Clinical trial NCT02781506
Conditions: Metastatic Clear Cell Renal Cell Carcinoma
Sponsor: University of Texas Southwestern Medical Center
Start date: 2016-06-20; Completion date: 2021-05-24
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Nivolumab (brand name Opdivo): IV, administered per standard of care according to institutional guidelines at the discretion of the treating medical oncologist, until disease progression or unacceptable toxicity; SABR, dose variable, in 1-3 fractions.

Detailed description:
A single institution, safety lead-in phase II trial with SAbR to multiple metastatic sites concurrently administered with Nivolumab for patients with metastatic clear cell renal cell cancer who have failed at least one anti-angiogenic therapy.

Arms: arm 1: Nivolumab alone: IV, administered per standard of care according to institutional guidelines at the discretion of the treating medical oncologist, until disease progression or unacceptable toxicity. SABR, dose variable, in 1-3 fractions.
Interventions: intervention 1: Nivolumab intervention 2: SAbR
Intervention descriptions: intervention 1: Nivolumab IV, administered per standard of care according to institutional guidelines at the discretion of the treating medical oncologist intervention 2: SAbR (1-3 lesions)

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: Phase II Trial of Nivolumab and Stereotactic Ablative Radiation Therapy (SAbR) for
Metastatic Clear Cell Renal Cell Carcinoma (mRCC)
NCT: 02781506
Document Date: 02/25/2019
Version: 5


 
STU122015-052, Hannan, FormA-ResearchProtocol, Mod_32, 05-10-21 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
STU 122015-052 
Phase II Trial of Nivolumab and Stereotactic Ablative Radiation Therapy (SAbR) for Metastatic 
Clear Cell Renal Cell Carcinoma (mRCC)  
 
Principal Investigator:  
Raquibul Hannan, MD, PhD 
 
 
 
 
University of Texas Southwestern 
 
 
 
 
2280 Inwood Road 
 
 
 
 
Phone: 214-645-8525  
 
 
 
 
Fax: 214-645-8526 
 
 
 
 
Raquibul.Hannan@utsouthwestern.edu 
 
Co-Investigator(s): 
 
James Brugarolas, MD, PhD 
 
 
 
 
Department of Medical Oncology 
 
 
 
 
 
Robert Timmerman MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
Hak Choy, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
 
 
 
 
Kevin Courtney, MD 
 
 
 
 
Department of Medical Oncology 
 
 
 
 
 
 
David Sher, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
 
 
Biostatistician: 
 
Chul Ahn PhD 
 
 
 
 
Department of Clinical Sciences 
5323 Harry Hines Blvd 
Dallas, TX 75390-9066 
  
 
 
 
(214) 648-9418 
Chul.ahn@utsouthwestern.edu 
 
Study Drug/Intervention: 
Stereotactic Ablative Body Radiation (SABR) and Nivolumab (Opdivo) 
 
Funding Source:  
Department of Radiation Oncology at UTSW 
 
Protocol Version: 
 
 
 
 
 
 
Version 
Date 
Initial (1) 
12/16/2015 
Version 2 
09/09/2016 
Version 3 
8/16/18 
Version 4 
9/2518 
Version 5 
02/25/2019 
 
UT Southwestern Medical Center at Dallas 
Department of Radiation Oncology 
Attn: Clinical Research Office 
2280 Inwood Rd 
Dallas, Texas 75235


 
STU122015-052, Hannan, FormA-ResearchProtocol, Mod_32, 05-10-21 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 


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i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................ 1 
STUDY SCHEMA........................................................................................................................ 2 
1.0 
BACKGROUND AND RATIONALE ............................................................................. 3 
1.1 
Disease Background .................................................................................................... 4 
1.2 
Stereotactic Ablative Body Radiation (SABR) ............................................................... 4 
1.3 
PD-1 inhibitor (Nivolumab) ........................................................................................... 5 
1.4 
Rationale ..................................................................................................................... 5 
1.5 
Correlative Studies ...................................................................................................... 7 
1.6 
Health-related Quality of Life (HRQOL) and Economic Analysis ................................... 9 
2.0 
STUDY OBJECTIVES ............................................................................................... 10 
2.1 
Primary Objectives ..................................................................................................... 11 
2.2 
Secondary Objectives ................................................................................................ 12 
2.3 
Exploratory Objectives ............................................................................................... 12 
2.4 
Endpoints .................................................................................................................. 12 
3.0 
Subject ELIGIBILITY ................................................................................................ 13 
3.1 
Inclusion Criteria ........................................................................................................ 13 
3.2 
Exclusion Criteria ....................................................................................................... 14 
4.0 
TREATMENT PLAN .................................................................................................. 15 
4.1 
SABR Dose and Techniques ...................................................................................... 15 
4.2 
Nivolumab ................................................................................................................. 20 
4.3 
Duration of Therapy ................................................................................................... 22 
4.4 
Duration of Follow Up ................................................................................................ 22 
4.5 
Removal of Subjects from Protocol Therapy ............................................................... 22 
5.0 
STUDY PROCEDURES ............................................................................................. 22 


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5.1 
Screening/Baseline Procedures ................................................................................. 22 
5.2 
Procedures During Treatment .................................................................................... 24 
5.3 
Follow-up Procedures ................................................................................................ 24 
5.4 
Time and Events Table .............................................................................................. 25 
5.5 
Removal of Subjects from Study Treatment or Study.................................................. 26 
6.0 
Measurement of Effect ............................................................................................. 27 
6.1 
Antitumor Effect ......................................................................................................... 27 
6.2 
Safety/tolerability ....................................................................................................... 31 
6.3 
Quality of Life (QoL) ................................................................................................... 31 
6.4 
Cost effectiveness data collection: ............................................................................. 32 
7.0 
ADVERSE EVENTS .................................................................................................. 33 
7.1 
SABR ........................................................................................................................ 33 
7.2 
Nivolumab ................................................................................................................. 33 
7.3 
Adverse Event Monitoring .......................................................................................... 35 
7.4 
Definitions.................................................................................................................. 37 
7.5 
Reporting Requirements for Serious Adverse Events ................................................. 39 
7.6 
Steps to Determine If an Adverse Event Requires Expedited Reporting ..................... 41 
7.7 
Reporting Requirements for Adverse Events .............................................................. 41 
7.8 
Stopping Rules .......................................................................................................... 42 
8.0 
DRUG INFORMATION .............................................................................................. 42 
8.1 
Nivolumab ................................................................................................................. 42 
9.0 
CORRELATIVES/SPECIAL STUDIES ....................................................................... 43 
9.1 
Sample Collection Guidelines .................................................................................... 43 
9.2 
Assay Methodology ................................................................................................... 44 
9.3 
Specimen Banking ..................................................................................................... 46 
10.0 
QUALITY OF LIFE AND COST-EFFECTIVENESS .................................................... 47 


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10.1 
Health-Related Quality of Life (HRQOL) Analysis ....................................................... 47 
10.2 
Cost-Effectiveness Analysis (CEA)............................................................................. 48 
10.3 
Quality adjusted survival time ..................................................................................... 48 
11.0 
STATISTICAL CONSIDERATIONS ........................................................................... 48 
11.1 
Study Design/Study Endpoints ................................................................................... 48 
11.2 
Sample Size and Accrual ........................................................................................... 49 
11.3 
Data Analyses Plans .................................................................................................. 49 
12.0 
STUDY MANAGEMENT ............................................................................................ 49 
12.1 
Conflict of Interest ...................................................................................................... 49 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................. 49 
12.3 
Required Documentation (for multi-site studies) ......................................................... 50 
12.4 
Registration Procedures............................................................................................. 50 
12.5 
Data Management and Monitoring/Auditing ................................................................ 50 
12.6 
Adherence to the Protocol .......................................................................................... 51 
12.7 
Amendments to the Protocol ...................................................................................... 52 
12.8 
Record Retention ....................................................................................................... 52 
12.9 
Obligations of Investigators ........................................................................................ 53 
13.0 
REFERENCES .......................................................................................................... 53 
14.0 
APPENDICES ........................................................................................................... 59 
14.1 
Appendix A: ECOG Performance Status .................................................................... 59 
14.2 
Appendix B:  MSKCC prognostic classification for mRCC patients who have been treated 
previously .............................................................................................................................. 60 
14.3 
Appendix C:  CYP3A4 and PGP inhibitors and inducers ............................................. 61 
14.4 
Appendix D:  US EQ-5D-5L........................................................................................ 62 
14.5 
Appendix E:  FACT-G ................................................................................................ 64 
14.6 
Appendix F:  FKSI ...................................................................................................... 66 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
BPI 
Brief Pain Inventory 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FACS 
Florescence Activated Cell Sorting 
H&P 
History & Physical Exam 
HRQOL 
Health-related Quality of Life 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
IV (or iv) 
Intravenously 
mRCC 
Metastatic Renal Cell Cancer 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
p.o. 
Per os/by mouth/orally 
PR 
Partial Response 
PRN 
“Pro re nata” or as needed 
QoL 
Quality of Life 
RR 
Response Rate 
RT 
Room Temperature 
SAbR 
Stereotactic Ablative Body Radiotherapy 
SAE 
Serious Adverse Event 
SBRT 
Stereotactic Body Radiation Therapy 
SD 
Stable Disease 
VAS 
Visual Acuity Score 
WBC 
White Blood Cells 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Nivolumab with concurrent 
SABR (1-6 lesions) 
 Continue Nivolumab per 
standard of care approved 
guidelines) 
 
 Metastatic clear cell RCC 
 Eligible for anti-PD-1  
 Eligible for SABR to 1-6 
lesions 
 ECOG 0-3 
 Primary end Point:  
- Response Rate (RR) 
 Secondary Endpoints:            
- OS, PFS, CR rate, 
QoL, etc. 
 Whole Blood collection for 
baseline immunologic 
assays 
 CT-guided biopsy of 
metastatic site 
 Baseline Imaging 
 
 Whole blood collection 
and repeat Imaging  
 2nd research biopsy at 8 
Weeks (optional). 
 


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STUDY SUMMARY 
Title 
Phase II Trial of Nivolumab and Stereotactic Ablative Radiation Therapy 
(SAbR) for Metastatic Clear Cell Renal Cell Carcinoma (mRCC) 
Short Title 
Nivolumab and SABR for metastatic RCC 
Protocol Number 
 STU 122015-052 
Phase 
Phase II 
Methodology 
Single arm 
Study Duration 
8 years (5 years for enrollment and 3 years for follow-up). 
Study Center(s) 
Single-center at UTSW 
Objectives 
To evaluate safety and response rate (RR) of mRCC after treatment with 
SAbR and Nivolumab  
Number of Subjects 
 21 patients  
Diagnosis and Main 
Inclusion Criteria 
Metastatic Clear Cell Renal Cell Carcinoma patients who have failed one 
anti-angiogenic therapy 
Study Product(s), Dose, 
Route, Regimen 
Nivolumab (brand name Opdivo): Nivolumab administered per 
standard of care according to institutional guidelines. The standard 
FDA approved administration and indications of Nivolumab is 
listed in the FDA website: www.fda.gov or Package Insert 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s05
8lbl.pdf. ; SABR, dose variable, in 1-3 fractions.   
Duration of administration 
Nivolumab: Nivolumab administered per standard of care according 
to institutional guidelines. The standard FDA approved 
administration and indications of Nivolumab is listed in the FDA 
website: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s05
8lbl.pdf; SABR: 1-3 fractions over one week.  
Reference therapy 
Nivolumab alone from published historical control phase III study 
Statistical Methodology 
Exact binomial test will be used to investigate if the response rate of the 
treatment arm is significantly different from that of the historical control. 
One-sample log-rank tests will be conducted to examine if OS or PFS in 
the treatment arm is significantly different from that of the historical 
control. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.0 
BACKGROUND AND RATIONALE 


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1.1 
Disease Background 
An estimated 64,770 cases of kidney cancer (RCC) will be diagnosed in the U.S. in 2012 
with an estimated 13,570 deaths (SEER). There has been a steady 2-4% per year increase in the 
incidence of RCC since 1975 that is not explained by increased and improved imaging studies. 
Clear cell cancers are the most common variant of kidney cancers comprising up to 80% of RCC.  
The five-year survival rate for RCC patients is 70%, however, this is including the majority of 
patients with localized disease whose five-year survival is 91%. At the time of diagnosis 
approximately 30% of RCC patients have metastatic disease and another 30% of patients recur, 
whose five-year survival is less than 10%. Therefore, there remains a great need for improvement 
in the therapeutic management of metastatic clear cell RCC (mRCC).   
RCC is a unique cancer that is well known for its immunogenicity. It is one of the first 
cancers in which immunostimulatory therapy, such as interferon and interleukin, has been shown 
to induce durable treatment response leading to FDA approval of HD IL-2 treatment for mRCC 
patients as early as 1992. A number of targeted therapies have been recently approved for the 
treatment of mRCC including vascular endothelial growth factor (VEGF) pathway inhibitors [1-3], 
mammalian target of rapamycin (mTOR) inhibitors [4], and most recently programmed death 1 
(PD-1) inhibitor Nivolumab [5]. Complete response remains rare even with immunotherapies. 
Strategies for enhancing the percentage of patients exhibiting a CR may prove to be the only 
hope in offering a definitive treatment for this patient population.   
1.2 
Stereotactic Ablative Body Radiation (SABR) 
Stereotactic ablative body radiation (SABR) is an emerging treatment paradigm defined 
in the American Society of Therapeutic Radiology and Oncology guidelines as a “treatment 
method to deliver a high dose of radiation to the target, utilizing either a single dose or a small 
number of fractions with a high degree of precision within the body” [6] . Potential indications for 
SABR include a broad spectrum of tumor types and locations. The safety and efficacy of SABR to 
multiple sites is excellent as documented in multiple studies [7-9].   
Previous studies have demonstrated multiple immunogenic properties of radiation 
therapy, especially when given at high doses such as with SABR [10, 11].  Since SABR is a 
highly focused therapy, it does not inherently immunocompromise the host. In addition, as 
opposed to conventional radiation fields, SABR is a highly focused therapy that spares the 
surrounding lymph nodes which are vital for an effective immune response. By not surgically 
removing the tumor, the body retains the antigen depot (dying tumor cells) within the host. 
Furthermore, since SABR causes local inflammation, dendritic cells (DCs) are attracted into the 
tumor. The antigen-presenting properties and the induction of immunogenic cell death by SABR 
are well documented [12].  SABR-induced tumor cell death is primarily via mitotic catastrophy or 
necrosis, both of which are known to be immunogenic cell deaths as opposed to apoptosis, which 
is immunologically tolerogenic [13].  In vivo studies have shown that radiation induces release of 
damage (or danger)-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 DCs for antigen presentation [14-16]. 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 [17]. The 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 demonstrated [17, 
18]. Furthermore, SABR causes a dose-dependent increase in MHC I tumor neo-antigen 
presentation by the tumor cells [19]. This, in conjunction with a demonstrated increase in FAS 
death receptors on the tumor cell surface in response to radiation, renders tumor cells particularly 
susceptible to CD8+ T cell-mediated cytotoxic attack [20, 21].  
 
There is also evidence from both pre-clinical and clinical studies that radiation, 
specifically at ablative doses typical of SABR, initiates and augments an immune response and 
can synergize with immunotherapy [18, 22-25]. In the clinic, this effect of SABR has been 
documented by multiple case reports of the abscopal effect, where SABR to one site results in a 
systemic response with tumor regression at untreated metastatic sites [26-28] including that in 


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mRCC [29]. In vivo animal studies have demonstrated that this abscopal effect of SABR is 
immune-mediated [30]. The abscopal effect of SABR was shown most recently by Postow et. al. 
in their NEJM report demonstrating that the abscopal effect was due to an increase in tumor-
specific T-lymphocytes and a decrease in MDSC following the combination treatment of SABR 
and CTLA-4 immunotherapy (Ipilimumab) in metastatic melanoma patients [28]. The team noted 
a temporal association of events with tumor shrinkage associated with antibody responses 
followed by changes in peripheral-blood immune cells, and a corresponding increase in antibody 
response to other antigens after radiation therapy. 
1.3 
PD-1 inhibitor (Nivolumab) 
Although HD IL-2 remains a first-line therapy for clear cell mRCC patients, only a small 
minority of patients exhibits complete response (CR). Educating the immune system by the 
means of immune-stimulatory treatment to eradicate the primary as well as metastatic tumors 
may be a promising strategy for this patient population. Immunotherapy such as Nivolumab, 
which provide a non-specific immune stimulation by blocking immune checkpoints, have shown 
promise in early phase trials in inducing a cancer-specific immune response in certain metastatic 
cancer sites [31] and has recently been shown to improve overall survival in mRCC patients who 
have failed at least one prior anti-angiogenic therapy compared to Everolimus [5].  
Nivolumab (BMS-936558; MDX-1106; commercial name Opdivo) is a fully human IgG4 
programmed death receptor 1 (PD-1) immune checkpoint inhibitor antibody. It selectively blocks 
the interaction between PD-1, expressed on immune cells, and PD ligand 1 (PD-L1) and 2 (PD-
L2), expressed on tumor cells and immune cells. Normally, this interaction leads to an inhibition in 
the activation of immune cells and thus would suppress the immune system. By blocking this 
interaction, Nivolumab activates the immune system. Multiple clinical trials have established the 
safety and efficacy of Nivolumab for the treatment of advanced or metastatic melanoma and/or 
renal cell carcinoma [5, 31]. Moreover, it has been recently FDA approved for patients with 
mRCC who have failed a prior anti-angiogenic therapy. 
1.4 
Rationale 
The combination of Nivolumab immunotherapy and SABR for the treatment of mRCC can be 
explained by both immunological and clinical rationales. 
1.4.1 
Immunologic Rationale 
Programmed death receptor 1 (PD-1) is a transmembrane protein of the immunoglobulin 
CD-28 family and is expressed on activated immune cells including macrophages, dendritic cells, 
activated B and T cells [32]. Two ligands specific for PD-1 have been identified: PD-L1 and PD-
L2. PD-L1 is a member of the B7 family costimulatory molecules. Except for some immune cell 
lineages, human cells do not normally express PD-L1. In addition, while not commonly expressed 
in tumor cell lines in vitro, PD-L1 is widely expressed in various in vivo tumor tissues. Multiple 
studies have shown that interferon-gamma (IFN-γ) produced by activated T-cells induce the over 
expression of PD-L1 on tumor cells [33]. Tumor cells, induced by IFN-γ, can express high levels 
of PD-L1, which interacts with PD-1 on immune cells, and through PI3K/Akt inhibition, suppresses 
their immune response by inducing T cell apoptosis, anergy, exhaustion, dendritic cell 
suppression, IL-10 production and Treg induction. PD-L1 and PD-1 interaction also protect tumor 
cells from lysis by cytotoxic T lymphocytes [34]. Given the expression of PD-L1 on host immune 
cells, anti-body mediated PD-1 inhibition should work in both PD-L1 positive and PD-L1 negative 
tumors.  
As discussed above, Nivolumab blocks the interaction between PD-1 and PD-L1, and 
thus activates the immune system in a non-specific manner. SABR should be able to provide a 
specific direction to the immune response by promoting antigen presentation. Recruited and 
activated by the DAMPs and other changes brought onto the tumor microenvironment by 
radiation therapy, the APCs migrate to the lymph node for antigen presentation and T-cell 
activation. RT also increases tumor infiltrating lymphocyte (TIL) trafficking within irradiated tumors 
[17, 25]. Typically, TILs produce IFN-γ which promotes antigen presentation but at the same time 
induces PD-L1 expression which is meant to prevent the propagation of the inflammatory 


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response and limit tissue damage. In the presence of PD-1 inhibitors, INF-γ will enhance antigen 
presentation and stimulate the immune response without the down-stream effects of PD-1/PD-L1 
interaction [35]. Nonetheless, not all PD-L1 expression on tumor cells is IFN-γ-dependent. Certain 
tumors intrinsically express PD-L1 and certain cancer mutations can also upregulate PD-L1 
expression [36, 37]. 
NK cells are part of the immune system’s innate defense against cancer and were first 
discovered because of their anti-tumor activity [38]. In fact, ex vivo expansion and re-infusion of 
autologous NK cells has shown to induce long-term remission in cancer patients [39]. Specific 
destruction of cancer stem cells has been demonstrated by NK cells [40]. Radiation therapy 
increases expression of retinoic acid early inducible-1 (RAE-1) in carcinoma cells, which binds to 
the NKG2D receptor present in NK cells and CTLs and leads to their activation [25, 41]. 
Interestingly, NK cells also express PD-1 and it has been shown that PD-1 inhibition enhances 
NK cell response against multiple myeloma [42]. This suggests another possible synergistic 
interaction of Nivolumab and SABR in producing an anti-tumor effect mediated by NK cell 
activation.  
 
Cytoreductive nephrectomy in mRCC has shown to occasionally induce regression of the 
metastatic foci [43].  It is hypothesized that this is secondary to an immune-mediated response. 
Two large randomized trials have demonstrated a survival benefit of nephrectomy followed by 
IFN-α in mRCC patients [44, 45].  In multiple settings, it has been demonstrated that a bulky 
tumor is able to produce immunosuppressants and induce proliferation of myloid-derived 
suppressor cells (MDSCs) leading to immune tolerance of the tumor [46, 47]. The cancer immune 
surveillance hypothesis states that a tumor is only able to survive and grow large when it has 
successfully evaded the immune system [48].  Therefore, surgical excision, or in this case 
ablative radiation of the bulky primary sites of disease can lead to decreased levels of MDSCs, 
immunostimulation and regression of metastatic foci. In the absence of PD-1/PD-L1 immune 
check point, a directed immune response against the cancer can flourish. 
1.4.2 
Clinical Rationale 
As applied in concert with Nivolumab in the present study, SABR is intended not only as 
a systemic cytoreductive agent but also an immunostimulant by antigen presentation. By 
aggressively cytoreducing the tumor burden, the growth dynamics may be altered to render the 
remaining cells more susceptible to the immunotherapy, thereby converting more PR patients into 
CR. Therefore, the purpose of SABR would be three-fold: (1) It would irradiate sites of disease 
that are bulky and therefore resistant to immunotherapy and potentially serving as origins of 
further tumor spread and metastasis. (2) By decreasing the burden of disease below a threshold, 
SABR would reduce or eliminate immunosuppressive effects of tumor. (3) Simultaneously, SABR 
would act as an in-situ tumor vaccination by initiating antigen presentation and immunocyte 
infiltration, thereby acting synergistically with PD-1 inhibition in facilitating an effective immune 
response and eventually affecting PR, CR, disease progression and overall survival.  
Metastatic RCC can be seen as composed of bulky sites of disease and innumerable 
micrometastatic foci that are below the resolution limit of radiographic imaging. Systemic 
therapies like cytokine therapy or newly emerging targeted therapies including PD-1 inhibitors are 
often effective towards micrometastatic disease but less so to the bulky sites of metastasis which 
requires multimodality treatment. In a recently published phase 3 RCT comparing Nivolumab to 
Everolimus in advanced and metastatic RCC patients who have failed at least one anti-
angiogenic therapy, the rate of pCR was 1% in the Nivolumab arm and <1% in the Everolimus 
arm. Therefore, systemic therapies can result in a response, rarely complete, and ultimately the 
tumors progress, resulting in declining quality of life and death from cancer. Historically, the use 
of local therapies such as surgical metastasectomy or conventional radiation for a purpose other 
than palliation was ineffective since the tumor distribution was systemic.   RCC is one of the few 
cancer sites where NCCN guidelines recommend cytoreductive nephrectomy and 
metastasectomy in selected stage IV patients, not only for palliative purposes but also for 
potential survival benefit as well. Similarly, RCC is one of the few cancer sites that has 
demonstrated a survival benefit for metastasectomies. Multiple retrospective studies, and one 
recently published randomized trial, have demonstrated an overall survival benefit (five years at 
32.5% versus 12.4%, p<0.001) of metastasectomy in RCC patients [49-51]. There is growing 


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evidence that this new, potent, highly focused, and convenient form of radiation called SABR can 
dramatically debulk and even eradicate bulky tumor deposits as effectively as surgical 
metastasectomy while being non-invasive [7, 52-54]. 
Since SABR is shown to be immunostimulatory, and tumor debulking in mRCC has 
shown to impart survival benefit, the combination of SABR and immunotherapy is expected to be 
synergistic for mRCC.  A combination treatment that offers local control through eradication of 
bulky progressive sites and simultaneously synergizes with concurrent systemic immunotherapy 
to eliminate micrometastatic disease is expected to improve outcome dramatically by converting 
partial responders to complete responders and non-responders into partial responders. 
 
The toxicities of Nivolumab are tolerable and well described. Given the multiple studies 
demonstrating excellent safety profile of SABR, including our own departmental experience, there 
are limited concerns for additional toxicity when they are administered sequentially [7-9]. No 
clinical trials combining SABR with PD-1 inhibitors are published and there is paucity of data 
regarding the side effect profile of the combination. However, preliminary data from our phase II 
trial of HD IL-2 (a form of immunotherapy with a serious toxicity profile) and SABR showed that 
the addition of SABR to immunotherapy did not increase toxicity (data unpublished). A phase I 
trial of HD IL-2 and SABR in melanoma and RCC patients has proven the safety and feasibility of 
this regimen [55]. In addition, we have already used SABR in five patients who are receiving 
Nivolumab for metastatic disease (4 with mRCC and 1 with metastatic melanoma – See table 
7.3.1). Our preliminary acute toxicity data (See table 7.3.2), with a follow up ranging between 1 
and 3 months, shows that the combination treatment is well tolerated with a favorable toxicity 
profile comparable to the published side effects of Nivolumab alone (Please see 7.2.2). Please 
note that the grade 4 toxicity in patient #1 was considered to be due to disease progression in the 
lung rather than due to the therapy itself. 
 
Therefore, we propose a single institution, safety lead-in phase II trial with SAbR to 
multiple metastatic sites concurrently administered with Nivolumab for patients with metastatic 
clear cell renal cell cancer who have failed at least one anti-angiogenic therapy. This phase two 
trial tests the hypothesis that addition of SABR to Nivolumab is a durably effective means of 
potentiating the effects of PD-1 blockade in inducing higher objective response rate (RR) 
eventually leading to improvements in progression-free survival, complete response rate, overall 
survival without degrading quality of life in the mRCC patient population. As reported in prior 
trials, the RR for Nivolumab (dosing as per the institution guidelines, q 3 weeks until progression) 
in mRCC is 22%-25% [5, 56].  In the same trials, median OS was 25 months, and PFS was 4-4.6 
months. The primary endpoint of this study is to measure improvement in response rate (RR) 
when SABR is added to Nivolumab compared to the RR in the reported historical control arm with 
Nivolumab alone. We will propose that the addition of SAbR to Nivolumab will increase the RR to 
43.8% i.e. 75% increase compared to the historical RR with Nivolumab alone. In our current 
ongoing phase II clinical trial (STU 012013-041) with similar patient population and treatment 
strategy of SABR + immunotherapy using IL-2, we are noticing a 53% RR with the combination 
whereas the historically reported response rate of IL-2 alone treatment is 20% (1). Therefore, we 
have increased the RR by >150%.  Therefore, in oncology clinical trials, it is not uncommon to 
see such increases since the baseline RR is often low. The secondary objectives of this trial will 
measure progression-free survival (PFS), overall survival (OS), time to progression (TTP), 
complete response rate (CRR), duration of treatment response, and health related quality of life 
outcomes (HR-QoL). In addition, the exploratory objectives will include correlation of the immune 
response to clinical outcome, evaluation of immunologic biomarkers to predict response and 
explore possible mechanism of immune resistance. This will help us identify patients who may be 
more responsive to this regimen. Given the high cost of Nivolumab, it would be also interesting to 
evaluate the cost-effectiveness of adding SABR upfront with the hope that it would have cost 
saving effects and improve the quality-adjusted life-years for patients.   
1.5 
Correlative Studies 
 
The correlative studies will explore the mechanisms of possible immune enhancement by 
SABR. Activation of the immune response will be evaluated separately utilizing different assays. 
The humoral response will be evaluated using ELISA to measure the titer of tumor-specific 


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antibodies generated by SABR and Nivolumab against tumor tissue collected from the respective 
patients and established human renal cancer cell lines Caki-2 (clear cell) and ACHIN 
(adenocarcinoma).  An overall increase in tumor antigen-specific antibody will be measured using 
immunoblotting with patient sera as a source of primary antibody.  
 
Enhancements of increased cytotoxicity to renal cancer cells can be measured by 
cytotoxicity assays.  Antibody-dependent cell-mediated cytotoxicity (ADCC) measures the cell-
killing ability of certain lymphocytes that require the target cell to be marked by an antibody and 
thus measures the humeral response [57]. On the other hand, lymphocyte-mediated cytotoxicity 
assay will measure the formation of tumor-specific CTLs among the lymphocytes collected from 
patients before and after SABR and Nivolumab. Since it is not practical or feasible to obtain 
sufficient quantities of tumor cells from each patient to quantitatively assess cytotoxicity by these 
assays, established allogenic human renal cancer cell line Caki-2 and ACHIN will be used for this 
purpose. It is a generally accepted principle of tumor immunology that there will be many 
common tumor antigens between different patient tumors of same site origin, and therefore tumor 
cell lines as well [57]. In fact, the tumor antigens (PSA, CEA, CA 19-9 etc.) that are in clinical 
practice are reported to be present in a significant portions of patients of the respective tumor 
site.  This concept of commonality of tumor antigens between allogenic tumor cell lines and 
patients is put into clinical practice by the GVAX anti-tumor vaccine which is currently in early 
phase clinical trials for pancreatic, melanoma and renal cancer [58, 59]. GVAX consists of 
multiple human tumor cell lines of the respective site that is modified to express GM-CSF, and 
killed with radiation prior to injection in patients. The presence of common tumor antigens in the 
cell lines and patient’s tumors, leads to induction of an immune response. The LNCaP and PC-3 
cell lines has been shown to express many of the common renal cancer antigens, and therefore, 
is an appropriate surrogate to be used instead of patient’s own cells and has been used in similar 
in vitro cytotoxicity assays [60-64].   
 
Cytokines are hormonal messengers responsible for most of the effects in the immune 
system such as activation of innate versus adaptive immune response, cellular versus humoral 
immune response [65, 66]. For example, an increased level of IL-2 and IFN-γ suggests activation 
of Th1 cells leading to activation of macrophages and suggests a cell-mediated adaptive immune 
response whereas IL-4 and IL-5 may indicate Th2 activation and induction of humoral immunity 
[57, 66].  An increase in IL-17 may suggest activation of autoimmune responses [67]. Therefore, 
measurements of serum cytokine levels have generally been used previously in clinical trials as 
surrogates to assess specific activation of immune pathways [68, 69].  Serum cytokines from this 
clinical trial before and after SABR and at different time-points of Nivolumab administration will be 
measured using an extensive array of cytokines to explore the specific immune pathways that are 
initiated/inhibited by our treatments. The planned array of cytokines will measure levels of the 
following cytokines at different time points for each patients: Th1/Th2/Th17 cytokines: IFN-γ, IL-
1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, IL-17 TNF-α; pro-inflammatory cytokines: GM-
CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, TNF-α; Chemokines: Eotaxin, MIP-1β, TARC, 
IP-10, IL-8, MCP-1, MCP-4, KC, and others including IL-6, IL-12, TGF-β and HMGB1.   
 
Many surrogate markers for activated and proliferating lymphocytes have been 
described. Some of these markers include CD25, CD71, CD45RO, CD107a, CD54, CD69, Ki67 
and ICOS/CD278 [70-73]. These markers are easily measured with specific antibodies tagged 
with a fluorophore utilizing FACS analysis. Also using FACS, activation markers such as CD80 
and CD 86 on DCs, and inhibitory markers such as PD-1, can be measured as surrogates of 
immune activation or inhibition.  These measurements from PBMCs collected from patients will 
give us further information regarding the intensity of the immune response.   
 
The relative levels of different monocyte subpopulations in the tumor biopsy sample after 
treatment as well as in the peripheral circulation often dictate the overall outcome of an immune 
response, and has been reported in previous immunotherapy trials [55]. Exploration of possible 
mechanisms of treatment failure can be explored from this analysis as well. Therefore the 
following subpopulation of cells will be quantified in patient PBMCs (and in tumor biopsy samples 
where applicable) collected before and after treatment utilizing some of the listed markers specific 
for those cells: 
 
Immune Cells 
Markers 


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Lymphocytes 
 
 
Cytotoxic T Lympocyte (CTL) 
CD3, CD8 
 
NK 
CD3-, CD8, CD16, CD56, CD11b 
 
NKT 
CD3, CD16, CD1d 
 
 Helper T Cells 
CD3, CD4 
 
 
Th1 
IL-18 receptor α, CXCR3, T cell Ig 
domain, TIM-3, T-bet 
 
Th2  
T1/ST2, TIM-1, TIM-2, GATA-3 
 
Th17 
Unknown, differentiated by IL-17 
production, ROR-γT 
 
Treg 
CD4+CD25+FoxP3+ 
 
Memory T Cells 
CD45RO 
 
TCM 
CD4/CD8, CD62L, CCR7 
 
TEM 
CD4/CD8, CCR7−, CD45RA−, CD27 
B Cells 
CD19, mIg, FcR, CR, CD3-, HLA-DR 
MDSC 
CD14+, CD11b, CD33, CD 15, CD4, 
CD8-, HLA-DR-/low 
 
Neutrophils 
FcR, CR-,CD3-, HLA-DR-, GR-1+high, 
CD11b, Ly6G 
 
Macrophages 
FcR, CR, HLA-DR, GR-1+mid 
DC 
 
 
Myeloid DC-1 
CD11c, TLR2,TLR4 
 
Myeloid DC-2 
CD 141, TLR2,TLR4 
 
Plasacytoid DC  
CD303, TLR7,TLR9 
 Table 1: PBMC subpopulations and their markers.  
 
Additionally, we plan to specifically quantify the expression of PD-L1 in all tumor samples 
from patients’ pre-treatment tumor biopsies. Tumor PD-L1 membrane expression (≥1% vs. <1% 
and ≥5% vs. <5%) will be quantified in sections which have at least 100 tumor cells as assessed 
with immunohistochemical staining. It has been shown previously that tumors with higher PD-L1 
expression have worse outcomes but it remains to be shown whether these tumors respond 
better to anti-PD-1 therapy. It would be very interesting to examine the correlation between PD-L1 
expression and tumor response to the combination therapy.   
1.6 
Health-related Quality of Life (HRQOL) and Economic Analysis 
 
In the United States, total national health expenditures (NHE) increased from $7.14 billion 
in 1990 to $2.23 trillion in 2007, which represents an average annual growth rate of 7.0%.  In 
contrast, over the same period, U.S. gross domestic product (GDP) increased from $5.8 trillion in 
1990 to $13.8 trillion, or average 5.2% annual growth rate.  Given that national health 
expenditures have grown faster than GDP, the share of GDP devoted to health expenditures has 
increased from 12.3% in 1990 to 16.2% in 2007 [74].  Moreover, national health expenditure 
growth is expected to continue to outpace income growth, with total NHE reaching $4.35 trillion 
by 2018, accounting for 20.3% of GDP (CMS 2009).  There is growing concern that these trends 
in health expenditures are not sustainable. For the Medicare program, current estimates of the 
present value of total unfunded liabilities through the year 2083 (the present value of the 
difference between projected future Medicare expenditures and Medicare revenues over the next 
75 years under current Medicare policy) total $89 trillion, with Medicare’s Hospital Insurance 
(“Part A”) trust fund projected to be depleted by 2017 [75]. 
 
Prior studies have estimated that about half of the recent growth in health expenditures is 
attributable to advances in various forms of health technology, including new pharmaceutical 
products, surgical procedures, imaging modalities, and new biomarkers [75].  While almost all of 
these new technologies offer some potential to improve clinical outcomes, they also more often 
than not add to health expenditures.  Within the context of unsustainable trends in health 
expenditures, a key policy question relates to whether the extent of improvement in outcomes 
associated with the use of a new technology is attained at a “reasonable” additional cost, 


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compared to existing technology.  Indeed, the value offered by new technologies is being 
subjected to increasing scrutiny by reimbursement authorities in many health systems worldwide.  
For example, in the United Kingdom, the National Health Service bases payment policy decisions 
for new technologies on recommendations from the National Institute for Health and Clinical 
Excellence (NICE), which in turn are substantially influenced by cost-effectiveness analysis 
yielding an estimated additional “cost per quality-adjusted life-year (QALY) gained” via use of the 
new technology.  Currently, NICE usually considers technologies offering improved outcomes at a 
cost less than £20,000 to £30,000 per QALY gained (about $33,000 - $50,000) acceptable, 
though exceptions are common[76]. 
 
Several recent studies have evaluated health-related quality of life (HRQoL) for biologics 
and targeted treatment for mRCC.  In the Sunitinib versus INF-alpha trial, health-related quality of 
life was superior in the Sunitinib group as assessed by the FKSI-15, FACT-G, and EQ-5D [3][80].    
In a review article regarding quality-of-life in patients with recent renal cell by Cella et al., it is 
clear that quality-of-life measures are increasingly being utilized within the clinical trial setting to 
assess quality adjusted life year expectancy [81].  Two recent trials evaluating health-related 
quality of life for Sorafenib utilizing the FACT-FKSI, FACT-G, and EQ-5D indicated that Sorafenib 
resulted in improvements in individual items related to registry function and quality of life 
compared with placebo [82].  Additionally, European trials evaluating temsirolimus in a phase 3 
setting versus INF-alpha or both, showed quality adjusted survival favoring patients who received 
temsirolimus [83]. In a group of heavily pretreated metastatic renal cell cancer patients enrolled 
on a phase 3 trial comparing everolimus versus placebo, quality of life as measured by EORTC 
QLQ C30 and FKSI-DRS showed no changes between the two treatment groups showing stable 
quality-of-life as compared to placebo [84]. Additionally, there are ongoing studies evaluating QoL 
in patients receiving axitinib as well.  
 
Due to the high cost of these new therapeutic agents several cost-effectiveness studies 
have evaluated the cost per quality adjusted life year of first-line therapeutic options of metastatic 
renal cell carcinoma.  In an economic analysis of sunitinib versus INF-alpha and IL-2, Sunitinib 
was shown to be a cost-effective alternative to INF-alpha and IL-2 from a US societal perspective 
[85].  An economic analysis from the Chinese perspective was undertaken evaluating INF-alpha, 
IL-2, INF-alpha plus IL-2, sunitinib, and bevacizumab plus INF-alpha, and it showed that sunitinib 
was cost effective when the willingness to pay threshold was over $16,000 which would be 
appropriate for several developed regions within China [86].   Given the rising costs associated 
with the biologic and targeted therapies for metastatic renal cell carcinoma, the cost implications 
of this protocol warrant further study.  
 
Therefore, we propose to evaluate patients’ health related quality of life (HR-QoL) and 
health resources utilization in order to evaluate the economical consequence of using the 
treatment proposed in this study and its impact on quality adjusted survival.  Based on the 
primary hypothesis of this study that response rates will be improved with the combination of 
SABR and Nivolumab, we further hypothesize that the addition of SABR will increase the 
durability of response or lengthen the time to progression, thus increasing the cost effectiveness 
of the combined therapies.  Thus, we hypothesize that upfront SABR, while adding modestly to 
the total cost of the combined therapies, may be cost saving over the patient’s entire treatment 
course compared to Nivolumab alone, making the combination a very attractive treatment for 
mRCC patients.  Additionally, we hypothesize that combination therapy will increase the quality-
adjusted life-years for mRCC cancer patients (compared to the prior reported chemotherapeutic, 
biologic, and targeted options for mRCC) at a reasonable incremental cost, as defined by 
generally accepted cost-effectiveness thresholds.  The sample size would be prohibitively large 
should these secondary endpoints be analyzed beyond simple descriptive statistical purposes.   
2.0 
STUDY OBJECTIVES 
 
This study is a safety lead-in phase II single institution clinical trial using Nivolumab and 
concurrent SABR to 1-6 metastatic sites in patients with metastatic clear cell renal cell cancer 
(mccRCC) who have received at least one prior anti-angiogenic therapy. Nivolumab will be dosed 
intravenously as per the institution guidelines, until disease progression, unacceptable toxicity or 
other reasons specified in the protocol. No dose modifications for Nivolumab will be allowed. 
SABR will be administered to 1-6 sites of metastatic disease one week after the first dose of 


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Nivolumab with a single (24-27 Gy) or three (11-16 Gy/fraction) fractions. The sites of larger 
(bulky) disease and the sites of symptomatic disease will be prioritized for treatment at the 
discretion of the treating radiation oncologist.  
2.1 
Primary Objectives 
The primary objective of the interim safety analysis of the trial (6 patients) is feasibility, safety and 
toxicity. The primary objective of the phase II portion of the trial will be to increase the historical 
RR of treatment with Nivolumab alone by 75% with the addition of SABR. The assessment of RR 
will be based on the evaluation of RECIST criteria and radiated lesions will be excluded from 
target lesions. The reported RR for Nivolumab for RCC is 25% [5, 31]; an increase of 100% will 
lead to a RR of about 50%. Therefore, the hypothesis of the phase II trial is that concurrent 
administration of SABR will increase the RR of Nivolumab to 50% for mRCC in patients 
who have failed one prior anti-angiogenic therapy.  
 
Treatment with immuotherapies has been reported to cause a “tumor flare” which 
denotes the apparent radiographic increase in tumor burden or occurrence of new lesions before 
a true clinical response can be established. This “flare” is thought to be due to a transient 
increase in immune cell infiltration while the immune system is being primed. Therefore, RECIST 
criteria may fail to accurately report RR and some patients will be taken off therapy before a true 
response is measured. In the CheckMate 025 trial, 44% of patients who progressed per RECIST 
criteria were continued on Nivolumab if they were thought to have clinical benefit. In addition, in 
the phase II trial of Nivolumab dose escalation trial, treatment beyond first RECIST-criteria 
progression was allowed in patients who tolerated Nivolumab and exhibited investigator-
assessed clinical benefit. 17%, 22% and 26% of patients in the 0.3, 2 and 10 mg/kg groups were 
treated beyond progression. Median number of doses received after RECIST progression was 
4.5, 7.5 and 8.5 in the 0.3, 2 and 10 mg/kg groups. Median PFS was 2.7 mos, 4.0 mos and 4.2 
mos in the 0.3, 2 and 10 mg/kg groups using the RECIST criteria but increased to 4.3, 5.4 and 
6.9 mos respectively using immune-response PFS. In a subgroup analysis, 69% (25/36) of 
patients who received treatment beyond first progression, defined as patients receiving their last 
Nivolumab dose >6 weeks after RECIST-defined progression, demonstrated sustained reductions 
in tumor burden or lesion stabilization with an acceptable safety profile. Median OS for patients 
treated beyond first progression was 22 mos vs 12 mos for those not treated. Thus, patients will 
be allowed to stay on Nivolumab after their first RECIST-criteria progression per the treating 
physician. Data will be evaluated using the RECIST criteria for primary endpoint and ir-RECIST 
for secondary endpoint.  


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2.2 
Secondary Objectives 
2.2.1 
RR based on ir-RECIST 
2.2.2 
To evaluate overall survival (OS), which is defined as the time between date of 
registration and the date of death due to any cause. In analyzing OS, we will take 
into account the MSKCC prognostic criteria for mRCC and compare our data to 
historical controls in the appropriate risk category 
2.2.3 
To evaluate progression free survival (PFS), which is defined as the time 
between date of registration and the first date of documented disease 
progression or date of death due to any cause  
2.2.4 
To evaluate complete response rate, which is defined as the percentage of 
patients who show complete response as per ir-RECIST criteria 
2.2.5 
To evaluate time to progression (TTP), which is defined as time between date of 
registration and date of documented progression. 
2.2.6 
To evaluate median response duration, which is defined as the time between the 
date a response (CR or PR) was first seen until date of progression 
2.2.7 
To evaluate the tolerability and toxicity as measured according to CTCAE v4.0. 
2.2.8 
To measure the improvement in health-related quality of life (HR-QoL)  
2.3 
Exploratory Objectives 
2.3.1 
To measure treatment-related tumor-specific immune response 
(immunogenicity). 
2.3.2 
To explore the immunological biomarkers (PD-L1 expression in tumor, DC-HIL 
expression in MDSC,  TCR diversity and clonality, etc ) as correlates or 
predictors for treatment response.  
2.3.3 
To evaluate the cost-effectiveness and cost-utility of the addition of SABR to 
Nivolumab in patients with mRCC  
2.4 
Endpoints 
2.4.1 
Response: Treatment response will be measured using both the RECIST and 
immune related RECIST criteria (ir-RECIST), a minor modification of RECIST 1.1 
for immunotherapy [89]. Radiated lesions will be excluded from target lesions. 
2.4.2 
Death: Death due to any cause, although in mRCC patient population, the 
overwhelming majority is expected to be secondary to disease progression. 
2.4.3 
Progression: Progression will be defined according to the ir-RECIST criteria and 
verified by a second set of imaging at least 6 weeks apart.  
2.4.4 
Immune Response:  Immune response will be measured using ELISpot assay, 
T-cell proliferation assay and ELISA.  
2.4.5 
Toxicity: Toxicity will be measured using CTAE v4.0 


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2.4.6 
HR-QoL: HR-QoL will be measured using FACT-G, EQ-5D and FKSI 
questionnaires at baseline, and at different time-points during treatment and 
follow up 
2.4.7 
Cost-effectiveness analysis: Health care utilization data needed to assess 
costs will be obtained from patients’ insurance claims during and after treatment. 
Markov modeling with probabilistic sensitivity analysis will be used to correlate 
quality-adjusted survival and cost.   
3.0 
Subject ELIGIBILITY 
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. 
3.1 
Inclusion Criteria  
 
3.1.1 
At least 18 years of age 
 
3.1.2 
Willing and able to provide consent  
 
3.1.3 
Pathologic diagnosis of metastatic RCC with clear cell component with 
progression or intolerance to at least one prior systemic anti-angiogenic therapy  
 
3.1.4 
Measurable disease in at least 1 non-radiated sites. 
3.1.5 
Eligible for extra-CNS SAbR to 1-6 sites of disease 
 
3.1.6 
Must have received at least one prior anti-angiogenic therapy (or inability to 
tolerate, as above) in the advanced or metastatic setting. Prior cytokine therapy 
(eg, IL-2, IFN-α), vaccine therapy, or treatment with cytotoxics is also allowed but 
not any other drug specifically targeting T-cell co-stimulation or checkpoint 
pathways.  
 
3.1.7 
Previous treatment with surgery, radiation, chemotherapy, targeted agents (see 
above) are allowed provided that:  
 
    3.1.7.1  Chemotherapy/Major surgery was administered > 7 days  
before the start Nivolumab      
3.1.7.2  Minor surgery, radiation, or any targeted agents were administered 
before the start of Nivolumab 
 
3.1.8 
Performance Status (ECOG 0 - 3 OR Karnofsky 100 - 30) 
 
 
3.1.9 
Women of child-bearing potential (WOCBP): 
- A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by choice) 
who meets the following criteria: 
• Has not undergone a hysterectomy or bilateral oophorectomy; or 
• Has not been naturally postmenopausal for at least 12 consecutive months 
(i.e., has had menses at any time in the preceding 12 consecutive months). 
- WOCBP must have a negative serum or urine pregnancy test at screening and 
within 24 hours prior to the start of investigational product. 
- Women must not be breastfeeding. 
- WOCBP must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry, for the duration of study 
participation and contraception should be continued for a period of 90 days plus 


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the time required for the investigational drug to undergo five half-lives. This is 
equivalent to 31 weeks after discontinuation of Nivolumab. 
- Should a woman become pregnant or suspect she is pregnant while participating 
in this study, she should inform her treating physician immediately. 
 
3.1.10 Men who are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year. Contraception should be continued for a period 
of 90 days plus the time required for the investigational drug to undergo five half-
lives. This is equivalent to 31 weeks after discontinuation of Nivolumab.  
3.2 
Exclusion Criteria 
 
3.2.1 
Subjects who have had major surgery (such as nephrectomy) or chemotherapy 
within7 days (or at the discretion of the treating medical oncologist)prior to first 
dose of drug 
 
3.2.2 
Subjects who have had radiation therapy within 1 week prior to first dose of drug 
 
3.2.3 
Uncontrolled adrenal insufficiency or active chronic liver disease 
 
3.2.4 
Any history of CNS metastases that is not adequately treated with surgery or 
SABR >14 days prior.  
 
3.2.5 
Prior treatment with any 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. 
 
3.2.6 
Any positive history for HIV/AIDS, HTLV, hepatitis B or hepatitis C virus 
indicating acute or chronic infection. 
 
3.2.7 
Any active known or suspected autoimmune disease. Subjects with vitiligo,  
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition 
only requiring hormone replacement, psoriasis not requiring systemic treatment, 
or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll.  
 
3.2.8 
Any condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 
days prior to the first dose of study drug. Inhaled steroids and adrenal 
replacement steroid doses up to 10 mg daily prednisone equivalent are permitted 
(although not encouraged) in the absence of active autoimmune disease.  
 
3.2.9 
Subjects with life expectancy < 6 months 
 
 
3.2.10 Subjects receiving any other investigational or standard antineoplastic agents. 
 
3.2.11 Prior malignancies 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 prostate, cervix, 
breast, or etc. 
 
 
3.2.12 Psychiatric illness/social situations that would limit consenting and compliance 
with study requirements. 


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3.2.13 Patients with history of hypersensitivity to monoclonal antibodies 
 
 
3.2.14 Subjects who are pregnant or nursing due to the potential for congenital 
abnormalities and the potential of this regimen to harm nursing infants. 
4.0 
TREATMENT PLAN 
4.1 
SABR Dose and Techniques 
Patients should have at least 1 measurable non-CNS lesions. Lesions receiving SABR will be 
called “radiated” lesions. “Target” lesions will be selected from non-treated lesions. In any case, 
there should be at least one (non-CNS) measurable lesion for effect measurement. Prior 
irradiated lesions (outside of the trial) will be excluded from target lesions.  SABR will be 
administered to 1-6 sites of metastatic disease on the 2 weeks after the second dose of 
Nivolumab with a single (24-27 Gy) or three (11-16 Gy/fraction) fractions. The sites of larger 
(bulky) disease and the sites of symptomatic disease will be prioritized for treatment. 
 
4.1.1 
SABR Dose 
 
The SABR dose and fractionation scheme is generated to deliver a potent dose to ablate 
the targeted lesions and at the same time maximize an immune response. Since multiple studies 
have shown an influx of lymphocytes and monocytes after tumor irradiation [12, 17, 18, 90] and 
since these cells play a critical role in antigen presentation and initiation of an adaptive immune 
response, multiple fraction irradiation which would kill these infiltrating immunocytes, is 
discouraged. Therefore a single fraction or a three fraction treatment regimen is allowed, and a 
single fraction treatment is preferred over three fractions.  Due to normal organ toxicity and limits 
of dose constraints, sometimes a three fraction treatment must be undertaken and in those cases 
it is recommended that the treatment course is completed within 7-10 days (preferably 5 business 
days).  Radiation dose-(immune) response studies have shown a linear increase in immune 
response with increased dose per fraction of radiation without demonstration of a plateau [17, 19, 
90, 91]. Two studies comparing 15Gy x 1 vs 5Gy x3, and 20Gy x1 vs 5Gy x4 have shown a 
superior immune response generated by the single fraction radiation [17, 90]. Clinical experience 
with oligometastatic patients treated at 1-5 sites of disease has also showed an increase in 
progression free survival with the increasing radiation dose per fraction [92]. A dose of less than 
7.5 Gy per fraction has demonstrated lower induction of systemic IFN-γ producing cells [91], and 
a previous phase II study of mRCC patients treated with HD IL-2 and singe fraction of 8Gy 
irradiation to a single lesion did not show an overall improvement in response rate [93]. Therefore 
8Gy per fraction is the lowest permitted dose for this study and can be used only when 
administering the three fraction regimen as described in the prescription dose table below.  
 
 
The SABR prescription dose will be delivered to the periphery of the planning target 
volume (PTV, see below for definitions).  Investigators will have discretion in choosing from either 
of the biologically equivalent dose levels using one or three fractions, although a single fraction is 
preferred over three fraction treatments.  Treating physician will have further discretion in 
selecting the number and location of sites to treat if multiple sites of disease are present. 
Maximum number of lesions treated is deemed as feasible per the treating radiation oncologist.  
Physicians will be REQUIRED to leave at least one site of disease for the purpose of measuring a 
radiographic response (see section 6) at a non-treated site, as this is part of the primary endpoint. 
If left untreated, this site can be treated once patient meets the definition of progressive disease 
(PD) (see section 6). To clarify the definition of “site”, each site is an area or organ with active 
extracranial disease (</=3 in the liver = one site and </=3 in the lung= one site) identified by CT 
scan, or PET/CT, within 4 weeks prior to initiation of SABR (up to 2 contiguous vertebral 
metastasis will be considered a single site of disease). For example: a patient with 4 right axillary 
lymph nodes, L1-L2 bone metastasis, 3 right lung lesions, 1 left lung lesion, 2 liver lesions, and 


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T2-T3 bone metastasis would be defined as having 6 sites of disease. Preference should be 
given to the largest feasible disease site, symptomatic sites and sites where palliative and 
preventative (i.e. to prevent a pathologic fracture in weight bearing bone, impending cord 
compression, impending SVC compression etc.) indications are applicable.  The gross 
target/tumor volume (GTV) should be at least 2 cm3 in size, corresponding to roughly a 1.5 cm 
diameter tumor. This is to ensure that adequate tumor volume and therefore adequate tumor cells 
(roughly 108 -109 cells/cm3 [94]) are killed for antigen presentation. Treating physicians should 
choose their dose based on established planning guidelines at their center including their ability 
to respect normal tissue tolerance listed below.  It is not required that all targets be treated with 
the same dose fractionation.  A dose from the following table should be used: 
 
Table 4.1.1 Prescription Dose 
 
Total Cumulative Dose Encompassing 95% of Planning 
Target Volume (Gy) 
Number of 
Fractions 
Protocol Compliant 
Minor Deviation * 
Major Deviation 
1 
24-27 Gy 
≥16 Gy, <24 Gy 
<16 Gy 
3 
33-48 Gy 
≥24.5 Gy, <33 Gy 
<24 Gy 
 
*This column is protocol compliant for tumors abutting the spinal cord (major deviation remain as 
listed) 
 
 
Dose tolerance limits should be adhered to for all treatments.  Protocol compliant dose 
should be used in all cases, if possible.  When treating tumors abutting the spinal cord, tolerance 
limits should not be exceeded.  To facilitate this requirement, minor deviation dose ranges listed 
above in the table will be considered fully compliant for tumors abutting the spinal cord. 
 
4.1.2 
Planning Constraints and Concerns  
 
The tolerance dose of SABR to the gastrointestinal tract is not established, and patients 
with metastatic disease involving the esophagus, stomach, intestines, or mesenteric lymph nodes 
will be eligible only if no other sites of lesions are present that can be safely targeted, and the 
treating radiation oncologist feels that a sufficiently conservative dose constraints to these organs 
can be met. Patients with renal or adrenal metastases are potentially eligible if normal tissue 
constraints are otherwise met.  
 
It is well established that for palliative effect for a painful bone metastasis, a single dose 
of 8 Gy is usually as effective as 30 Gy [95]. However, in this protocol the goal is not just to 
relieve pain within an osseous metastasis but also to dramatically debulk the tumor present and 
induce in immune response, and the higher dose is more likely to accomplish this goal given a 
higher biological potency [96]. Long term survival after bone metastasectomy has been reported 
[97].  Irradiation of non-spinal skeletal sites does not generally require specialized techniques of 
treatment. Metastases in major lower extremity weight-bearing bones should undergo surgical 
stabilization if there is plain film evidence of cortical erosion. 
4.1.3 
SABR Treatment Technique 
4.1.3.1 Simulation, beam arrangements, tumor prescription dose 
 
Treatment to skeletal lesions and paraspinous lesions may be accomplished with any 3D 
conformal radiotherapy or intensity-modulated radiotherapy (IMRT) technique suitable for this 
application with performance specifications adequate to provide proper tumor dose distribution 
and normal tissue sparing.  
 
At the time of simulation for patients who will receive SABR to the lung and/or liver, the 
movement of the dome of the diaphragm (superior portion of the liver) is to be observed under 
fluoroscopy or other acceptable means to estimate respiratory movement during treatment if no 


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breathing control device is used.  Patients will be assessed for suitability for tolerance of a 
respiratory control device using a breath-hold technique, respiratory gating, or abdominal 
compression to limit diaphragmatic excursion during respiration. Patients with severe lung 
disease and patients who cannot tolerate diaphragmatic or breathing control devices for other 
reasons will be treated without them. A larger margin to account for breathing related intra-
fractional organ movement is required. 
 
With the patient is immobilized in a vacuum-type or equivalent body mold, a planning CT 
scan with 2-5 mm slices is performed. Intravenous contrast is recommended for lesions near 
mediastinal structures and lesions within the liver. The form of respiratory control to be used 
during treatment should also be used during the simulation. Oral GI contrast to highlight the 
stomach and duodenum is recommended for patients with medial liver lesions or lesions of the 
caudate lobe.  
 
The planning target volume (PTV) is constructed to account for the positional uncertainty 
of the GTV during treatment. The PTV for each contoured GTV should be at least 5mm larger 
than the GTV in the axial plane and 1.0 cm larger than the GTV in the cranio-caudal plane. Larger 
margins may be used in cases where greater motion of the hemi-diaphragm is observed in 
simulation despite standard maneuvers to diminish motion.  For lung SABR the same principles 
apply; the entire lung volumes are contoured, as are each individual GTV within the lung. 
 
The prescription dose for each lesion is listed in the table in section 4.1.1, prescribed to 
the periphery of the PTV. There is no restriction on the dose “hotspot” except that it must be 
located within the PTV. A Linear Accelerator with effective photon energies of ≥ 6 MV is required. 
The use of a multi-leaf collimator (MLC) or custom blocks are acceptable.  A stereotactic 
relocalization system that relies upon stereoscopic radiographs, implanted fiducials, or near real-
time CT based verification will be used. The PTV may be treated with any combination of 
coplanar or non-coplanar three-dimensional conformal fields, shaped to deliver the specified dose 
while restricting the dose to the normal tissues.  Field arrangements will be determined by the 
planning system to produce the optimal conformal plan in accordance with volume definitions.  
4.1.3.2 Normal Tissue Dose Constraints 
 
In accordance with prior Phase I studies [98], certain normal tissue dose constraints must 
be respected. The possibility that SABR-induced fibrosis might cause occlusion of large central 
airways, thus impeding ventilation distal to the occlusion has been well considered [99]. An 
adjustment to the fractionation scheme may be made if, in the opinion of the treating radiation 
oncologist, the following conditions apply: (1) the location of a lung lesion is close enough to a 
large proximal bronchial airway such that occlusion might occur, and (2) compromised ventilation 
to the segment(s) of lung potentially affected would cause clinically significant adverse 
consequences. In such a case, the treating radiation oncologist should discuss any proposed 
dose modifications with the PI to decide whether a regimen of similar biological potency can be 
safely given. 
 
 
The same special condition applies in the setting of a patient whose primary disease has 
been irradiated previously and is present as a site of disease. Since re-irradiation toxicity is a 
concern, these patients will be considered by the PI on a case-by-case basis and SABR to a site 
previously irradiated with conventional fractionation within two years is not recommended. Re-
irradiation to a site that has received previous SABR is not allowed.  Deviations from the intended 
dose regimen will be documented, with calculations of the BED of the applied regimen included in 
the patient’s research chart along with documentation of the discussions pertaining to the 
idiosyncrasies of the case. 
 
The following table lists the specific organ and dose fractionation constraints on normal tissues. 
 
For One Fraction: 
Serial Tissue 
Volume 
Volume Max 
(Gy) 
Max Point 
Dose 
Endpoint (≥Grade 
3) 


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(Gy)** 
Optic Pathway 
<0.2 cc 
8 Gy 
10 Gy 
neuritis 
Cochlea 
 
 
9 Gy 
hearing loss 
Brainstem (not medulla) 
<0.5 cc 
10 Gy 
15 Gy 
cranial neuropathy 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
10 Gy 
8 Gy 
14 Gy 
myelitis 
Spinal Cord Subvolume (5-6 mm 
above and below level treated per 
Ryu) 
<10% of 
subvolume 
10 Gy 
14 Gy 
myelitis 
Cauda Equina 
<5 cc 
14 Gy 
16 Gy 
neuritis 
Sacral Plexus 
<5 cc 
14.4 Gy 
16 Gy 
neuropathy 
Esophagus* 
<5 cc 
11.9 Gy 
15.4 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
13.6 Gy 
16.4  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
16 Gy 
22 Gy 
pericarditis 
Great vessels 
<10 cc 
31 Gy 
37 Gy 
aneurysm 
Trachea and Large Bronchus* 
<4 cc 
17.4 Gy 
20.2 Gy 
stenosis/fistula 
Bronchus- smaller airways 
<0.5 cc 
12.4 Gy 
13.3 Gy 
stenosis with 
atelectasis 
Rib 
<5 cc 
28 Gy 
33 Gy 
Pain or fracture 
Skin 
<10 cc 
25.5 Gy 
27.5 Gy 
ulceration 
Stomach 
<5 cc 
17.4 Gy 
22 Gy 
ulceration/fistula 
Bile duct 
 
 
30 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
11.2 Gy 
9 Gy 
17 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
12.5 Gy 
22 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
18 Gy 
29.2 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
39 Gy 
22 Gy 
44.2 Gy 
proctitis/fistula 
Ureter 
 
 
35 Gy 
stenosis 
Bladder wall 
<15 cc 
12 Gy 
25 Gy 
cystitis/fistula 
Penile bulb 
<3 cc 
16 Gy 
 
impotence 
Femoral Heads  
<10 cc 
15 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
14 Gy 
 
malignant 
hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 
3) 
Lung (Right & Left) 
1500 cc 
7 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
7.6 Gy 
V-8Gy 
<37% 
Pneumonitis 
Liver 
700 cc 
11 Gy 
 
Basic Liver Function 
Renal cortex (Right & Left) 
200 cc 
9.5 Gy 
 
Basic renal function 
 
For Three Fractions: 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 
3) 
Optic Pathway 
<0.2 cc 
15.3 Gy  
17.4 Gy  
neuritis 
Cochlea 
 
 
14.4 Gy  
hearing loss 
Brainstem (not medulla) 
<0.5 cc 
15.9 Gy 
23.1 Gy  
cranial neuropathy 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
15.9 Gy 
13 Gy 
22.5 Gy 
myelitis 
Spinal Cord Subvolume (5-6 
mm above and below level 
<10% of 
subvolume 
18 Gy 
22.5 Gy 
myelitis 


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treated per Ryu) 
Cauda Equina 
<5 cc 
21.9 Gy  
25.5 Gy 
neuritis 
Sacral Plexus 
<5 cc 
22.5 Gy 
24 Gy 
neuropathy 
Esophagus* 
<5 cc 
17.7 Gy 
25.2 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
22 Gy 
26  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
24 Gy 
30 Gy 
pericarditis 
Great vessels 
<10 cc 
39 Gy 
45 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<5 cc 
25.8 Gy 
30 Gy 
stenosis/fistula 
Bronchus- smaller airways 
<0.5 cc 
18.9 Gy 
23.1 Gy 
stenosis with 
atelectasis 
Rib 
<5 cc 
40 Gy 
50 Gy 
Pain or fracture 
Skin 
<10 cc 
31 Gy 
33 Gy 
ulceration 
Stomach 
<5 cc 
22.5 Gy 
30 Gy 
ulceration/fistula 
Bile duct 
 
 
36 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
15.6 Gy 
12.9 Gy 
22.2 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
17.4 Gy 
27 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
24 Gy 
34.5 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
45 Gy 
27.5 Gy 
49.5 Gy 
proctitis/fistula 
Ureter 
 
 
40 Gy 
stenosis 
Bladder wall 
<15 cc 
17 Gy 
33 Gy 
cystitis/fistula 
Penile bulb 
<3 cc 
25 Gy 
 
impotence 
Femoral Heads  
<10 cc 
24 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
19.5 Gy 
 
malignant 
hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 
3) 
Lung (Right & Left) 
1500 cc 
10.5 Gy 
 
Basic Lung 
Function 
Lung (Right & Left) 
1000 cc 
11.4 Gy 
V-11Gy<37% 
Pneumonitis 
Liver 
700 cc 
17.1 Gy 
 
Basic Liver 
Function 
Renal cortex (Right & Left) 
200 cc 
15 Gy 
 
Basic renal 
function 
 
*Avoid circumferential irradiation. 
** “point” defined as 0.035cc or less 
Exceeding these dose tolerances by more than 2.5% constitutes a minor protocol violation.  
Exceeding these dose tolerances by more than 5% constitutes a major protocol violation. 
 
4.1.4 
Radiation Therapy Quality Assurance 
Dr. Timmerman or Dr. Hannan will perform a RT Quality Assurance Review after complete data 
for the first 20 cases enrolled has been received at the University of Texas Southwestern. Dr.  
Timmerman or Dr. Hannan will perform the final review after complete data for the subsequent 15 
cases enrolled at the University of Texas Southwestern. These cases will be reviewed within 3 
months after this study has reached the target accrual or as soon as complete data for all cases 
enrolled has been received, whichever occurs first. 


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4.2 
Nivolumab 
4.2.1 
Treatment Dosage and Administration 
Nivolumab administered per standard of care according to institutional guidelines at the discretion of the 
treating medical oncologist. The standard FDA approved administration and indications of Nivolumab is 
listed in the FDA website: www.fda.gov or Package Insert 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf. Nivolumab may be 
administered in a community practice setting as long as the treating study oncologist assumes 
responsibility for all reporting and follow-up requirements.  
 
If Nivolumab dosing is delayed for a drug-related adverse event, treatment may resume when the 
event has resolved to Grade 1 or baseline. If treatment is delayed > 6 weeks, the subject must be 
permanently discontinued from study therapy, except in cases where the delay is due to the need 
for a prolonged steroid taper to manage drug-related adverse events or the delay is not drug 
related.  
4.2.1.1 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each patient will 
be assessed for the development of toxicity according to the Time and Events table (5.4). Toxicity 
will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), 
version 4.0. No dose modifications for Nivolumab will be allowed. Treatment with Nivolumab will 
be modified by withholding doses rather than continuing therapy at a reduced dose.  We 
recommend to follow the FDA institutional guidelines or at the discretion of the treating medical 
oncologist for any dose delay criteria, criteria to resume treatment with Nivolumab and/or 
discontinuation for nivolumab. 
 
 
Treatment of Nivolumab Related Infusion Reactions 
Since Nivolumab contains only human immunoglobulin protein sequences, it is unlikely to 
be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 
3 or 4 infusion reactions should be reported within 24 hours 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 infusion, begin an IV infusion of 
normal saline, and treat the subject with diphenhydramine 50 mg IV (or equivalent) 
and/or paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor 
subject until resolution of symptoms. Corticosteroid or bronchodilator therapy may also 
be administered as appropriate. If the infusion is interrupted, then restart the infusion at 
50% of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
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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 case report form (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 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 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 ventilator support indicated) Immediately discontinue infusion of Nivolumab. 
Begin an IV infusion of normal saline, and treat the subject as follows: Recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 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 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 pruritus within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine or corticosteroids). 
 
Continued Treatment Beyond Progression of Disease 
As indicated above, we will use the RECIST and ir-RECIST criteria for tumor 
measurement and RR determination. Accordingly, an initial progression on the first set of 
scans should be verified by a second set of scans before considering it as disease 
progression and before the decision to discontinue treatment is made. If progression is 
confirmed on the second set of scans, the first date will be used in evaluations of PFS. 
(Scans are collected at the time points listed in the study procedures)  
 
In addition, accumulating evidence indicates a minority of subjects treated with 
immunotherapy may derive clinical benefit from continued treatment despite initial 
evidence of progressive disease. For this reason, subjects will be permitted to continue 
study therapy beyond initial investigator-assessed ir-RECIST) progression as long as 
they meet the 2 criteria listed below at the discretion of the treating medical oncologist:  
- Investigator-assessed clinical benefit, 
and 
- Subject is tolerating study drug. 
 
Subjects should discontinue study therapy upon evidence of further progression at the 
discretion of the treating medical oncologist, defined as an additional 10% or greater 
increase in tumor burden 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 
lymph nodes, which must have an increase in short axis to at least 15 mm). For statistical 
analyses that include the investigator-assessed progression date, subjects who continue 
treatment beyond initial investigator-assessed, ir-RECIST 1.1-defined progression will be 


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considered to have investigator-assessed progressive disease at the time of the initial 
progression event. 
4.3 
Duration of Therapy 
Nivolumab will be dosed  per standard of care approved guidelines. Nivolumab administration will 
be repeated, at the discretion of the treating medical oncologist until [5]: 
 
Disease progression as per the ir-RECIST criteria 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Subject  decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the subject 
unacceptable for further treatment in the judgment of the principal investigator or medical 
oncologist.  
SABR will be performed after the second Nivolumab dose but before the fourth dose (i.e. before 
the second Nivolumab cycles). 
4.4 
Duration of Follow Up 
 
For patients who respond to treatment, subjects will be followed for five years or until 
death (although findings will be analyzed and reported at a median follow up of 2-4 years), 
whichever occurs first. For these patients, follow-up will be every 8 - 12 weeks from study 
registration with imaging studies and physical exam (recommended) every 8-12 weeks for the 
first year, then every 8-12 weeks for the second year, then every four-six months thereafter for a 
total of five years.  
 
Subjects who show progressive disease will be followed for survival and will no longer 
strictly adhere to study calendar requirements.   
 
Subjects removed from treatment for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
4.5 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply, 
however will continue to be followed up as per protocol described above. Study coordinators will 
notify the Principal Investigator, and document the reason for study removal and the date the 
subject was removed in the Case Report Form.  
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed strictly for research purposes will be done only after obtaining 
informed consent. Assessments performed for clinical indications (not exclusively for 
research purposes) may be used for baseline values even if the studies were done 
before informed consent was obtained. 
 
All screening procedures must be performed within 8 weeks prior to registration unless 
otherwise stated. If patients remain eligible after the screening occurs, they will be 
registered. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history, history of infections and pulmonary risk 
factors 


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5.1.3 Demographics 
Age, gender, race, ethnicity 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam (recommended) including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure, O2 saturation), 
height, weight: should be done at screening and prior to first dose of Nivolumab 
5.1.7 Performance status  
Performance status evaluated prior to study entry according to Appendix A.  
5.1.8 Adverse event assessment 
Baseline adverse events will be assessed. See section 7 for Adverse Event 
monitoring and reporting.   
5.1.9 Hematology (within 14 days of registration) 
 
 Recommended  
5.1.10 Blood draw for correlative studies 
Must be done 0-28 days prior to first dose. See Section 9.0 for details. 
5.1.11 
Serum/urine chemistries (within 14 days of registration) 
 
Recommended  
5.1.12 
Pregnancy test (for females of child bearing potential) 
Per standard of care at the discretion of the treating medical oncologist.  
5.1.13 
Radiographic Imaging 
 
5.1.13.1 CT chest, abdomen and pelvis (recommended with IV contrast) must 
be done within 6 weeks of registration.  MRI can replace CT at the discretion of 
the treating physician. 
5.1.13.2Brain MRI is allowed up to 3 months prior to registration.  
5.1.14 
Biopsy of metastatic lesion 
5.1.14.1 Pre-treatment biopsy: 
A CT-guided biopsy of a tumor lesion will be performed prior to study 
registration, unless previous biopsy of metastatic site exists in which case 
a pretreatment biopsy is not required.   
5.1.14.2 Post-treatment elective biopsy: 
An elective post-treatment biopsy will be performed at 8 weeks (+/- 2 
weeks, >4weeks after SABR) (first follow up visit) and for this biopsy, any 
site other than a lymph node and a treated site is acceptable. In case of 
CR no lesions may remain to be biopsied.   
 


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5.1.15 
QoL Questionnaires  
FACT-G, EQ-5D, FKSI, Cost Effectiveness questionnaire:  These forms will be 
referred to collectively as QoL Questionnaires and will be collected prior to first 
Nivolumab dose and at specific time-points as indicated in section 5.4 
5.1.16 
Tumor assessment 
To be performed on CT or MRI from 5.1.13. 
 
 
5.2 
Procedures During Treatment 
SABR treatment requires one week for planning and one week for delivery of the 1 or 3 
fractionation schemes.  Thus, CT simulation and treatment planning will take place any 
time before the radiation. SABR will be performed after 1st cycle of Nivolumab infusion.  
Vital Signs, AE Assessment, Medication Review and Laboratory Review may be 
performed by a Nurse or Physician. 
   
5.2.1 
Prior to first Nivolumab dose (0-28 days prior) 
 Focused physical exam (recommended)  
 Vital Signs 
 Performance Status (recommended) 
 
AE Assessment  
  
 For WOCBP, pregnancy test within 24 hours of first dose of Nivolumab 
 Blood draws for immunologic studies 
 FACT-G, EQ-5D, FKSI, Cost-Assessment questionnaires 
5.2.2 
Day 1 of Nivolumab cycle 
 Focused PE (recommended) 
  
 All labs (except corollary blood collections) will be done per standard of care 
at the discretion of treating medical oncologist.  
 First Nivolumab infusion cycle administered 
 Blood draws for immunologic studies at baseline, follow up q 8-12 weeks (until 
discontinued or within first year of enrollment, whichever is first)and at 1 year 
(if discontinued before 1 year).  
5.2.3 
Pre-RT 
 CT simulation for SABR planning  
  
5.2.4 
Radiation Treatment 
 AE assessment  
 Vital Signs 
 SABR treatments will be performed after 1st cycle of Nivolumab infusion.  
 
These cycles will continue (without SABR) until patient is discontinued from Nivolumab as 
discussed above. 
5.3 
Follow-up Procedures 
- 
For patients who are still receiving Nivolumab: 


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Subject will be followed every 8-12 weeks starting from the date of registration for the first 
two years. , then every four-six months thereafter for five years or death, whichever 
comes first. The following procedures will be performed at each follow up: 
 Physical exam (recommended), Performance Status (recommended), Vital 
Signs, Medication Review, AE assessment 
 HR-QoL questionnaire at baseline, and  then at six month intervals until 
patient meets primary endpoint 
 Blood collection for correlative immunologic studies (see section 9.0): In total, 
all patients will get blood draws for correlative studies at baseline, follow up q 
8-12 weeks (until discontinued or within first year of enrollment, whichever is 
first) and at 1 year (if discontinued before 1 year).  
 Radiographic imaging: Tumor assessments will be completed by the 
investigator using the RECIST and ir-RECIST criteria as above. 
o 
CT chest, abdomen and pelvis with IV contrast (contrast recommended), 
if allowable by renal function. MRI with contrast (contrast recommended) 
can replace CT.   
o 
MRI, if necessary to confirm CT findings, at the discretion of physician 
 
- 
For patients who have been discontinued from Nivolumab (See Section 4.3): 
Subject will be followed within 3 months from last dose ((+/- 2 months), or may be on 
date of discontinuation).  
 
 
The following procedures will be performed: 
 Physical exam (recommended), Performance Status (recommended), Vital 
Signs, Medication Review, AE ssessment 
 Subsequent anti-cancer treatment/s 
 Blood samples for correlation immunologic studies 
After that, survival visits/phone calls continue annually to include Survival Status, AE 
Assessment, and Subsequent anti-cancer treatment/s. 
5.4 
Time and Events Table 
The above recommended labs are listed in the following table but investigators in the various participating 
institutions may obtain labs per their standard of care to assess suitability for treatment. 
 
 
 
 
Pre-study 
 Cycle 
Day 1 
Infusion 
 
Pre-RT 
Radiation 
Treatment 
 
  
Follow Up Schedule for Patients 
who respond to treatment (for 
other patients refer to Section 5.3) 
Months 
1-12: 
q8-12 
Weeks 
Months 
13-24: 
q8-12 
Weeks 
Months 25-
60: q16-24 
Weeks 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X 
 
X 
X 
X 
Medical History  
X 
 
 
 
 
X 
X 
X 
Physical Exam 
(recommended) 
X 
X 
 
 
 
X 
X 
X 
Performance 
Status 
(recommended) 
X 
 
 
 
 
X 
X 
X 
AE Assessment 
X 
X 
 
X 
 
X 
X 
X 


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** MRI should be considered, in place of CT, on an individual basis if felt to be better by the 
radiation or medical oncologist. 
1 For cycle 1, no need to repeat blood tests at day 1 
# Immunologic blood collection is needed at baseline, follow up q 8-12 weeks (until discontinued 
or within first year of enrollment, whichever is first)  and at 1 year (if discontinued before 1 year). 
^ if previous biopsy of metastatic site with adequate review of slides is not available.  
^^ Cost Effectiveness Questionnaire administered at Baseline, 8 week follow up and 6 month 
follow up.  
@ Biopsy is optional at 8 weeks 
% QoLs will be done at baseline and then at 6 month intervals  
 
5.5 
Removal of Subjects from Study Treatment or Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; patients must be 
withdrawn from the trial and replaced if they failed to receive the SABR treatment. Any 
patient with at least one cycle of Nivolumab and SABR will be included in the analysis. 
5.5.4 
Subject demonstrates disease progression (unless continued treatment with 
Nivolumab is deemed appropriate at the discretion of the medical oncologist); 
5.5.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
Medication 
Review 
 
X 
 
 
 
X 
X 
X 
CT Chest, Abd**, 
pelvis w/ Contrast 
X 
 
 
 
 
X 
X 
X 
MRI Brain 
w/contrast 
X 
 
 
 
 
 
 
 
Tumor 
Assessment 
X 
 
 
 
 
 
 
 
Biopsy of 
metastatic lesion 
X^ 
 
 
 
 
X@ 
 
 
CT Simulation 
 
 
X 
 
 
 
 
 
SABR Treatment 
 
 
 
X 
 
 
 
 
 Blood Draw for 
Correlative 
Studies (Section 
9.0) 
X# 
X# 
 
X# 
 
X# 
 
 
QOL 
Questionnaires  
X 
 
 
 
 
X% 
X% 
X% 
Cost-
Effectiveness 
Questionnaire 
X 
 
 
 
 
X^^ 
 
 
Tumor 
assessment 
X 
 
 
 
 
 
 
 


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5.5.6 
Treating physician judges’ continuation on the study would not be in the subject’s 
best interest; 
5.5.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.9 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented . 
 
5.6.  
Subject Replacement: Subject replacements are allowed in the following 
situations:   
5.6.1 
If the subjects decide to withdraw from the study without finishing the course of 
SAbR 
5.6.2 
If the subjects decide to withdraw from the study or lost to follow up (for reasons 
of death from other causes, moving to other state etc.) or refuse follow up scans 
leading to <2 follow-up scans (making it impossible to assess the primary 
endpoint of the trial) 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000].  The only change from RECIST v.1.1 being 
implemented in this study is a confirmation of new lesions or progressive disease (PD) by 
a second scan >6 weeks apart, based on the immune RECIST (ir-RECIST) criteria 
proposed by Wolchok. et. al that is appropriate for immune-related treatment response 
[89]. This is primarily because immune response often can take longer time as compared 
to chemotherapy before producing a radiographic response and during this time new 
lesions may arise which will eventually regress. If it were not for a second confirmation, 
these patients would be labeled to have failed therapy. Additional criteria for bone lesions 
and clinical endpoints of pathologic fracture and cord compression are added to this 
study (see Section 6.1.4). Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST v1.1 criteria outlined in 
http://www.recist.com/.  The primary endpoint will be evaluated using RECIST v1.1 and 
secondary endpoint will be ir-RECIST. 
6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their registration. 
 
Evaluable for objective response.  Only those subjects who have undergone 
SABR and 1 cycle of Nivolumab and have had their disease re-evaluated at least 
at two occasions will be considered evaluable for response. These subjects will 
have their response classified according to the definitions stated below. 
6.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 


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as >10 mm with spiral (Helical) CT scan (CT/MRI scan slice thickness should be 
no greater than 5 mm). All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters). For malignant lymph nodes to be 
considered pathologically enlarged and measurable, a lymph node must be ≥15 
mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the 
short axis will be measured and followed. Bone scan, PET scan or plain films are 
not considered adequate imaging techniques to measure bone lesions. However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross sectional imaging techniques 
such as CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
spiral CT scan) and lymph nodes <15 mm, are considered non-measurable 
disease. Leptomeningeal disease (patients excluded), ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal 
masses (not followed by CT or MRI), and cystic lesions are all non-measurable. 
Blastic bone lesions are non-measurable. Lesions that meet the criteria for 
radiographically defined simple cysts should not be considered as malignant 
lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same subject, 
these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the longest diameter (LD) (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum LD. The baseline sum LD will be used as reference by which 
to characterize the objective tumor response. 
 
Note: Lesions receiving SABR will be called “radiated lesion” which should 
not be confused with “target lesions” defined here for the for the purpose 
of radiographic measurement. Radiated lesions and target lesions are 
mutually exclusive lesions. Therefore, radiated lesions will not be used as 
target lesions for evaluating response.   At least 2 non-CNS measurable 
lesions are required for enrollment.  
 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 6 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up. 
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements will be done digitally on the PACs system. All baseline 
evaluations should be performed as closely as possible to the beginning of 
treatment.  
 


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Whenever possible, the same method of assessment and the same technique 
should be used to characterize each identified and reported lesion at baseline 
and during follow-up using appropriate radiologic imaging.  
 
MRI Brain, and CT scan or MRI with IV contrast (whenever possible) will be 
performed at baseline.  Since bone scan is not reliable for RCC, it will only be 
used to evaluate overall response when positive in baseline scan, and any new 
lesions found on bone scan must be verified with a CT. Bone scans will not be 
used for measuring lesion size.   
 
Spiral CT and MRI. All CT scans will be Spiral CT and should be performed using 
a 5 mm contiguous reconstruction algorithm.  
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted no less than 4 
weeks apart. Any pathological lymph nodes must have reduction in short 
axis to < 10 mm. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the smallest sum LD recorded since 
the treatment started, or the appearance of one or more new lesions 
verified by a second scan > 6 weeks apart. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5 mm. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non- 
pathological in size (< 10 mm short axis). 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions 
6.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The subjects’ best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 


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Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented 
at least once 
>4 wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment. 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
6.1.4.4 
Evaluation of Bone Lesions:  
Bone lesions will be evaluated either by CT or MRI, whichever is deemed to be 
better suited by baseline studies. Since the size of the lesion is difficult to 
measure in a bone scan, particularly if it is not well visible in CT, the following 
guideline will be used. Any ambiguity will require MRI for resolution:  
6.1.4.4.1 
Progression of bone lesions will be defined as follows:  
 
Appearance of 1 or more new bone lesion in CT scan, confirmed by 
a repeat scan in ≥6 weeks. 
6.1.4.4.2 
Response of bone lesions in CT scan will be defined by either a 
complete resolution (CR) at the metastatic sites or partial resolution 
(PR) of radiotracer uptake by a radiologist.   
6.1.4.5 
Evaluation of Pathologic Fracture:  
Any clinical suspicion of pathologic fracture will prompt radiologic 
evaluation with plain film, CT or MRI as appropriate and if confirmed by a 
radiologist, will constitute progression, unless it is at a treated site, in 
which case a treatment-related toxicity will be considered. In that case, 
patients will be referred for orthopedics specialist evaluation. 


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6.1.4.6 
Evaluation of spinal cord Compression or Cauda Equina 
compression:  
Any clinical suspicion of cord or cauda equina compression will prompt 
radiologic evaluation with MRI (CT myelography if patient is not eligible 
for MRI) as appropriate and if confirmed by a radiologist, will constitute 
progression. 
6.1.5 
Response Rate:  
Response rate (RR) is defined by combining CR and PR. 
6.1.6 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
study registration until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started.  
6.1.7 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from the date of 
registration to time of progression or date of death due to any cause. 
6.2 
Safety/tolerability 
 
 Analyses will be performed for all subjects having received at least one fraction of SABR 
and one cycle of Nivolumab. The study will use the CTCAE version 4.0 for reporting of 
non-hematologic adverse events (http://ctep.cancer.gov/reporting/ctc.html) and modified 
criteria for hematologic adverse events. 
6.3 
Quality of Life (QoL) 
6.3.1 
Functional Assessment of Cancer Therapy-P (FACT-G) and Kidney Symptom 
Index (FKSI) 
Patient-reported functional status will be assessed the Functional Assessment of 
Cancer Therapy-General (FACT-G) (See appendix E). The FACT-G is a 28-item 
questionnaire that uses 5-point Likert-type response choices (0 = not at all; 1 = a little 
bit; 2 =somewhat; 3 = quite a bit; 4 = very much). It will take less than 10 minutes to 
complete the questionnaire. The Trial Outcome Indices (TOI) also will be utilized to 
measure the summed functional well-being, and physical well-being [102, 103]. A 5-
point deterioration in the FACT-G TOI between pre-treatment and at post treatment or 
at year 1 will be considered clinically significant [104].  
 
The FKSI is a 15 question validated symptom index for kidney cancer patients which 
has been used in several metastatic renal cell cancer studies [105].  This scale focuses 
on symptoms predominantly related to kidney cancer such as energy, fatigue, pain, 
bone pain, weight loss, shortness of breath, cough, fever, hematuria.  This subscale of 
the FKSI-DRS was validated in another study as well [106]. The FACT-G and FKSI will 


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be collected prior to first Nivolumab dose (baseline), and at every subsequent follow up 
appointment until the patient meets primary endpoint [105][3][82]. 
 
The first analysis of change in QOL from baseline to 8 weeks will only be performed on 
patients who are still alive at 8 weeks. Changes in QOL will be also analyzed using all 
available data at baseline, 2, 4, 6, 8, 10 and 12 months with semiparametric 
generalized estimating equations (GEE).  
 
Additionally, similarly we will also compare the percentage of patients with an effect 
size for the change in FKSI (FKSI) scores between pre-treatment and post treatment 
which will allow us to compare the percentage of patients whose functional status 
remains more similar to baseline levels. 
6.3.2 
EQ-5D  
The EQ-5D is a patient self-administrated questionnaire that takes approximately 5 
minutes to complete (See appendix D). The first part consists of 5 items covering 5 
dimensions including: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension can be graded on 5 levels. Health states are 
defined by the combination of the leveled responses to the 5 dimensions, generating 
243 health states to which unconsciousness and death are added. 
 
The 5-item index score is transformed into a utility score between 0, “Worst health 
state,” and 1, “Best health state.” The index score or the cost-utility equation can be 
used in the quality adjusted survival analysis depending on the health state(s) of 
interest.  
 
Additionally the EQ 5D is utilized to establish health state utility which is used in cost-
effectiveness analysis to calculate quality adjusted life years.  This is the recommended 
health state utility form used in the United Kingdom and approved by the National 
Institute for Clinical Excellence (NICE) and has been used to establish health state 
utility and metastatic renal cell cancer patients.  The EQ 5D will be given at baseline 
and at follow ups. The EQ-5D will also be available in the Spanish language.  
 
The EQ-5D also includes a visual analog scale (VAS), a validated measure of general 
well-being, scored on a scale of 0-100. These data will be analyzed over time in a 
similar manner as the FACT-G and FKSI. EQ-5D will be collected prior to first 
Nivolumab dose (baseline), and at every subsequent follow up appointment until the 
patient meets primary endpoint. 
6.4 
Cost effectiveness data collection: 
Healthcare utilization data needed to assess costs will be obtained from insurance claims 
and medical records. Also the cost effectiveness questionnaire will be completed by the 
patients at baseline, 8 week follow up and 6 months follow up (see Appendix G). These 
costs will be divided into the following domains: 
 
 
Hospitalizations:  For hospitalizations with physician billing records, impatient 
physician costs will be estimated by applying Medicare payment rates under the RBRVS-
based Medicare Fee Schedule to billed procedures in the physician billing records.  
 
Radiation Treatment Cost: Direct costs of radiation treatment including 
consultation, simulation, treatment planning, and treatment delivery.  Patient bills related 
to treatment will be obtained and estimated by total billed charges adjusted by facility-
specific cost-to-charge ration from Medicare cost reports as described above. 
 
Emergency Room visits: The date of ER visit and name of the facility, and 
whether the ER visit resulted in a hospital admission.  ER costs will be estimated using 


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Medicare average payment rates for facility and physician charges, using the merged 
MEDPAR and MBS data as described above. 
 
Physician and Clinic Visits: The date of the visit, the name of the physician or 
physician clinic, and the service provided (physician exam, lab test, physical therapy, 
etc.).  Costs for physician and clinic visits will be calculated based on billing records 
obtained for such visits, using Medicare payment rates for procedures indicated in the 
clinic billing records.   
 
Medications: Nivolumab is a new generation immunotherapy drug and is very 
costly (over $100,000 per year). Nivolumab drug cost will depend greatly on the number 
of cycles received. Prescription drugs used, including information about name, dose, and 
frequency of all, will be recorded.  The medications used by the study patients will be 
assigned an NDC drug code.  Unit costs for these drugs will be estimated as the “AWP” 
price published in the Red Book less 15%.  Outpatient drug costs will be calculated by 
multiplying unit cost by the number of pills used per day times the length of time the 
patient received the medication.  Note that costs of drugs administered through a clinic 
(e.g., reimbursed under Medicare Part B) are included under “clinic visit costs” and 
impatient drug costs are included under “inpatient facility costs.”   
7.0 
ADVERSE EVENTS 
7.1 
SABR 
The contraindications and adverse events for SABR are mostly related to the treatment 
site and its radiation dose tolerance, as discussed in detail in section 4.1  
7.1.1 
Contraindications:  
Treatment of patients who have received conventional radiation therapy at same site of 
new metastasis is at the discretion of the radiation oncologist. Treatment of patients who 
have received SABR at same site of new metastasis is contra-indicated. Treatment of 
patients with scleroderma or active Lupus is at the discretion of the radiation oncologist. 
7.1.2 
Special Warnings and Precautions for Use: N/A 
7.1.3 
Interaction with other medications: None 
7.1.4 
Adverse Reactions: Sites-specific. Please see section 4.1 
7.2 
Nivolumab 
7.2.1 
Contraindications 
 
None 
 
7.2.2 
Special Warnings and Precautions for Use 
See 7.2.4 
7.2.3 
Drug Interactions  
 
No formal pharmacokinetic drug-drug interaction studies have been conducted 
with Nivolumab. 
7.2.4 
Adverse Reactions 
In CA209001 (n = 39), in which subjects received a single dose of Nivolumab (BMS-
936558) with possible retreatment at 3 months, the most frequent AEs were fatigue 
(56%), nausea (44%), proteinuria (38%), constipation (33%), back pain (33%), dry mouth 


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(28%), vomiting (28%), rash (26%), and dyspnea (26%). There was no clear or consistent 
relationship between the incidence or severity of AEs and the Nivolumab (BMS-936558) 
dose level (0.3, 1, 3, or 10 mg/kg IV single dose, with possible retreatment at 3 months). 
Of 39 (100%) subjects who had at least one AE, 32 (82%) had Grade 3 or 4 AEs 
regardless of causality. Three treatment-related SAEs were reported: hypothyroidism 
(Grade 2), colitis (Grade 3), and anemia (Grade 2). Among 12 deaths, none were 
considered drug-related.  
In CA209003 (n = 296), as of the database lock date of 24-Feb-2012, BMS-936558- 
related AEs of any grade occurred in 70% of subjects. The most frequent drug-related 
AEs occurring in ≥5% of subjects included fatigue (24%), rash (12%), diarrhea (11%), 
pruritus (10%), nausea (8%), decreased appetite (8%), hemoglobin decreased (6%) and 
pyrexia (5%). The majority of events were low grade, with Grade 3/4 drug-related AEs 
observed in 14% of subjects. The most common Grade 3/4 drug-related AEs occurring in 
≥1% of subjects were fatigue (2%), pneumonitis (1%), hypoxia (1%), diarrhea (1%), colitis 
(1%), abdominal pain (1%), AST/ALT increased (1% each), blood alkaline phosphatase 
increased (1%), lipase increased (1%), pneumonia (1%), hypophosphatemia (1%), and 
lymphopenia (1%). Drug-related serious AEs (SAEs) occurred in 11% of subjects. Grade 
3/4 drug-related SAEs occurring in ≥1% of subjects were: pneumonitis (1%), pneumonia 
(1%), lipase increased (1%), and diarrhea (1%). The spectrum, frequency, and severity of 
BMS-936558-related AEs were generally similar across dose levels and histological 
subtypes. Other drug-related AEs included vitiligo, hepatitis, hypophysitis, and thyroiditis.  
Hepatic or gastrointestinal events were managed with treatment interruption and 
administration of corticosteroids, and were generally completely reversible. Endocrine 
events were managed with replacement therapy. Several subjects in these categories 
successfully reinitiated treatment with BMS-936558. Drug-related pneumonitis occurred 
in 3% of subjects; Grade ≥3 pneumonitis developed in 3 subjects (1%). No clear 
relationship between the occurrence of pneumonitis and tumor type, dose level, or the 
number of doses received was noted. Early-grade pneumonitis was generally reversible 
with treatment discontinuation and corticosteroid administration. In three subjects, 
infliximab and/or mycophenolate were utilized for additional immunosuppression, with 
unclear effectiveness. There were three (1%) drug-related deaths due to pneumonitis. In 
two of these cases, the subject did not receive the early and aggressive intervention 
(including systemic corticosteroid therapy) that is likely key in the management of this 
toxicity, while in the third case, other anti-cancer agents (erlotinib and vinorelbine) may 
have contributed to the fatal event. Preliminary new non-clinical safety findings of 
adverse pregnancy outcomes and infant losses in the absence of overt maternal toxicity 
have been reported. The findings of increased late stage pregnancy loss and early infant 
deaths/euthanasia in Nivolumab exposed pregnant monkeys suggest a potential risk to 
human pregnancy if there is continued treatment with Nivolumab during pregnancy. 
 
Opportunistic Infections Related to Immunosuppression 
 
As of 03-Apr-2013, three subjects on Nivolumab (BMS-936558) clinical trials have 
developed opportunistic infections (2 cases of Aspergillus, and 1 case of Pneumocystis 
jiroveci) after receiving prolonged treatment with high dose steroids for Nivolumab-related 
adverse events without antifungal prophylaxis. Details of these cases are available in the 
BMS-936558 Investigator Brochure. Because of the potential for opportunistic infections 
with prolonged high dose corticosteroid administrations, the following recommendations 
should be considered for subjects with inflammatory events expected to require more 
than 4 weeks of corticosteroids or other immunosuppresants: 
 
- Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic 
infections such as Pneumocystis jiroveci, bacterial and fungal infections.  
- Early consultation with an infectious disease specialist should be considered. 
Depending on the presentation, consultation with a pulmonologist for bronchoscopy or a 
gastroenterologist for endoscopy may also be appropriate.  


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- In addition, a concomitant opportunistic infection should be considered in the differential 
diagnosis when patients develop recurrent adverse events in the setting of ongoing or 
prior immunosuppressive use.  
 
7.3 
Combination Nivolumab and SABR: preliminary experience 
Currently, there are no published studies reporting the toxicity of combination Nivolumab 
and SABR. However, either treatment alone is well tolerable with a favorable toxicity 
profile as seen above.  
 
In our experience, we have already used SABR in five patients who are receiving 
Nivolumab for metastatic diseases (4 with mRCC and 1 with metastatic melanoma- See 
table 7.3.1).  
 
 
Our preliminary acute toxicity data (See table 7.3.2), with a follow up ranging between 1 
and 3 months, shows that the combination treatment is well tolerated with a favorable 
toxicity profile comparable to the published side effects of Nivolumab alone. The majority 


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of events were low grade, with only one Grade 3/4 that was considered to be related to 
disease progression rather than the treatment itself. Grade 1 fatigue was seen in 3/5 
patients. There was one grade 4 fatigue that was due to disease progression in the lung 
causing dyspnea.  Grade 1/2 nausea, low appetite and anemia were seen in 2/5 patients. 
Grade1/2 dyspnea was seen in 2/5 patients, one of which was considered due to 
exacerbation of congestive heart failure. There was one grade 4 dyspnea that was due to 
disease progression in the lung. Peripheral edema was seen in 2/5 patients, one of which 
was due to disease progression causing lymphatic obstruction.  
 
7.4 
Adverse Event Monitoring 
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 subjects’ 
safety and care.  
 


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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 changes 
observed; or 
 death. 
7.3.1 
Definitions 
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 
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 or 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 occurring through 
the time period of the start of treatment through the first follow up occuring 12 weeks post 
treatment will be considered acute adverse events.  All acute adverse events will be 
assessed and reported as per below. 
 
Late Adverse Events  
Adverse effects occurring in the time period from the end of acute monitoring, to 3 years 
post treatment for progression or death (whichever comes first), will be defined as late 
adverse events. These events will include all adverse events reported directly to a 
member of the study team and will be captured, assessed, graded and reported as 
appropriate.  
In addition, the study team will review encounters in a select specialty category relevant 
to study endpoints. These select specialties include hospitalizations, medical oncology, 
and radiation oncology records and will be limited in scope based on categorization of 
events (GU/GI) and also the type of records that will be queried (hospitalizations, medical 
oncology, and radiation oncology).  
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. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 


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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 
 
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 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. 
7.4.2 
Unanticipated Problems Involving Risks to Subjects or Other (UPIRSOs) 
The phrase “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 


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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.  
7.5 
Reporting SAEs and UPIRSOs to the Simmon’s 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 
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. (See Appendix III of the SCCC DSMC Plan for a template 
Serious Adverse Event Form which may be utilized when a sponsor form is unavailable 
and SAE submission to the eIRB is not required). 
  
 
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.  
 
The following instructions section may be modified as needed to ensure clear guidance 
for institutions participating in the trial who will not report directly to the UTSW Institutional 
Review Board. If needed, this reporting may be facilitated by the UTSW study team for:  
 


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Telephone reports to: 
Investigator: Dr. Raquibul Hannan 
study team: Satish Veerla 
Phone No: 214-648-1895 or Fax: 214-645-8913  
 
Written reports to: 
 
UTSW Radiation Oncology Study Coordinator or Clinical Research Manager 
Email: sarmistha.sen@utsouthwestern.edu  
Fax: 214-645-8913  
 
UTSW SCCC 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 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP/IRB 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a 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 must report to 
their relying IRB according to the relying IRB’s policy. In addition, the external IRB’s 
responses or determinations on these local events must be submitted to the UT 
Southwestern IRB within 10 working days of receipt. 
 
 


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Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, 
and 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-
combined.pdf. 
For further guidance for Investigators regarding safety reporting requirements for INDs 
and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM227351.pdf 
 
7.6 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
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 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days 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 (if applicable); 
 
the current Investigator’s Brochure (if applicable); 
 
the Study Agent(s)/Therapy(ies) Background and Associated Known       
Toxicities section of this protocol.  
7.7 
Reporting Requirements for Adverse Events 
7.7.1 
Expedited Reporting 
 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study drug.  
 
If necessary, suspected adverse reactions will also be reported to FDA at 1-
800-FDA-1088 or www.fda.gov/medwatch.  


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 
The IRB must be notified within 10 business days of “any unanticipated 
problems involving risk to subjects or others” (UPR/UPIRSO). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), 
which in the opinion of the Principal Investigator was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, and 
updated sponsor safety report), interim result or other finding that 
indicates an unexpected change to the risk/benefit ratio for the 
research. 
5. Any breach in confidentiality that may involve risk to the subject or 
others. 
6. Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator. 
 
The FDA should be notified within 7 business days of any unexpected fatal 
or life-threatening adverse event with possible relationship to study drug, 
and 15 business days of any event that is considered: 1) serious, 2) 
unexpected, and 3) at least possibly related to study participation. 
7.7.2 
Routine Reporting 
 
All other adverse events- such as those that are expected, or are unlikely or 
definitely not related to the study participation- are to be reported annually 
as part of regular data submission. 
7.8 
Stopping Rules 
The study will be stopped if the combination treatment of SAbR and Nivolumab resulted 
in >50% of increased Grade 3-5 toxicity as compared to those reported in the literature 
for patients receiving Nivolumab alone in the first 6 patients assigned to the experimental 
arm and the regimen is deemed to be unsafe by the Data Safety Monitoring Committee.  
8.0 
DRUG INFORMATION 
8.1 
Nivolumab 
 
Other names for the drug(s):  Opdivo 
 
 
Classification - type of agent: Monoclonal antibody, Antineoplastic Agent, 
Immunotherapy, PD-1 inhibitor, Miscellaneous; Biological Response Modulator 
 
 
Mode of action: Immune-stimulator; Binds to PD-1 receptor on immune cells and 
prevents the interaction of PD-1 with PD-L1 on cancer cells. By inhibiting this 
interaction (which inhibits the immune response), Nivolumab is thought to activate the 
immune response in a non-specific manner  
 
 
Storage and stability: Nivolumab vials must be stored at a temperature of 2ºC to 8ºC 
and should be protected from light. If stored in a glass front refrigerator, vials should 


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be stored in the carton. Care must be taken to assure sterility of the prepared solution 
as the product does not contain any anti-microbial preservative or bacteriostatic 
agent. No incompatibilities between Nivolumab and polyvinyl chloride (PVC), non-
PVC/non-DEHP (di(2-ethylhexyl)phthalate) IV components, or glass bottles have 
been observed. 
 
 
Protocol dose:   Per standard of care approved guidelines.  
 
 
Preparation: BMS-936558 (Nivolumab) 100 mg (10 mg/mL) will be packaged in an 
open-label fashion. Ten BMS-936558 10 mL vials will be packaged within a carton. 
 
Route of administration for this study: Nivolumab administered per standard of care 
according to institutional guidelines. The standard FDA approved administration and 
indications of Nivolumab is listed in the FDA website: www.fda.gov or Package Insert 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf.  
 
Incompatibility:  None 
 
 
Availability: Commercially available from Bristol-Myers Squibb. 
 
 
Side effects: See 7.2.4 
 
 
Nursing implications: As dictated by clinical course 
 
 
Nivolumab may be administered in a community practice setting as long as the 
treating study oncologist assumes responsibility for all reporting and follow-up 
requirements.  
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
The goal of the planned laboratory correlative studies is to measure the induced immune 
response to patient’s pre-treatment tumor tissue antigens (see section 1.5 for detail).  In addition, 
the correlative studies will evaluate the immune response generated by the regimen. The 
submission of collected whole blood is mandatory and will be performed at baseline, follow up q 
8-12 weeks (until discontinued or within first year of enrollment, whichever is first) and at 1 year (if 
discontinued before 1 year).  
9.1 
Sample Collection Guidelines 
Samples will be labeled with the subject’s de-identified study number and collection date 
and delivered for analysis during regular business hours to: NC7: 208; Attn Dr. Raquibul 
Hannan  
9.1.1 
Whole blood sample: Patient’s whole blood will be collected in EDTA (Lavender 
top) tubes for ~ 40-50 ml. In addition, ~10 ml will be collected in anti-coagulant-
free tubes (Red top) for the collection of sera.  The blood will immediately be 
processed (within 2 hours) by centrifugation (1000 g, 15 min, 4oC), collecting the 
supernatant and freezing at -80oC in 5 aliquots for future experiments. The pellet 
will be re-suspended in PBS and PBMC will be isolated using standard protocol. 
Briefly, the cell suspension will be carefully placed on 10ml polystyrene tube 
containing 1ml ficoll and centrifuged (400g, 30min, RT).  PBMC region will be 
collected from the ficoll and washed 3x with PBS. Cells will be counted and 
frozen in 5 aliquots with 10% DMSO, 90% FBS at -80oC.  
9.1.2 
Tumor Biopsy Sample:  A CT-guided biopsy of tumor lesion consisting of 4-5 
18G needle cores is recommended at the time of registration of the patients to 


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the study unless a biopsy has been done in the previous 12 months (See 5.1.15).  
A second biopsy at 8 weeks (+/- 2 week) is elective.  
9.1.2.1 
 
Initial required biopsy: 3-4 core biopsies will be processed as routine 
diagnostic specimens by Pathology for the purpose of diagnosis and 
immumo-histochemistry (IHC). After on site adequacy check using touch 
imprint slides, the cores will be fixed in 10% buffered formalin for up to 8 
hours and processed routinely to obtain formalin fixed paraffin embedded 
blocks. Eight, 3-micron thick sections will be cut. The first and last 
sections will be stained with hematoxylin and eosin (H&E) stain to 
evaluate the presence, extent, and grade of renal carcinoma. The 
remaining sections will be used to perform immunohistochemical staining 
if needed (see section 9.2 for IHC detail).  Two additional cores will be 
placed in normal saline on wet ice and brought to NC9.208 (Dr. Raquibul 
Hannan) for generation of tumor lysates to be used as a source of 
antigen in the immunoassays. The biopsy cores will be chopped into 
minute pieces. Small volume of normal saline is added and the mixture is 
passed through a 19G needle, attached to a 5 ml syringe, several times, 
until the passage of the mixture occurred without difficulty. The process 
is repeated with 21G, 23G, and if possible 25G needle. The entire 
mixture is placed in liquid nitrogen until frozen, and then thawed in a 
water bath at 42°C. The freezing and thawing is repeated for a total of 
five times. The sample is passed through another 23G or 25G needle to 
disperse any clumps. The sample is then centrifuged at high speed, the 
supernatant collected, protein concentration measured using 
NanoDrop2000 and frozen at -80 oC in 5 aliquots. 
9.1.2.2 
 
8 week Elective Biopsy: One core from the biopsy will be processed by 
pathology to generate slides for histology and IHC. The second and third 
core will be placed in normal saline on wet ice and brought to NC9.208 
(Dr. Raquibul Hannan) for processing for flow cytometry of cells.  The 
tumor tissue is first cut into small pieces and incubated in PBS containing 
DNAse I 1mg/ml (Roche Diagnostics, Indianapolis, IN) and Collagenase 
2mg/ml (Fisher Scientific, Pittsburgh, PA) for 1h at 37oC. The lysate is 
then passed through cell strainer in PBS and washed 2x in 10ml of PBS 
followed by RBC lysis buffer. The cells are then frozen in 4 aliquots with 
10%DMSO 90%FBS in -80oC for future flow cytometry analysis.  
9.2 
Assay Methodology 
9.2.1 
Elispot: IFN-γ ELISpot assays will be performed according to manufacturer’s 
protocol using a commercial ELISpot kit (MabTECH). Brieﬂy, 96 well plates are 
coated overnight with 0.015 mg/ml of an anti-human IFN-g monoclonal antibody.  
PBMC from patients will be incubated in triplicates wells and stimulated in the 
presence of either PA2024 (10µg/ml), protein lysate from patient biopsy (50µg/ml) 
or 5 ng/ml PMA and 0.5 ng/ml ionomycin as positive control and albumin as 
negative control.  For ELISPOT assays, plates are incubated for 48 hours, 
washed, probed with biotinylated anti-IFNg, further washed, and then incubated 
with streptavidin alkaline phosphatase. Spot development is achieved with 5-
bromo-4-chloro-3-indolyl phosphate/nitroblue tetrazolium (BCIP/NBT; Invitrogen) 
and spots are enumerated by an automatic ELISpot reader. 
9.2.2 
ELISA: In this procedure, patient tumor tissue lysate is first adsorbed to an EIA 96 
well microplate (Fischer).  Patient plasma is then added to each well as a source 


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of primary antibody and serially diluted.  After extensive washes, detection 
enzyme (HRP)-linked anti-human mAb is then added to each well and allowed to 
bind.  Appropriate substrate is then added to each well and color development 
occurs within 5-60 min.  UV Microplate Reader will be used to read the plates 
9.2.3 
3H-thymidine Proliferation Assay: PBMC from patients will be incubated in a 
similar manner as above for five days at 37 oC then overnight with 0.5 mCi tritiated 
3H-thymidine, harvested onto a glass-fiber filter using a 96-well FilterMate cell 
harvester. The radioactivity of the 3H-thymidine is detected by a direct betaplate 
counter. The degree of antigen-specific clonal T cell expansion will be expressed 
as a stimulation index (SI) of the ratio of 3H-thymidine incorporation by cells 
incubated with patient tumor lysate compared with media controls. An alternate 
method utilizing FACS analysis with carboxy fluorescein diacetate succinimidyl 
ester (CFSE) is also available [107]. 
9.2.4 
Chromium Release Cytotoxicity Assays: For cell-mediated cytotoxicity 
analysis, A 50 µl sample of 51Cr-labeled target cells (Caki-2 and ACHIN human 
renal cancer cells) is mixed with 100µl of effector cells (patient PBMC) at various 
target to effector ratio (E:T ratios). After centrifugation at 100 X G, the cells are 
incubated for 2 hr at 37°C. The radioactivity of culture supernatant is measured 
using a gamma counter and percentage of cytotoxicity is calculated. For antibody-
dependent cytotoxicity analysis this procedure will be performed with patient’s 
plasma instead of PBMC and the percentage of cytotoxicity is calculated in similar 
manner. An alternate and non-radioactive labeling method utilizes GAPDH 
enzyme release from lysed cells called Bioluminescence Non-Radioactive 
Cytotoxicity Assay (aCella-TOX, T Cell Technology, INC) [108, 109]. 
9.2.5 
Flow cytometric analysis (FACS):  For FACS analysis of cell-surface molecules, 
the cell samples are stained with fluorescent dye – conjugated monoclonal 
antibodies against the selected markers on ice followed by fixation with 4% 
paraformaldahyde. Data are acquired on a LSRII (BD Biosciences) and analyzed 
using FACSDiva software (BD Biosciences). The PBMC of each patient before 
and after treatment will be analyzed to identify the relative sub-population of CTLs, 
regulatory T-Cells, effector memory T cells, MDSCs, neutrophils and NK cells 
utilizing appropriate cell surface markers. 
9.2.6 
Immunohistochemical staining (IHC): Standard immunohistochemistry staining 
procedure for will be performed using the Benchmark XT automated stainer 
(Ventana) for both antibodies. Briefly, formalin-fixed, paraffin-embedded tissue 
sections will be cut at 3-4 micron and air-dried overnight. The sections will be 
deparaffinized, rehydrated, and subjected to heat-induced epitope retrieval. 
Sections will then be incubated with appropriate primary antibody. For signal 
detection, ultraView universal detection system (Ventana) will be used. The slides 
will be developed using 3-3’-diaminobenzidine chromogen and counterstained 
with hematoxylin. Appropriate positive and negative controls will be utilized for 
each run of immunostains.  The evaluation of the immunostaining will be carried 
out by a genitourinary pathologist without knowledge of any clinicopathologic data. 
Only nuclear reactivity will be considered positive. An H score will be assigned as 
the product of average intensity of staining (0 for negative, 1 for weakly positive, 2 
for moderately positive, and 3 for strongly positive) and extent of 
immunoexpression (0-100% percentage of cells staining). In addition,  Dual-
antibody ISH will be performed to identify and analyze TILs, CTL (CD3+,CD8+), 
Tregs (CD4+FoxP3), DC (CD11c) , NK/T (CD3+, CD1d), neutrophils (CD11b, 
Ly6G} and MDSC (CD14+,CD11b) in the tumor tissue before and after treatment, 
when available. PD-L1 expression will be quantified from biopsies of tumors prior 
to treatment. 


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9.2.7 
Serum Cytokine Analysis: Multiplex cytokine analysis in patient’s plasma will be 
performed in precoated 96 well plates (Human TH1/TH2 10 plex ultrasensitive 
assay, Meso Scale Discovery – MSD, Maryland, USA) according to 
manufacturer’s instructions. 25 µL of diluent 2 is dispersed into each well. The 
plate is sealed and incubated by vigorous horizontal shaking for 30 minutes at RT. 
25 L of the patient plasma is added per well and all samples measured in 
triplicates. Plates are sealed and incubated by vigorous horizontal shaking for two 
hours at RT. Plates are washed three times with 0.05% Tween 20 in PBS . 25 µL 
of 1× detection antibody solution is placed per well and sealed plates are 
incubated by vigorous horizontal shaking for two hours at RT. Plates are washed 
three times with 0.05% Tween 20 in PBS. 150 µL of 2× Read Buffer T is added to 
each well. Plates are analysed using the MSD SECTOR Imager 2400 and 
Discovery Workbench 3.0 software (both from Meso Scale Discovery, USA). The 
mean value of two wells is taken as the recorded reading, provided that the 
coefficient of variation (CV) was less than 10%. Concentrations recorded lower 
than the standard curve are kept as absolute values. For purposes of logarithmic 
analysis, readings of 0 are adjusted to 0.01 pg/ml.  The following cytokines will be 
measured before and after treatment for each patients: Th1/Th2/Th17 cytokines, 
IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, IL-17 TNF-α; pro-
inflammatory cytokines: GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, 
TNF-α; Chemokines: Eotaxin, MIP-1β, TARC, IP-10, IL-8, MCP-1, MCP-4 and 
others including IL-6, TGF-β and HMGB1 (see section 1.5). 
9.2.8 
Western-blot/Immuno-blot: Caki-2 and ACHIN human renal cancer cells lysate 
will be used to perform immune-blott using plasma collected from patients before 
and after treatment.  The Caki-2 and ACHIN cell 106 cells/mL will be lysed in 
immunoprecipitation assay buffer on ice for 30 min. Standard western blott 
methodology will be utilized. Briefly, 400 µg of protein will be separated using pre-
made gradient 4% to 12% Bis-Tris gels (Invitrogen, Burlington, ON, Canada) and 
transferred to nitrocellulose. Patient sera/plasma will be diluted 1/500 in Blotto 
(5% dry milk powder; 0.1% Tween 20; 50 mmol/L Tris; 150 mmol/L NaCl) and 
incubated with nitrocellulose membranes for 1 h at room temperature using a 
multichannel immuoblotting device (Mini Protean II Multiscreen, Bio-Rad, 
Missassauga, ON, Canada). The membrane will then incubated for 1 h at room 
temperature with horseradish peroxidase–conjugated goat anti-human IgG (H+L; 
Jackson ImmunoResearch, West Grove, PA) diluted 1/10,000 in Blotto and 
visualized by enhanced chemiluminescence. 
 
9.3 
Specimen Banking 
Subject samples collected for this study will be retained at the department of pathology 
and at the lab of Dr. Hannan (NC7. 208). Specimens will be stored indefinitely or until 
they are used up. If future use is denied or withdrawn by the subject, best efforts will be 
made to stop any additional studies and to destroy the specimens. 
 
As outlined in the consent form, the protocol also gives the study personnel access to 
patient’s tumor tissue available at current or outside institutions that has been performed 
previously or will be done in the future. These may have been collected during prior 
surgery or as part of other IRB approved protocol such as the GU tissue registry study of 
(032011-187), PDX tissues and cancer center’s tissue repository. 
 
Raquibul Hannan will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators outside of UTSW. Collaborators will be 
required to complete an agreement (a Material Transfer Agreement or recharge 


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agreement) that states specimens will only be released for use in disclosed research. 
Any data obtained from the use of clinical specimen will be the property of UTSW for 
publication and any licensing agreement will be strictly adhered to.  
 
The specimens, DNA, and their derivatives may have significant therapeutic or 
commercial value. The Informed Consent form contains this information and informs the 
subject that there is the potential for financial gain by UTSW, the investigator or a 
collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be provided, 
among other, to research collaborators when specimens are made available: 
 
Diagnosis  
 
Collection time in relation to study treatment 
 
Clinical outcome – if available 
 
Demographic data 
10.0 
QUALITY OF LIFE AND COST-EFFECTIVENESS 
10.1 
Health-Related Quality of Life (HRQOL) Analysis 
The study design is to prospectively analyze the HRQOL among patients with mRCC treated 
with SABR and Nivolumab. While hypofractionation is hypothesized to yield greater tumor cell 
kill, it may also increase the normal tissue toxicity, in which case there may be a decrease in 
HRQOL. The primary normal tissue toxicities in patients receiving radiation depend on the 
location of the treatment. Prior studies have demonstrated that the most sensitive and clinically 
meaningful method for accurately capturing the normal tissue toxicities is via patients reported 
outcomes (PROs), such as HRQOL. A review of patient reported outcomes and health-related 
quality of life studies in the modern era of metastatic renal cell carcinoma is available 
highlighting the great need to assess patient reported outcomes in this patient population [81].   
 
In this trial, we plan to assess the HR-QoL questionnaires at specific time points to minimize 
patient burden: baseline (pretreatment), and at subsequent follow ups.  FACT-G is a measure 
that sums the functional well being (FWB), physical well being (PWB), the social/family well-
being (S/FWB), and emotional well being (EMB).  The FACT-G has been validated as well and 
has been used in other studies evaluating treatment options for patients with mRCC [105]. It 
takes about 5-10 minutes to complete and has been written at the 6th grade level.  FACT has 
been translated into 26 languages and is available free of charge to institutions with the 
completion of an agreement to share data, accessible at 
http://www.facit.org/translation/licensure.aspx.  
 
FKSI adds to the FACT–G (27 items) by including 15 items specific to kidney cancer patients. 
In a HRQOL study focused on patient with mRCC, a symptoms subscale questionnaire was 
developed and will also be administered in this study.  It is 15 questions and should take less 
than 5 minutes to complete.  This form focuses on symptoms frequently experienced by renal 
cell carcinoma patients and has been used in several recent mRCC studies [111] 
 
In addition, the EQ-5D is a standardized instrument for use as a measure of health outcome. 
Applicable to a wide range of health conditions and treatments, it provides a simple descriptive 
profile and a single index value for health status.  The US version of the EQ-5D will be used, to 
enable mapping of general HR-QoL scores from EQ-5D scores into health state utility scores 
(ranging from 0 to 1) for the US population.  These utility scores are needed for cost-utility 
analysis (estimates of costs per “quality adjusted” life-year gained) [112, 113]. 
 
There is little reported on the effect on HRQOL for patients treated with Nivolumab. However, 
there are several detailed reports evaluating quality of life for sunitinib, sorafanib, temsirolimus, 
everolimus, pazopanib [114].  Thus, we propose utilizing the FACT-G, FKSI, and EQ-5D in the 


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patients enrolled on this study for descriptive purposes given the lack of HR-QoL data for either 
Nivolumab, SABR or Nivolumab+SABR in this patient population [115].     
10.2 
Cost-Effectiveness Analysis (CEA) 
For the primary CEA analysis, we will estimate cost accumulated within 1 year after enrollment. A 
larger limit is possible if we have a reasonable number of people surviving at that time. 
 
Since patients are enrolled into the study over time and some patients are still alive at the end of 
the study, their survival time and costs are censored.  Due to censoring, we cannot use a simple 
average of the patients’ total costs, a simple average of the patients’ costs for those with 
complete cost information, or a Kaplan-Meier estimator on censored costs, since these all 
produce biased estimators of the mean costs [112].  Instead, we will use the inverse-probability 
weighting method to calculate average costs [113, 117]. The assumption used in this method is 
that censoring is independent of the survival time, or cost collection process, which is often 
satisfied in well-conducted clinical trials. If the new treatment can both extend patients’ survival 
time (or quality-adjusted survival time), and save costs at the same time, the new treatment will 
be preferred to the current standard treatment under any willingness to pay threshold. However, if 
the new treatment extends survival time but costs more, cost-effectiveness analysis provides an 
estimate of the incremental cost of greater incremental effectiveness.  For traditional cost-
effectiveness analysis, treatment effectiveness is measured simply as survival time.  The 
incremental cost-effectiveness ratio indicates the additional cost required to attain one additional 
year of survival.  For cost-utility analysis, treatment effectiveness is measured as quality-adjusted 
survival time (which accounts for the impact of treatment on both mortality and morbidity, 
including any differences in adverse effects of treatment affecting HR-QoL).  For cost-utility 
analysis, the incremental cost-effectiveness ratio indicates the additional cost required to attain 
one additional year of quality adjusted survival.    
10.2.1 
Projection Model and Sensitivity Analysis 
If the new treatment is implemented in usual practice, some of its potential benefits to patients 
may extend beyond the time horizon of the clinical trial.  We will explore the potential to use 
results from the clinical trial based cost-effectiveness analysis, augmented with information from 
secondary sources, to develop a model to project costs and effectiveness beyond the time 
horizon included in the clinical trial.  Any such model projections would be subjected to 
probabilistic sensitivity analysis, to assess the impact of parameter uncertainty on estimated cost 
effectiveness results.  This is typically done via Markov Modeling with probabilistic sensitivity 
analysis. 
10.3 
Quality adjusted survival time  
The quality-adjusted survival time estimates need to account for the presence of censoring.  Due 
to the induced informative censoring problem, the ordinary survival method (e.g., Kaplan-Meier 
estimator) cannot be applied in this case [113, 117, 118].  Accordingly, we will use the inverse-
probability weighted method of Zhao and Tsiatis to carry out the survival time analysis [113, 117].  
To estimate quality adjusted survival time, data from EQ-5D will first be translated into utility 
measures. These measures are obtained at discrete time points, so they will be interpolated into 
the time intervals between the visits. The quality-adjusted survival time is just an integration of the 
utility measures over a patient’s survival time, or until the time limit similar as the cost calculation, 
whichever occurs earlier. 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Study Endpoints 
This is a safety lead-in phase II clinical trial using SAbR of multiple metastatic sites concurrently 
administered with PD-1 blocking antibody Nivolumab for patients with metastatic clear cell renal 
cell cancer (RCC) who have failed at least one anti-angiogenic treatment. The primary endpoint is 


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RR, while the secondary endpoints include in OS, PFS, CR rate, immunologic response, toxicity 
and quality of life (Please see endpoint details above).   
11.2 
Sample Size and Accrual 
The first six patients assigned will be assessed for feasibility, safety, and toxicity for interim safety 
of the trial 8 weeks post-registration.  If more than 3 patients experience ≥Grade 3 SAE attributed 
to the SAbR+Nivolumab out of 6 patients, the study will be held until approval from DSMC.  
 
The previous studies show that the maximum RR for mRCC patients treated with Nivolumab is 
25%. We expect that the addition of SAbR to Nivolumab will increase the RR to 50% i.e. a 100% 
increase compared to the historical RR to Nivolumab alone. In our current ongoing phase II 
clinical trial (STU 012013-041) with similar patient population and treatment strategy of SABR + 
immunotherapy using IL-2, we are noticing a 53% RR with the combination whereas the 
historically reported response rate of IL-2 alone treatment is 20% (1). Therefore, we have 
increased the RR by >150%.  Therefore, in oncology clinical trials, it is not uncommon to see 
such increases since the baseline RR is often low. 
 
The calculation of the sample size is based on the RR. In this phase II trial, we will recruit a total 
of 19 patients including the 6 patients that will be used for interim safety analysis. A total sample 
size of 19 achieves 80% power to detect 25% absolute difference in RR (25% vs. 50%) using an 
exact binomial test at a 0.2 two-sided significance level. To allow for potential subject dropouts, 
the accrual goal will be increased by an additional 2 patients for a total of 21 patients. The sample 
size was estimated using a sample size software PASS 14 ("Hintze, J. (2015). PASS 14. NCSS, 
LLC. Kaysville, Utah, USA. www.ncss.com.") 
11.3 
Data Analyses Plans 
Exact binomial method will be used to calculate the response rate, toxicity rate, CR rate, and 
the corresponding 95% confidence interval. Exact binomial test will be used to investigate if 
the response rate of the treatment arm is significantly different from that of historical control. 
PFS and OS will be estimated using the Kaplan-Meier approach along with the 95% 
confidence interval using Greenwood’s formula.  
One sample log-rank tests will be conducted to investigate if OS or PFS in the treatment arm 
is significantly different from that of historical control. 
 
Generalized estimating equation (GEE) analysis will be conducted to investigate if there are 
significant changes in surrogate makers such as CD25, CD71, CD45RO, CD107a, CD54, 
CD69, Ki67, ICOS/CD278 and PBMC over time.  
HRQol, CEA and quality adjusted survival time analysis is described in Section 10.  
 
12.0 
STUDY MANAGEMENT 
12.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the principal investigator. All investigators will follow the 
University conflict of interest policy. 
 
12.2 
Institutional Review Board (IRB) Approval and Consent 
The IRB must approve the consent form and protocol. In obtaining and documenting 
informed consent, the investigator should comply with the applicable regulatory 
requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical 
principles that have their origin in the Declaration of Helsinki. Before recruitment and 
enrollment onto this study, the subject will be given a full explanation of the study and will 


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be given the opportunity to review the consent form. Each consent form must include all 
the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the subject and the 
investigator is assured that the subject understands the implications of participating in the 
study, the subject will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. Prior to a patient’s participation in the trial, the written 
informed consent form should be signed and personally dated by the subject  and by the 
person who conducted the informed consent discussion. 
12.3 
Required Documentation (for multi-site studies) – N/A 
12.4 
Registration Procedures 
All subjects must be registered with the Clinical Research Office, Department of 
Radiation Oncology, UTSW, before enrollment to study.  
New subjects will receive a 3-digit number.  The first subject enrolled receives the 
number 101, the second subject enrolled receives the number 102, etc.  
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration 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. 
 
 
12.5 
Data Management and Monitoring/Auditing 
All subjects consenting to participate in any aspect of the trial must be 
registered on REDCap before initiating protocol activities. All research data will be 
recorded and entered into Case Report Forms using REDCap. Toxicity will be reviewed 
on an ongoing basis and will be reported per SCCC-DSMC guidelines.   
 
The monitoring activities are designed to provide safety monitoring, data quality 
assurance, and oversight of protocols for study progress. The Radiation Oncology 
Clinical Research Office (CRO) reports serious adverse events (SAEs) to Radiation 
Oncology Safety Assurance Committee (ROSAC) monthly. These SAEs are also 
reported to the University of Texas Southwestern Medical Center (UTSW) IRB and 
Simmons Cancer Center DSMC.  SCCC-DSMC will audit in accordance with the DSMC 
plan guidelines. The purpose of the Radiation Oncology Data and Safety Monitoring Plan 
is to ensure that clinical trial data is accurate and valid and to ensure the safety of trial 
participants. The plan complies with the Simmons Cancer Center (SCC) Data Safety 
Monitoring Plan and the University of Texas Southwestern Medical Center (UTSW) IRB 
guidelines.  
 
 
ROSAC is in charged with developing, implementing, and maintaining the Data and 
Safety Monitoring Plan. The membership consists of a Medical Director of Clinical 
Research as well as representation from the following groups: clinical research, nursing, 
regulatory, pharmacy, physicists, radiation therapists, and faculty. Ad hoc members are 
contacted to participate as needed.  
 
Clinical trials are assessed for safety on a continual basis throughout the life of the trial. 
All SAE’s and any AEs that are unexpected and possibly/likely related to study 
participation are reported to UTSW IRB through an electronic research system per UTSW 
IRB guidelines. SAEs are reported to the sponsor per specific sponsor requirements. 
These SAEs are reported to the SCC DSMC on a real time basis. All local SAEs will be 
reported to the SCCC DSMC. SAE reports can be either scanned/emailed to the 
coordinator of SCC DSMC or sent through interoffice mail.  


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REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic 
case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements, as appropriate for the project 
 
In 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. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and UPIRSOs 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 SCCC 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.  
 
12.6 
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.  
12.6.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
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 


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urgent. If IRB approval is not obtained beforehand, this constitutes a major 
deviation. 
12.6.2 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 occurrence. 
 
12.6.3 Major Deviations (also called violations): include any departure from IRB-
approved research that: 
 
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. 
 
12.6.4 Minor Deviations: include any departure from IRB-approved research that: 
 
Did not harm or place subject(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: Minor deviations should be tracked and 
summarized in the progress report at the next IRB continuing review.
 
 
12.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  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.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
12.8 
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. 


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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. 
12.9 
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. 
13.0 
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14.0 
APPENDICES 
14.1 
Appendix A: ECOG Performance Status 
ECOG/ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction 
(Karnofsky 90-100). 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
work of a light or sedentary nature.  For example, light housework, office 
work (Karnofsky 70-80). 
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours (Karnofsky 50-
60). 
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours (Karnofsky 30-40). 
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed or 
(Karnofsky 10-20). 
 
5 
Death (Karnofsky 0). 
 
KARNOFSKY PERFORMANCE SCALE 
 
100 
Normal; no complaints; no evidence of disease 
 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
 
80 
Normal activity with effort; some sign or symptoms of disease 
 
70 
Cares for self; unable to carry on normal activity or do active work 
 
60 
Requires occasional assistance, but is able to care for most personal needs 
 
50 
Requires considerable assistance and frequent medical care 
 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization is indicated, although death not imminent 
 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead 
 
 
 


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14.2 
Appendix B:  MSKCC prognostic classification for mRCC patients who have been 
treated previously 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3 
Appendix C:  CYP3A4 and PGP inhibitors and inducers 
 


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14.4 
Appendix D:  US EQ-5D-5L 
 
 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 


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14.5 
Appendix E:  FACT-G 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 


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Patient ID: _________ 
Time Point:_________ 
Date:______________ 


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14.6 
Appendix F:  FKSI 
 
 
 
 
 
 
 
 
 
 
 
 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 


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14.7   Appendix G  – Patient Perspective Cost and Convenience  of Care Questionnaire 
 
We would like to ask you about your health coverage and the “out-of-pocket” costs you 
have had related to your cancer treatment. 
 
1. Do you have any coverage that helps pay for your medicines, when you are NOT in the 
hospital: (Check ALL that apply) 
  Yes by Government (e.g. ,Medicare Part D,Tricare, etc.) 
  Yes by private or employer-paid health insurance (supplemental) 
   No coverage 
   Don’t Know 
 
2. Do you have any coverage that helps pay for home or community care, when you are NOT in 
the hospital (i.e. nursing, physiotherapy, cleaning, etc.): (Check ALL that apply) 
   Yes by Government (Medicare, Medicaid, Tricare) 
   Yes by private or employer-paid health insurance 
   No coverage 
 Don’t Know 
 
 
If you do NOT have private or employer paid health insurance           Go to Question 4 
 
3. If you have Private/Employer-paid health insurance, please describe your coverage for each 
type of service:  (For each service, check the box that best describes your level of coverage.) 
 
 
 TYPE OF SERVICE 
Don’t 
Know 
Not  
Covered 
Partial 
Coverage 
Full 
Coverage 
Hospital supplemental charges (e.g. Private 
room, telephone, TV, etc.) 
 
 
 
 
Prescription drugs (e.g. Antibiotics, pain 
medication, etc.) 
 
 
 
 
In home healthcare (e.g. nursing, 
physiotherapist, etc.) 
 
 
 
 
Homemaking services (e.g. cleaning, cooking, 
etc.) 
 
 
 
 
Alternate Therapy (e.g. Homeopathy, Chinese 
medicine, over the counter drugs, etc.) 
 
 
 
 
Other (Specify)  ______________________ 
___________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Proceed to Question 4 
 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 


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4. Please supply the following details regarding your “out-of-pocket” costs for trips to and from 
your treatments and family doctor visits related to your cancer in the last 30 days. 
 
 
 
 
 
Type of Visit 
Number 
of trips 
in the 
last 30 
days 
Distance  ONE 
WAY  OR 
origin and 
destination 
points 
Method of 
transport 
(car, taxi, 
bus, train 
etc.) 
 
Parking or 
Fare 
 
Paid for by  
Insurance/ 
Government  
(circle one) 
Cancer Clinic/ 
Radiation 
Facility 
 
 
    Miles 
 
$ 
None – Partial - Full 
Hospital 
 
 
Miles 
 
$ 
None – Partial - Full 
Family Doctor 
 
 
Miles 
 
$ 
None – Partial - Full 
Other (Specify, 
i.e. 2nd Hospital 
or 2nd Doctor, 
ER) 
____________ 
 
 
Miles 
 
$ 
None – Partial - Full 
 
5. For questions listed below indicate if you had cancer related costs, paid by yourself, private 
insurance or government programs (e.g. Home Oxygen, Homecare, etc.) during the last 30 
days. If you do not know the exact amount make your best estimate, rounded to the nearest 
dollar.  
 
a) Copays 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by 
yourself 
  paid by private insurance 
  paid by government 
 
Amount (if known): 
 
 
 
$ ____________ 
 
N/A 
N/A 
 
b) Prescription Drugs 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by yourself 
  paid by private insurance 
  paid by government 
 mount (if known): 
 
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 


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c) In home healthcare (nursing, physical therapy, respiratory therapy, etc.) 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by yourself   paid by private insurance 
  paid by government 
 
Amount (if known):  
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
 
d) Homemaking (cleaning, cooking, etc.) 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by yourself 
  paid by private insurance 
  paid by government 
 
Amount (if known):  
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
 
e) Complementary and Alternative Therapy (homeopathy, massage, acupuncture,  
counseling, etc.) 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by yourself 
  paid by private insurance 
  paid by government 
 
Amount (if known):  
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
      f) 
Vitamins and Supplements including special diets 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by yourself 
  paid by private insurance 
  paid by government 
 
 Amount (if known): 
 
 
  $ ______________ 
 
$ _______________ 
$  _____________ 
 
g) Family Care (child or elder) 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by yourself 
  paid by private insurance   paid by government 
 
Amount (if known): 
 
 
 
  $ ______________ 
 
$ _______________ 
$  _____________ 
 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 


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h) Accommodation/Meals 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by yourself 
  paid by private insurance   paid by government 
 
 Amount (if known): 
 
 
 
  $ ______________ 
 
$ _______________ 
$  _____________ 
 
i) Devices or Equipment (home oxygen, wheelchair, walker, etc.) 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by yourself 
  paid by private insurance   paid by government 
 
 Amount (if known): 
 
 
 
  $ ______________ 
 
$ _______________ 
$  _____________ 
 
j) Other (telephone costs, pagers,  etc..) 
 
 
   No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
 
  paid by yourself 
  paid by private insurance 
  paid by government 
 
Amount (if known):  
 
 
 $ ____________ 
 
$ _______________ 
$  _____________ 
 
 
6. 
Would you say this last month  your “out-of-pocket” expenses related to your cancer       
were:  
 
   More than other months        Typical         Less than other months       Don’t Know 
 
We would like to ask you some questions about your healthcare visits related to this cancer 
as well as the impact these visits have had on your work. 
 
7. 
Since you finished radiation, have you had:  (Check all that apply) 
                 NOTE: We will ask you specific questions about these in a separate form. 
 
 Doctor visits 
 
 
 Emergency room visits 
 Overnight hospitalization – indicate duration 
  one      or ______ nights.  
 Home nursing services 
 Respiratory/ Physiotherapists/ Occupational Therapy services 
 Medication changes 
 Started oxygen treatment 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 


STU 122015-052 
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STU122015-052, Hannan, FormA-ResearchProtocol, Mod_32, 05-10-21 
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8. 
How much time over the last 30 days did you take off work to receive treatment   
related to your cancer 
 
   Unemployed           No time off work          ________ days        Don’t Know 
   Retired          
 
 
9. 
Was this time away from work: (Check ALL that apply) 
 
Not Applicable (not working)  Vacation   Time off with pay  Time off without pay 
 
 
10. 
Did friends or family take time away from work in the last 30 days related to your 
treatment 
 
         No time off work        
OR 
 
   _________ days 
 
 
We would now like to ask you a little bit about you, your work and your education: 
 
11. 
Year of Birth   _________ 
 
12. 
Sex: 
 
 Male    
       Female 
 
13. 
Marital Status: 
 
   Married 
 
 Common Law 
 
   Single (never married) 
 
  Widowed 
 
 Separated  
 
  Divorced 
 
14. 
How many other people do you share your home with (do not include people who are 
only visiting): 
 
 Live alone ( Go to Question 16) 
 
 
 
  Myself and one other   
 
 2 others  
 
 
  3 others 
 
 
  More than 3 others 
 
15. 
Are these people you share your home with: 
 
  Family    
  Friends      Both Family and Friends  
 
16. 
City or Town where you live _____________________________ 
 
17.  
How would you rate your current health? 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 


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  Excellent 
  Very good 
 
   Good 
 
   Fair    Poor 
 
 
18. 
What do you do for a living: 
 
  Full time work : Specify ______________    Part time work: Specify ____________ 
  Retired  
 
  Homemaker 
 Unemployed 
 Student 
 
19. 
What is the highest level of schooling you have completed? 
 
 
  No schooling, some elementary school, or completed elementary school 
 
  Some high school 
 
  Completed high school 
 
  Some university or community college 
 
  Completed university or community college 
  Post Graduate (MSc/MBA/PhD) or professional training (MD/LLB/DDS) 
 
 
20. 
What was your total family income before taxes in the last year. 
 
(include wages, salaries and self-employment earnings) 
 
Less than $5,000 
$5,000- $9,999 
$10,000- $14,999 
$15,000- $19,999 
$20,000-$29,999 
$30,000-$39,999 
$40,000-$49,999 
$50,000-$59,999 
$60,000-$79,999 
More than $80,000 
Don’t Know 
 
21. 
How much of a financial burden are these out-of-pocket expenses listed in Q 4 & 5: 
    
Not a burden at all 
Only a slight burden 
Somewhat of a burden 
Significant burden, but manageable 
Unmanageable burden 
 
 
24. What treatments or services that are not currently available would you like to see paid for 
through government or private insurance: 
____________________________________________________________________________________________________________
________________________________________________ 
Patient ID: _________ 
Time Point:_________ 
Date:______________ 


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25. Was this questionnaire completed by: 
 
 The patient 
 
 
 A caregiver  
 
  Both the patient and a 
caregiver  
 
 
We would like to learn more about your personal reactions to the treatment and the 
impact it had on your typical activities: 
 
26. To what extent has your treatment disrupted your normal daily activities? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
27. To what extent has your treatment disrupted your normal recreation activities? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
28. To what extent has your treatment disrupted your normal activities with your family and 
friends? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
29. To what extent has your treatment disrupted your sleep pattern? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
30. To what extent has your treatment disrupted your enjoyment of life? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
31. How satisfied are you with the length of time your treatment has taken to this point of time? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
32. How disruptive has your treatment been to the other important people in your life (example: 
family, spouse, close friends, coworkers)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Additional Comments 
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
___________________________________________________________________________________-
____________________________ 
 
 
Thank you for helping us with our survey.  If you have 
completed all sections please place the survey in the 
envelope, seal it, and return it to the attending clinic staff 
 
Patient ID: _________ 
Time Point:_________ 
Date:______________