~3% of all cancers in the U.S. This translates to 58,000 
new cases with 13,000 associated deaths.1 Metastatic disease is found in 30% of subjects at 
diagnosis. Close to 90 - 95% of metastatic disease is of the clear-cell histology.2 
Multiple scoring systems are available to characterize prognosis in treatment-naive and pre-
treated RCC. Two of the most commonly used are the Memorial Sloan-Kettering Cancer 
Center (MSKCC) prognostic scoring system and the International Metastatic RCC Database 
Consortium (IMDC) prognostic scoring. Each of these systems categorizes patients as 
favorable, intermediate, or poor-risk based on how many adverse prognostic factors are 
present (0: favorable-risk, 1-2: intermediate risk, 3 or more: poor-risk).3,4 The six parameters 
of importance for IDMC prognostic score classification are Karnofsky Performance Status 
(KPS), time from diagnosis to treatment, hemoglobin value, calcium concentration, absolute 
neutrophil count, and platelet count.4 The three parameters included in the MSKCC prognostic 
score for pre-treated patients are KPS, hemoglobin value and corrected calcium 
concentration.3 With each system, total number of adverse prognostic factors present has 
been shown to correlate with OS. Overall, approximately 25% of patients are in the favorable-
risk group, 50% are in the intermediate-risk group, and 25% are in the poor-risk group (mOS: 
~ 9 months (mo). In an analysis of 1028 patients scored using the IMDC system, median OS 
for favorable, intermediate, and poor-risk patients is 43.2 mo, 22.5 mo, and 7.8 mo, 
respectively.4 
Until 2005, immunotherapy (IL-2 or IFNα) was the only active treatment for mRCC. IL-2 was 
approved based on a 15% durable response rate.5,6 However, due to severe acute toxicities, 
its use is limited to only exceptionally medically fit subjects and to intensive care settings in 
tertiary care facilities.7 IFNα was not approved for the treatment of RCC. However, several 
clinical trials have documented an objective response rate of 6 - 20% and a modest 
improvement in overall survival (~2.5 mo).8 Though not as severe as IL-2, IFNα is also 
associated with significant adverse events.9 As newer clinically active and less toxic agents 
have subsequently been approved for the treatment of mRCC, few treatment-naïve patients 
(< 5%) still receive IL-2 or IFNα monotherapy. However, due to each of these agents’ limited 
role in clinic, newer targeted agents have largely replaced cytokines in the treatment of 
advanced or metastatic RCC. 


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The recognition of the importance of hypoxia inducible factor alpha (HIFα) signaling to the 
pathogenesis of clear-cell RCC led to the development of two new classes of therapeutics to 
manage this disease. Constitutive HIFα activation leads to the upregulation or activation of 
several proteins including vascular endothelial growth factor (VEGF). VEGF contributes to the 
development and progression of RCC in several ways including stimulation of tumor 
proliferation and neovasculature formation. Constitutive HIFα activation or upregulation occurs 
by several means including mutation or deletion of the tumor suppressor gene, VHL, as well 
as activation of the upstream PI3K/Akt/mTOR signaling pathway. 
In the treatment-naïve setting, three VEGF pathway agents are currently recommended by 
the National Comprehensive Cancer Network (NCCN): sunitinib, bevacizumab/IFNα and 
pazopanib.10,11 Sunitinib and bevacizumab/IFNα showed improvement in median PFS over 
the active comparator IFNα (11 mo vs 5.9 mo and 10.2 mo vs 5.4 mo, respectively), whereas 
pazopanib showed superior mPFS over placebo (11.1 mo vs 2.8 mo).10,11 
As a class, the most common or clinically important toxicities elicited by VEGF pathway 
inhibitors are the following: fatigue (33 - 55%), diarrhea (20 - 53%), nausea (26 - 44%), 
hypertension (17 - 40%), liver function test (LFT) abnormalities (11 - 53%), hand-foot skin 
reaction (0 - 30%), Grade 3 - 4 neutropenia (1 - 11%), Grade 3 - 4 thrombocytopenia (1 - 8%) 
and low incidences of medically important events such as thrombosis, proteinuria, reversible 
posterior leukoencophalopathy syndrome (RPLS), bleeding, hypothyroidism, and drug-related 
cardiomyopathy.  
Two mTOR inhibitors are approved for the treatment of mRCC. Temsirolimus was approved 
for the treatment of 1st-line MSKCC poor-risk subjects based on the demonstration of 
improved median OS compared to IFNα (10.9 mo vs 7.3 mo).12 Everolimus was approved in 
subjects who failed to at least one prior VEGFR TKI therapy (sunitinib or sorafenib) based on 
the demonstration of improvement in median PFS as compared to placebo (4.9 mo vs 1.9 
mo).13 As a class, the most common or clinically important toxicities observed with mTOR 
inhibitors are fatigue (23 - 51%), nausea (15 - 37%), stomatitis (20 - 36%), diarrhea (21 - 27%), 
dyspnea (9 - 28%), pneumonitis (11%), infections (10 - 27%), Grade 3 - 4 anemia (10 - 
20%).12,13 
These newer agents have provided significant clinical benefit for many patients with mRCC, 
but infrequently lead to durable response. Therefore, researchers have remained interested 
in novel immunotherapeutic strategies.  


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 1.2 Nivolumab in Renal Cell Carcinoma  
Nivolumab monotherapy has been studied in subjects with RCC in several studies, with the 
largest amount of data coming from two studies in subjects with mRCC: CA209009 and 
CA209010. In CA209010, 168 subjects who received at least one prior-anti-angiogenic 
therapy were randomized to receive nivolumab 0.3mg/kg (n=60), 2mg/kg (n=54) and 10mg/kg 
(n=54).14 The mPFS was 2.7 mo, 4.0 mo, and 4.2 mo at 0.3, 2, and 10 mg/kg respectively. 
The ORR ranged from 20 to 22% across dose levels. Median OS was 18.2 mo at 0.3 mg/kg, 
but was not yet reached at the two highest dose levels. CA209009 enrolled a similar population 
to CA209010, but also included 23 subjects with treatment-naive RCC. Among treatment-
naive subjects, all of whom received nivolumab 10 mg/kg every 3 weeks, the ORR was 13% 
(3/23).14  
CA209010 includes the largest safety database for nivolumab monotherapy in mRCC. All 
treated subjects (n = 167) were included in the safety analyses. Drug-related AEs of any grade 
occurred in 74.6%, 66.7%, and 77.8% of subjects treated at 0.3 mg/kg, 2 mg/kg, and 10mg/kg 
respectively. The most common (≥10% in any group) drug-related AEs included fatigue, dry 
skin, rash, pruritus, arthralgia, nausea, diarrhea, decreased appetite, dry mouth, and 
hypersensitivity. Grade 3 drug-related AEs occurred in 5.1%, 16.7%, and 13% of subjects 
treated at 0.3 mg/kg, 2 mg/kg, and 10 mg/kg, respectively. Related Grade 3 events in at least 
2 patients across dose levels included nausea, AST/ALT increased, and anemia. No drug-
related Grade 4 or Grade 5 events occurred. No dose-toxicity relationship was identified 
except for hypersensitivity/infusion reactions which occurred most frequently in the 10 mg/kg 
treatment group.14  
 1.3 Ipilimumab in Renal Cell Carcinoma  
Ipilimumab monotherapy for the treatment of mRCC was studied in the Phase 2 clinical trial 
MDX010-11.15 Two sequential cohorts were studied, each with a loading dose of 3 mg/kg 
followed by 3 doses of either 1 mg/kg (group 3-1; n = 21) or 3 mg/kg (group 3-3; n = 40). 
Subjects with stable disease (SD) or partial or complete response were allowed additional 
treatment. In group 3-1 (n = 21), one subject (5%) had a partial response (PR). In group 3-3 
(n = 40), 5 subjects (12.5 %) had a PR. Among 14 treatment-naive subjects in group 3-3, 3 
(21%) had a PR.16  
In the Ipilimumab monotherapy Phase 2 clinical trial MDX010-11, the major toxicities were 
colitis (all Grade 3 & 4; 14% in group 3-1, 33% in group3-3) and hypophisitis (1 grade 3/4, 1 
grade 1/2 in group 3-3; none in group 3-1). Most reported adverse events (AEs) were Grade 


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1/2 (57% in group 3-1, 35% in group 3-3) or Grade 3 (38% in group 3-1, 48 % in group 3-3). 
There were 6 subjects (15%) with Grade 4 AEs in group 3-3. The most common treatment-
related AEs in group 3-1 (total 81%) and group 3-3 (total 93%) were diarrhea (38%and 40%, 
respectively) and fatigue (33% and 38%, respectively).15 Most AEs were manageable with 
appropriate treatment, including high dose corticosteroids and hormone replacement.  
 1.4 Nivolumab Combined with Ipilimumab in Renal Cell 
Carcinoma  
The combination of nivolumab with ipilimumab is currently being studied in the Phase 1 study 
CA209016. Subjects with mRCC (favorable/intermediate MSKCC score; Karnofsky 
performance status ≥ 80%; untreated or any number of prior therapies) were randomized to 
receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg (arm N3 + I1) or nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg (arm N1 + I3) IV Q3W for 4 doses then nivolumab 3 mg/kg IV Q2W until 
progression/toxicity. The primary objective was to assess safety/tolerability; secondary 
objective was to assess antitumor activity. Subjects were randomized to N3 + I1 (n = 21) and 
N1 + I3 (n = 23). Most patients (n = 34; 77%) had prior systemic therapy (N3 + I1: 16; N1 + I3: 
18). The confirmed ORR was 43% (N3 + I1) and 48% (N1 + I3). DOR was 4.1+ to 42.1+ wks 
(7 of 9 responses ongoing) in N3 + I1, and 12.1+ to 35.1+ wks (9 of 11 responses ongoing) in 
N1 + I3. Best response of SD was seen in 5 (24%) pts (N3 + I1) and 8 (35%) pts (N1 + I3). 
Median PFS was 36.6 wks (N3 + I1) and 38.3 wks (N1 + I3); with 11 of 21 events reported for 
N3 + I1 and 10 of 23 events reported for N1 + I3.17 
The safety of nivolumab combined with ipilimumab was assessed in the Phase 1 study 
CA209016. Treatment-related AEs were seen in 39/44 pts (89%), including 16/21 (76.2%) in 
N3 + I1 and 23/23 (100%) in N1 + I3. Across the N3 + I1 and N1 + I3 arms, the most common 
(≤ 20%) treatment related AEs of any grade were fatigue (61%), diarrhea (32%), nausea 
(30%), rash (27%), pruritis (25%), ALT increased (23%), AST increased (20%), 
hypothyroidism (20%), and asymptomatic lipase increased (20%). Grade 3–4 related AEs 
occurred in 19 pts (29%), including 6/21 (29%) at N3 + I1 and 14/23 (61%) at N1 + I3. The 
most common (≥5%) drug-related Grade 3-4 events were asymptomatic lipase increased 
(21%), ALT increased (14%), AST increased (7%), diarrhea (9%), fatigue (5%), amylase 
increased (5%), colitis (5%), lymphocyte count decreased (5%). No grade 3–4 pneumonitis 
was seen. No treatment-related deaths were reported. Treatment-related AEs (including 
Grade 3-4), treatment-related AEs leading to discontinuation, and treatment-related SAEs all 
occurred more commonly in subjects in the N1 + I3 arm than in the N3 + I1.17 


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Per a study amendment, the N3 + I1 and N1 + I3 arms were expanded to better evaluate 
safety and efficacy. Mature efficacy data was presented at ASCO 2015. The confirmed ORR 
was 38.3% (N3 + I1) and 40.4% (N1 + I3). Best response of SD was achieved in 36.2 % of 
patient in both treatment arms. Median DOR was 67.7 weeks (range 4.1+ to 91.1+) in the N3 
+ I1 arm and 81.1 weeks (range 6.1+ to 81.1+) in the N1 + I3 arm. Responses were durable, 
with >60% of patients continuing to experience ongoing response. The PFS rate (95% CI) at 
24 weeks was 54% (39–68) in the N3 + I1 arm (N = 47) and 68% (52–79) in the N1 + I3 arm 
(N = 47). Median OS was not reached in either the N3 + I1 arm or in the N1 + I3.18 
 
Table 1. ORR and best Overall Response 
NIVO3 + IPI1 
NIVO1 + IPI3 
NIVO3 + IPI3 
N = 47 
N =47 
N = 6 
Confirmed ORR
a, n (%) 
95% CI 
18 (38.3) 
24.5–53.6 
19 (40.4) 
26.4–55.7 
0 
Best overall response
b, n (%) 
Complete response 
Partial response 
Stable disease 
Progressive disease 
 
4 (8.5) 
14 (29.8) 
17 (36.2) 
10 (21.3) 
 
1 (2.1) 
18 (38.3) 
17 (36.2) 
7 (14.9) 
 
0 
0 
5 (83.3) 
1 (16.7) 
aConfirmed response only; bNo unconfirmed complete responses were reported in either arm; unconfirmed partial 
responses were reported in one patient (2.1%) in the NIVO3 + IPI1 arm and in two patients (4.3%) in the NIVO1 + 
IPI3 arm. Best overall response was not determinable in one patient (2.1%) in the NIVO3 + IPI1 arm and in two 
patients (4.3%) in the NIVO1 + IPI3 arm. 
 
Grade 3–4 related AEs occurred in 36 pts, including 16/47 (34%) at N3 + I1 and 30/47 (63.8%) 
at N1 + I3. The most common (≥20%) drug-related Grade 3-4 events were lipase increased 
including 6/47 (12.8%) at N3 + I1 and 12/47 (25.5%) at N1 + I3; ALT increased including 2/47 
(4.3%) at N3 + I1 and 9/47 (19.1%) at N1 + I3; AST increased including 2/47 (4.3%) at N3 + 
I1 and 4/47 (8.5%) at N1 + I3 and diarrhea including 1/47 (2.1%) at N3 + I1 and 7/47 (14.9%) 
at N1 + I3. Grade 3-4 colitis was observed in 6/47 (12.8) at N1 + I3 only. No grade 3–4 
pneumonitis was seen. No treatment-related deaths were reported. Treatment-related AEs 
(including Grade 3-4), treatment-related AEs leading to discontinuation, and treatment-related 
SAEs all occurred more commonly in subjects in the N1 + I3 arm than in the N3 + I1 arm.18 
 
Table 2. Treatment-related Select AEsa,b 


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aSelect AEs were defined as AEs with potential immune-mediated etiology that may require special monitoring and specific unique 
interventions.bTreatment-related select AEs are ordered by decreasing frequency in the NIVO3 + IPI1 arm. 
 
More recently the Checkmate 214 study data were released confirming the activity of 
nivolumab/ipilimumab with a 42% response rate in intermediate and poor-risk patients and 
improvement in overall survival. The combination of Nivolumab plus Ipilimumab is now 
approved for kidney cancer in the first line. 
1.5 Stereotactic Body Radiation Therapy in Renal Cell 
Carcinoma 
SBRT is an external beam radiation therapy (RT) method used to very precisely deliver a high 
dose of radiation to an extracranial target within the body, using either single-fraction treatment 
or a hypofractionated regimen. Although RCC has traditionally been considered radioresistant, 
it is expected that the use of higher dose-per-fraction regimens associated with SBRT may 
improve response rates and local control compared to conventional RT. Tinkle et al;19 
compared patients who received SBRT with those who received EBRT for either locally 
recurrent or metastatic RCC. This study reported that 1-year local control estimate was 88% 
for patients receiving SBRT, compared to 50% for those receiving external beam radiation 
therapy (EBRT) (p=0.001). In addition, the use of SBRT was the most important independent 
factor predictive of local control on multivariable analysis. A systematic review of SBRT for 
primary RCC found that amongst 10 reports in the literature, local control was 94%, with grade 
1-2 adverse events of 21%.  The most widely employed fractionation regimen was 40 Gy in 
five fractions.20 However, the optimal fractionation regimen for SBRT in combination with 
immunotherapy remains unclear, with data from preclinical models suggesting superiority for 
single-fraction SBRT 21,22 and conflicting data showing superiority for fractionated SBRT. 23,24 
In the clinical cases that have been reported in patients receiving combined SBRT and 
Category, n (%) 
NIVO3 + IPI1 
NIVO1 + IPI3 
NIVO3 + IPI3 
N = 47 
N = 47 
N = 6 
 
All 
Grade 3/4 
All 
Grade 3/4 
All 
Grade 3/4 
Skin disorder 
18 (38.3) 
0 
24 (51.1) 
1 (2.1) 
3 (50.0) 
0 
GI disorder 
11 (23.4) 
1 (2.1) 
21 (44.7) 
11 (23.4) 
3 (50.0) 
2 (33.3) 
Endocrinopathy 
11 (23.4) 
1 (2.1) 
20 (42.6) 
0 
5 (83.3) 
0 
Hepatic 
7 (14.9) 
2 (4.3) 
15 (31.9) 
10 (21.3) 
3 (50.0) 
0 
Renal disorder 
5 (10.6) 
1 (2.1) 
7 (14.9) 
1 (2.1) 
2 (33.3) 
0 
Infusion reaction 
4 (8.5) 
0 
3 (6.4) 
0 
1 (16.7) 
0 
Pulmonary 
2 (4.3) 
0 
3 (6.4) 
0 
0 
0 


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immunotherapy, the doses utilized have been fractionated and have not consistently been 
doses that would be considered completely tumor ablative. This suggests that SBRT serves 
as a priming mechanism for the immune response both locally and systemically also called 
abscopal effect.25,26 The abscopal effect refers to a phenomenon in which local radiotherapy 
is associated with the regression of metastatic cancer at a distance from the irradiated site. 
This phenomenon has been associated with increase in tumor-specific T-lymphocytes and a 
decrease in myeloid-derived suppressor cells in melanoma patients treated with ipilimumab 
and radiation. 
In summary, an approach utilizing established doses of fractionated SBRT (5 fractions of 8-
10 Gy per fraction depending on site) which are considered acceptable from a toxicity 
perspective for the given target site and regional normal seems warranted.27-29 
 1.6 Rationale to Support Trial Design 
The immune-checkpoint modulators PD-1 and CTLA-4 have very different roles in regulating 
the immune response with different temporo-spatial effect that indicate a more tumor-directed 
effect by PD-1, while CTLA-4 has significant T-cell activation in the peripheral circulation. The 
differing mechanisms of effector T-cell activation provide scientific rationale to evaluate the 
combination of nivolumab with ipilimumab for the treatment of mRCC. 
Data from CA209016 demonstrate a level of clinical activity for the combination of nivolumab 
combined with ipilimumab, as measured by ORR, that is substantially greater than that of 
either nivolumab or ipilimumab monotherapy in mRCC.17,18 However, as data accumulate, it 
is becoming abundantly clear that, even with combined immune checkpoint blockade, a 
substantial proportion of patients fail to derive clinical benefit.  RT has been shown to result in 
a number of potential beneficial immunologic effects, especially when given at high doses 
such as with SBRT.30 For example, SBRT in combination with HD IL-2 has showed clinical 
activity and manageable toxicity for treatment of metastatic RCC in two different early-stage 
clinical trials.31,32  
Preclinical models suggest that focal high-dose radiation can make tumors more 
immunogenic.21,22,24 Among the effects of radiation therapy, SBRT may induce necrotic tumor-
cell death, a prerequisite for eliciting an antitumor immune response. 30 
Although a detailed understanding of the effect of SBRT on the immune system is still needed, 
in vivo studies have shown that radiation induces release of damage-associated molecular 
patterns (DAMPs) such as HMGB1, HSP and calreticulin into the extracellular matrix and 
thereby promotes the recruitment and activation of antigen-presenting cells (APCs) such as 


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dendritic cells (DCs) for antigen presentation. Subsequently, the APCs migrate to the draining 
lymph nodes for the presentation of the antigens and efficiently present tumor antigens in the 
cell surface MHC molecules to T cells. Then, T cells initiate an adaptive immune response 
resulting in antibody production and the expansion of cytotoxic T cells. These are delivered to 
both the primary and metastatic tumor sites. Increased trafficking of CD8+ T cells to both 
irradiated tumor and their draining lymph node has been observed after RT.30 
Other changes in the tumor microenviroment induced by radiation have been reported. For 
example, increase in MHC-I expression which mediates antitumor immunity by enhancing 
presentation of neo-antigen by the tumor cells and DCs. Induction of death pathways is 
another mechanism by which RT can triggers intratumoral immunostimulatory signals. 
Upregulation of the FAS death receptors on the tumor cell surface in response to radiation 
renders tumor cells particularly susceptible to massive CD8+ T cell-mediated cytotoxic 
attack.30 
Preclinical studies also suggest the possibility that radiation can enhance the efficacy of CTLA-
4 and PD-1 blockade. Because checkpoint blockade is thought to require a pre-established 
antitumor immune response, the immune-modulating effects of RT as a means to induce 
endogenous antigen-specific immune responses and generate an in situ, patient specific 
tumor vaccine may improve on the number of patients who benefit from combined immune-
checkpoint blockade.33 
Although some clinical cases and retrospective series suggest that RT may have enhanced 
efficacy of immune checkpoint blockade in patients and is generally believed to be safe, 
prospective trials are underway to test this hypothesis and little is known about this strategy.  
Very recently, preliminary results of a dose escalation Phase I/II trial of SBRT followed by 
ipilimumab in patients with metastatic melanoma has been reported (NTC01497808).34 The 
authors identified tumor regressions in radiated and unirradiated lesions (an abscopal effect) 
in some of the patients treated with ipilimumab and radiation. However, the majority of patient 
did not respond (64%).  Detection of PD-L1 in melanoma cells from the participants was 
associated with resistance to this regimen. This finding suggests that PD-1 expression in 
tumor cells is a major impediment to antitumor immune response induced by SBRT and 
ipilimumab. 34 
The same group aimed to reproduce these clinical observations in a melanoma mouse model 
data. They investigated immune-mechanism both of response and resistance between 
radiation and immune checkpoint inhibitors. Results from mice studies demonstrated that 
while anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells) and promotes 


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expansion of T cells (thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio), radiation 
enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. 
Additionally, resistance was due to upregulation of PD-L1 in tumor cells and was associated 
with T-cell exhaustion that impairs the CD8+/Treg ratio. Based on these preclinical findings, it 
is expected that dual checkpoint blockade of PD-1 and CTLA-4 synergizes with SBRT and the 
combination induces non-redundant immune mechanism in cancer patients.34  
 
1.7 Dosing for the Nivolumab Combination with Ipilimumab  
Data from CA209016 demonstrated a level of clinical activity, as measured by ORR, for the 
combination of nivolumab combined with ipilimumab that is substantially greater than that of 
either nivolumab or ipilimumab monotherapy in mRCC. The dosing regimen including 
nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg was chosen because it exhibits similar 
clinical activity than nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg along with a more 
favorable safety profile.17,18  
 1.8 Dosing for the Stereotactic Body Radiation Therapy 
As mention in the section 1.5; an approach utilizing established doses of fractionated SBRT 
(5 fractions of 8-10 Gy per fraction depending on site) (which are considered acceptable from 
a toxicity perspective) in combination with immune-checkpoint inhibitors seems reasonable. 
1.9Overall Risk/Benefit Assessment  
The combination of nivolumab and ipilimumab has encouraging anti-tumor activity (durable 
responses and stable disease) in a Phase 1 study for subjects with mRCC. Given the potential 
for the induction of non-redundant immune mechanism with dual checkpoint blockade of PD-
1 and CTLA-4 in combination with SBRT, there exists an opportunity to further improve 
outcomes in mRCC. The immunostimulatory potential of SBRT may lead to enhance clinical 
activity in subjects also receiving nivolumab plus ipilimumab. As nivolumab, ipilimumab and 
SBRT have non-overlapping mechanisms of action; their combination may be associated with 
increased efficacy that outweighs the potential incremental increase in toxicity in first- or 
second-line mRCC setting. 
We are hoping that the use of nivolumab plus ipilimumab in combination with SBRT to up to 
two metastatic lesions lead to greater clinical benefit than use the combination of nivolumab 
and ipilimumab alone without excessive toxicity. 


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INVESTIGATIONAL PLAN and PATIENT SELECTION 
2.1 Study Design 
This is a multi-institution, single-arm phase II study to determine the safety and efficacy of 
SBRT (up to 2 metastatic sites preferentially lung, mediastinum or bone in combination of 
nivolumab and ipilimumab in patients with metastatic RCC (with a clear-cell component and 
at least 1 measurable metastatic lesion that is not being irradiated).  The primary endpoints 
are safety and tolerability as well as ORR of the combination of nivolumab plus ipilimumab 
with SBRT.   
The study is planned based on a two-stage design that allows early termination for lack of 
efficacy. A safety run-in phase will be included comprising the first 6 patients at minimum to 
ensure that the combination of nivolumab plus ipilimumab and SBRT is safe. Then, we will 
determine whether the combination of nivolumab plus ipilimumab and SBRT yields a clinically 
compelling antitumor activity measured as ORR, and evaluate other endpoints including TTP, 
DOR, PFS, OS and local control of irradiated sites. 
Safety Run-in phase  
There is no previous experience with SBRT used concurrently with nivolumab and 
ipilimumab in this study population. Therefore, to ensure that the combination is safe, 
the first six patients will be treated and observed for toxicity for 6 weeks after 
radiation before continuing with further accrual. Therefore, six patients will be enrolled at 
the proposed dose of nivolumab and ipilimumab in combination with SBRT. If 4 out of the 
first 6 patients experience Grade 3/4 toxicity or a lower grade toxicity requiring immune 
suppressive therapy during the safety run-in observation period (6 weeks after completion of 
SBRT), enrollment will cease and the study will be halted until further safety analysis of the 
combination regimen can be performed. If less than 4 out of the first 6 patients experience 
Grade 3/4 toxicities or require steroids, we will proceed with additional accrual with this 
regimen. 
Toxicity Event: ≥grade 3 adverse event (CTCAE v 4.0) with an attribution of possible, 
probable, or definite, as well as need for steroids/ immunosuppressive therapy and lower 
grade toxicity 
Efficacy phase:  
A minimax Simon two-stage design is planned with the maximum sample size of 25 
(including the 6 in the safety run-in phase). A total of 15 patients will be entered in the first 


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stage. If 6 or less achieve an objective response, then the response data will be reviewed 
carefully and study termination will be discussed. If a number of patients have near partial 
responses or evolving tumor shrinkage the team may decide to continue with accrual to get 
a larger sample size. If 7 or more patients have an objective response, then the second 
stage will proceed automatically with additional 10 patients. If a total of 17 or more patients 
respond, we will conclude this regimen is promising and warrants further study. 
 2.2 Duration of Study  
Enrollment in the run-in phase of the study is expected to take approximately 3-6 months. 
Enrollment in the efficacy phase of the study is expected to take approximately 18 additional 
mo. Subjects may discontinue from treatment because of disease progression, unacceptable 
toxicity, withdrawal of consent, or at the discretion of the investigator. The end of the trial will 
occur on the day of the last visit of the last subject.  
 2.3 Study Population  
For entry into the study, the following criteria MUST be met.  
 2.3...1  
Inclusion Criteria  
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria to 
be registered to the study. Study treatment may not begin until a subject is registered 
1) Signed Written Informed Consent 
• 
Willing and able to provide informed consent 
 
2) Target Population 
• 
Histological confirmation of RCC with a clear-cell component  
• 
Metastatic (AJCC Stage IV) RCC  
• 
Prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC is allowed 
provided recurrence occurred = or > 6 months after the last dose of the adjuvant or 
neoadjuvant therapy 
• 
Any number of prior systemic treatment regimen in the advanced/metastatic setting is 
allowed (cytokine, anti-angiogenic, mTOR inhibitor or clinical trial) including previously 
untreated patients 
• 
Karnofsky Performance Status (KPS) of at least 70%  
• 
Life expectancy of at least 3 months 
• 
At least 2 metastatic sites of which at least 1 must be measurable as per RECIST 1.1 


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• 
Archival Formalin-fixed paraffin-embedded (FFPE) tumor tissue must be available for 
correlative studies (Note: Fine Needle Aspiration [FNA] and bone metastases samples 
are not acceptable for submission) 
• 
Patients with favorable, intermediate and poor risk categories will be eligible for the 
study. Patients must be categorized according to favorable versus intermediate/poor 
risk status at registration. International Metastatic RCC Database Consortium 
(IMDC) must be used to determine prognostic factors (Appendix 1) 
 
2.3.2 Exclusion Criteria:  
1) Target Disease Exceptions 
• 
Subjects with previously treated brain or CNS metastases are eligible provided that 
the subject has recovered from any acute effects of radiotherapy and is not requiring 
steroids, and any whole brain radiation therapy was completed at least 4 weeks prior 
to study drug administration, or any stereotactic radiosurgery was completed at least 
2 weeks prior to study drug administration.  Liver metastases will not be included as 
part of the radiated lesions to be treated. 
 
2) Medical History and Concurrent Diseases 
• 
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. Prior treatment with HD IL-2 is allowed. 
• 
Any active or recent history of a known or suspected autoimmune disease or recent 
history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone 
equivalent) or immunosuppressive medications except for syndromes which would not 
be expected to recur in the absence of an external trigger. Subjects with vitiligo or type 
I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only 
requiring hormone replacement are permitted to enroll. Patients with psoriasis not 
requiring active, systemic treatment are allowed. 
• 
Any condition requiring systemic treatment with corticosteroids (> 10 mg daily 
prednisone equivalents) or other immunosuppressive medications within 14 days prior 
to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses up 
to 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease 


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• 
Uncontrolled adrenal insufficiency 
• 
Requirement for anti-coagulation with Coumadin, low molecular weight heparin and 
anti-thrombin inhibitors will be accepted if anticoagulation has been stable for at least 
4 weeks and no recent history of prior bleeding complications. 
• 
Prior malignancy active within the previous 3 years except for locally curable cancers 
that have been apparently cured such as basal or squamous cell skin cancer, 
superficial bladder cancer, or carcinoma in situ of the cervix, breast or low risk Gleason 
6 prostate cancer 
• 
Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS) 
• 
Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection 
• 
Known medical condition (eg, a condition associated with diarrhea or acute 
diverticulitis) that, in the investigator’s opinion, would increase the risk associated with 
study participation or study drug administration or interfere with the interpretation of 
safety results 
• 
Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug 
• 
Anti-cancer therapy less than 14 days prior to the first dose of study drug or palliative, 
focal radiation therapy less than 14 days prior to the first dose of study drug 
• 
Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, 
that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration 
of study drug 
 
3) Physical and Laboratory Test Findings 
• 
Any of the following laboratory test findings:  
- 
WBC < 2,000/mm3  
- 
Neutrophils < 1,500/mm3  
- 
Platelets < 100,000/mm3  
- 
AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)  
- 
Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can 
have total bilirubin < 3.0 mg/dL)  
- 
Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 
40 mL/min (measured or calculated by Cockroft-Gault formula) 
 
4) Allergies and Adverse Drug Reaction 


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the study sponsor. 
 
• 
History of severe hypersensitivity reaction to any monoclonal antibody or study drug 
components 
 
5) Other Exclusion Criteria  
• 
Prisoners or subjects who are involuntarily incarcerated 
• 
Not suitable for SBRT treatment 
• 
Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical illness 
 2.3.3. Age and Reproductive Status  
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 
months of amenorrhea in a woman over 45 in the absence of other biological or 
physiological causes. In addition, women under the age of 62 must have a documented 
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.  
Women of childbearing potential (WOCBP) receiving nivolumab will be instructed to 
adhere to contraception for a period of 23 weeks after the last dose of investigational 
product. Men receiving nivolumab and who are sexually active with WOCBP will be 
instructed to adhere to contraception for a period of 31 weeks after the last dose of 
investigational product. These durations have been calculated using the upper limit of the 
half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP 
use contraception for 5 half-lives plus 30 days and men who are sexually active with 
WOCBP use contraception for 5 half-lives plus 90 days. 
 
Highly effective methods of contraception include: 
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena 
by WOCBP subject or male subject’s WOCBP partner Female partners of male 
subjects participating in the study may use hormone based contraceptives as one 
of the acceptable methods of contraception since they will not be receiving study 
drug 
• 
Nonhormonal IUDs, such as ParaGard 


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• 
Tubal ligation  
• 
Vasectomy 
• 
Complete Abstinence* 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse 
and is an acceptable form of contraception for all study drugs. Subjects who choose 
complete abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable alternate methods 
of highly effective contraception must be discussed in the event that the subject 
chooses to forego complete abstinence. 
 
Less effective methods of contraception include: 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Vaginal sponge 
• 
Male Condom without spermicide  
• 
Progestin only pills by WOCBP subject or male subject’s WOCBP partner  
• 
Female Condom*. 
*A male and female condom must not be used together 
 
 2.4 Follow-up Visits  
At least three follow-up visits (X1, X2 and X3) are required for all subjects. Visit X1 will take 
place 30 days (+/- 1 week) after the last dose of study medication in the cycle where nivolumab 
was discontinued, visit X2 will take place 8 weeks (+/- 1 week) after last dose of nivolumab 
was administered and visit X3 will take place 15 weeks (+/- 1 week) after last dose of 
nivolumab was administered. The duration of the follow-up period up to the X3 visit is equal 
to approximately 5 half-lives of nivolumab. If additional X follow-up visits are required due to 
ongoing study drug- related toxicity, they should take place every 8 weeks (+/- 1 week) until 
study drug-related toxicity has resolved, stabilized or been deemed irreversible.  
 2.5 Survival Follow-up  
After follow-up visits, study subjects will be contacted every 3 months for survival data. Other 
potential data such as the subjects’ follow-up treatment or care may be requested during these 
contacts. The contacts can be via telephone or correspond with disease assessment visits, if 


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subject went off treatment for other than progressive disease, or other scheduled visits.  
2.6 Subsequent therapy 
Subjects for whom treatment is discontinued should be treated according to clinical 
circumstances and should be managed at the local clinician’s discretion. 
 2.7 Concomitant Treatments 
 2.7.1 Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study:  
• 
Immunosuppressive agents (except to treat a drug-related adverse event). Systemic 
corticosteroids > 10 mg daily prednisone equivalent (except as stated in Section 2.7.3 
below or to treat a drug-related adverse event). 
• 
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, radiation therapy except for palliative radiation therapy surgical 
resection except for palliative surgical resection).  
• 
Supportive care for disease-related symptoms may be offered to all subjects on the 
trial. 
• 
Any concurrent meds should be evaluated for being absolutely necessary. Particularly 
drugs with potential liver toxicity should be avoided if possible  
 2.7.2 Other Restrictions and Precautions  
Palliative (limited-field) radiation therapy and palliative surgical resection are permitted, if the 
following criteria are met:  
• 
The subject will be considered to have progressed at the time of palliative therapy and 
must meet criteria to continue with treatment beyond progression. (Section 3.5)  
 2.7.3 Permitted Therapy  
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of 
systemic corticosteroids are permitted, up to 10 mg/day prednisone equivalents. A brief course 
of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.  
Concomitant medications are recorded at baseline and throughout the treatment phase of the 
study in the appropriate section of the case report form (CRF). All medications (prescriptions 


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or over the counter medications) continued at the start of the study or started during the study 
and different from the study drug must be documented in the concomitant therapy section of 
the CRF.  
 2.8 Discontinuation of Subjects following any Treatment with 
Study Drug  
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:  
• 
Subject’s request to stop study treatment  
• 
Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the subject  
• 
Protocol defined disease progression (subjects may be permitted to continue treatment 
beyond initial disease progression see Section 3.5)  
• 
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness  
• 
Additional protocol specified reasons for discontinuation (see Section 3.4.5)  
In the case of pregnancy, the study subject will be permanently discontinued in an appropriate 
manner. All subjects who discontinue study drug should comply with protocol specified follow-
up procedures as outlined in Section 3 (Study Assessment and Procedures). The only 
exception to this requirement is when a subject withdraws consent for all study procedures 
including post-treatment study follow-up or loses the ability to consent freely (ie, is imprisoned 
or involuntarily incarcerated for the treatment of either a psychiatric or physical illness).  
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate CRF page.  
 
 2.9 Post Study Drug Study Follow up  
In this study, overall response rate is a key endpoint of the study. Post study follow-up is of 
critical importance and is essential to preserving subject safety and the integrity of the study. 
Subjects who discontinue study drug must continue to be followed for collection of outcome 


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and/or survival follow-up data as required and in line with Section 3 (Study Assessment and 
Procedures) until death or the conclusion of the study.  
 2.9.1 Withdrawal of Consent  
Subjects who request to discontinue study drug will remain in the study and must continue to 
be followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons 
previously authorized by subject to provide this information. Subjects should notify the 
investigator of the decision to withdraw consent from future follow-up in writing, whenever 
possible. The withdrawal of consent should be explained in detail in the medical records by 
the investigator, as to whether the withdrawal is from further treatment with study drug only or 
also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page. In the event that vital status (whether the subject is alive or dead) is 
being measured, publicly available information should be used to determine vital status only 
as appropriately directed in accordance with local law.  
 2.9.2 Lost to Follow-Up  
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is determined 
that the subject has died, the site will use permissible local methods to obtain the date and 
cause of death.  
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. If after all attempts, 
the subject remains lost to follow-up, then the last known alive date as determined by the 
investigator should be reported and documented in the subject’s medical records.  


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TREATMENT PLAN/THERAPEUTIC INTERVENTION 
 3.1 Treatment Plan 
 3.1.1 Study Drug  
Study drug includes both Investigational (Investigational Medicinal Product) and Non-
Investigational Therapy and can consist of the following:  
• 
All products, active or placebo, being tested or used as a comparator in a clinical 
trial 
• 
Study required premedication, and other drugs administered as part of the study 
that are critical to claims of efficacy (eg, background therapy, rescue medications) 
• 
 Diagnostic agents: (such as glucose for glucose challenge) given as part of the 
protocol requirements must also be included in the dosing data collection 
Nivolumab 100 mg (10 mg/mL) will be packaged in an open-label fashion. Five or ten 
nivolumab 10 mL vials will be packaged within a carton. The vials are not subject or treatment 
group specific. Each site will complete a drug request form and submit the form to BMS to 
receive the medication and obtain re-supply.   
Ipilimumab will be supplied as a sterile, preservative-free solution in 40 mL vials at a 
concentration of 5 mg/mL. Each vial contains a concentrated solution with the equivalent of 
200 mg of ipilimumab. 
 
Table 3. Product Description: Treatment Period 
 
 
 


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3.1.2 Investigational Products 
An investigational product, also known as investigational medicinal product (IMP) in some 
regions, is defined as pharmaceutical form of an active substance or placebo being tested or 
used as a reference in a clinical study, including products already with a marketing 
authorization but used or assembled (formulated or packaged) differently than the authorized 
form, or used for an unauthorized indication, or when used to gain further information about 
the authorized form.  
The investigational product should be stored in a secure area according to local regulations. 
It is the responsibility of the investigator to ensure that investigational product is only 
dispensed to study subjects. The investigational product must be dispensed only from official 
study sites by authorized personnel according to local regulations.  
In this protocol, investigational products are: 
• Nivolumab (BMS-936558) 
• Ipilimumab  
 
 3.1.3 Non-investigational Product  
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products.  
In this protocol, non-investigational product(s) is/are: medications used to treat nivolumab or 
ipilimumab infusion-related reactions (eg, steroids, anti-emetics); these non-investigational 
products should be sourced by the investigator sites if available and permitted by local 
regulations.  
 3.1.4 Storage and Dispensing  
The product storage manager should ensure that the study drug is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study drug arise, the study drug should 
not be dispensed and contact BMS and the principal investigator immediately.  
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety 
measures for preparation and handling of nivolumab and ipilimumab include laboratory coats 
and gloves. 
Investigational product documentation must be maintained that includes all processes 


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required to ensure drug is accurately administered. This includes documentation of drug 
storage, administration and, as applicable, storage temperatures, reconstitution, and use of 
required processes (eg, required diluents, administration sets).  
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) should be purchased 
locally if permitted by local regulations.  
For nivolumab and ipilimumab, please refer to the current version of the Investigator 
Brochures and/or pharmacy reference sheets for complete storage, handling, dispensing, and 
infusion information.  
 
Nivolumab is to be administered as an approximately 60-minute IV infusion. At the end of the 
infusion, flush the line with a sufficient quantity of normal saline.  
Ipilimumab is to be administered as an approximately 30-minute IV infusion. At the end of the 
infusion, flush the line with a sufficient quantity of normal saline or 5% dextrose solution.  
When both study drugs are to be administered on the same day, separate infusion bags and 
filters must be used for each infusion. Nivolumab is to be administered first.  
3.2 Timing of Dose for Each Subject and Duration of Therapy 
Table 4. Schedule for SBRT 
SBRT is to be delivered anytime between Day 1 of Week 1 and Day 1 of Week 4 of the 
NIVO/IPI combination dosing  
 
Week 1 D1 
Week 2 
Week 3 
Week 4 D1 
Week 5 
Week 6 
 
SBRT 
 
5 fractions of 10 Gy 
 
 
 
 
Table 5. Dosing Schedule for Cycle 1 and Cycle 2 
1 cycle = 6 weeks 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
 
Nivolumab 3 
mg/kg IV + 
Ipilimumab 
1 mg/Kg IV 
Day 1 
Nivolumab 3 
mg/kg IV + 
Ipilimumab 
1 mg/Kg IV 
 
 
Day 1 
Nivolumab 3 
mg/kg IV + 
Ipilimumab 
1 mg/Kg IV 
 
 
 
 
Table 6. Dosing Schedule for Cycle 3 and Beyond (up to 2 years) every 4 weeks 
1 cycle = 8 weeks 


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Week 1 
 
Week 5 
 
 
 
 
 
Day 1 
Nivolumab 
480 mg IV 
 
Day 1 
Nivolumab 
480mg IV 
 
 
480mg IV 
 
 
When nivolumab and ipilimumab are to be administered on the same day, separate infusion 
bags and filters must be used for each infusion. Nivolumab is to be administered first. The 
second infusion will always be ipilimumab, and will be administered at least 30 minutes after 
completion of the nivolumab infusion.  
Ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution. 
Nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution.  
The dosing calculations should be based on the actual body weight. If the subject’s weight on 
the day of dosing differs by > 10% from the weight used to calculate the dose, the dose must 
be recalculated. (The weight used to calculate the dose should always be the most recently 
recorded weight). All doses should be rounded to the nearest milligram. There will be no dose 
modifications allowed.  
During cycles 1 and 2, subjects may be dosed no less than 19 days from the previous dose 
of drug. Starting from cycle 3, subjects may be dosed no less than 26 days from the previous 
dose of drug. Patients may be dosed up to 3 days after the scheduled date if necessary or 2 
days prior to expected date. Treatment compliance will be monitored by drug accountability 
as well as the subject’s medical record and CRF.  
Maintenance nivolumab will be allowed up to 2 years from the start of treatment.  
 3.3 Stereotactic Body Radiation Therapy 
Prior to entry into the protocol, all patients need to be discussed with Dr. Danny Song (JHU), 
Dr. Raquib Hannan (UTSW) or co-investigator Radiation Oncologist from the Radiation 
Therapy Department to determine eligibility/feasibility for SBRT. The cancer lesion(s) to be 
radiated should be determined by the Radiation Oncologist in collaboration with the Principal 
Investigator/Medical Oncologist using the criteria stated below. 
 
3.3.1 Lesion selection criteria and dosing 
The most common sites of involvement with metastatic RCC are lung (45%), bone (29%), 
lymph node (22%), liver (20%), and adrenal (9%)1.  Dosing, patient setup/immobilization, and 
dose constraints for lung sites will be in accordance with established experience specific to 


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those sites.  Bone and lymph node sites will be treated and dosed in accordance with their 
anatomic location (extremity, thorax, or abdomen/pelvis) and surrounding dose-sensitive 
structures.  The gross target volume (GTV) for SBRT will be a minimum of 1cm in short-axis 
diameter (in order to help assure an adequate volume of tumor cells for immune stimulation), 
and a maximum of 5cm in long-axis diameter.  Liver lesions will not be considered for SBRT 
for patients on the protocol, as this could potentially lead to higher rates of liver failure and/or 
autoimmune hepatitis in the setting of concomitant immunotherapy. 
Five fractions of SBRT at 10 Gy per fraction will be delivered within the first 3 weeks after the 
initiation of nivolumab and ipilimumab.  Given the parallel goals of radiation of enhancing 
antitumor immune response and stimulating auto-vaccination (rather than to treat all known 
tumor tissue), as well as maintaining consistency in target dose prescription for purposes of 
analysis, the planning target volume and treatment margins may be defined in a manner which 
may involve potentially less than complete prescription dose coverage of the involved tumor.  
A working hypothesis of the trial is that optimal immune stimulation will occur with an ablative 
dose of radiation; the most robust dose-response relationships for SBRT come from the lung 
SBRT experience, where a biologically equivalent dose (BED) of approximately 100 Gy 
(equivalent to 10 Gy x 5 fractions) has been shown to be a threshold dose for optimal local 
control2,3 
If all relevant normal tissue constraints cannot be met while treating the entire metastatic 
focus, then planned target volume (PTV) margins will be modified downward in an iterative 
process to a minimum of 0mm (from GTV) in order to achieve normal tissue constraints. If 
normal tissue constraints still cannot be met, then consideration will be given to treating 
another lesion if a suitable alternative exists.  If no suitable alternative target exists, then an 
nPTV will be generated which impinges upon the GTV in areas of proximity to critical normal 
tissues, until all protocol-specific SBRT tissue constraints have been met. For example, if the 
entire GTV can not be treated with 5 x 10 Gy because of surrounding normal tissue 
constraints, then only part of the gross target volume can be exposed to 5 x 10 Gy while the 
surrounding margin receives 5 x 8 Gy.  Liver lesions will not be considered as a radiated target.   
3.3.2 Simulation procedure 
Patients will undergo simulation and immobilization in accordance with site-specific protocols 
established in the Dept. of Radiation Oncology.   
Patients being treated to lung/thoracic or abdominal lesions will have respiratory movement 
of the target volume accounted for either with 4D-CT scanning or with Active Breathing Control 
(ABC) and inspiratory breath hold.  Patients with greater than or equal to 5 mm of breathing 


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motion identified on 4D-CT should have ABC performed to minimize breathing motion.  All 
other patients will have an Internal Target Volume (ITV) delineated using end-inspiratory and 
end-expiratory phases of the 4D-CT scan.  A wingboard and/or alpha cradle may be utilized 
for patient positioning. Patients who have target volumes in close proximity to the upper GI 
tract (stomach, duodenum, small bowel) shall be instructed to be NPO for 3 hours prior to 
simulation and each daily treatment.   
IV contrast should be utilized during CT simulation for patients with targets in the mediastinum.   
Patients being treated to pelvic lesions will be positioned with the Combifix device.  Bladder 
filling (patient instructed to drink 30 oz. of water prior to simulation) is to be utilized if doing so 
will help eliminate or minimize small bowel from the treatment field.   
For extremity lesions, immobilization with alpha cradle and/or Vac-Loc bags will be utilized.   
CT simulation will be performed with minimum 3mm slice thickness.  MRI simulation may be 
utilized if target volume or normal anatomy delineation will be enhanced with its use.  
Diagnostic MRI scans may also be utilized to provide complementary anatomic information to 
CT simulations.  MRI and CT simulation images will be fused using either Pinnacle or Velocity.    
The target volume (PTV or nPTV) for centrally located or mediastinal sites should not directly 
involve critical structures such as central bronchial tree (within 2cm of carina or hilum, as 
defined in RTOG 0813), esophagus, great vessels, or brachial plexus. 
 
3.3.3 Target delineation 
Spinal metastases may involve vertebral body alone, vertebral body and pedicle, or posterior 
elements only (as defined in NRG-BR-001).  For each of these metastases, GTV delineation 
will include at a minimum the involved vertebral body and both pedicles, or the involved 
posterior elements and both pedicles.   
Other targets will be delineated primarily based on CT simulation images, using the windowing 
settings specific for the anatomic location within which the target is contained.  Additional 
imaging modalities such as MRI may be utilized at the radiation oncologist’s discretion; rigid 
image registration is recommended if utilizing complementary imaging modalities in addition 
to CT simulation scans. 
 
3.3.4 Normal tissue delineation and constraints 
The following normal tissue delineation definitions are for purposes of consistency in those 
cases where ambiguity could potentially lead to inter-individual variations in contouring, and 
to adhere to well-defined generally accepted SBRT practice when available. 


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Spinal cord will be contoured based on the bony limits of the spinal canal, starting at least 10 
cm above the superior extent of the PTV and continuing on every CT slice to at least 10 below 
the inferior extent of the PTV. 
Cauda equina is defined as beginning at the conus (usually L1 or L2) and including the entire 
spinal canal to the filum terminale in the sacrum.   
Sacral plexus will includes the nerve roots beginning at L5 and extending to S3 bilaterally from 
neuroforamina to the coalescing of nerves at the obturator internus. 
Esophagus is to be defined to include all layers from mucosal to adventitia, starting at least 
10cm cranial and caudal to the extent of PTV. 
Brachial plexus is to be contoured if target volume (PTV) is within 10 cm, using the technique 
as described by Hall et al4.  It originates from nerves existing neuroforamina from C5 to T2, 
and commonly defined on CT using subclavian and axillary vessels as surrogate structures.   
Heart will be contoured including the pericardial sac. The superior aspect (or base) for 
purposes of contouring will begin at the level of the inferior aspect of the aortic arch (i.e. 
aortopulmonary window) and extend inferiorly to the apex of the heart. 
Trachea and proximal bronchial tree will be defined as two structures; distal 2cm of trachea 
will be included in what is defined as proximal bronchial tree.  Proximal bronchial tree will 
include the caudal 2cm of distal trachea plus proximal airways bilaterally as defined by 
Timmerman et al5 / RTOG 0813.   
Lungs will be contoured separately as well as combined into a single structure for DVH 
purposes.  GTV and trachea / proximal bronchial tree are to be excluded. 
Skin is to be defined as the outer 5mm of body surface. 
Great vessels (aorta, vena cava) will be contoured including entire thickness to the adventitia.  
Contours should extend from 10cm caudal to 10cm cranial from extent of PTV. 
Duodenum will be defined from stomach, to where the superior mesenteric artery crosses over 
the 3rd part of duodenum. 
Small bowel will be defined from duodenum (see above) to ileocecum.  If small bowel and 
large bowel cannot be delineated with confidence, then the more generous contour should be 
utilized. 
Large bowel will be defined from ileocecum to rectum (including sigmoid). 
Rectum is to be defined from the peritoneal reflection cranially, typically extending 12-15 cm 
from anal verge to the valve of Houston, located approximately at level of S3.  Caudal extent 
is at the junction with the anal canal, defined on axial CT at approximately level of bottom of 
ischial tuberosities. 


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Renal hilum will be contoured where renal vessels and renal pelvis are adjacent as they 
enter/exit the kidney. 
Ureter is to be contoured from 10cm cranial to 10cm caudal to extent of PTV, and terminates 
at renal hilum and vesicoureteral junction, respectively. 
Bile ducts are identified by portal vein from its juncture with the splenic vein to its right and left 
birfurcation in the liver as a surrogate. 
Liver is entire liver minus GTV. 
 
Kidneys will be defined in their entirety, but excluding the pelvis / collecting system. 
Penile bulb is best delineated on MRI images, but can be visualized on CT if MRI unavailable.  
As defined by Wallner et al6, it is to be contoured as the cranial portion of the corpus 
spongiosum, between the corpora cavernosal and beneath the genitourinary diaphgram. 
 
Normal tissue constraints 
The dose will be prescribed to the minimal isodose line that completely covers the GTV (or 
ITV if applicable) plus a 0-5 mm margin to create a planning target volume (PTV).  In order to 
achieve normal tissue dose constraints, PTV margins may be utilized which may not 
encompass the entire target volume with setup uncertainty and anatomic motion; PTV margins 
may be utilized which are negative (i.e. PTV smaller than GTV volume) in order to achieve 
protocol-specified doses while respecting normal tissue tolerances; such PTV volumes will be 
termed ‘nPTV’. All relevant adjacent normal structures including but not limited to the heart, 
esophagus, aorta, spinal cord, kidneys, rectum, bowel, liver, and stomach within 5 cm of the 
GTV will be identified for the purpose of limiting incidental radiation to these structures. 
Dose heterogeneity within the PTV may be high, and within the paradigm of SBRT is 
considered acceptable without constraints.  The dose to any tissue outside of the PTV should 
not exceed 5% of the prescription dose. 
 
3.3.5 Treatment delivery technical factors 
Treatment will be initiated within three weeks of the initial treatment planning simulation study. 
Treatment will be delivered with a minimal inter-fraction interval of 36 hours, and no greater 
than 84 hours between fractions. 
Only photon (x-ray) beams with energies greater than or equal to 6MV are allowed.  Tumors 
located within the lungs should be treated with energies of no greater than 10MV, except for 
specific beams where large soft tissue distances must be traversed to reach target.  Dynamic 
conformal arcs and flattening-filter-free beams are acceptable.  All dose calculations should 


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be performed with tissue heterogeneity corrections. 
Image-guided therapy (IGRT) utilizing on-board cone-beam imaging is required for each 
fraction prior to delivery of treatment.  Patients should be aligned to the visible target volume.  
In cases where soft tissue contrast is poor on CBCT imaging, fiducial markers should be 
utilized for more accurate setup.   
3.4 Intervention Plan 
 3.4.1 Antiemetic Premedications and Supportive Care Medications  
Antiemetic premedications should not be routinely administered prior to dosing of drugs. 
Symptomatic antiemetics may be administered at the Investigator’s discretion. Palliative and 
supportive care for disease-related symptoms will be offered to all patients on this trial. 
3.4.2 Bisphosphonates 
The use of bisphosphonates (e.g., zoledronic acid) or denosumab is permitted if patient has 
been using them prior to the study for at least 1 month. 
 3.4.3 Dose Delay Criteria for Nivolumab and Ipilimumab  
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the 
event is attributed to nivolumab and ipilimumab). All study drugs must be delayed until 
treatment can be resumed. Imaging studies and the collection of blood and tissue for 
correlative studies should continue as planned even if dosing is interrupted. Radiation 
treatment should continue if the treatment is unlikely to worsen adverse event. 
Nivolumab and ipilimumab administration should be delayed for the following: 
• 
Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay  
• 
Any Grade 3 skin, drug-related adverse event  
• 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
AST, ALT, or total bilirubin:   
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥ 2 toxicity  
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity  
• 
Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis do not require a dose delay.  


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• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication 
 
During cycles 1 and 2, both nivolumab and ipilimumab must be delayed at the same time. 
Following the up to 4 administrations of the induction combination therapy with NIVO/IPI, Dose 
1 of maintenance nivolumab will begin 3 weeks after the 4th dose of induction therapy. If the 
4th dose of induction therapy has not been administered due to treatment delays or the 
discontinuation of combination therapy because of primarily ipilimumab related side effects 
such as colitis, high grade diarrhea or hepatitis before Day113, that dose/doses will be omitted 
and maintenance dosing will begin. 
  
The schema is noted in Figure 3.4.2 below.  
 
Figure 3.4.2 Dosing/Treatment Schema for nivolumab/ ipilimumab plus SBRT 
* Cycle 1 of maintenance will begin 3 weeks after the 4th dose of induction therapy or after 
Day 113 if the 4th dose of induction therapy has not been administered due to treatment 
delays.  
 
I n du c t ion  
 
Pha s e 
NI V O 
 
3 
 
mg/k g
 
/ 
 
I P I
 
1 
 
m g /k g
(g i v en
 
e v er y 3
 
weeks 
 
u p 
 
t o 4 dose s)
M ai n t e n anc e P ha s e 
Niv ol um a b
 
Mon ot h er a py 3 
 
m g /k g
( ever y 
 
2
 
w e ek s ,
 
1 
 
c yc les 
 
= 6
 
week s) 
R a di ati on
B io m a rke r s/ B iop sy 
Do se 
 
1
D o se 
 
2
D os e
 
3 
D o se 
 
4
D a y1
Day 1 5 
D ay 
 
2 9 
Cy c le 
 
1
C ycl e 2 
 
e tc .
Bio ma r k e rs/ B io psy 
P ro g re ss io n
Nivolumab Monotherapy 480mg 
(every 4 weeks, 1 cycle = 6 weeks) 


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 3.4.4 Dose Modifications for Nivolumab and Ipilimumab 
Dose reductions or dose escalations of nivolumab or ipilimumab are not permitted. 
 3.4.5 Criteria to Resume Treatment on Nivolumab and Ipilimumab  
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled timepoint per protocol. However, if the treatment is delayed past the next scheduled 
timepoint per protocol, the next scheduled timepoint will be delayed until dosing resumes. If 
treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in discontinuation section. 
Subjects may resume treatment with study drug when the AEs resolve to Grade ≤ 1 or baseline 
value, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity 
• 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or AST/ALT or total bilirubin  
• 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued. 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before treatment is resumed.  
• 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.  
3.4.6 Discontinuation Criteria for Nivolumab and Ipilimumab 
Treatment with nivolumab and ipilimumab should be permanently discontinued for any of the 
following: 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as to allow for prolonged steroid tapers to manage drug-related adverse 
events. Prior to re-initiating treatment in a subject with a dosing interruption lasting > 6 
weeks, the overall PI (Dr. Hammers) must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted. 
Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the Investigator. Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 6 weeks, the Investigator must be consulted. Tumor assessments and 


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the collection of blood and tissue samples for correlative studies should continue as per 
protocol even if dosing is interrupted. Radiation treatment should continue if the treatment is 
unlikely to worsen the adverse event. 
• Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the pre-treatment period or requires 
systemic treatment  
• Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic toxicity, hypersensitivity reactions, and infusion reactions:  
− Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic toxicity, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation  
 
• Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:  
• 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation  
• 
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:  
o AST or ALT>8xULN  
o Total bilirubin > 5 x ULN  
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN  
 
• Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events, which do not require discontinuation:  
− Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis.  
− Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset   
•   Any 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 or ipilimumab dosing   


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 3.4.7 Treatment of Nivolumab or Ipilimumab-Related Infusion Reactions  
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, 
each is unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, 
if such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 
4 infusion reactions should be reported within 24 hours as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE (version 4.0) 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). Remain at bedside and monitor subject until recovery from symptoms. The 
following 
prophylactic 
premedications 
are 
recommended 
for 
future 
infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) 
at least 30 minutes before additional nivolumab administrations.  
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal  anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤ 24 hours).  
Stop the nivolumab and ipilimumab infuse, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms.  
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur then 
no further nivolumab or ipilimumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until resolution of 
symptoms. The amount of study drug infused must be recorded on the CRF. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered 
at least 30 minutes before additional nivolumab or ipilimumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be 
used.  
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 


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responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; pressor or ventilatory 
support indicated). Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV 
infusion of normal saline, and treat the subject as follows. Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 
mg of a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg 
IV with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be 
monitored until the investigator is comfortable that the symptoms will not recur. Nivolumab or 
Ipilimumab will be permanently discontinued.  
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor subject until recovery from symptoms. In the case of late-
occurring hypersensitivity symptoms (eg, appearance of a localized or generalized pruritis 
within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine, 
or corticosteroids).  
 3.5 Treatment Beyond Disease Progression  
Accumulating evidence indicates that a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.  
Subjects, regardless of study arm, will be permitted to continue treatment beyond initial 
investigator assessed progression as long as they meet the following criteria:  
• Investigator-assessed clinical benefit  
  and 
• Subject is tolerating study drug.  
 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment.  
Subjects should discontinue study therapy upon evidence of further progression, defined as 
an additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions).  
New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes, which must have a short axis 
of at least 15 mm). Any new lesion considered non-measurable at the time of initial 
progression may become measurable and therefore included in the tumor burden 
measurement if the longest diameter increases to at least 10 mm (except for pathological 


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lymph nodes, which must have an increase in short axis to at least 15 mm).  
 3.6 Treatment Compliance  
Trained medical personnel will administer nivolumab and ipilimumab and dispense other study 
medication. Treatment compliance will be monitored by drug accountability, as well as by 
recording nivolumab and ipilimumab administration in the CRF.  
In case the treatment has to be interrupted during an infusion, the medical personnel should 
evaluate the percentage of dose received by the patient and document it in the patient record. 
Any reason for non-compliance should also be documented.  
 3.7 Destruction and Return of Study Drug  
 3.7.1 Destruction of Study Drug  
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site.  
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Investigator unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics).  
On-site destruction is allowed provided the following minimal standards are met:  
- 
On-site disposal practices must not expose humans to risks from the drug.  
- 
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous 
substances.  
- 
Written procedures for on-site disposal are available and followed. The procedures 
must be filed with the site’s SOPs and a copy provided to BMS upon request.  
- 
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the 
containers. The method of disposal, ie, incinerator, licensed sanitary landfill, or 
licensed waste disposal vendor must be documented.  
- 
Accountability and disposal records are complete, up-to-date, and available for the 
Monitor to review throughout the clinical trial period.  It is the investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of 


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disposal are kept.  
 3.7.2 Return of Study Drug  
Study drug will not be returned to BMS. Study drug will be destroyed per local institutional 
policy.  
3.8 Immunotherapy Adverse Event Management 
Early recognition and intervention are recommended according to the management 
algorithms; and in addition include ophthalmologic evaluations for any visual symptoms in 
order to evaluate for nivolumab or ipilimumab related uveitis. 
Because of the potential for clinically meaningful nivolumab or ipilimumab-related AEs 
requiring early recognition and prompt intervention, management algorithms have been 
developed for suspected pulmonary toxicity, GI toxicity, hepatotoxicity, endocrinopathy, 
skin toxicity, neurological toxicity, and renal toxicity. 
These adverse event management algorithms are included in the Appendix Toxicities. 
 
3.9 Adverse events associated with Stereotactic Body 
Radiation Therapy (SBRT): 
Common side effects (may occur in more than 20 % people receiving treatment; some 
may be serious):  Fatigue, nausea, vomiting, skin reddening or sensitivity, mild pain, diarrhea, 
decreased appetite, lung scarring, temporary changes in blood work (blood counts or liver 
enzymes) without symptoms 
 
Occasional side effects (may occur in from 4%- 20% people receiving treatment; some 
may be serious):  Skin thickening or numbness, sores or ulcers near the cancer location, 
cough, shortness of breath, rib pain and/or rib fracture, abdominal pain, fever, irritation of the 
esophagus (swallowing tube); fracture or damage to the spine. 
 
Rare side effects (may occur in 3 % or fewer of patients receiving treatment; may be 
serious):  Irritation of the lining around the heart or the heart muscle; severe shortness of 
breath;  irritation or damage to spinal cord or nerves; paralysis; damage to nerves in the chest 
or abdomen; damage to the esophagus, stomach, or intestines requiring hospitalization or 
surgery; irritation of the large blood vessels around the heart; coughing blood; irritation of the 


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voice box causing hoarseness or pain; jaundice; abdominal swelling; low blood counts; kidney 
damage; death. 
 
There is also anticipated possible additive toxicities of irradiation during immunotherapy.  
Anticipated examples could include increased incidence of pneumonitis in irradiated lung 
fields and increased incidence of colitis if normal bowel is included in irradiated abdominal 
fields. 
4 STUDY ASSESSMENTS AND PROCEDURES 
 4.1 Flow Chart/Time and Events Schedule 
 
Procedure 
Screening 
Visit 
Notes 
Eligibility Assessment 
Informed Consent 
X 
 
Inclusion/Exclusion Criteria 
X 
All inclusion/exclusion criteria should be 
assessed prior to treatment  
Medical History 
X 
 
Candidate for SBRT as assessed by Radiation 
Oncology 
X 
 
Tumor Tissue  
X 
Patient must have lesion which is not radiated 
and accessible for core biopsies 
Safety Assessment 
Physical Examination 
X 
 
Vital Signs and Oxygen Saturation 
X 
Including BP, HR, & temperature. Obtain at the 
screening visit and within 72 hours prior to first 
dose  
Physical Measurements (including 
Performance Status) 
X 
Height and weight and Karnofsky Performance 
Status 
ECG 
X 
Within 28 days prior to treatment  
Assessment of Signs and Symptoms 
X 
Within 28 days prior to treatment 
 
Concomitant Medication Collection 
X 
Within 28 days prior to treatment   
 
Laboratory Test 
X 
CBC w/differential, Chemistry panel including: 


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LDH, AST, ALT, ALP, T.Bili, BUN or serum urea 
level, creatinine, Ca, albumin, Mg, Na, K, Cl, 
glucose, amylase, lipase, TSH, Free T4, Free T3, 
Hep B/C(HBV sAG, HCV antibody or HCV RNA), 
within 28 days prior to treatment. Within 72 
hrs prior to re-dosing to include CBC w/ 
differential, LFTs, BUN or serum urea level, 
creatinine, Ca, Mg, Na, K, Cl, LDH, Glucose, 
amylase, lipase, TSH (with reflexive Free T4 and 
Free T3),FSH(women under 62) 
Pregnancy Test (WOCBP only) 
X 
Within 28 days prior to treatment. A serum or 
urine pregnancy testing is required within 24 
hrs of study treatment then every 4 weeks. 
[more frequently if required by local standard]. 
After discontinuation from nivolumab these 
should be repeated at approximately 30 days 
and approximately 70 days [or more frequently 
if required by local standard]. 
Efficacy Assessment 
Screening/Baseline Tumor Assessments 
X 
CT with contrast of the chest, abdomen, pelvis 
and all known sites of disease (or CT Chest w/o 
contrast and MRI of abdomen with or without 
contrast if reduced GFR or allergy). MRI 
(preferred) or CT scan of the Brain if known 
history of brain involvement. 
Exploratory Biomarker Testing 
Research Biopsy* 
X 
Within 28 days prior to treatment (optional) 
and during week 7 on therapy (optional) 
Blood Sample  
X 
Within 28 days prior to treatment and during 
week 7 on therapy 
 
 
*Comment on Biopsies: Participating sites should follow best clinical/institutional practices to 
minimize the harm from tumor biopsies. We recommend (but not mandate) the periprocedural 
use of tranexamic acid to potentially decrease the risk of bleeding. We recommend tranexamic 
acid 650 mg po bid for 6 doses, first dose 2 hours prior to biopsy. 
 
 
 
 
 
 
 


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4.2 Initial Registration 
Eligible patients will be registered on study centrally at UT Southwestern Medical by the 
Lead Site Study Coordinator. 
To register a patient, the following documents must be completed and emailed at 
Allison.Beaver@utsouthwestern.edu M—F 8am to 5pm CST. 
• 
Signed/dated patient consent form 
• 
Eligibility checklist 
• 
Copies of pre hormone therapy/chemotherapy or radiation therapy 
• 
Screening labs(including pregnancy test)/vital signs and EKG  
• 
CT  reports 
• 
Other materials may also be sent if considered pertinent for confirming patient 
eligibility, e.g. CT/MRI of C/A/P 
 
The Lead Center will review the documents to confirm eligibility.  To complete the 
registration process the Lead Center will: 
• 
Assign a patient study number 
• 
Patients found to be ineligible for participation after being consented will be 
considered screen failures, and documented as such in the Screening and 
Enrollment Log 
• 
New subjects will receive a number beginning with 001 upon study consent such 
that the first subject consented is numbered 001, the second subject consented 
receives the number 002, etc.  
• 
Upon confirmation of eligibility and enrollment as per the afore-mentioned 
instructions, the subject will be assigned a secondary number in the order of 
enrollment. For example, subject 001 will become 001-01 upon enrollment. If 
subject 002 screen fails, and subject 003 is the next subject enrolled, subject 003 
will become 003-02 and so-on.  
 
• 
For UTSW, each newly consented subject should be numbered using the 
schema provided above. Upon registration, the registrar will assign the additional 
registration/randomization code according to the numbering schema outlined 
above, which should then be entered as the patient study id in Velos upon 
updating the status to enrolled. 


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• 
The numbering schema should clearly identify the site number; the sequential 
number of the subject enrolled as well as the status of the subjects enrolled so 
that the number of subjects consented versus the number of subjects actually 
enrolled may be easily identified.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.3 Study Calendar  
The Investigator may perform more frequent examinations than shown in Table below if clinically indicated. Data from such additional examinations 
are also to be reported in the eCRF. 
 
* baseline visit and W1D1 can be 
combined 
Screening 
Baseline 
Visit* 
 
Induction Phase 
Cycle a 1 and 2 
Maintenance Phase 
Cycle a 3 and every 
subsequent cycle (8 
weeks) 
(up to 2 years) 
30 day 
Follow-
upr 
(X1) 
Follow-up 
Visits s 
(X2 and X3) 
Survival 
Follow-
Upt 
 
D -28 to 0 
D-3 to D 
1 
W1D1* 
(C1W1) 
W4D1 
(C1W4) 
W7D1 
(C2W1) 
W10D1 
(C2W4) 
W1D1 
 
W5D1 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X p 
 
 
 
 
 
 
 
 
 
 
 
Archival Tumor Tissueb 
X 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab c 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Ipilimumab d 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
SBRT e 
 
 
X e 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Performance status g 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Pulse Oximetry h 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Assessment 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Disease Assessment i 
X 
every 6 weeks (± 1 wk)  for the first 13 months from treatment and every 12 weeks (± 1 wk) thereafter, until 
disease progression is documented or treatment is discontinued (whichever occurs later) 
 
CBC with diff J 
X 
X q 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Comp Panel K 
X 
X q 
X 
X 
X 
X 
X 
X 
 
X 
X 
 


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TSH, free T4, free T3 u 
X 
X q 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Pregnancy test l 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Screening 
Baseline 
Visit 
 
Induction Phase 
Cycle a 1 and 2 
Maintenance Phase 
Cyclea 3 and every 
subsequent cycle (8 
weeks) 
(up to 2 years) 
30 day 
Follow-up 
r 
(X1) 
Follow-up 
Visits s 
(X2 and X3) 
Survival 
Follow-
Up t 
 
D-28 to 0 
D-3 to D1 
W1D1 
(C1W1) 
W4D1 
(C1W4) 
W7D1 
(C2W1) 
W10D1 
(C2W4) 
W1D1 
 
W5D1 
 
 
 
 
 
Hep B or Hep C m 
X 
 
 
 
 
 
 
 
 
 
 
 
Research biopsy n 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Blood sample o 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Survival Follow-Up t 
 
 
 
 
 
 
 
 
 
 
 
X 
a. 
1 cycle = 6 weeks 
b. 
Archival Formalin-fixed paraffin-embedded (FFPE) tumor tissue must be available for correlative studies (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for submission) 
c. 
Nivolumab is to be administered as an approximately 60-minute IV infusion. Cycle 1 of maintenance will begin 3 weeks after the 4th dose of induction therapy or after Day 113 if the 4th dose of induction 
therapy has not been administered due to treatment delays or the discontinuation of combination therapy because of primarily ipilimumab related side effects 
d. 
Ipilimumab is to be administered as an approximately 30-minute IV infusion. When both study drugs are to be administered on the same day, separate infusion bags and filters must be used for each infusion. 
Nivolumab is to be administered first. 
e. 
SBRT (5 fractions of 10 Gy) is to be delivered anytime between Day 1 of Week 1 (Cycle 1) and Day 1 of Week 4 (Cycle 1) of the nivolumab and ipilimumab combination dosing (within the first 3 weeks after the 
initiation of nivolumab and ipilimumab). SBRT is preferred to be delivered in the first 2 weeks.  
f. 
Temp, Pulse, B.P., Weight  
g. 
Karnofsky Performance Status  
h. 
Oxygen saturation by pulse oximetry should be obtained prior to dosing (at rest and with exertion) Also perform if any new or worsening pulmonary symptoms present 
i. 
CT with contrast of the chest, abdomen, pelvis and all known sites of disease (or CT Chest w/o contrast and MRI of abdomen with or without contrast if reduced GFR or allergy). MRI (preferred) or CT scan of 
the Brain if known history of brain involvement (all known sites of disease should be assessed at baseline) 
j. 
CBC w/differential and platelets 
k. 
 Full Chemistry Panel including: LDH, AST, ALT, ALP, T.Bili, BUN, creatinine, Ca+, Mg+, Na-, K+, HCO3-, Cl-, glucose, albumin, T.Protein, amylase, lipase 
l. 
WOCBP only (serum or urine)  at screening and within 24 hours of dosing 
m. 
HepB sAg & HCV Ab or HCV RNA 
n. 
 Multiple tumor biopsies – pre-treatment (optional), at week 7 of treatment (optional) and at the time of progression (optional) 
o. 
Blood samples will be collected for research at pre-treatment, at week 7 of treatment and at the time of progression 
p. 
Prior to entry into the protocol, all patients need to be discussed with Dr. Danny Song (JHU), Dr. Raquib Hannan (UTSW) or co-investigator Radiation Oncologist from the Radiation Therapy Department to 
determine eligibility/feasibility for SBRT. The cancer lesion(s) to be radiated should be determined by the Radiation Oncologist in collaboration with the Principal Investigator/Medical Oncologist 
q. 
Cycle 1 Day 1 labs do not need to be performed if done ≤ 72 hours of dosing as part of the Day -3 to +1 labs 
r. 
Perform 30 days ± 1week from last dose of study drug 


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s. 
X2 will take place 8 weeks (+/- 1 week) after last dose of nivolumab was administered and visit X3 will take place 15 weeks (+/- 1 week) after last dose of nivolumab was administered. If additional X follow-up 
visits are required due to ongoing study drug- related toxicity, they should take place every 8 weeks (+/- 1 week) until study drug-related toxicity has resolved, stabilized or been deemed irreversible. 
t. 
Study subjects will be contacted every 3 months for survival data. Other potential data such as the subjects’ follow-up treatment or care may be requested during these contacts. The contacts can be via 
telephone or correspond with disease assessment visits or other scheduled visits 
u. 
Free T3 & Free T4 if TSH not within normal limits 


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 4.4 Safety Assessments / Considerations  
At baseline, a medical history will be obtained to capture relevant underlying 
conditions. The baseline examinations should include weight, height, Karnofsky 
Performance Status, BP, HR, and temperature. Baseline signs and symptoms are 
those that are assessed within 28 days prior to treatment. Concomitant medications 
will be collected from within 28 days prior to treatment.   
Baseline local laboratory assessments should be done within 28 days prior to 
treatment to include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase), BUN or serum urea level, creatinine, Ca, albumin, Mg, Na, K, Cl, LDH, 
glucose, amylase, lipase, TSH, Free T4, Free T3, and Hep B and C testing (HBV sAg, 
HCV Ab or HCV RNA).  
Pregnancy testing for WOCBP must be performed within 24 hours prior to the initial 
administration of study drug at baseline and then every 4 weeks during the treatment 
period and at the safety follow-up visits. After discontinuation from nivolumab these 
should be repeated at approximately 30 days and approximately 70 days [or more 
frequently if required by local standard]. If, following initiation of the investigational 
product, it is subsequently discovered that a study subject is pregnant or may have 
been pregnant at the time of investigational product exposure, including during at 
least 6 half lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety). The investigator must immediately notify Worldwide Safety @BMS of 
this event via the Pregnancy Surveillance Form in accordance with SAE reporting 
procedures. Follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome and, where applicable, offspring information must be 
reported on the Pregnancy Surveillance Form [provided upon request from BMS].Any 
pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
Subjects will be evaluated for safety if they have received any study drug. Toxicity 
assessments will be continuous during the treatment phase. During the safety follow-
up phase (6 weeks), toxicity assessments should be done. Once subjects reach the 
survival follow-up phase either in person or documented telephone calls to assess the 


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subject’s status are acceptable. Adverse events and laboratory values will be graded 
according to the NCI-CTCAE version 4.0.  
On-study weight and Karnofsky Performance status and vital signs should be 
assessed at each on-study visit. Vital signs should also be taken as per institutional 
standard of care prior to, during and after dosing. Oxygen saturation by pulse oximetry 
at rest and after exertion should be assessed at each on-study visit prior to dosing. 
The start and stop times of nivolumab and ipilimumab infusions should be documented. 
Physical examinations are to be performed as clinically indicated. If there are any new 
or worsening clinically significant changes since the last exam, report changes on the 
appropriate non-serious or serious adverse event page.  
On study local laboratory assessments should be done within 72 hours of dosing to 
include; CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, 
TSH with reflexive Free T4, Free T3 on Day 1 of Weeks 1 and 4 for Cycles 1 and 2 
and on Day 1 of Weeks 1 and 5 starting from Cycle 3. Additional measures including 
non-study required laboratory tests should be performed as clinically indicated or to 
comply with local regulations. Laboratory toxicities (eg, suspected drug inducted liver 
enzyme elevations) will be monitored during the follow-up phase via on site/local labs 
until all study drug related toxicities resolve, return to baseline or are deemed 
irreversible. In addition, LFTs should also be assessed prior to the second dose of 
each cycle. The results of these labs should be reviewed prior to dosing. Amylase, 
Lipase and thyroid tests must be drawn, but do not need to be resulted prior to infusion 
unless patient is symptomatic.  The following laboratory abnormalities should be 
documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of 
an SAE 
• 
any laboratory abnormality that required the subject to have study drug 
discontinued or interrupted 
• 
any laboratory abnormality that required the subject to receive specific 
corrective therapy. 
Oxygen saturation by pulse oximetry should be obtained prior to each dosing and at 
any time a subject has any new or worsening respiratory symptoms. A reading at rest 


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and on exertion should be obtained at each time point. The extent of the exertion 
should be based on the judgment of the investigator, but should remain consistent for 
each individual subject throughout the study. If the patient’s status changes, the 
investigator can alter the extent of exertion based on their medical judgment. If a 
subject shows changes on pulse oximetry or other pulmonary related signs (hypoxia, 
fever) or symptoms (eg, dyspnea, cough, fever) consistent with possible pulmonary 
adverse events, the patient subject should be immediately evaluated to rule out 
pulmonary toxicity. An algorithm for the management of suspected pulmonary 
toxicity can be found in the appendix of the nivolumab Investigator’s Brochure. 
Some of the previously referred to assessments may not be captured as data in the 
CRF. They are intended to be used as safety monitoring by the treating physician. 
Additional testing or assessments may be performed as clinically necessary or where 
required by institutional or local regulations.  
Overdose: An overdose is defined as the accidental or intentional administration of 
any dose of a product that is considered both excessive and medically important. All 
occurrences of overdose must be reported as an SAE. 
Other Safety Considerations: Any significant worsening noted during interim or final 
physical examinations, electrocardiograms, x rays, and any other potential safety 
assessments, whether or not these procedures are required by the protocol, should 
also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
4.5 Imaging Assessment for the Study  
Any incidental findings of potential clinical relevance that are not directly associated 
with the objectives of the protocol should be evaluated and handled by the Study 
Investigator as per standard medical/clinical judgment.  
 4.5.1 CT/MRI 
Both, contrast-enhanced Computed Tomography (CT) and Magnetic Resonance 
Imaging (MRI) scans acquired on dedicated CT/MRI equipment are adequate imaging 
modalities for this study. 
CT scans should be acquired with 5 mm slices with no intervening gap (contiguous). 
Subjects who cannot receive IV contrast at the start of study should be imaged by MRI 


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of abdomen/pelvis with IV contrast and CT of chest without contrast. MRIs should be 
acquired with 5 mm slices with no intervening gap (contiguous). Subsequent 
assessments should include chest, abdomen, and pelvis, and all known sites of 
disease and should use the same imaging method as was used at baseline. Patients 
initially imaged with CT of chest, abdomen, and pelvis with IV contrast who can no 
longer receive contrast can be monitored by CT of chest, abdomen, and pelvis without 
IV contrast. Every attempt should be made to image each subject using an identical 
acquisition protocol on the same scanner for all imaging time. 
 
 4.5.2 MRI/CT Brain  
MRI (preferred) or CT of brain (with contrast) is required at screening only when 
metastatic disease to the brain is suspected or known. MRI or CT brain scans during 
on-study treatment and follow up periods are required only if clinically indicated for new 
signs and symptoms that suggest CNS involvement or progression. 
4.6 Efficacy Assessments 
4.6.1  Baseline Assessments 
Baseline assessments should be performed within 28 days prior to the initiation of 
study utilizing CT or MRI. In addition to chest, abdomen, pelvis, and brain, all known 
sites of disease should be assessed at baseline.  
 4.6.2 Response Criteria  
Subjects will be evaluated for tumor response beginning 6 weeks weeks (± 1 wk) from 
treatment and continuing every 6 weeks (± 1 wk) for the first 13 months from treatment 
and every 12 weeks (± 1 wk) thereafter, until disease progression is documented or 
treatment is discontinued (whichever occurs later).  
4.6.3 Therapeutic Response  
Tumor assessments for ongoing study treatment decisions will be completed by the 
investigator using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. 
Traditional measures of response reflect when a treatment is working and measures 
of progression indicate when a drug should be stopped.  
 
Measurable disease  


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Following RECIST 1.1, tumor lesions must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be recorded) with a 
minimum size of:  
- 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm)    
- 
10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable)  
- 
20 mm by chest x-ray    
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  
 
Nonmeasurable disease  
Following RECIST 1.1, all other lesions (or sites of disease) will be considered 
nonmeasurable disease. This includes small lesions (longest diameter < 20 mm with 
conventional techniques or < 10 mm using spiral CT scan) and any of the following:  
• bone lesions  
• ascites  
• pleural or pericardial effusion  
• lymphangitis cutis or pulmonis  
• abdominal masses that are not confirmed and followed by imaging techniques  
• cystic lesions  
• lesions occurring within a previously irradiated area unless they are documented as 
new lesions since the completion of radiation therapy  
 
4.6.4 Evaluation of Target lesions  
Following RECIST 1.1, progression in a nodal or visceral site (ie, liver and lung) is 
sufficient to document disease progression. The presence or absence of nodal and 
visceral disease before and after treatment should be recorded separately.  
All measurable lesions (up to a maximum of 5 lesions per organ and 10 lesions in total) 
will be identified as target lesions to be measured and recorded at baseline. The target 
lesions should be representative of all involved organs. Target lesions will be selected 


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on the basis of size (ie, the largest area) and suitability for accurate, repeated 
measurements (either by imaging techniques or clinically). The sum of the longest 
diameter (LD) of all target lesions will be calculated and reported as the baseline sum 
LD. The baseline sum LD will be used as a reference by which to characterize the 
objective tumor response.  
Because small lymph nodes are difficult to measure accurately and may not be 
malignant, the greatest diameter of a lymph node must measure at least 1.5 cm by 
spiral CT to be considered a target lesions. 
 
 
Table 7.  RECIST response criteria for target lesions  
 
Response  
Evaluation of Soft-Tissue Lesions  
Complete response (CR)  
The disappearance of clinical and radiological evidence of all target lesions 
and normalization of tumor marker levels  
Partial response (PR)  
A decrease from baseline ≥ 30% in the sum of the LD of all target lesions  
Progressive disease (PD)  
An increase ≥ 20% in the sum of the LD of all target lesions based on the 
smallest sum LD since treatment started or the appearance of one or more 
new lesions or the appearance of new lesions  
Stable disease (SD)  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD based on the smallest sum LD recorded since treatment started  
4.6.5 Special Notes on the Assessment of Target Lesions  
Lymph nodes  
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that 
when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero 
even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm. Case report forms or other data collection methods 
may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For 
PR, SD and PD, the actual short axis measurement of the nodes is to be included in 
the sum of target lesions.  
 
Target lesions that become ‘too small to measure’  
While on study, all lesions (nodal and non-nodal) recorded at baseline should have 
their actual measurements recorded at each subsequent evaluation, even when very 


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small (eg, 2 mm). However, sometimes lesions or lymph nodes which are recorded as 
target lesions at baseline become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the case report 
form. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have 
a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness 
(but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially non-reproducible, therefore providing this default value will 
prevent false responses or progressions based upon measurement error. To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.  
 
Lesions that split or coalesce on treatment  
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum. Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter 
in this instance should be the maximal longest diameter for the ‘coalesced lesion’.  
4.6.6 Evaluation of Non-Target Lesions  
This section provides the definitions of the criteria used to determine the tumor 
response for the group of non-target lesions. While some non-target lesions may 
actually be measurable, they need not be measured and instead should be assessed 
only qualitatively at the time points specified in the protocol.  
 
 
Table 8.  RECIST response criteria for non-target lesions  


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Response  
Evaluation of Soft-Tissue Lesions  
Complete response (CR)  
Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (< 10mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits 
Progressive disease (PD)  
Unequivocal progression (see comments below) of existing non- target 
lesions. (Note: the appearance of one or more new lesions is also considered 
progression) 
 
4.6.7. Special Notes on Assessment of Progression of Non-Target Disease  
The concept of progression of non-target disease requires additional explanation as 
follows:  
When the patient also has measurable disease  
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in 
the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare.  
When the patient has only non-measurable disease  
This circumstance arises in some trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above, however, 
in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening 
in non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based 
on the change in non-measurable disease is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 
20% increase diameter in a measurable lesion). Examples include an increase in a 
pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from 
localized to widespread, or may be described in protocols as ‘sufficient to require a 


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change in therapy’. If ‘unequivocal progression’ is seen, the patient should be 
considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease 
makes it impossible to do so; therefore the increase must be substantial.  
 4.6.8 New Lesions  
The appearance of new malignant lesions denotes disease progression; therefore, 
some comments on detection of new lesions are important. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, 
change in imaging modality or findings thought to represent something other than 
tumor (for example, some ‘new’ bone lesions may be simply healing or flare of pre-
existing lesions). This is particularly important when the patient’s baseline lesions show 
partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.  
A lesion identified on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression.  
 4.6.9 Evaluating best overall response  
The best overall response is the best response recorded from the start of treatment 
until either disease progression or recurrence. The investigator’s determination of best 
overall response will be based both on response criteria and on confirmation criteria. 
To be assigned a status of partial response or complete response, changes in tumor 
measurements must be confirmed by repeat assessment performed at least 6 weeks 
after the criteria for response are first met. To confirm stable disease, follow-up 
measurements must meet SD criteria at a minimum interval of 6 weeks after SD was 
first documented. Table 9 can be used as an assessment tool. 
Table 9. Assessing Overall Response  
Target Lesions  
Non-target Lesions  
New Lesions  
Overall Response  
CR  
CR  
No  
CR  
CR  
Incomplete 
response/SD  
No  
PR  
PR  
Non-PD  
No  
PR  
SD  
Non-PD  
No  
SD  
PD  
Any  
Yes or No  
PD  
Any  
PD  
Yes or No  
PD  
Any  
Any  
Yes  
PD  
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.  


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Patients with global deterioration of health status who require treatment to be 
discontinued without objective evidence of disease progression should be classified 
as having symptomatic deterioration. Every effort should be made to document their 
objective progression, even after discontinuing treatment.  
Patients who do not have tumor response assessment due to rapid progression or 
toxicity will be considered non-responders, will be included in the denominator for the 
response rate, and will be classified into one of the categories listed below:  
• death attributed to disease progression  
• early discontinuation attributed to disease progression  
• death attributed to drug toxicity  
• early discontinuation attributed to drug toxicity  
Note: If a patient receives subsequent therapy before tumor progression is 
documented, the reason for changing therapy must be reported. Reasons include 
clinical progression, drug toxicity, or secondary therapy for maintaining tumor 
response. 
 4.6.10 Confirmation Scans 
Verification of Response: To be assigned a status of CR or PR, changes in tumor 
measurements must be confirmed by consecutive repeat assessments that should be 
performed at least at 6 weeks  after the criteria for response are first met. For this 
study, the next scheduled tumor assessment can meet this requirement.  
Verification of Progression: Progression of disease should be verified in cases 
where progression is equivocal. If repeat scans confirm PD, then progression should 
be declared using the date of the initial scan. If repeat scans do not confirm PD, then 
the subject is considered to not have progressive disease.  
4.7 Correlatives Studies  
A variety of factors that may impact the immunomodulatory properties and efficacy of 
nivolumab plus ipilimumab in combination with SBRT will be investigated in tumor 
tissue and in peripheral blood specimens taken from all subjects prior to and/or during 
treatment and/or progression as outlined in Table 10. 
Table 10. Correlative studies 


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Analysis 
Sample 
Assay 
Time Points 
Tissue staining 
(PDL1, CD8 etc) 
Archival and FFPE 
biopsy tissue 
IHC/IF 
Archival tissue, 
Baseline Biopsy, 
Week 7 Biopsy, 
Biopsy at time of 
progression 
Soluble Factors/ 
Cytokines 
Serum 
Luminex xMAP, 
Immunology Core 
Baseline Blood 
sample, Week 7 Blood 
sample, Blood sample 
at time of progression 
Immune Gene 
Expression 
Mutational Analysis 
FFPE biopsy tissue 
RNA Later 
Nanostring nCounter, 
RNAseq 
Whole Exome seq 
Baseline Biopsy, 
Week 7 Biopsy, 
Biopsy at time of 
progression 
T-Cell receptor 
sequencing 
Frozen tumor biopsy, 
PBMC 
Adaptive Bio, 
Immunoseq 
Baseline 
Biopsy/Blood, Week 7 
Biopsy/Blood, 
Biopsy/Blood at time 
of progression 
ELISPOT Assay 
Frozen PBMC 
Immunology Core 
Baseline Biopsy, 
Week 7 Biopsy, 
Biopsy at time of 
progression 
Humoral Immune 
Response 
Plasma 
Protoarray (Life Tech), 
Microarray Core 
UTSW Immunology 
Core 
Baseline Blood 
sample, Blood sample 
at Week 7 Biopsy, 
Blood sample at time 
of progression 
Cell Culture 
Biopsy material 
Hammers Lab 
Baseline Biopsy  
 
Optional research biopsy at week 7 Optional Tumor Biopsy:  
A week 7 optional tumor biopsy will removal a small piece of your tumor for 
examination and correlative studies.  The biopsy can usually be done with local 
anesthesia with or without sedation. Some side effects that patients may experience 
by havingthe biopsy performed may include pain, bruising, bleeding, redness, low 
blood pressure, swelling,  infection at the site of the biopsy, and rarely, death. 
Additional risks my occur and would be explained by the doctors who conduct the 
biopsies.  At the time of biopsy, a CT scan may be done to determine where the biopsy 
will be done (CT-guided biopsy) or the biopsy may be done via Ultra sound guidance. 
 
 
 
 


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Flow diagram samples collection 
 
4.7.1 Samples Collection and Banking 
Please refer to laboratory manual.  
5 ADVERSE EVENTS 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of subjects enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse events 
are reported in a routine manner at scheduled times during a trial. Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring of subject  safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
drug, will be monitored until:  
 
the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;  
 
any abnormal laboratory values have returned to baseline;  
 
there is a satisfactory explanation other than the study drug for the 
Cycle 1 
Phase  
Maintenance Phase  
Biopsy 
Within 28 
days prior 
Week 1, D1  
Week 1, 
Day 1  
Cycle 2 
Induction 
Phase  
Week 7 
Day 1  
Biopsy at 
Progression  
Week 12 
Day 1  
10 ml x 10 
tubes 
peripheral 
blood  
10 ml x 10 
tubes 
peripheral 
blood  
Biopsy 
Week 7  
10 ml x 10 
tubes 
peripheral 
blood  
Screening  
Post-‐study 
Follow-‐up  


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changes observed; or 
 
death. 
 
5.1 Definition and Grade  
Adverse Events will be reported as indicated by the appropriate following table 
(see below).   An adverse event is defined as any untoward or unfavorable medical 
occurrence in a human research study participant, including any abnormal sign 
(for example, abnormal physical exam, imaging finding or clinically significant  
laboratory finding), symptom, clinical event, or disease, temporarily associated 
with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse 
events occur most commonly in the context of biomedical research, although on 
occasion, they can occur in the context of social and behavioral research. Adverse 
events may be expected or unexpected. 
Acute Adverse Events 
Adverse events occurring in the time period from the signing of the informed 
consent through 100 days post treatment will be considered acute adverse events. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE version 4) and 
version number specified in the protocol. Adverse events not specifically defined 
in the NCI CTCAE will be scored on the Adverse Event log according to the 
general guidelines provided by the NCI CTCAE and as outlined below.   
• 
 Grade 1: Mild  
• 
 Grade 2: Moderate 
•   Grade 3: Severe or medically significant but not immediately life threatening 
•   Grade 4: Life threatening consequences 
•   Grade 5: Death related to the adverse event 


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Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those 
events, occurring at any dose, which meets any of the following criteria:  
• Results in death   
• Immediately life-threatening  
• Results in inpatient hospitalization 1,2 or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity  
• Results in a congenital anomaly/birth defect  
• Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the 
above criteria. Serious adverse events may or may not be related to the research 
project. A serious adverse event determination does not require the event to be 
related to the research. That is, both events completely unrelated to the condition 
under study and events that are expected in the context of the condition under 
study may be serious adverse events, independent of relatedness to the study 
itself. As examples, a car accident requiring >24 hour inpatient admission to the 
hospital  would be a serious adverse event for any research participant; likewise, 
in a study investigating end-stage cancer care, any hospitalization or death which 
occurs during the protocol-specified period of monitoring for adverse and serious 
adverse events would be a serious adverse event, even if the event observed is 
a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If events 
occur during a pre-planned hospitalization or surgery, that prolong the existing hospitalization, 
those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital stay 
equal to or greater than 24 hours. Hospitalization is used as an indicator of the seriousness of 
the adverse event and should only be used for situations where the AE truly fits this definition 
and NOT for hospitalizations associated with less serious events. For example: a hospital visit 
where a patient is admitted for observation or minor treatment (e.g. hydration) and released in 
less than 24 hours. Furthermore, hospitalization for pharmacokinetic sampling is not an AE 
and therefore is not to be reported either as a routine AE or in an expedited report. 
 


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 5.2 Unanticipated Problems: 
The phase “unanticipated problems involving risks to subjects or others ” is found, 
but not defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 
21 CFR 56.  108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected (in terms of nature, severity or frequency)  given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied;  
•                                                            AND 
• 
Related or possibly related to participation in the research(possibly related 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
•                                                               AND  
• Suggests that  the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. Note: According to OHRP, if the adverse event 
is serious, it would always suggest a greater risk of harm. 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
5.3 Reporting SAEs and UPIRSOs to the Simmons 
Comprehensive Cancer Center(SCCC) Data Safety 
Monitoring Committee (DSMC) 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs/UPIRSOs occurring during the protocol-specified 
monitoring period should be submitted to the SCCC DSMC within 5 business days of the 
PI or delegated study team members awareness of the event(s). In addition, for  


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participating centers other than UTSW, local IRB guidance should be followed for 
local reporting of serious adverse events. . 
The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB Reportable Event report; FDA 
Form #3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be submitted to the DSMC Coordinator.  The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines if 
immediate action is required.  Follow-up eIRB reports, and all subsequent SAE/UPIRSO 
documentation that is available are also submitted to the DSMC Chair who determines if 
further action is required 
5.3.1 Reporting Unanticipated problems Involving Risks to Subjects or  
Others(UPIRSOs)  
           UT Southwestern reportable event guidance applies to all research conducted 
by or on behalf of UTSouthwestern, its affiliates, and investigators, sites, or institutions 
relying on the UT Southwestern IRB.  Additional reporting requirements apply for research 
relying on non-UT Southwestern IRB.  
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences,         
outcomes, etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected 
in a subject’s underlying condition or not expected as a risk of the study; 
therefore, not included in the investigator’s brochure, protocol, or 
informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized.  Note: According to OHRP, if the 
adverse event is serious, it would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects (     
UADEs) and death or serious injury related to a humanitarian use device (HUD). 
 
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of PI 
awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single IRB):  
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of PI awareness.  Investigators much report to their 
relying IRB according to the relying IRBs policy.  In addition, the external IRB’s responses or 
determinations are these local events must be submitted to the UT Southwestern IRB within 
10 working days of receipt.   
 
Events not meeting UPIRSO criteria: 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized and 


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submitted to the UTSW HRPP/IRB at continuing review. 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-administration/irb/assets/policies-
combines.pdf. 
4.  
 
  
5.3.2  SAE  
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW 
Simmons Comprehensive  Cancer Center, the DOT Manager or lead coordinator 
ensures that all participating sites are notified of the event and resulting action, 
according to FDA guidance for expedited reporting. DSMC Chairperson reviews 
all SAEs/UPIRSOs upon receipt from the DSMC Coordinator.  The DSMC 
Chairperson determines whether action is required and either takes action 
immediately, convenes a special DSMC session (physical or electronic), or defers 
the action until a regularly scheduled DSMC meeting.  
 
 
 
 
Telephone reports to: 
PI:  Hans Joerg Hammers, MD 
Email:  hans.hammers@utsouthwestern.edu 
Lead Site Protocol Coordinator:  Allison Beaver, RN 
Email:  Allison.beaver@utsouthwestern.edu 
Phone:  214-645-8787 
Written reports to: 
PI:  Hans Joerg Hammers, MD 
Email:  hans.hammers@utsouthwestern.edu 
Lead Site Protocol Coordinator:  Allison Beaver, RN 
Email:  Allison.beaver@utsouthwestern.edu 
Fax:  214-645-8767  
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
 


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5.4  Steps to Determine If an Adverse Event Requires 
Expedited Reporting to the SCC DSMC and/or HRPP 
Step 1:  Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4).        
 Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely-The AE may NOT be related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 100days of the last dose of protocol 
treatment. Any event that occurs more than100days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly. 
 
Step 4:  Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity 
of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of 
this protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
• 
the study agent(s)/therapies background and associated known toxicities 
section of this protocol 
 
 
 
 


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5.5 Other Events of Special Interest that require 
Expedited Reporting 
• Potential drug induced liver injury (DILI) is also considered an important 
medical event.  
• Suspected transmission of an infectious agent (eg, pathogenic or 
nonpathogenic) via the study drug is an SAE.  
• Although pregnancy, overdose, and cancer are not always serious by 
regulatory definition, these events must be handled as SAEs. 
 
 
5.6 Nonserious Adverse Event Collection and Reporting 
A nonserious adverse event is an AE not classified as serious. The collection of 
nonserious AE information should begin at initiation of study drug. All nonserious 
adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days 
following the last dose of study treatment.  
 
Nonserious AEs should be followed to resolution or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for nonserious AEs that 
cause interruption or discontinuation of study drug and for those present at the end 
of study treatment as appropriate. 
5.7 Handling of Expedited Safety Reports 
In accordance with local regulations, BMS and the IND Sponsor will notify 
investigators of all reported SAEs that are suspected (related to the investigational 
product) and unexpected (i.e., not previously described in the IB). Investigator 
notification of these events will be in the form of an expedited safety report (ESR).  
• 
Other important findings which may be reported by the as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack 
of efficacy that poses significant hazard to study subjects, clinically significant 


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safety finding from a nonclinical (eg, animal) study, important safety 
recommendations from a study data monitoring committee, or sponsor decision to 
end or temporarily halt a clinical study for safety reasons. 
• 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the IB. Where required by local regulations or when there is a central IRB/IEC 
for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. 
The investigator should also comply with the IRB/IEC procedures for reporting any 
other safety information.  
• 
In addition, suspected serious adverse reactions (whether expected or 
unexpected) shall be reported by the Principal Investigator to the relevant 
competent health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports).  
 
5.8 Reporting: 
All AEs (both expected and unexpected) will be captured on the appropriate study-
specific CRFs. 
 
5.9 Nonserious Adverse Event 
• 
Nonserious Adverse Events are to be provided to BMS in aggregate via 
interim or final study reports as specified in the agreement or, if a regulatory 
requirement [e.g. IND US trial] as part of an annual reporting requirement.  
• 
The collection of nonserious AE information should begin at initiation of 
study drug. All nonserious adverse events (not only those deemed to be 
treatment-related) should be collected continuously during the treatment 
period and for a minimum of 100 days following the last dose of study 
treatment.  
 


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• 
Nonserious AEs should be followed to resolution or stabilization, or reported 
as SAEs if they become serious. Follow-up is also required for nonserious 
AEs that cause interruption or discontinuation of study drug and for those 
present at the end of study treatment as appropriate.  
5.10 Laboratory Test Abnormalities 
• 
All laboratory test results captured as part of the study should be recorded 
following institutional procedures. Test results that constitute SAEs should 
be documented and reported as such. 
• 
The following laboratory abnormalities should be documented and reported 
appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition 
of an SAE 
• 
any laboratory abnormality that required the subject to have study drug 
discontinued or interrupted 
• 
any laboratory abnormality that required the subject to receive specific 
corrective therapy.  
5.11 Pregnancy 
• 
Any pregnancy that occurs in a female partner of a male study participant 
should be reported to BMS. Information on this pregnancy will be collected 
on the Pregnancy Surveillance Form. 
5.12 Overdose 
• 
An overdose is defined as the accidental or intentional administration of any 
dose of a product that is considered both excessive and medically important. 
All occurrences of overdose must be reported as an SAE. 
 
 


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5.13 Other Safety Considerations 
• 
Any significant worsening noted during interim or final physical 
examinations, electrocardiograms, x rays, and any other potential safety 
assessments, whether or not these procedures are required by the protocol, 
should also be recorded as a nonserious or serious AE, as appropriate, and 
reported accordingly. 
5.14 Seven Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the investigator to be possibly 
related to the investigational agent.  Such reports are to be telephoned or faxed 
(214-645-8766) to the FDA within seven calendar days of first learning of the 
event. Follow-up information will be submitted to the FDA as soon as relevant 
information is available.  
 
5.15 15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any SAE that is unexpected 
and related to the investigational agent in a written IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed 
with the IND concerning similar events should be analyzed.  The new report 
should contain comments on the significance of the new event in light of the 
previous related reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to 
the FDA within 15 calendar days of first learning of the event. Follow-up 
information will be submitted to the FDA as soon as relevant information is 
available. 
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
 


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MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures. All SAEs must be collected that occur 
within 100 days of discontinuation of dosing.  
 
All SAEs must be collected that occur during the screening period. If applicable, SAEs 
must be collected that relate to any protocol-specified procedure (eg, a follow-up skin 
biopsy).  The investigator should report any SAE that occurs after these time periods 
that is believed to be related to study drug or protocol-specified procedure.  
SAEs, whether related or not related to study drug, and pregnancies must be reported 
to BMS within 24 hours. SAEs must be recorded on BMS or an approved form; 
pregnancies must be recorded on a Pregnancy Surveillance Form. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours 


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to the BMS (or designee) using the same procedure used for transmitting the initial 
SAE report.  All SAEs should be followed to resolution or stabilization. 
The Sponsor/Investigator will ensure that all SAEs in the clinical database are reported 
to BMS and any applicable health authority during the conduct of the study. This 
reconciliation will occur at least quarterly and be initiated by the sponsor/investigator.  
 
Sponsor/investigator 
will 
request 
a 
reconciliation 
report 
from: 
aepbusinessprocess@bms.com. During reconciliation, any events found to not be 
reported previously to BMS must be sent to Worldwide.Safety@BMS.com. 
 6 ETHICAL CONSIDERATIONS 
 6.1 Good Clinical Practice  
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH) and in accordance 
with the ethical principles underlying European Union Directive 2001/20/EC and the 
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50).  
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to 
initiation of the study.  
All potential serious breaches must be reported to Principal Investigator (Dr. Hans 
Hammers). A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant 
degree, the safety or physical or mental integrity of the subjects of the study or the 
scientific value of the study.  
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of 
study personnel where sanctions have been invoked or where there has been scientific 
misconduct or fraud (eg, loss of medical licensure, debarment).  


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 6.2 Institutional Review Board/Independent Ethics 
Committee  
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
principal investigator should also provide the IRB/IEC with a copy of the Investigator 
Brochure or product labeling information to be provided to subjects and any updates.  
The principal investigator should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures.  
6.3 Informed Consent  
Investigators must ensure that subjects are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which 
they volunteer to participate.  
In situations where consent cannot be given to subjects, their legally acceptable 
representatives are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to 
participate.  
The informed consent form will include all elements required by Registration of 
Pharmaceuticals for Human Use (ICH), Good Clinical Practice (GCP) and applicable 
regulatory requirements and will adhere to the ethical principles that have their origin 
in the Declaration of Helsinki.  
Investigators must:  
1. Provide a copy of the consent form and written information about the study in 
the language in which the subject is most proficient prior to clinical study 
participation. The language must be non-technical and easily understood.  
2. Allow time necessary for subject or subject's legally acceptable representative 
to inquire about the details of the study.  
3. Obtain an informed consent signed and personally dated by the subject or the 
subject's legally acceptable representative and by the person who conducted 
the informed consent discussion.  


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4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed 
consent form and any other information to be provided to the subjects, prior to 
the beginning of the study, and after any revisions are completed for new 
information.  
5. If informed consent is initially given by a subject’s legally acceptable 
representative or legal guardian, and the subject subsequently becomes 
capable of making and communicating his or her informed consent during the 
study, consent must additionally be obtained from the subject.  
6. Revise the informed consent whenever important new information becomes 
available that is relevant to the subject's consent. The investigator, or a person 
designated by the investigator, should fully inform the subject or the subject's 
legally acceptable representative or legal guardian, of all pertinent aspects of 
the study and of any new information relevant to the subject's willingness to 
continue participation in the study. This communication should be documented.  
The confidentiality of records that could identify subjects must be protected, respecting 
the privacy and confidentiality rules applicable to regulatory requirements, the subjects' 
signed ICF and, in the US, the subjects’ signed HIPAA Authorization.  
The consent form must also include a statement that investigators and regulatory 
authorities have direct access to subject records. The rights, safety, and well-being of 
the study subjects are the most important considerations and should prevail over 
interests of science and society.  
6.4 Multicenter Guidelines 
The Protocol Chair 
The Protocol Chair, Hans-Joerg Hammers, MD PhD, is responsible for 
performing the following Tasks: 
• 
Coordinating, developing, submitting, and obtaining approval for the 
protocol as well as its subsequent amendments 
• 
Assuring that all participating institutions are using the current IRB 
approved version of the protocol 
• 
Taking responsibility for the overall conduct of the study at all 
participating institutions and for monitoring the progress of the study 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 


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from all sites  
• 
Reviewing all study data from all sites 
 
6.5 Coordinating Center Responsibilities (UTSW) 
Coordinating Centers must: 
• 
Verify that each participating institution has a Federal Wide Assurance 
(FWA) number. 
• 
Confirm that IRB approval has been obtained at each participating site 
prior to their first patient registration 
• 
Maintain copies of IRB approvals from each site 
• 
Implement central patient registration 
• 
Prepare all submitted data for review by the Protocol Chair (Hans-
Joerg Hammers, MD PhD  
• 
Establish procedures for documentation, reporting, and submitting of 
adverse events to the Protocol Chair (Hans-Joerg Hammers, MD 
PhD) and all applicable parties 
• 
Facilitate audits by securing selected source documents and research 
records from participating sites for audit, or by conducting audits at 
participating sites. 
 
6.6 Participating Sites Responsibilities 
Participating sites are responsible for performing the following tasks: 
6.6.1 Follow the protocol as written and conduct the study within the 
guidelines of Good Clinical Practice  
 
6.6.2 Required Documentation (for multi-site studies) 
Before the study can be initiated at any site, the following 
documentation must be provided to the Department of Urology 
{Research Office}. 
 


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• 
A copy of the official IRB approval letter for the protocol and 
informed consent 
• 
IRB membership list or Federal wide Assurance letter 
• 
CVs and medical licensure for the principal investigator and any 
associate investigators who will be involved in the study 
• 
Form FDA 1572 appropriately filled out and signed with 
appropriate documentation (NOTE: this is required if {institution} 
holds the IND. Otherwise, the affiliate Investigator’s signature on 
the protocol is sufficient to ensure compliance) 
• 
A copy of the IRB-approved consent form 
• 
CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
• 
Executed clinical research contract 
7 Data Management, Monitoring/Auditing and Reporting 
Requirements 
REDCap is the UTSW SCC institutional choice for the electronic data capture of case 
report forms for  SCC Investigator Initiated Trials. REDCap will be used for electronic 
case report forms in accordance with Simmons Cancer Center requirements as 
appropriate for the projectIn order to facilitate remote source to case report form 
verification, the Simmons Comprehensive Cancer Center study team will require other 
institutions participating in this trial as sub-sites  to enter data into the selected EDC 
system  and upload selected de-identified source materials when instructed   
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT, and/or the 
CRO Multi-Center IIT Monitor.  This review includes but is not limited to accuracy of 
case report forms, protocol compliance, timeless and accuracy of Velos entries and 
AE/SAE management and reporting. Documentation of trial monitoring will be 
maintained along with other protocol related documents and will be reviewed during 
internal audit.  
For further information, refer to the UTSW SCCC IIT Management manual. 
 Toxicity reviews will be performed  after the first 6 patients have been enrolled and 
then on a quarterly basis These reviews will be documented in the form of short 
summaries after investigator discussions. The principle investigators of all accruing 


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sites are required to participate.The UTSW Simmons Cancer Center (SCC) Data Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and patient 
safety for all UTSW SCC clinical trials.  As part of that responsibility, the DSMC 
reviews all local serious adverse events and unanticipated problems in real time as they 
are reported and reviews adverse events on a quarterly basis.  The quality assurance 
activity for the Clinical Research Office provides for periodic auditing of clinical 
research documents to ensure data integrity and regulatory compliance.  A copy of the 
DSMC plan is available upon request. 
 
The SCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC works as 
part of the DSMC to conduct regular audits based on the level of risk. Audit findings 
are reviewed at the next available DSMC meeting.  In this way, frequency of DSMC 
monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of 
investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles.  
8 STUDY MANAGEMENT 
8.1 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study subject requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.  
8.2 Emergency Exceptions(also called single-subject 
exceptions or single-subject waivers) 
These include any departure from IRB-approved research that is not due to an emergency 
and is: 
• intentional on part of the investigator; or 
• in the investigator’s control; or 
• not intended as a systemic change (e.g., single-subject 
exceptions to eligibility [inclusion/exclusion] criteria) 
 Reporting requirement: Exceptions are non-emergency deviations that require 
prospective IRB approval before being implemented. Call the 
IRB if your request is urgent. If IRB approval is not obtained 
beforehand, this constitutes a major deviation. 


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Emergency Deviations: include any departure from IRB-approved research that is 
necessary to:  
• avoid immediate apparent harm, or 
• protect the life or physical well-being of subjects or others 
 Reporting requirement: Emergency deviations must be promptly reported 
to the IRB within (5) working days of the occurrence.  
 
8.3  Major Deviations/ (also called violations):  include 
any departure from IRB-approved research that: 
● Harmed or placed subjects(s) or others at risk of harm ( e., did or has the potential 
to negatively affect the safety, rights or welfare of subjects or 
others), or  
● Affect data quality (e.g., the completeness, accuracy, reliability, o validity of the 
data) or the science of the research (e.g., the primary 
outcome/endpoint of the study) 
 Reporting requirement: Major deviations must be promptly reported to the IRB within 
5 working days of PI awareness. 
 
8.3.1  Minor Deviations:  include any departure from the IRB approved research that: 
       ● Did not harm or place subjects(s) or others at risk of harm (i.e., did not or did not 
have the potential to negatively affect the safety, rights, or welfare of subjects or 
others), or  
 
●  Did not affect data quality (e.g., the completeness, accuracy, reliability, or validity 
of the data) or the science of the research (e.g., the primary outcome/endpoint of the 
study) 
 Reporting requirement: Major deviations must be promptly reported to the IRB within 5 
working days of PI awareness. 
• 
Harmed or placed subject(s) or Others at risk of harm (i.e., did or 
has the potential to negatively affect the safety, rights, or welfare 
of subjects or others), or 
• 
Affect data quality (e.g., the completeness, accuracy, reliability, or 
validity of the data) or the science of the research (e.g., the 
primary outcome/endpoint of the study) 
 Reporting requirement: Major deviations must be promptly 
reported to  
the IRB within 5 working days of PI awareness. 
8.4  Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be required. 
 


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8.5 Case Report Form Submission  
Data required by the study will be collected in Case Report Forms provided by the 
Coordinating Center (SKCCC). The participating site will be required to complete a 
paper Eligibility Checklist case report form (CRF) at the time of patient registration.  All 
other data will be collected on the electronic case report forms (eCRFs) in CRMS. Site 
staff access to CRMS will be initiated at the time of the site activation.  
 
8.5.1 Case Report Forms  
Case report forms (e-CRF) will be generated by Staff at the Lead Site Coordinating 
Center at UTSW for the collection of all study data. Investigators will be responsible 
for ensuring that the CRFs are kept up-to-date. 
 
8.5.2 Case Report Form Completion 
The paper Eligibility Checklist CRF must be completed using black ink. Any errors must 
be crossed out so that the original entry is still visible, the correction clearly indicated 
and then initialed and dated by the individual making the correction. 
 
eCRFs( REDCAP) will be completed within 2 weeks of the patient coming to the clinic 
and all relevant supporting documentation such as scans, progress notes, nursing 
notes, blood work, pathology reports, etc., will be submitted to the Coordinating Center 
(UTSW) via email at Allison.Beaver@utsouthwestern.edu to the Lead Center Program 
Coordinator, Allison Beaver. All patient names or other identifying information will be 
removed prior to being sent to the Coordinating Center (UTSW) or non- redacted 
source documents can be sent via a password ¬-protected/ secured document transfer 
based on each institution’s guidelines.  
 
Authorized representatives of the Coordinating Center (UTSW) may be performing 
audits or inspections, including source data verification. The purpose of these audits 
or inspections is to systematically and independently examine all trial-related activities 
and documents to determine whether these activities were conducted and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), and any applicable regulatory requirements. 


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9 Statistical Considerations 
 9.1 Study Design 
This is a multi-institution, open-label, single-arm Phase II study to determine the safety 
and efficacy of SBRT followed by nivolumab in combination with ipilimumab in patients 
with metastatic RCC. The primary endpoints of safety evaluated by the level of G3/4 
treatment related adverse events and the need for corticosteroids in this patient 
population and ORR assessed by RECIST criteria. Secondary endpoints include TTP, 
DOR, PFS, OS and local control of irradiated lesion. Simon’s minimax two-stage 
design will be used to allow for early termination of the study if addition of SBRT to 
nivolumab in combination with ipilumumab is unlikely to be promising. A safety run-in 
phase will be included in the first 6 patients, and safety will be monitored continuously 
after this safety run-in phase using a Bayesian posterior probability approach. 
 9.2 Safety Run-in Phase 
There is no previous experience with SBRT used concurrently with nivolumab plus 
ipilimumab in this study population. Therefore, to ensure that the combination is safe, 
the first six patients enrolled will be treated with a combination regimen consisting in 
nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV and SBRT within 3 weeks 
after the initiation of this combination regimen.  Safety will be evaluated using standard 
safety assessments every 21 days for 4 cycles and then every 2 weeks. If 4 out of the 
first 6 patients experience Grade 3/4 toxicity during the safety run-in observation period 
(defined as the first 4-cycles, 12 weeks), enrollment will cease and the study will be 
halted until further safety analysis of the combination regimen can be performed. If less 
than 4 out of the first 6 patients experience Grade 3/4 toxicities or require steroids, we 
will proceed with additional accrual with this regimen to complete a total of 15 patients 
for Stage 1 interim analysis. 
9.3  Justification for the Sample Size 
The point estimate of the ORR with nivolumab in combination with ipilumumab in this 
patient population is 40%, based on the Phase I presented at ASCO meeting which is 
chosen as the reference rate (P0) in the study proposed. The response rate where the 
regimen would be considered promising to pursue further is 70% (P1). In the first stage, 


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responses will be evaluated on the first 15 subjects treated. If 6 or fewer responses 
are observed after 6-18 weeks of follow-up, the study will be terminated for futility. 
Otherwise, 10 additional subjects will be accrued to target a total of 25 treated subjects. 
During the evaluation of response in the first stage, we will continue the recruitment 
and treatment of subjects. This design has at least a 90% chance (power) of 
concluding the combination therapy is effective when the true response rate is 70% 
and a 5% chance (Type I error) of concluding the treatment is effective when the true 
response rate is 40% or less. The probability of stopping early is 61% if the true 
response rate is 40% or less and 1.5% if the true response rate is 70%. The null 
hypothesis will be rejected and the regimen will be declared a success if at the end of 
the study 17 or more responses are observed in 25 treated subjects. The anticipated 
accrual rate for this group of patients is expected to be 2 patients per month.  
 
Early Stopping Guidelines for Safety: The safety profile of the combination of SBRT 
with dual immune checkpoint inhibition using nivolumab and ipilimumab is not yet 
established, and therefore we will conduct continuous toxicity monitoring after safety 
run-in to ensure this combination is safe. If the risk of Grade 3/4 adverse events 
convincingly exceeds 50%, a threshold we are comfortable given the potential benefit 
of the regimen as well as our experience in managing the side effects in this patient 
population, we will temporarily halt the study and carefully review the available data at 
that point in order to suggest potential modification of the combination regimen. 
Specifically, a Bayesian toxicity monitoring rule will suggest suspending enrollment if 
the posterior probability of risk being larger than 0.50 is 75% or higher. The prior for 
this monitoring rule is beta (1, 2), representing the risk of DLT has mean of 33% and 
there is 90% probability that this risk is between 2.5% and 78%. The stopping rules for 
safety and the operating characteristics based on 5000 simulations are as below. 
 
 
 
 
 
 


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No. patients 
experiencing G3/4 
AE/steroid needs 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Out of  
7-8 
9-10 
11-12 
13-14 
15-16 
17 
18-19 
20-21 
22-23 
24-25 
 
True risk of AE 
Prob. declaring regimen too toxic 
Avg. sample size 
0.30 
2.1% 
24.7 
0.40 
12.8% 
23.3 
0.50 
38.5% 
20.1 
0.60 
71.3% 
15.6 
0.65 
85.3% 
13.2 
0.70 
94.6% 
10.9 
 
 9.4 Statistical Analyses of Primary Endpoint 
Safety analyses will be performed in all treated subjects. Adverse events will be 
tabulated and presented with frequencies and percentages using NCI CTCAE version 
4.0. Safety population consists of all subjects who receive at least one does of study 
medication. The ORR will be estimated as the proportion of subjects who achieve a 
response (CR/PR) assessed by RECIST. The corresponding two-sided 95% exact 
confidence interval will be calculated assuming a binomial distribution. The efficacy 
evaluable population includes all subjects who receive at least one dose of study drug, 
have an adequate baseline disease assessment and at least one post-baseline 
response assessment. 
 9.5 Statistical Analyses of Secondary Endpoints 
Clinical Endpoints: Time-to-event outcomes (e.g., TTP, DOR, PFS, OS, local 
control of irradiated lesion) will be described using the Kaplan-Meier method. 
Median values will also be estimated with 95% confidence intervals. 
 
Exploratory Correlative studies: Optional biopsies will be performed in all subjects 
at baseline (within 28 days prior to combination therapy) and during week 7 on 
therapy. Immune related biomarkers at baseline and post-therapy will be 
summarized with descriptive statistics and graphically displayed by exploratory 
plots.     Frequencies and percentages will be presented for categorical variables. 
Changes will be estimated as a ratio change (post/pre) and data will be log 
transformed as appropriate to induce symmetry and stabilize the variability. 


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Difference between pre- and post-therapy will be explored using paired t-tests or 
nonparametric Wilcoxon signed rank tests for continuous variables and McNemar’s 
test for dichotomous or categorical variables (e.g., proportion of subjects with 
marker-positive at pre- and post-therapy). Distributions of immune parameters 
across clinical responders and non-responders will be evaluated and graphically 
displayed using box plots. Differences of baseline and change in these parameters 
across tumor response groups will be explored using Jonckheere-Terpstra trend 
test, Wilcoxon rank sum test as well as logistic regression where appropriate. 
10 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction 
of the clinical research study. 
 
Government agency regulations and directives require that the study investigator 
retain all study documentation pertaining to the conduct of a clinical trial. In the case 
of a study with a drug seeking regulatory approval and marketing, these documents 
shall be retained for at least two years after the last approval of marketing application 
in an International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
 
 
 
 


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11 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site 
in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration 
of Helsinki. The Principal Investigator is responsible for personally overseeing the 
treatment of all study patients. The Principal Investigator must assure that all study site 
personnel, including sub-investigators and other study staff members, adhere to the 
study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that 
all the required data will be collected and entered onto the Case Report Forms. 
Periodically, monitoring visits may be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of data. 
At the completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12 REFERENCES 
 
1. 
Cancer Facts and Figures. American Cancer Society. Atlanta: American Cancer 
Society;, 2010 
 
2. 
Cancer of the Kidney: Section 3. W. Marston Linehan BIR, James C. Yang, in 
Cancer.: Principles & Practice Oncology / edited by Vincent T. DeVita, SAmuel Hellman, Steven 
A. Rosenberg. Philadelphia: Lipincott-Raven; 8th edition  
 
3. 
Motzer RJ, Bacik J, Mazumdar M: Prognostic factors for survival of patients 
with stage IV renal cell carcinoma: memorial sloan-kettering cancer center experience. Clin 
Cancer Res 10:6302S-3S, 2004 
 
4. 
Heng DY, Xie W, Regan MM, et al: Prognostic factors for overall survival in 
patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-
targeted agents: results from a large, multicenter study. J Clin Oncol 27:5794-9, 2009 
 
5. 
Fyfe G, Fisher RI, Rosenberg SA, et al: Results of treatment of 255 patients 
with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 
therapy. J Clin Oncol 13:688-96, 1995 
 
6. 
Negrier S, Escudier B, Lasset C, et al: Recombinant human interleukin-2, 
recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe 
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13 APPENDIX 1          INTERNATIONAL METASTATIC 
RCC DATABASE CONSORTIUM (IMDC) PROGNOSTIC 
CRITERIA 
Adverse Prognostic Factors 
Clinical 
KPS < 80% 
Time from diagnosis to treatment < 1 year 
Laboratory 
Hemoglobin < LLN  
Corrected calcium > ULN 
Absolute neutrophil count > ULN  
Platelet count > ULN 
  LLN = Lower limit of normal    
  ULN = Upper limit of normal 
 
  Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum  albumin[g/dL]),      
where 4.0 represents the average albumin level in g/dL. 
  Corrected calcium (mmol/L) = measured total Ca (mmol/L) + 0.02 (40 - serum albumin[g/L]), 
where 40 represents the average albumin level in g/L 
 
Risk Group Based on Number of Adverse Prognostic Factors 
Number of Adverse Prognostic Factors 
Present 
Risk Group 
0 
Favorable 
1-2 
Intermediate 
3-6 
Poor 
 
 
 
 
 
 


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14 APPENDIX 2   MANAGEMENT ALGORITHMS FOR 
IMMUNO-ONCOLOGY AGENTS 
A general principle is that differential diagnoses should be diligently evaluated 
according to standard medical practice. Non-inflammatory etiologies should be 
considered and appropriately treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse 
events. The oral equivalent of the recommended IV doses may be considered for 
ambulatory patients with low-grade toxicity. The lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of 
oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive 
diagnostic or therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms 
will depend on the immuno-oncology agent or regimen being used. 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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