Clinical trial NCT01896271
Conditions: Metastatic Clear Cell Renal Cell Carcinoma
Keywords: kidney cancer metastatic cancer
Sponsor: University of Texas Southwestern Medical Center
Start date: 2013-10-02; Completion date: 2021-04-20
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this i-SABR (immunotherapy + Stereotactic Ablative Body Radiation) trial, the stereotactic radiation to multiple metastatic sites is delivered not only to eradicate sites of bulky progressive disease, but also to provide antigen presentation and immune stimulation which is expected to act synergistically when immediately followed by the non-specific immune stimulation provided by treatment with HD IL-2 and thereby increase the response rate and complete response for metastatic clear cell renal cell cancer patients. Both HD IL-2 and SABR are FDA approved therapeutic cancer treatment

Detailed description:

Arms: arm 1: HD IL-2 (brand name Proleukin), 600,000 U/kg q8h X 14 dose, IV infusion; SABR dose varying from 8Gy-20Gy in 1-3 fractions.
Interventions: intervention 1: IL-2 intervention 2: Stereotactic Ablative Body Radiation Therapy
Intervention descriptions: intervention 1: HD IL-2 (brand name Proleukin), 600,000 U/kg q8h X 14 dose, IV infusion intervention 2: SABR dose varying from 8Gy-20Gy in 1-3 fractions

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official title: A Phase II Trial of High Dose IL-2 and Stereotactic Ablative Body 
Radiation Therapy (SABR) for Patients with Metastatic Clear Cell Renal Cell 
Cancer (mRCC) 
NCT number: NCT01896271 
Document date: May 20, 2019 
Version 11 
 
 
      
      
      


 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19                     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. 
 
PROTOCOL NUMBER-- STU 012013-041 
A Phase II Trial of High Dose IL-2 and Stereotactic Ablative Body Radiation Therapy 
(SABR) for Patients with Metastatic Clear Cell Renal Cell Cancer (mRCC)  
 
Principal Investigator:  
Raquibul Hannan, MD, PhD 
 
 
 
 
University of Texas Southwestern 
 
 
 
 
5801 Forest Park 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 
 
 
 
 
 
Neil Desai, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
Aurelie Garant, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
 
 
 
 
Kevin Courtney, MD 
 
 
 
 
Department of Medical OncologyArthur Sagalowsky, MD 
 
 
 
 
Department of Urology 
 
 
 
 
 
Vitaly Margulis, MD 
 
 
 
 
Department of Urology 
 
 
 
 
 
 
 
 
 
 
 
Alberto Diaz de Leon, MD 
 
 
 
 
Department of Radiology 
 
 
 
 
 
Ivan Pedrosa, MD 
 
 
 
 
Department of Radiology 
 
 
 
 
 
Payal Kapur, MD 
 
 
 
 
Department of Pathology 
 
 
 
 
 
Lori Watumull, MD 
 
 
 
 
Department of Radiology 
 
 
 
 
 
David Scott, MD 
 
 
 
 
Department of Radiology 
 
 
 
 
 
Waddah Arafat, MD 
 
 
 
 
Department of Medical Oncology 
 
 
Biostatistician: 
 
Chul Ahn PhD 
 
 
 
 
Department of Clinical Sciences 
5323 Harry Hines Blvd 


 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19                     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. 
 
Dallas, TX 75390-9066 
  
 
 
 
(214) 648-9418 
Chul.ahn@utsouthwestern.edu 
 
 
Study Drug/Intervention: 
Stereotactic Ablative Body Radiation (SABR) 
 
 
Funding Source:  
Department of Radiation Oncology at UTSW 
 
 
Protocol Version: 
 
 
 
 
 
 
 
Version 
Date 
Initial 
02/08/2013 
Version 2 
07/26/2013 
Version 3 
10/02/2013 
Version 4 
11/11/2013 
Version 5 
06/16/2014 
Version 6 
10/02/2014 
Version 7 
03/18/2015 
Version 8 
04/13/2016 
Version 9 
02/14/2017 
Version 10  
9/14/18 
Version 11 
5/3/19 
 
 
UT Southwestern Medical Center at Dallas 
Department of Radiation Oncology 
Attn: Clinical Research Office 
5801 Forest Park Road 
Dallas, Texas 75390-9183 
 


 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19                     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 
 
 
 
 
 
      Version 11 
 
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:____________________ 
 
 
 
 
 


Study Number – STU 012013-041 
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i 
TABLE OF CONTENTSLIST OF ABBREVIATIONS ...................................................................... 1 
STUDY SCHEMA ............................................................................................................................. 3 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 5 
1.1 
Disease Background........................................................................................................ 5 
1.2 
Stereotactic Ablative Body Radiation (SABR) ................................................................. 5 
1.3 
HD IL-2 ............................................................................................................................ 6 
1.4 
Rationale .......................................................................................................................... 6 
1.5 
Correlative Studies .......................................................................................................... 9 
1.6 
Health-related Quality of Life (HRQOL) and Economic Analysis .................................. 10 
2.0 
STUDY OBJECTIVES .................................................................................................... 12 
2.1 
Primary Objectives ......................................................................................................... 12 
2.2 
Secondary Objectives .................................................................................................... 12 
2.3 
Exploratory Objectives ................................................................................................... 13 
2.4 
Endpoints ....................................................................................................................... 13 
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 
HD IL-2 .......................................................................................................................... 21 
4.3 
Duration of Therapy ....................................................................................................... 22 
4.4 
Duration of Follow Up .................................................................................................... 23 
4.5 
Removal of Subjects from Protocol Therapy ................................................................. 23 
5.0 
STUDY PROCEDURES ................................................................................................. 23 
5.1 
Screening/Baseline Procedures .................................................................................... 23 


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5.2 
Procedures During Treatment ....................................................................................... 25 
5.3 
Follow-up Procedures .................................................................................................... 26 
5.4 
Time and Events Table .................................................................................................. 27 
5.5 
Removal of Subjects from Study ................................................................................... 28 
6.0 
Measurement of Effect ................................................................................................. 28 
6.1 
Antitumor Effect ............................................................................................................. 28 
6.2 
Safety/tolerability ........................................................................................................... 32 
6.3 
Quality of Life (QoL)....................................................................................................... 32 
6.4 
Cost effectiveness data collection: ................................................................................ 33 
7.0 
ADVERSE EVENTS ....................................................................................................... 34 
7.1 
SABR ............................................................................................................................. 34 
7.2 
HD IL-2 .......................................................................................................................... 34 
7.3 
Adverse Event Monitoring ............................................................................................. 38 
7.4 
Definitions ...................................................................................................................... 39 
7.5 
Reporting Requirements for Serious Adverse Events ..... Error! Bookmark not defined. 
7.6 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 43 
7.7 
Reporting Requirements for Adverse Events ................................................................ 45 
7.8 
Stopping Rules .............................................................................................................. 46 
8.0 
DRUG INFORMATION ................................................................................................... 46 
8.1 
HD IL-2 .......................................................................................................................... 46 
9.0 
CORRELATIVES/SPECIAL STUDIES .......................................................................... 47 
9.1 
Sample Collection Guidelines ........................................................................................ 47 
9.2 
Assay Methodology ....................................................................................................... 49 
9.3 
Specimen Banking ......................................................................................................... 51 
10.0 
QUALITY OF LIFE AND COST-EFFECTIVENESS ...................................................... 51 
10.1 
Health-Related Quality of Life (HRQOL) Analysis ......................................................... 51 


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10.2 
Cost-Effectiveness Analysis (CEA) ............................................................................... 52 
10.3 
Quality adjusted survival time: ....................................................................................... 53 
11.0 
STATISTICAL CONSIDERATIONS ............................................................................... 53 
11.1 
Study Design/Study Endpoints ...................................................................................... 53 
11.2 
Sample Size and Accrual .............................................................................................. 53 
11.3 
Data Analyses Plans...................................................................................................... 54 
12.0 
STUDY MANAGEMENT ................................................................................................ 54 
12.1 
Conflict of Interest .......................................................................................................... 54 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 54 
12.3 
Required Documentation (for multi-site studies) ........................................................... 54 
12.4 
Registration Procedures ................................................................................................ 55 
12.5 
Data Management and Monitoring/Auditing .................................................................. 55 
12.6 
Adherence to the Protocol ............................................................................................. 56 
12.7 
Amendments to the Protocol ......................................................................................... 56 
12.8 
Record Retention ........................................................................................................... 57 
12.9 
Obligations of Investigators ........................................................................................... 57 
13.0 
REFERENCES ............................................................................................................... 57 
14.0 
APPENDICES ................................................................................................................ 65 
14.1 
Appendix A: ECOG Performance Status ....................................................................... 65 
14.2 
Appendix B:  High Dose Interleukin-2 Bolus Administration Algorithm ......................... 66 
14.3 
Appendix C:  High Dose Interleukin-2 Bolus Administration Physician Orders ............. 68 
14.4 
Appendix D:  US EQ-5D-3L ........................................................................................... 71 
14.5 
Appendix E:  FACT-G .................................................................................................... 74 
14.6 
Appendix F:  FKSI .......................................................................................................... 76 


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LIST OF ABBREVIATIONS 
 
ADT 
Androgen depravation therapy 
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. 
peros/by mouth/orally 
PR 
Partial Response 
PRN 
“Pro re nata” or as needed 
QL 
Quality of Life 
RR 
Response Rate 
RT 
Room Temperature 
SABR 
Steriotactic Ablative Body Radiation 
SAE 
Serious Adverse Event 
SBRT 
Steriotactic Body Radiation Therapy 
SD 
Stable Disease 


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SPH 
St. Paul Hospital 
VAS 
Visual Acuity Score 
WBC 
White Blood Cells 
 
 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SABR to metastasis 
Eligibility:  
 Metastatic clear cell RCC 
 Eligible for IL-2 
 Eligible for SABR to 1-6 lesions  
 ECOG 0-1 
 Primary End Point: RR 
o CR  
o PR 
 Repeat IL-2 treatment if any response  
 Whole blood collection for 
baseline immunologic assays 
 CT-guided Biopsy 
 Baseline Imaging 
 Whole blood collection 
immunologic assays 
IL-2 600,000 IU/kg every 8 hours for 
up to 14 doses then rest for 9 days (1 
cycle 14 days; total 2 cycles) 
(Starting within 84 hours of SABR) 
 Whole blood collection and 
repeat Imaging Q2-3 months 
 2nd research biopsy at 2 
months (optional). 


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STUDY SUMMARY 
Title 
A Phase II Trial of High Dose IL-2 and Stereotactic Ablative Body 
Radiation Therapy (SABR) for Patients with Metastatic Clear Cell Renal 
Cell Cancer (mRCC) 
Short Title 
HD IL-2 and SABR for metastatic RCC 
Protocol Number 
 
STU 012013-041 
Phase 
Phase 2 
Methodology 
Single Arm, open label. 
Study Duration 
Six years (two years for enrollment and 4 years for follow-up). 
Study Center(s) 
Single-center  
Objectives 
To evaluate the improvement in response rate (RR) and complete 
response (CR) of mRCC after treatment with SABR and HD IL-2 
Number of Subjects 
Average 33; maximum 38 
Diagnosis and Main 
Inclusion Criteria 
Metastatic Clear Cell Renal Cell Carcinoma 
Study Product(s), Dose, 
Route, Regimen 
HD  IL-2 (brand name Proleukin), 600,000 U/kg q8h X 14 dose, IV 
infusion; SABR dose varying from 8Gy-20Gy in 1-3 fractions.   
Duration of administration 
HD IL-2: 1 weeks/cycle; maximum of 2 cycles/course over three weeks; 
Maximum of three courses. SABR: 1-3 fractions over one week.  
Reference therapy 
HD IL-2 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
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. Although HD IL-2 remains a first-line therapy for clear cell mRCC 
patients, only a small minority of patients exhibits complete response (CR). 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” [1] . 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 [2-4].   
Previous studies have demonstrated multiple immunogenic properties of radiation 
therapy (RT), especially when given at high doses such as with SABR [5, 6].  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 [7].  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 tolarogenic [8].  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 [9-11]. 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 [12]. 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 [12, 
13]. Furthermore, RT causes a dose-dependent increase in MHC I tumor neo-antigen 
presentation by the tumor cells [14]. 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 [15, 16].  
 
There is also evidence from both pre-clinical and clinical studies that RT, specifically at 
ablative doses typical of SABR, initiates and augments an immune response and can synergize 


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with immunotherapy [13, 17-20]. 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 
complete response of tumor regression at metastatic sites [21-23] including that in mRCC [24]. In 
vivo animal studies have demonstrated that this abscopal effect of RT is immune-mediated [25]. 
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 in metastatic melanoma patient [23]. 
1.3 
HD IL-2 
IL-2 is a cytokine that is a potent growth factor for T cells. It exerts its activity by binding 
to the IL-2 receptor (IL-2R) present on the cell surface of T cells and leads to its 
autophosphorylation via JAK/STAT5-dependent pathways, eventually leading to activation and 
proliferation of the T cells [26]. Although the exact mechanism by which HD IL-2 results in the 
durable CR is not known, the discovery that recombinant IL-2 can have potent anti-tumor activity 
has been shown in murine models as early as 1980s [27].  The stimulatory effects of IL-2 have 
been demonstrated in multiple steps along the pathways required for a successful generation of 
adaptive and CTL-mediated anti-tumor response. For example, IL-2 is produced by the antigen-
presenting cells (APCs) after they have phagocytosed dying tumor cells (or pathogens), 
presented their antigen in MHC class II and have bound to their corresponding T cell receptor 
(TCR) in the surface of CD4+ T cells [28]. In this setting, IL-2 is considered the third essential 
signal that is necessary for clonal expansion and effector function of T cells, the first being TCR 
recognition of antigen in MHC  and the second being binding of costimulatory molecule CD 28 to 
B7 [26, 28]. Similarly, CD8+ CTL function is also critically dependent on IL-2 as shown by the 
experiments that their effector or cytotoxic function is limited in IL-2 or IL-2R-deficient mice [29-
31].  IL-2 is postulated to increase trafficking of CTL to the extralymphatic sites of infection or 
tumor [26, 32]. IL-2 induces Th1 differentiation of CD4 T helper cells which leads to activation of 
macrophages. Th1 cells also activate antibody production by activating B cells. IL-2 is produced 
by Th1 cells in response to activation by DC that results in CD8 activation and proliferation [28]. A 
distinct mechanism of antitumor activity of IL-2 may be mediated by activation of natural killer 
(NK) cells [33].    
 
While the exact mechanism of anti-tumor activity of HD IL-2 is unclear, seven phase II 
and multiple phase III trials have clinically proven the efficacy of IL-2 in inducing durable CR and 
PR in clear cell RCC patients. In contrast, molecularly targeted therapies fail to induce CR and do 
not cure patients. The reported RR for treatment with HD IL-2 (600,000-800,000 IU/kg q8h x 14 
as tolerated) in multiple phase III trials ranges from 20% to 23.2% and the CR ranges from 7%-
9% [34-36]. Among the patients who achieve CR, >80% remained disease free at last follow-up 
with a median survival over 10 years [34, 37, 38] suggesting a durable response or a cure of 
mRCC.  Alternate schedules and decreased doses of IL-2 have been tried without any 
improvement in outcome [35, 36, 39]. Predictive immunologic markers would enormously aide 
clinicians in selecting patients who will respond to HD IL-2. 
 
There is significant toxicity of HD IL-2 affecting multiple organ systems that requires ICU 
admission for the duration of administration. These side effects include hypotension, cardiac 
arrhythmias, metabolic acidosis, fever, nausea and vomiting, dyspnea, edema, oliguria and renal 
failure, neurotoxicity, and dermatologic complications including a mortality of up to 1.  Alternate 
schedules and decreased doses of IL-2 have been tried without any improvement in outcome [35, 
36, 39].  Predictive immunologic markers would enormously aide clinicians in selecting patients 
who will respond to HD IL-2 and spare the toxicity to those who will not. 
 
1.4 
Rationale 
The combination of HD IL-2 immunotherapy and SABR for the treatment of mRCC can be 
explained by both immunological and clinical rationales. 


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1.4.1 
Immunologic Rationale 
There are multiple immunologic steps where SABR is expected to augment the immune 
response generated by IL-2 and vice versa. As discussed above, IL-2 stimulates T cell-mediated 
immune response in a non-specific manner. It is expected that SABR, inducing immunogenic 
tumor cell death, will be able to provide a specific direction to the immune response by initiating 
antigen presentation. Recruited and activated by the DAMPs and other changes brought on to the 
tumor micro-environment by radiation therapy, the APCs migrate to the lymph node for antigen 
presentation and T-cell activation. This is one of the first steps that will be augmented by the 
administration of IL-2 since the presence of IL-2 is critical for the successful activation of T cells 
by DCs [26, 28]. It is estimated that this step will take 2-3 days, which is why IL-2 treatment will 
be initiated within 2-3.5 days of SABR.  
RT also increases TIL trafficking within irradiate tumors [12, 20].  IL-2 increases tumor 
vascularization, thereby decreasing hypoxia within tumors and making them more radiosensitive 
[40]. The radiosensitizing effect of IL-2 gene expression within tumors has also been objectively 
demonstrated in vivo [41]. The effect of increased vascularization by IL-2 also is expected to 
increase TIL and APC infiltration within all tumor sites. IL-2-mediated increase in CTL trafficking 
to the tumor sites, as described above, will work synergistically with this step in increasing TIL in 
both irradiated and non-irradiated sites of tumor. 
The combination of RT and cytokine therapy with macrophage inflammatory protein-1α 
has been shown to induce strong abscopal effect regardless of tumor type [42]. In fact, the 
combination of IL-2 and RT has also been explored in animal models and has shown improved 
local control of irradiated tumor and regression of non-irradiated tumors within the same mouse 
[43, 44].  
NK cells are part of the immune system’s innate defense against cancer and were first 
discovered because of their anti-tumor activity [45]. In fact, ex vivo expansion and re-infusion of 
autologous NK cells has shown to induce long-term remission in cancer patients [46]. Specific 
destruction of cancer stem cells has been demonstrated by NK cells [47]. 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 [20, 48]. 
Interestingly, NK cells contain IL-2 receptors and are activated by IL-2 treatment [26], thereby 
suggesting another possible synergistic interaction of IL-2 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 [49].  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 [50, 51].  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 [52, 53]. The cancer 
immunesurveillance hypothesis states that a tumor is only able to survive and grow large when it 
has successfully evaded the immune system [54].  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. 
1.4.1 
Clinical Rationale 
As applied in concert with IL-2 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 prior to the outset of IL-2 treatment, in addition 
to maintaining the burden of death below the lethal threshold, 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 


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tumor vaccination by initiating antigen presentation and immunocyte infiltration, thereby 
acting synergistically with IL-2 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 disease sites that are below the resolution limit of radiographic imaging. 
Systemic therapies like cytokine therapy or newly emerging targeted therapies are often 
effective towards micrometastatic disease but less so to the bulky sites of metastasis which 
requires multimodality treatment. Therefore systemic therapies can result in response, but 
ultimately the tumors progress, resulting in declining quality of life and death from cancer.   
Historically, the use of local therapies such as surgical metastectomy 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 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 [55-57]. There is growing 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 [2, 58-
60]. 
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 eradication of the bulky 
progressive sites and simultaneously synergizes with the concurrent systemic treatment of 
immunotherapy to eliminate the micrometastatic disease is expected to improve outcome 
dramatically by increasing the PRs into CRs and non-responders into PRs. 
Therefore, we propose a single-arm, open-label, phase II trial of HD IL-2 and SABR 
to multiple sites of bulky disease. The toxicities of HD IL-2 are significant and well known. 
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 [2-4]. In fact, a phase I trial of HD IL-2 and SBRT in melanoma and 
RCC patients has proven the safety and feasibility of this regimen [61]. This small study 
showed a CT evidence of PR in 3 out of 5 (60%) and a PET CR in 1 out of 5 (20%) mRCC 
patients treated with HD IL-2 immediately after SBRT. Given the short duration of their 
median follow up (480 days) it remains to be seen how many mRCC patients remain disease 
free in the long run.   
 
The primary endpoint of this study is to measure improvement in response rate (RR) 
and compare it to the historically reported data. As reported in three randomized trials, the 
RR for HD IL-2 in mRCC is 20%-23% (see below).  A significant improvement on the 
historically reported RR would justify seeking a phase III trial to show the efficacy of this 
regimen in improving overall survival. The secondary objectives of this trial will measure 
progression-free survival (PFS), overall survival (OS), time to progression (TTP), duration of 
treatment response and tumor-specific immune response, each of which also has the 
potential to be used as justification for a phase III trial. In addition, the exploratory objectives 
will include correlation of the immune response to clinical outcome, exploration of 
immunologic biomarkers to predict response, improvement in health-related quality of life 
(HR-QoL) and cost effectiveness analysis. Given the high cost of HD IL-2, requiring multiple 
ICU admissions for patients, it will be worthwhile to explore the cost effectiveness of adding 
SABR in improving the outcome of HD IL-2 treatment alone and perhaps in decreasing the 
number of treatments required to achieve the same or improved RR, and then analyzing the 
improvement in HR-QoL, the quality-adjusted survival and cost effectiveness of this regimen. 


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1.5 
Correlative Studies 
The correlative studies will explore the mechanisms of possible immune enhancement by SABR. 
Activation of each arm 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 antibodies generated by SABR and HD IL-2 against tumor tissue collected from the 
respective patients and established human renal cancer cell line 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 [28]. On the other hand, lymphocyte-mediated cytotoxicity assay will 
measure the formation of tumor-specific CTLs among the lymphocytes collected from patients 
with the controls being lymphocytes collected from the same patients before SABR and before 
HD IL-2. Since it is not practical or feasible to obtain sufficient quantities of tumor cells from each 
patients to assess a quantitative cytotoxicity by these assays, established allogenic human 
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 [28]. 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 [62, 63]. 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 [64-68].   
 
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 humeral immune 
response [69, 70]. 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 
[28, 70].  An increase in IL-17 may suggest activation of autoimmune responses [71]. Therefore, 
measurements of serum cytokine levels have generally been used previously in clinical trials as 
surrogates to assess specific activation of immune pathways [72, 73].  Serum cytokines from this 
clinical trial before and after SABR will be measured using an extensive array of cytokines to 
explore the specific immune pathways that are initiated by SABR. The planned array of cytokines 
will measure levels of the following cytokines 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, 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 
[74-77]. These markers are easily measured with antibodies specific for the markers that are 
tagged with a fluorophore utilizing FACS analysis. Also using FACS, activation markers on other 
immune cells such as CD80 and CD 86 on DCs, and inhibitory markers on monocytes such as 
PD-1 can be measured as surrogates of immune activation or inhibition.  These measurements 
from PBMCs collected from patients before and after treatment will give us further information 


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regarding the intensity of the immune response.  Additionally, PD-L1, the ligand of PD-1, often 
expressed in tumor cells, can be quantified from patient pre-treatment tumor biopsy.  
 
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 [61]. 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 
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.  
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[78].  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[79]. 
 


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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[79].  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, 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[80]. 
 
There was no quality-of-life data reported in the French trial evaluating IL-2, INF-alpha, or both [39].    
However, in an abstract evaluating the QoL of patients taking different regimens of IL-2 there was 
no difference found.  [81] In a phase 3 study evaluating high-dose IL-2 versus subcutaneous IL-2 
and INF-alpha in patients with mRCC, the authors comment that there was no difference in quality 
of life assessments for patients treated with high-dose arm,  no specific measures, utilities, or 
values were published [35].   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 [82],[83].    In a review article regarding quality-of-life measures recent renal cell 
cancer protocols by Cella at 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 [84].  Two 
recent trials evaluating health-related quality of life for sorafenib utilizing the FACT-FKSI, FACT-G, 
and EQ-5D indicated that Strachan of treatment resulted in improvements in individual items related 
to registry function and quality of life compared with placebo [85].  Additionally, European trials 
evaluating temsirolimus in a phase 3 setting versus INF-alpha or both, showed quality adjusted 
survival favoring patient who received temsirolimus [86]. 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. [87] Additionally,there are 
ongoing studies evaluating 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 INFA-alpha and IL-2 from a US societal perspective [88].  
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, showed thatsunitinib was cost 
effective when the willingness to pay threshold was over $16,000 which would be appropriate for 
several developed regions within China [89].   Given the rising costs associated with the biologic 
and targeted therapies for metastatic renal cell carcinoma the cost implications of of this protocol 
warrant study.  
 
 
Therefore, we propose to evaluate patients’ health related quality of life (HR-QoL) and health state 
utilities in order to evaluate the economical consequence of using the two treatments proposed in 
this study and their 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 HD-IL2, we further 
hypothesize that the addition of SBRT will increase the durability of response or lengthen the time 


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to progression thus increasing the cost effectiveness of the combined therapies.  Thus, we 
hypothesize that the added treatment of SBRT while adding modestly to the total cost of the 
combined therapies may be cost saving over the patient’s entire treatment course compared to HD-
IL2 alone, making the combination a very attractive treatment for mRCC patients.  Additionally, we 
hypothesize that combination of SBRT and HD-IL2 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 
2.1 
Primary Objectives 
2.1.1 
To evaluate the response rate (RR) in patients with mRCC after treatment with 
HD IL-2 immediately following SABR to multiple metastatic sites.  RR has been 
highly correlated (p<0.0001) to overall survival [34].  RECIST 1.1 criteria will be 
used to measure RR and it will consist of complete response (CR) and partial 
response (PR). 
2.2 
Secondary Objectives 
2.2.1 
To evaluate the overall survival (OS), which is defined as the time between date 
of registration and the date of death due to any cause. In analyzing the OS, it is 
important to take into account the MSKCC prognostic criteria defined by Motzer 
et. al. mRCC patients and compare the outcome in the appropriate risk 
categories [90].  
2.2.2 
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. 
2.2.3 
To evaluate time to progression (TTP), which is defined as time between date of 
registration and date of documented progression. 
2.2.4 
To evaluate the local control rate of irradiated lesions. 
2.2.5 
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. 
2.2.6 
To measure treatment-related tumor-specific immune response. 
2.2.7 
To evaluate the tolerability and toxicity of this regiment as measured according to 
CTCAE v4.0. 
2.2.8 
To measure the improvement in health-related quality of life (HRQoL). 
 


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2.3 
Exploratory Objectives 
2.3.1 
To explore the immunological biomarkers as correlates or predictors for 
treatment response.  
2.3.2 
To evaluate the cost-effectiveness analysis of this treatment regimen to the other 
current first and second line treatments for mRCC.  
 
2.4 
Endpoints 
2.4.1 
Response: Treatment response will be measured using the immune related 
RECIST criteria (iRECIST) which are a minor modification of RECIST 1.1 for 
immunotherapy [91].  
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 iRECIST 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 
2.4.6 
HRQoL: HRQoL will be measured using FACT-G, EQ-5D and FKSI 
questionnaire at baseline, after HD IL-2, and at four-month intervals after 
treatment. 
2.4.7 
Cost-effectiveness analysis: Health care utilization data needed to assess 
costs will be obtained from treatment records to include costs of hospitalization, 
treatment, ER visits, physician and clinic visits and medications. 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 
Pathologic evidence of clear cell RCC 
 
3.1.2 
Radiographic evidence of metastatic disease. CT and Bone Scan must be 
performed with 21 days (+ 7 days) of registration. MRI of brain can be performed 
within 6 months prior to registration. 
 
 
 
3.1.2.1  Patients with any number of metastatic site are allowed to enroll. However, 
only up to six sites will be selected for SBRT treatment, at the discretion of the 
treating radiation oncologist. 


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3.1.3 
Patient must have >1 lesion. Combined diameter of the lesions must be of size 
>1.5cm.  
 
3.1.4 
Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any 
targeted agents are allowed provided that:  
 
    3.1.4.1  Chemotherapy was administered > 28 days before the start of HD IL-2 
    3.1.4.2  Surgery, radiation, immunotherapy or any targeted agents was 
administered > 14 days before the start of HD IL-2 
 
3.1.5 
Age ≥ 18 years. 
 
3.1.6 
Performance status ECOG 0, 1.  
 
3.1.7 
Patient must be eligible for HD IL-2 treatment 
 
3.1.8 
Patient must be eligible for SABR to one or more extra cranial sites.  
 
3.1.9 
Adequate organ and marrow function as defined below: 
- leukocytes 
 
≥ 3,000/mcL 
- absolute neutrophil count ≥ 1,500/mcL 
- platelets  
 
≥ 50,000/mcl 
- total bilirubin 
 
≤ 2mg/dL  
- AST(SGOT)/ALT(SPGT) ≤ 2.5 X institutional upper limit of normal 
 
 
3.1.10 Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
 
3.1.10.1 
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). 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
 
3.1.12 Adequate Renal function with Cr ≤ 1.6 mg/dL. 
 
3.1.13 Adequate cardiac function (adequate perfusion; no ischemia) on thallium (or Tc) 
stress test 
 
3.1.14 Adequate pulmonary function on PFT (FEV1 >65%; DLCO>60%).  
 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Subjects who have had chemotherapy within 4 weeks prior to entering the study  


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3.2.2 
History of HIV, Hepatitis B, Hepatitis C and HTLV 
 
3.2.3 
Subjects receiving any other investigational or standard antineoplastic agents. 
 
3.2.4 
Subjects with brain metastases are excluded from this clinical trial unless all the 
metastases are adequately treated with surgery or radiation. 
 
 
Follow-up imaging showing treatment adequacy is not required. 
 
3.2.5 
Subjects with life expectancy < 6 months.  
 
3.2.6 
History of allergic reactions to recombinant IL-2 
 
3.2.7 
Uncontrolled recurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia,. 
 
3.2.8 
Psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.9 
Subjects who are pregnant or nursing due to the potential for congenital 
abnormalities and the potential of this regimen to harm nursing infants. 
 
3.2.10 Systemic or topical steroid use or other immunosuppressive therapy  within the 
past 14 days 
 
3.2.11 Subjects required to take corticosteroids or other immunosuppressive therapy 
such as those with organ allograft 
 
4.0 
TREATMENT PLAN 
4.1 
SABR Dose and Techniques 
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 within 24-48 hours after tumor irradiation [7, 
12, 13, 92] and 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.  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 [12, 14, 92, 93]. Two studies 
have compared 15Gy x 1 with 5Gy x3, and 20Gy x1 with 5Gy x4 and have showed a superior 
immune response generated by the single fraction radiation [12, 92]. 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 [94]. A dose of less than 
7.5 Gy per fraction has demonstrated lower induction of systemic IFN-γ producing cells [93], and 
a previous phase II study of mRCC patients treated with HD IL-2 and singe fraction of 8Gy 


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irradiation to a single lesion did now show an overall improvement in response rate [95]. 
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 >6 sites of disease are present. Maximum 
number of lesions treated is deemed as feasible per the treating radiation oncologist.  Physician’s 
will be REQUIRED to leave at least one site of disease for the purpose of measuring a 
radiographic response (see section 6.1) 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 SBRT (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 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 2cm3 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 [96]) 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: 
 
Prescription Dose 
 
Total Cumulative Dose Encompassing 95% of Planning 
Target Volume (Gy) 
Number of 
Fractions 
Protocol Compliant 
Minor Deviation * 
MinorDeviation 
1 
21-27 Gy 
≥16 Gy, <21 Gy 
>27 Gy, <16 Gy 
3 
26.5-33 Gy 
≥24.0 Gy, <26.5 Gy 
>33 Gy, <24.0 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 SBRT 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.  
 


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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 [97]. However, in this protocol the goal is not just to relieve pain 
within an osseous metastasis but also to dramatically debulk the cancer cells present and induce 
in immune response, and the higher dose is more likely to accomplish this goal given a higher 
biological potency [98]. Long term survival after bone metastasectomy has been reported [99].  
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 
SBRT Treatment Technique 
 
SBRT will be administered the week prior to starting the first cycle of HD IL-2 with the last fraction 
given < 84 hours prior to the start of the first cycle of HD IL-2. 
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. The bone lesions can be treated with a conformal 3D or IMRT 
technique, which is different than SBRT/SABR technique. The difference lies primarily in 
dosimetric planning but otherwise all the descriptions of SBRT in terms of set-up, contouring and 
tissue constraints that needs to be met remains the same. 
At the time of simulation for patients who will receive SBRT 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 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 immobilized in a vacuum-type or equivalent body mold, a planning CT scan with 
3-5 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.  
For treatment to the liver, the following structures are contoured: entire liver, each individual liver 
gross tumor volume (GTV), each kidney, and the spinal cord. 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 craniocaudal plane. Larger margins may be used in cases where 
greater motion of the hemidiaphragm is observed in simulation despite standard maneuvers to 
diminish motion.  For lung SBRT 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, 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.  


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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 the prior Phase I studies [100], certain normal tissue dose constraints must be 
respected.  
 
The possibility that SBRT-induced fibrosis might cause occlusion of large central airways, thus 
impeding ventilation distal to the occlusion has been well considered [101]. 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 prostate 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 SBRT to a site 
previously irradiated with conventional fractionation within two years is not recommended. Re-
irradiation to a site that has received previous SBRT 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 
(Gy)** 
Endpoint (≥Grade 
3) 
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 


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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 
<10% of 
subvolume 
18 Gy 
22.5 Gy 
myelitis 


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mm above and 
below level 
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 


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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 an RT Quality Assurance Review after complete data 
for the first 12 cases enrolled has been received at the University of Texas Southwestern. Dr.  
Timmerman will perform the final review after complete data for the subsequent 12 cases enrolled 
has been received 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. 
4.2 
HD IL-2 
The standard and current guidelines for HD IL-2 administration developed based on Schwartzentruber 
[102], which has been proven to be safe at UTSW over the past years will be used for this protocol at the 
physician’s discretion.  HD IL-2 treatment will begin within 84 hours of the last SABR fraction according to 
the established UTSW HD IL-2 bolus administration algorithm (Appendix B and C) and the standard 
procedure for admissions for HD IL-2 will be followed.   
 
4.2.1 
Treatment Dosage and Administration 
HD IL-2 will be administered at a dose of 600,000 IU/kg every 8h for a total of up to 14 doses (considered 
as one cycle), followed by a one week break and then another cycle of the same dose over another week.  
Each HD IL2 course consists of two cycles of up to 14 doses each separated by a week of rest.  A total of 
three courses may be administered for patients without progression at the discretion of the medical 
oncologist.  Patients will be admitted to the ICU of the corresponding hospital for IL-2 treatment and close 
monitoring according to the HD IL-2 algorithm (appendix B).  Patients will undergo placement of a central 
venous catheter, typically a PICC line, before each course of therapy.   
 
 
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. Dose adjustments should be made according to 
the system showing the greatest degree of toxicity.  
 
Treatment with HD IL-2 will be modified by withholding doses of IL-2 rather than 
continuing therapy at a reduced dose, according to the current guidelines followed at 
UTSW.  Doses of IL-2 will be withheld for multiple indications as listed in the table below 
including hypotension refractory to fluids and pressors, anuria for more than 24 hours and 
unresponsive to fluid replacement and low-dose dopamine, respiratory distress requiring 
more than 4 L of oxygen to maintain O2 saturation greater than 95%, confusion, 
sustained ventricular tachycardia or any sign or symptom of myocardial ischemia or 
myocarditis, metabolic acidosis with HCO3 less than 18 despite attempts to correct with 
IV HCO3; atrial fibrillation, documented systemic infection, or any other serious toxicity 
that is not controlled at time of next dose. 
 
The following table published by Schwartzentruber [102] and  included in the standard 
HD IL-2 administration guidelines of UTSW as described in Appendix B summarizes the 
guidelines that will be followed for discontinuation of HD IL-2:  


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HD IL-2 should be delayed or discontinued if:  
 
Schwartzentruber, J Immunotherapy, Vol. 24, No. 4, 2001. 
 
Corrective measures taken, also developed following the guidelines published by 
Schwartzentruber [102] in Table 5, included in the standard HD IL-2 administration 
guidelines of UTSW as described in Appendix C are following:  
 
 
 
 
 
4.3 
Duration of Therapy 
The SABR administration followed by one course of HD IL-2 (consisting of two cycles of HD 
IL-2 with one week break in between) will typically be completed within four weeks.  The HD 
IL-2 course may be repeated for a maximum of 3 times, at the discretion of the treating 
medical oncologist unless: 


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 
Disease progression 
 
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.  
4.4 
Duration of Follow Up 
Subjects will be followed for ten years or death (although findings will be analyzed and 
reported at a median follow up of 2-4 years), whichever occurs first. Subjects removed from 
treatment for unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event. The follow-up will be every 8 weeks (+/- 2 Weeks) from study registration 
with imaging studies and physical exam every 8 weeks for the first eight months, then every 
12 weeks (+/- 2 Weeks) until two years, then every four months thereafter for a total of five 
years, and then every six months (+/- 1 month) for a total of ten years. See section 5.0 for 
detail.   
 
Subjects who show progressive disease will be followed for survival and will no longer strictly 
adhere to study calendar.  QOL questionnaires will be completed every 4 months until 1 year 
after treatment. 
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. 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 3 months prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history, history of infections 
5.1.3 Demographics 
Age, gender, race, ethnicity 


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5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 Performance status 
Performance status evaluated prior to study entry according to Appendix A 
(ECOG). 
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 
 
CBC with differential. 
5.1.10 
Blood draw for correlative studies 
See Section 9.0 for details. 
5.1.11 
Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, LDH, electrolytes 
(sodium, potassium, calcium, chloride, bicarbonate, magnesium and 
phosphate), glucose, uric acid, C-Reactive protein (CRP), beta-2 microglobulin 
and total bilirubin. 
5.1.12 
Pregnancy test (for females of child bearing potential) 
See section 3.1.10.1 for definition.  
5.1.13 
Serologic Tests 
HLA typing. 
5.1.14 
Radiographic Imaging 
Bone scan, CT chest, abdomen and pelvis with IV contrast. MRI of brain with 
contrast, if tolerated.  MRI of the abdomen should be considered on an 
individual basis if felt to be better by the radiation or medical oncologist. CT and 
Bone Scan must be performed within 21 days (+ 7 days) of registration.  
5.1.15 
Biopsy of metastatic lesion 
5.1.15.1 Pre-treatment biopsy: 
A CT-guided biopsy of a tumor lesion will be performed prior to study 
registration, unless previous biopsy of metastatic site within the last six 
months exists and a review of slides shows it to be adequate, in which 
case a pretreatment biopsy is optional. Soft tissue lesion will be preferred 
over bone biopsy for the pre-treatment biopsy.  Biopsy results do not affect 
eligibility if previous diagnosis of clear cell histology is present. If the 
patient participated in protocols [such as the Urology Tissue Repository 
Protocol (STU 032011-187)] or procedures and the tissue confirming 
kidney cancer diagnosis is in storage and available at UTSW Medical 


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Center or an outside institution, the study team may request a tissue 
sample. 
5.1.15.2 Post-treatment elective biopsy: 
An elective post-treatment biopsy will be performed 8 weeks after the 
completion of HD IL-2 and for this biopsy, any site other than a lymph node 
and a treated site is acceptable. In the case where all lesions are treated, 
any progressive or non-responding lesion will be biopsied. In case of CR 
no lesions may remain to be biopsied.   
5.1.16 
QoL Questionnaires  
FACT-G, EQ-5D, FKSI, cost and convenience questionnaire.  These forms will 
be referred to collectively as QoL Questionnaires.  Cost and convenience 
questionnaire will only be completed at first follow-up. 
5.1.17 
Tumor assessment 
To be performed on bone scan, CT or MRI. Please see section 6.1 for detail. 
5.1.18 
Pulmonary Function Tests 
5.1.19 
Cardiac Stress Test 
 
5.2 
Procedures During Treatment 
SABR treatment requires one week for planning and one week for delivery of the 1 or 3 
fractionation schemes.  HD IL-2 must begin within 84 hours of the last SABR fraction. 
Each course of HD IL-2 consists of two cycles of approximately two weeks each (12-14 
IV infusions q8h followed by about 9 days of break) requiring a total of four weeks.  
   
5.2.1 Prior to Each Treatment Cycle 
 Physical exam, vital signs 
 Hematology 
 Serum chemistries 
5.2.2 Prior to treatment 
 Registration to the study (registration must be done prior to first fraction of 
SABR) 
 CT simulation for SABR planning.  
 If multiple planning sessions are required, they will be completed within the 
first week. SABR planning completed 
5.2.3 Day 1-14 (+/- 7days) 
 SABR treatments completed 
 One hour after first SABR treatment, blood collection for correlative studies 
 If SABR to multiple sites, an additional 5 days is allowed to complete 
treatment 
5.2.4 Day 15-22 (+/- 7days) 
 Physical exam, vital signs 
 Hematology 


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 Serum chemistries 
 First cycle of HD IL-2 started within 84hr of the last SABR treatment 
5.2.5 Day 22-29 (+/- 7days) 
 Break 
 Patient will be assessed either by clinic visit or telephone call to ensure s/he is 
doing well and ready for the second cycle.  Telephone call can be done by 
any clinic staff or study personnel. 
5.2.6 Day 30-37 (+/- 14 days) 
 Physical exam, vital signs 
 Hematology 
 Serum chemistries 
 Second cycle of HD IL-2 
 Blood collection for correlative immunologic studies (see section 9.0) on the 
last day of HD IL-2 
5.2.7 Week 8 (+/- 2 weeks)  
 Physical exam, vital signs 
 Hematology 
 Serum chemistries 
 QoL questionnaire 
 Blood collection for correlative immunologic studies (see section 9.0)  
 Radiographic imaging 
o 
CT chest, abdomen and pelvis with IV contrast, if soft tissue metastasis 
o 
Bone scan if bone lesion was present and detected by the baseline Bone 
scan 
o 
MRI, if necessary to confirm CT/bone scan findings, at the discretion of 
radiologist 
5.2.8 Weeks 8-45 from registration date 
 HD IL-2 can be repeated for a maximum of 3 courses 12 weeks apart at the 
discretion of the medical oncologist 
5.3 
Follow-up Procedures 
Subject will be followed every eight-ten weeks (+/- 2 Weeks) starting from the date of 
registration for the first eight months, then every 12 weeks until 18 months and then 
every sixteen weeks for another three years and then every three – six months for the 
next five years. Thereafter at the discretion of the treating physician. The following 
procedures will be performed at each follow up: 
 Physical exam, vital signs 
 Hematology 
 Serum chemistries 
 QoL questionnaire (every other follow up) 
 Blood collection for correlative immunologic studies (see section 9.0) 
Radiographic imaging 
o 
CT chest, abdomen and pelvis with IV contrast, if soft tissue metastasis 
o 
Bone scan if bone lesion was present and detected by the baseline Bone 
scan 
o 
MRI, if necessary to confirm CT/bone scan findings, at the discretion of 
radiologist 
 


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5.4 
Time and Events Table 
 
* Bone scan performed every 8 weeks only if bone lesions present in baseline bone scan.  
@ optional 
# Immunologic blood collection is needed at baseline, post SABR, post HD IL-2, at 8 week, six 
months and at 1 year  
& Comprehensive chemistry will be done once a year, after this point. 
% Cost and Convenience Questionnaire will only be administered at the first follow up. All other 
QoL surveys will take place every other follow-up.  
1 Additional procedures, ICU admission, and lab requirements may apply in association with IL-2 
administration, as detailed in appendix C. 
 
 
Pre-study 
Cycle 1 , 
Day15 
(+/- 5) 
Cycle2, 
Day30 
(+/- 14) 
Cycle2, 
Day37 
(+/- 14) 
Months 
1-8: q8 
Weeks 
Months 
8-18: q12 
Weeks 
Months 18-
120: 3-6 
months 
Assessment 
X 
 
 
 
X 
X 
X 
Informed 
Consent 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
History and PE 
X 
 
 
 
X 
X 
X 
Performance 
Status 
X 
 
 
 
X 
X 
X 
Toxicity (include 
DLT) Evaluations 
X 
 
 
 
X 
X 
X 
Bone Scan 
X 
 
 
 
X* 
X* 
X 
CT Chest, Abd, 
pelvis w/ Contrast 
X 
 
 
 
X 
X 
X 
Biopsy of 
metastatic lesion 
X^ 
 
 
 
X@ 
 
 
CBC with diff 
X 
X1 
X1 
X1 
X 
X 
X 
Basic Chemistry 
X 
X1 
X1 
X1 
X 
X 
X 
Comprehensive 
chemistry  
X 
 
 
X 
X& 
 
 
Blood collection 
for Immune 
Assays 
X 
 
 
X 
X# 
X# 
X# 
QOL 
Questionnaires 
X 
 
 
X% 
X% 
X% 
X% 
Cardiac Stress 
Test 
X 
 
 
 
 
 
 
PFT 
X 
 
 
 
 
 
 


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^ if previous biopsy of metastatic site within six months with adequate review of slides is not 
available. If the patient participated in protocols [such as the Urology Tissue Repository Protocol 
(STU 032011-187)]  or procedures where tissue confirming kidney cancer diagnosis was 
collected and the biopsy in storage is still available, the study team may request a tissue sample. 
5.5 
Removal of Subjects from 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 at least one cycle of HD IL-2 
5.5.4 
Subject demonstrates disease progression (unless continued treatment with HD 
IL-2 is deemed appropriate at the discretion of the medical oncologist); 
5.5.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
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.  
6.0 
Measurement of Effect 
6.1 
Antitumor Effect 
For the primary endpoint, 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], which was also used by the 
two randomized trials of HD IL-2 being used as historic controls for this trial [35, 36].  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 >6wks apart, based on the 
immune RECIST (irRC) criteria proposed by Wolchok. et. al that is appropriate for 
immune-related treatment response [91]. 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 and if it were not for a second confirmation, these patients would be labeled to 
have failed therapy. In addition, the majority of mRCC responders to HD IL-2 usually 
produce a durable response (median response duration of 24 months), therefore, this 
change will not affect the outcome [35].  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/.   


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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 one course of HD IL-2, and have had their disease re-evaluated at 
least at two occasions (8wk and 16wk) 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) 
as >10 mm with spiral (Helical) CT scan. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
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), are considered non-measurable disease. Bone lesions, 
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. 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions per organ 
and 6 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) 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 “treated lesion” which should 
not be confused with “target lesions” defined here for the for the purpose 
of radiographic measurement. Treated lesions and target lesions are 
mutually exclusive lesions. Therefore, treated lesions will not be used as 
target lesions for evaluating response.   Since patients with ANY number of 
metastasis is eligible for this study, in the instance where patient has only 
one or few site of disease and all of them are treated, appearance of new 
lesions (either measurable or non-measureable) will constitute PD.  
 
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 and never more than 14 days before the beginning of the treatment. 
 


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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.  
 
Bone scans and CT scan of Chest, abdomen and pelvis with IV contrast 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.   
 
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 not less than 4 
weeks apart. 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. 
 
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. 
 
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. 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 


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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 bone scan, 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 Bone scan, confirmed 
by a repeat bone scan in ≥6 weeks. 
6.1.4.4.2 
Response of bone lesions in bone 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.  
6.1.4.6 Evaluation of spinal cord Compression or Cauda equina 
compression:  
Any clinical suspicion of cord or cauda equine compression will prompt 
radiologic evaluation with MRI (CT myelography if patient is not eligible 


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for MRI) as appropriate and if confirmed by a radiologist, will constitute 
progression. 
6.1.5 
Response Rate and clinical response:  
Response rate (RR) is defined by combining CR and PR. Clinical response is 
defined by combining CR, PR, and SD. 
 
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 HD IL-2. 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 (Appendix #/letter). 
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 with prostate cancer subscales of the 
Functional Assessment of Cancer Therapy-General (FACT-G) (See appendix for form). 
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, physical well-being [103, 104]. 
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 [105].  
The FACT-G and FKSI will be given on Day 1 and 28 similar to several other quality of 
life studies [106],[82], [85] 
 
The FKSI is a 15 question validated symptom index for kidney cancer patients which has 
been used in several metastatic renal cell cancer studies [106].  This scale focuses on 
symptoms predominantly related to kidney cancer such as energy, fatigue, pain, bone 


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pain, weight loss, shortness of breath, cough, fever, hematuria.  This subscale of the 
FKSI-DRS was validated in another study as well [107] 
 
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, 8, 16, 24, and 36 weeks 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 for form). 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 3 levels: 1-no problems, 2-
moderate problems, and 3-extreme problems. 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.  Unfortunately, to our knowledge there is no health 
state utilites established for patients receiving IL-2, much less HD-IL-2.  Likewise , there 
is no data for metastatic renal cell carcinoma patients within the setting of SABR 
treatment.  
 
The EQ-5D will also be available in the Spanish language.  
6.4 
Cost effectiveness data collection: 
Health care utilization data needed to assess costs will be obtained from treatment 
records.  Additionally, in order to assess the treatment related indirect costs and patient 
out of pocket costs, a form will be administered at the first available follow up visit after 
completion of radiation treatment (see Appendix VII). 
 
 
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. This 
is of great importance given that these patients will be admitted to the intensive care unit.   
 
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: Prescription drugs used, including dosage strength and frequency 
of administration.  Information about name, dose, and frequency of all prescription 
medications 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.”  For example: Cost 
estimated for the HD-IL-2 infusions will be based on Medicare allowable utilizing the 
appropriate J code and associated facility charges for administration of HD-IL-2.  
 
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: None  
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 
HD IL-2 
The standard treatment regiment for HD IL-2 which has been proven to be safe at UTSW 
over the past years will be used for this protocol (as detailed in section 4, Appendix B and 
C).  For the most recent safety update, please refer to the current Study Agent 
Prescribing Information in the company website: 
http://www.proleukin.com/assets/pdf/proleukin.pdf 
 
7.2.1 Contraindications 
 
HD IL-2  is contraindicated in patients with a known history of hypersensitivity to IL-2 
or any component of the HD IL-2 formulation. HD IL-2 is contraindicated in patients 
with an abnormal thallium stress test or abnormal pulmonary function tests and those 
with organ allografts. Retreatment with HD IL-2 is contraindicated in patients who 
have experienced the following drug-related toxicities while receiving an earlier 
course of therapy: 


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• Sustained ventricular tachycardia (≥5 beats) 
• Cardiac arrhythmias not controlled or unresponsive to management 
• Chest pain with ECG changes, consistent with angina or myocardial 
infarction 
• Cardiac tamponade 
• Intubation for >72 hours 
• Renal failure requiring dialysis >72 hours 
• Coma or toxic psychosis lasting >48 hours 
• Repetitive or difficult to control seizures 
• Bowel ischemia/perforation 
• GI bleeding requiring surgery 
7.2.2 Special Warnings and Precautions for Use 
Because of the severe adverse events which generally accompany HD IL-2 therapy at the recommended 
dosages, thorough clinical evaluation should be performed to identify patients with significant cardiac, 
pulmonary, renal, hepatic, or CNS impairment in whom HD IL-2 is contraindicated. Patients with normal 
cardiovascular, pulmonary, hepatic, and CNS function may experience serious, life threatening or fatal 
adverse events. Adverse events are frequent, often serious, and sometimes fatal.  
 
Should adverse events, which require dose modification occur, dosage should be withheld rather than 
reduced (See “DOSAGE AND ADMINISTRATION” section, “Dose Modifications” subsection of the 
manufacturer’s prescribing information). 
 
HD IL-2 has been associated with exacerbation of pre-existing or initial presentation of autoimmune 
disease and inflammatory disorders. Exacerbation of Crohn’s disease, scleroderma, thyroiditis, 
inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA 
glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous pemphigoid, 
has been reported following treatment with IL-2. 
 
All patients should have thorough evaluation and treatment of CNS metastases and have a negative scan 
prior to receiving HD IL-2 therapy. New neurologic signs, symptoms, and anatomic lesions following HD 
IL-2 therapy have been reported in patients without evidence of CNS metastases. Clinical manifestations 
included changes in mental status, speech difficulties, cortical blindness, limb or gait ataxia, 
hallucinations, agitation, obtundation, and coma. Radiological findings included multiple and, less 
commonly, single cortical lesions on MRI and evidence of demyelination. Neurologic signs and symptoms 
associated with HD IL-2 therapy usually improve after discontinuation of HD IL-2 therapy; however, there 
are reports of permanent neurologic defects. One case of possible cerebral vasculitis, responsive to 
dexamethasone, has been reported. In patients with known seizure disorders, extreme caution should be 
exercised as HD IL-2 may cause seizures. 
 
Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of therapy. (See 
“PRECAUTIONS” section, “Laboratory Tests” subsection of manufacturer’s prescribing information). 
Capillary leak syndrome (CLS) begins immediately after HD IL-2 treatment starts and is marked by 
increased capillary permeability to protein and fluids and reduced vascular tone. In most patients, this 
results in a concomitant drop in mean arterial blood pressure within 2 to 12 hours after the start of 
treatment. With continued therapy, clinically significant hypotension will occur. In addition, extravasation 
of protein and fluids into the extravascular space will lead to the formation of edema and creation of new 
effusions. 
 
Medical management of CLS begins with careful monitoring of the patient’s fluid and organ perfusion 
status, as described in Section 4, Appendices B and C, in accordance with the established and standard 
practice guidelines followed at UTSW. This is achieved by frequent determination of blood pressure and 
pulse, and by monitoring organ function, which includes assessment of mental status and urine output. 
Hypovolemia is assessed by catheterization and central pressure monitoring. 


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Flexibility in fluid and pressor management is essential for maintaining organ perfusion and blood 
pressure. Correction of hypovolemia may require large volumes of IV fluids but caution is required 
because unrestrained fluid administration may exacerbate problems associated with edema, in particular 
leading to pulmonary edema. With extravascular fluid accumulation, edema is common and ascites, 
pleural or pericardial effusions may develop.  
 
Management of these events depends on a careful balancing of the effects of fluid shifts so that neither 
the consequences of hypovolemia (e.g., impaired organ perfusion) nor the consequences of fluid 
accumulations (e.g., pulmonary edema) exceed the patient’s tolerance. 
 
Clinical experience has shown that early administration of dopamine (1 to 5 μg/kg/min) to patients 
manifesting capillary leak syndrome, before the onset of hypotension, can help to maintain organ 
perfusion particularly to the kidney and thus preserve urine output. Weight and urine output should be 
carefully monitored.  If organ perfusion and blood pressure are not sustained by dopamine therapy, the 
dose of dopamine can be titrated as described in section 4 and in Appendix C, to 5mcg/kg/min to 
maintain SBP equal to or greater than 90 mm Hg, or add phenylephrine hydrochloride 20 mg/500 ml NS 
at 1 mcg/kg/min  and titrate to 1.5 mcg/kg/min. (See “ADVERSE REACTIONS” section below). Prolonged 
use of pressors, either in combination or as individual agents, at relatively high doses, may be associated 
with cardiac rhythm disturbances. If there has been excessive weight gain or edema formation, 
particularly if associated with shortness of breath from pulmonary congestion, use of diuretics, once blood 
pressure has normalized, has been shown to hasten recovery. NOTE: Prior to the use of any product 
mentioned, the physician should refer to the package insert for the respective product. 
 
HD IL-2 treatment should be withheld for failure to maintain organ perfusion as demonstrated by altered 
mental status, reduced urine output, a fall in the systolic blood pressure below 90 mm Hg or onset of 
cardiac arrhythmias (See “DOSAGE AND ADMINISTRATION” section 4.2 and “Dose Modifications” 
subsection 4.3). Recovery from CLS begins soon after cessation of HD IL-2 therapy. Usually, within a few 
hours, the blood pressure rises, organ perfusion is restored and reabsorption of extravasated fluid and 
protein begins. Kidney and liver function are impaired during HD IL-2 treatment. Use of concomitant 
nephrotoxic or hepatotoxic medications may further increase toxicity to the kidney or liver. Mental status 
changes including irritability, confusion, or depression which occur while receiving HD IL-2 may be 
indicators of bacteremia or early bacterial sepsis, hypoperfusion, occult CNS malignancy, or direct HD IL-
2-induced CNS toxicity. Alterations in mental status due solely to HD IL-2 therapy may progress for 
several days before recovery begins. Rarely, patients have sustained permanent neurologic deficits (See 
“Drug Interactions” section below). 
 
Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and inflammatory 
disorders has been reported following HD IL-2 alone or in combination with interferon. Hypothyroidism, 
sometimes preceded by hyperthyroidism, has been reported following HD IL-2 treatment. Some of these 
patients required thyroid replacement therapy. Changes in thyroid function may be a manifestation of 
autoimmunity. Onset of symptomatic hyperglycemia and/or diabetes mellitus has been reported during 
HD IL-2 therapy. 
 
HD IL-2 enhancement of cellular immune function may increase the risk of allograft rejection in transplant 
patients. 
7.2.1 
Drug Interactions  
HD IL-2 may affect central nervous function. Therefore, interactions could occur following concomitant 
administration of psychotropic drugs (e.g., narcotics, analgesics, antiemetics, sedatives, tranquilizers). 
 
Concurrent administration of drugs possessing nephrotoxic (e.g., aminoglycosides, indomethacin), 
myelotoxic (e.g., cytotoxic chemotherapy), cardiotoxic (e.g., doxorubicin) or hepatotoxic (e.g., 
methotrexate, asparaginase) effects with HD IL-2 may increase toxicity in these organ systems. The 


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safety and efficacy of HD IL-2 in combination with any antineoplastic agents have not been established. 
In addition, radiographic contrast material should be avoided one week pre and post HD IL-2 therapy, 
unless absolutely necessary, to avoid inducing an allergic reaction.  
 
In addition, reduced kidney and liver function secondary to HD IL-2 treatment may delay elimination of 
concomitant medications and increase the risk of adverse events from those drugs. 
 
Hypersensitivity reactions have been reported in patients receiving combination regimens containing 
sequential high dose HD IL-2 and antineoplastic agents, specifically, dacarbazine, cis-platinum, tamoxifen 
and interferon-alfa. These reactions consisted of erythema, pruritus, and hypotension and occurred within 
hours of administration of chemotherapy. These events required medical intervention in some patients. 
 
Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe 
rhabdomyolysis appear to be increased in patients receiving HD IL-2 and interferon-alfa concurrently. 
 
Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has been 
observed following concurrent use of interferon-alfa and HD IL-2, including crescentic IgA 
glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, 
and Stevens-Johnson syndrome. 
 
Although glucocorticoids have been shown to reduce HD IL-2-induced side effects including fever, renal 
insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant administration of these agents 
with HD IL-2 may reduce the antitumor effectiveness of HD IL-2 and thus should be avoided 
 
Beta-blockers and other antihypertensives may potentiate the hypotension seen with HD IL-2. 
7.2.2 Adverse Reactions 
>10%:  
Cardiovascular: Hypotension (71%; grade 4: 3%), peripheral edema (28%), tachycardia (23%), edema 
(15%), vasodilation (13%), supraventricular tachycardia (12%; grade 4: 1%), cardiovascular disorder 
(11%; includes blood pressure changes, HF and ECG changes) 
Central nervous system: Chills (52%), confusion (34%; grade 4: 1%), fever (29%; grade 4: 1%), malaise 
(27%), somnolence (22%), anxiety (12%), pain (12%), dizziness (11%) 
Dermatologic: Rash (42%), pruritus (24%), exfoliative dermatitis (18%) 
Endocrine & metabolic: Acidosis (12%; grade 4: 1%), hypomagnesemia (12%), hypocalcemia (11%) 
Gastrointestinal: Diarrhea (67%; grade 4: 2%), vomiting (19% to 50%; grade 4: 1%), nausea (19% to 
35%), stomatitis (22%), anorexia (20%), weight gain (16%), abdominal pain (11%) 
Hematologic: Thrombocytopenia (37%; grade 4: 1%), anemia (29%), leukopenia (16%) 
Hepatic: Hyperbilirubinemia (40%; grade 4: 2%), AST increased (23%; grade 4: 1%)  
Neuromuscular & skeletal: Weakness (23%) 
Renal: Oliguria (63%; grade 4: 6%), creatinine increased (33%; grade 4: 1%) 
Respiratory: Dyspnea (43%; grade 4: 1%), lung disorder (24%; includes pulmonary congestion, rales, and 
rhonchi), cough (11%), respiratory disorder (11%; includes acute respiratory distress syndrome, infiltrates 
and pulmonary changes) 
Miscellaneous: Antibody formation (66% to 74%), infection (13%; grade 4: 1%) 
 
1% to 10%:  
Cardiovascular: Arrhythmia (10%), cardiac arrest (grade 4: 1%), MI (grade 4: 1%), ventricular tachycardia 
(grade 4: 1%) 
Central nervous system: Coma (grade 4: 2%), stupor (grade 4: 1%), psychosis (grade 4: 1%) 
Gastrointestinal: Abdomen enlarged (10%) 
Hematologic: Coagulation disorder (grade 4: 1%; includes intravascular coagulopathy) 
Hepatic: Alkaline phosphatase increased (10%) 
Renal: Anuria (grade 4: 5%), acute renal failure (grade 4: 1%) 


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Respiratory: Rhinitis (10%), apnea (grade 4: 1%) 
Miscellaneous: Sepsis (grade 4: 1%) 
 
<1% (Limited to important or life-threatening):  
Allergic interstitial nephritis, anaphylaxis, angioedema, asthma, atrial arrhythmia, AV block, blindness 
(transient or permanent), bowel infarction/necrosis/perforation, bradycardia, bullous pemphigoid, capillary 
leak syndrome, cardiomyopathy, cellulitis, cerebral edema, cerebral lesions, cerebral vasculitis, 
cholecystitis, colitis, crescentic IgA glomerulonephritis, Crohn’s disease exacerbation, delirium, 
depression (severe; leading to suicide), diabetes mellitus, duodenal ulcer, encephalopathy, endocarditis, 
extrapyramidal syndrome, hemorrhage (including cerebral, gastrointestinal, retroperitoneal, subarachnoid, 
subdural), hepatic failure, hepatitis, hepatosplenomegaly, hypertension, hyperuricemia, hypothermia, 
hyperthyroidism, inflammatory arthritis, injection site necrosis, insomnia, intestinal obstruction, intestinal 
perforation, leukocytosis, malignant hyperthermia, meningitis, myocardial ischemia, myocarditis, 
myopathy, myositis, neuralgia, neuritis, neuropathy, neutropenia, NPN increased, oculobulbar myasthenia 
gravis, optic neuritis, organ perfusion decreased, pancreatitis, pericardial effusion, pericarditis, peripheral 
gangrene, phlebitis, pneumonia, pneumothorax, pulmonary edema, pulmonary embolus, respiratory 
acidosis, respiratory arrest, respiratory failure, rhabdomyolysis, scleroderma, seizure, Stevens-Johnson 
syndrome, stroke, syncope, thrombosis, thyroiditis, tracheoesophageal fistula, transient ischemic attack, 
tubular necrosis, ventricular extrasystoles  
 
7.3 
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 subject  
safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed 
 
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 occurring 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  


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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).  
 
7.4 
Definitions 
7.4.1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
7.4.2 Severity of Adverse Events 
 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The 
CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the subject was at risk of death at the time of the 
event. 
Fatal (grade 5): the event caused death. 
7.4.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
7.4.3.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 


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7.4.3.2 
Is life-threatening. 
(the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe). 
7.4.3.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
7.4.3.4 
Results in persistent or significant disability or incapacity. 
7.4.3.5 
Is a congenital anomaly/birth defect 
7.4.3.6 
Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the subject, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
  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. 
7.5 Unanticipated Problems Involving Risks to Subjects or Others (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 


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unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
                                                AND 
• 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); 
      AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.5.1      Reporting 
The UTSW IRB requires reporting of all UPIRSOs according to the guidance below. For 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. All SAEs occurring during the protocol-specified 
monitoring period should be submitted to the UTSW study team within 2 business days of 
the center learning of the event. 
 
7.5.2  UPIRSOs occurring on the study require expedited reporting, and are submitted to the 
UTSW IRB through the UTSW eIRB by the UTSW study team and to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB report; FDA Form #3500A 
forms, or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be submitted to the UTSW study team and will be forwarded 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 documentation that is available are also submitted to the DSMC Chair 
who determines if further action is required. (See Appendix IV 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). 
  
All serious adverse events which occur on 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. Hardcopies or electronic versions of the FDA Form #3500A forms, 
or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be forwarded to the DSMC Coordinator.   
 
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
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 serious adverse events 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.  
 


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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 
example.  
Telephone reports to: 
(Investigator/study team: Insert names and phone numbers for required notifications) 
 
 
Written reports to: 
(Investigator/study team: Insert names, fax numbers, an addresses for required 
notifications) 
 
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 
 
1. 
SAEs 
Serious adverse events (SAEs) for studies where the SCCC DSMC is the DSMC of 
record require reporting to the DSMC coordinator within 5 working days of PI awareness, 
or as described in the protocol.   
2. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) 
Local Serious Adverse Event UPIRSOs require reporting to the UTSW IRB within 48 hours 
of PI awareness of the event (life threatening or fatal events experienced by subjects 
enrolled by the investigator(s) under UTSW IRB jurisdiction).   
Local UPIRSOs (non-serious events experienced by subjects enrolled by the 
investigator(s) under UTSW IRB jurisdiction) require reporting to the UTSW IRB within 5 
business days of PI awareness of the event. 
External UPIRSOs including those that occur as non-local events require reporting to the 
UTSW IRB within 10 working days of PI awareness of the event. 
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 
 
 
. 


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7.6 
Steps to Determine If an Adverse Event Requires Expedited Reporting to the SCCC DSMC 
and/or HRPP. 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4).  
 
Step 2:Grade the adverse event using the NCI CTCAE v4. 
 
Step 3:Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
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; 
 
the current Investigator’s Brochure 
 
7.6.1    Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center    
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs/UPIRSOs occurring during the protocol-specified 
monitoring period should be submitted to the SCCC DSMC within 5 business days of the 
PI or delegated study team members awareness of the event(s). In addition, for 
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 


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participating sites are notified of the event and resulting action, according to FDA 
guidance for expedited reporting. DSMC Chairperson reviews all SAEs/UPIRSOs upon 
receipt from the DSMC Coordinator.  The DSMC Chairperson determines whether action 
is required and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
 
Telephone reports to: 
(Investigator/study team: Insert names and phone numbers for required notifications) 
 
Sarmistha Sen 
214-645-1477 
 
Written reports to: 
(Investigator/study team: Insert names, fax numbers, an addresses for required 
notifications)  
 
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 a Reportable Event 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 
 


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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. 
 
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. 
 
7.7 Reporting Requirements for Adverse Events 
7.4.4 
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.  
 
Suspected adverse reactions will also be reported to Prometheus 
Laboratories. A copy of any SAE report submitted to any IRB must be sent 
to Prometheus Laboratories. If the “IL-2” is a suspect or co-suspect drug 
reported on the FDA Form 3500A MedWatch report, Prometheus 
Laboratories also requests a courtesy copy of the FDA Form 3500A 
MedWatch report that was submitted to the US Food and Drug 
Administration, via email or fax, to Drug Safety and Pharmacovigilance at 
Prometheus Laboratories, Inc. provided below.  Please also include your 
contact information. 
 
Drug Safety Email: drugsafety@prometheuslabs.com 
 
Drug Safety Fax: (858) 754-3046 
 
Suspected adverse reactions will also be reported to FDA at 1-800-FDA-
1088 or www.fda.gov/medwatch.  
 
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, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 


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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. 
7.5 
Stopping Rules 
The study will be stopped if the combination treatment of SABR and HD IL-2 in the 
interim annual analysis is determined to confer significantly increased Grade 3-5 toxicity 
as reported in the literature from the treatments performed alone.  
8.0 
DRUG INFORMATION 
8.1 
HD IL-2 
 
 
Other names for the drug(s):  Proleukin, Aldesleukin 
 
 
Classification - type of agent: Cytokine, Antineoplastic Agent, Miscellaneous; 
Biological Response Modulator 
 
 
Mode of action: Immune-stimulator; Binds to IL-2-receptor and activates proliferation 
of lymphocytes. Aldesleukin is a human recombinant interleukin-2 product which 
promotes proliferation, differentiation, and recruitment of T and B cells, natural killer 
(NK) cells, and thymocytes; causes cytolytic activity in a subset of lymphocytes and 
subsequent interactions between the immune system and malignant cells; can 
stimulate lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes 
(TIL) cells. 
 
 
Storage and stability: Refrigerator at 2° to 8°C (36° to 46°F). Avoid exposure to heat 
and light. Stability after reconstitution—24 hours.  
 
 
Protocol dose:  600,000 U/kg q8h up to 14 doses. Please see Appendix B. 
 
 
Preparation: PROLEUKIN is supplied as a sterile, white to off-white, lyophilized cake 
in single-use vials intended for intravenous (IV) administration. When reconstituted 
with 1.2 mL Sterile Water for Injection, USP, each mL contains 18 million IU (1.1 mg) 
PROLEUKIN, 50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered with 
approximately 0.17 mg monobasic and 0.89 mg dibasic sodium phosphate to a pH of 
7.5 (range 7.2 to 7.8).  
 
 
Route of administration for this study: IV infusion over 15 minutes  
 
 
Incompatibility:  Reconstitution and dilution procedures other than those 
recommended may result in incomplete delivery of bioactivity and/or formation of 
biologically inactive protein.  Use of Bacteriostatic Water for Injection or Sodium 
Chloride Injection 0.9% should be avoided because of increased aggregation.  
Proleukin must not be mixed with other medicinal products except those mentioned in 
section 6.6.  It is recommended that devices or administration sets containing in-line 


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filters are not used for delivery of Proleukin. Bioassays have shown significant loss of 
aldesleukin when filters are used. 
 
 
Availability: Commercially available from Novartis. 
 
 
Side effects:  
Cardiovascular: Hypotension (71%; grade 4: 3%), peripheral edema (28%), 
tachycardia (23%), edema (15%), vasodilation (13%), supraventricular tachycardia 
(12%; grade 4: 1%), cardiovascular disorder (11%; includes blood pressure 
changes, HF and ECG changes). Central nervous system: Chills (52%), confusion 
(34%; grade 4: 1%), fever (29%; grade 4: 1%), malaise (27%), somnolence (22%), 
anxiety (12%), pain (12%), dizziness (11%). Dermatologic: Rash (42%), pruritus 
(24%), exfoliative dermatitis (18%). Endocrine & metabolic: Acidosis (12%; grade 
4: 1%), hypomagnesemia (12%), hypocalcemia (11%). Gastrointestinal: Diarrhea 
(67%; grade 4: 2%), vomiting (19% to 50%; grade 4: 1%), nausea (19% to 35%), 
stomatitis (22%), anorexia (20%), weight gain (16%), abdominal pain (11%). 
Hematologic: Thrombocytopenia (37%; grade 4: 1%), anemia (29%), leukopenia 
(16%). Hepatic: Hyperbilirubinemia (40%; grade 4: 2%), AST increased (23%; 
grade 4: 1%). Neuromuscular & skeletal: Weakness (23%) 
Renal: Oliguria (63%; grade 4: 6%), creatinine increased (33%; grade 4: 1%) 
Respiratory: Dyspnea (43%; grade 4: 1%), lung disorder (24%; includes pulmonary 
congestion, rales, and rhonchi), cough (11%), respiratory disorder (11%; includes 
acute respiratory distress syndrome, infiltrates and pulmonary changes). 
Miscellaneous: Antibody formation (66% to 74%), infection (13%; grade 4: 1%) 
 
 
Nursing implications: Close monitoring in ICU setting. 
 
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 regiment. The 
submission of collected whole blood before, during and post treatment as indicated in Section 5 is 
mandatory and will be performed at baseline, during RT (one hour after first SABR fraction), after 
HD IL-2 cycle 2, at 8 weeks, 6 months and 1 year. Biopsy specimen of metastatic sites prior to 
initiation of treatment is required if previous biopsy of metastatic site within six months with 
adequate review of slides is not performed or available, in which case it is optional. If the patient 
participated in protocols [such as the Urology Tissue Repository Protocol (STU 032011-187)] or 
procedures and the tissue confirming kidney cancer diagnosis is in storage and available at 
UTSW Medical Center or an outside institution, the study team may request a tissue sample. 
 The 8wks post-treatment biopsy is optional.   
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 ~ 100 ml at baseline, during RT (one hour after first SABR fraction), 
post HD IL-2, at 8 week and at 24 week (+/- 2 weeks) and at 1 year starting from 
the first day of study registration for immunologic assays. In addition, 10 ml will 
be collected in anti-coagulant-free tubes (Red top) for the collection of sera.  The 


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only exception is the blood collection one hour post first SABR fraction which will 
be for 20ml in EDTA and 20 ml in anti-coagulant-free tubes The blood will 
immediately be processed (within 2 hours) by centrifugation (1000g, 15min, 4 
oC), collecting the supernatant and freezing at -80 oC 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).  
Collect the PBMC region from the ficoll and washed 3x with PBS. Count and 
freeze cells in 5 aliquots with 10%DMSO 90%FBS in -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 
the study. If the patient participated in protocols [such as the Urology Tissue 
Repository Protocol (STU 032011-187)] or procedures and the tissue confirming 
kidney cancer diagnosis is in storage and available at UTSW Medical Center or 
an outside institution, the study team may request a tissue sample. A second 
biopsy at 8 weeks (+/- 2 week) after the last HD IL-2 treatment 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 


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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- 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 
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 [108]. 
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) [109, 110]. 
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, 


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regulatory T-Cells, effector memory T cells, MDSCs, neutrophils and NK cells 
utilizing appropriate cell surface markers (see section 1.5).   
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 (see section 1.5). 
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 µL 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 


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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). Specimen may be shipped to companies or 
outside institutions to perform specialized assays, a non-extensive list of which is 
provided above. Specimen will be shipped de-identified. 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. 
 
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 
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 HD-IL-2. 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 depends 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. 
 
In this non-randomized trial, we plan to assess the FACT-G at specific time points to minimize 
patient burden: baseline (pretreatment), end of HD-IL-2 cycle 2 treatment, and at subsequent 
follow ups (See Appendix).  In order to analyze the QOL, we plan to use a brief, validated 
instrument that is user friendly and has clinical relevance [111].  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).  FKSI adds to the FACT–G (27 items) by including 
15 items specific to prostate cancer patients.  The FACT-G has been validated as well and 


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used in other studies evaluating treatment options for patients with mRCC [106]. 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.  
 
In a HRQOL study focused on patient with mRCC a symptoms subscale questionnaire was 
developed and will also be administed 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 [112] 
 
In addition, the EQ-5D.  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) [113, 114]. 
 
HRQoL of patients with mRCC is unfortunately not well described in the literature for either 
treatment modalities in this study or other standard of care treatments as well.  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 [84].   
 
There is little reported on the effect on HRQOL for patients treated with HD-IL-2,  No specific 
data has been published other than in abstract form and this data showed stable QoL between 
several IL-2 dosing patterns [81] However, there are several detailed reports evaluating quality 
of life for sunitinib, sorafanib. temsirolimus, everolimus, pazopanib [115].  Thus, we propose 
utilizing the FACT-G, FKSI, and EQ-5D in the patients enrolled on this study for descriptive 
purposes given the lack of HR-QoL data for either IL-2, HD-IL-2, or SABR in this patient 
population [116].     
 
Additionally, in order to calculate the indirect costs associated with hypofractionated radiation 
treatment, a single administration of a short economic questionnaire will take place at the end 
of radiation treatment or first available follow up or whichever occurs first.  This questionnaire 
which has been adapted for administration in the United States has been used in economic 
assessments in rural Canadian cancer health service research [117].   
 
10.2 Cost-Effectiveness Analysis (CEA) 
For the primary CEA analysis, we will estimate cost accumulated within 1 years 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 the presence 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[113].  Instead, we will use the inverse-probability 
weighting method to calculate average costs.[114, 118]  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. 
 


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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 affects 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 [114, 118, 119].  
Accordingly, we will use the inverse-probability weighted method of Zhao and Tsiatis to 
carry out the survival time analysis [114, 118].  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 an open label phase II non-randomized single arm prospective clinical trial. The 
primary end point is RR, while the secondary end points include improvement in OS, PFS, 
immunologic response, toxicity and quality of life (Please see endpoint details in section 2 
and 6).   
11.2 
Sample Size and Accrual 
The previous studies show that the maximum RR for mRCC patients treated with HD IL-2 is 
23% [35]. We expect a >60% improvement in this rate leading to a 36.8% RR for mRCC 
patients when treated with SABR and IL2. The calculation of the sample size is based on the 
RR and Simon’s optimal two-stage design will be used with (α,β)=(0.20, 0.20) [120]. The RR 
of 23% is set as the lowest desirable rate and 36.8% is the rate we are targeting. We chose 
type I error of 0.20 and type II error of 0.20. That is, if the true response rate is less than 23%, 
the probability of wrongly accepting the treatment for further study is 20%, and if the true 
response rate exceeds 36.8%, the probability of wrongly rejecting it for further study is 20%. 
According to the optimal two-stage design, a maximum of 33 patients will be needed. In the 
first stage, 17 patients will be evaluated. If 3 or fewer responses are observed, then the trial 
will be terminated for futility. Otherwise an additional 16 patients (second stage) will enter the 
trial. Finally, if more than 9 responses are observed among 33 patients, then the regimen 


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(SABR+IL-2) may be considered as the experimental arm of a Phase III trial. The average 
sample size for this phase II trial is 26.2 patients, and the probability of early termination is 
0.43 for a drug with response probability of 23%.  
11.3 
Data Analyses Plans 
This is a single-arm Phase II trial of SABR and HD IL-2 for mRCC patients.  PFS and OS, will 
be estimated using the Kaplan-Meier approach along with the 95% confidence interval. Exact 
binomial method will be used to calculate the response rate, toxicity and the corresponding 
95% confidence interval.  One-sample log-rank test [121] will be used to test if the survival 
endpoints such as OS or PFS are significantly different from those in the historical control 
reported in McDermott et. al [35].   
 
Generalized estimating equation (GEE) analysis will be conducted to test if the median 
number of spots in Elispot of the PBMC collected from patients are significantly different over 
time (before starting of treatment and after SBRT, at 8 weeks and six months).  T-Cell 
proliferation SI will also be evaluated in the same manner. 
 
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. 
 
11.2 
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 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) 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office, Department of Radiation Oncology, UTSW. 
 
 
A copy of the official IRB approval letter for the protocol and informed consent 
 
IRB membership list or Federalwide Assurance letter 


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 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(NOTE: this is required if (institution) holds the IND. Otherwise, the affiliate 
Investigator’s signature on the protocol is sufficient to ensure compliance) 
 
A copy of the IRB-approved consent form 
 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
 
Executed clinical research contract 
12.4 
Registration Procedures 
All subjects must be registered with the Clinical Research Office, Department of 
Radiation Oncology, UTSW, before enrollment to study. Prior to registration, eligibility 
criteria must be confirmed with the Clinical research office Study Coordinator. To register 
a subject, call 214-633-1753 Monday through Friday, 9:00AM-5:00PM.  
12.5 
Data Management and Monitoring/Auditing 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case report 
forms for this and all SCCC Investigator Initiated Trials. REDCap will be used for electronic case 
report forms in accordance with Simmons Comprehensive Cancer Center requirements. 
 
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. 
 
 
 
Audits will be performed according to the DSMC plan. These reviews will be documented by 
(insert method for documenting reviews and distribution of reports to the study team and SCCC-
DSMC, if needed) 
 
            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.  
 


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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 
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 


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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. 
 
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 
REFERENCES 
1. 
Potters, L., et al., American Society for Therapeutic Radiology and Oncology (ASTRO) 
and American College of Radiology (ACR) practice guideline for the performance of 
stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys, 2010. 76(2): p. 326-32. 
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Kavanagh, B.D., R.C. McGarry, and R.D. Timmerman, Extracranial radiosurgery 
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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:  High Dose Interleukin-2 Bolus Administration Algorithm 


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14.3 
Appendix C:  High Dose Interleukin-2 Bolus Administration Physician Orders 
 


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14.4 
Appendix D:  US EQ-5D-3L 
 
         
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
 
English version for the US 
 
 
 


Study Number – STU 012013-041 
________________________________________________________________________ 
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By placing a checkmark in one box in each group below, please indicate which 
statements best describe your own health state today. 
 
Mobility 
I have no problems in walking about 
 
 
I have some problems in walking about 
 
 
I am confined to bed 
 
 
 
Self-Care 
I have no problems with self-care 
 
 
I have some problems washing or dressing myself 
 
 
I am unable to wash or dress myself 
 
 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities 
 
 
I have some problems with performing my usual activities 
 
 
I am unable to perform my usual activities 
 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
 
I have moderate pain or discomfort 
 
 
I have extreme pain or discomfort 
 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
 
I am moderately anxious or depressed 
 
 
I am extremely anxious or depressed 
 
 
 
 


Study Number – STU 012013-041 
________________________________________________________________________ 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 
 
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To help people say how good or bad a health 
state is, we have drawn a scale (rather like a 
thermometer) on which the best state you can 
imagine is marked 100 and the worst state you 
can imagine is marked 0. 
 
We would like you to indicate on this scale how 
good or bad your own health is today, in your 
opinion. Please do this by drawing a line from 
the box below to whichever point on the scale 
indicates how good or bad your health state is 
today. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Your own 
health state 
today 
Worst 
imaginable 
health state 
0 
Best  
imaginable 
health state 


Study Number – STU 012013-041 
________________________________________________________________________ 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 
 
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14.5 
Appendix E:  FACT-G 
 
 


Study Number – STU 012013-041 
________________________________________________________________________ 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 
 
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Study Number – STU 012013-041 
________________________________________________________________________ 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 
 
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14.6 
Appendix F:  FKSI 
 
 
 
 


Study Number – STU 012013-041 
________________________________________________________________________ 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 
 
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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 


Study Number – STU 012013-041 
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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): 
 
 


Study Number – STU 012013-041 
________________________________________________________________________ 
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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): 
 
 


Study Number – STU 012013-041 
________________________________________________________________________ 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 
 
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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.  


Study Number – STU 012013-041 
________________________________________________________________________ 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 
 
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 Home nursing services 
 Respiratory/ Physiotherapists/ Occupational Therapy services 
 Medication changes 
 Started oxygen treatment 
 
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 _____________________________ 


Study Number – STU 012013-041 
________________________________________________________________________ 
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17.  
How would you rate your current health? 
  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 
 
 


Study Number – STU 012013-041 
________________________________________________________________________ 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 
 
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24. What treatments or services that are not currently available would you like to see paid for 
through government or private insurance: 
____________________________________________________________________________________________________________
________________________________________________ 
 
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 
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
___________________________________________________________________________________-
____________________________ 


Study Number – STU 012013-041 
________________________________________________________________________ 
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 
 
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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 

ICF_001.pdf: 
Official title: A Phase II Trial of High Dose IL-2 and Stereotactic Ablative Body
Radiation Therapy (SABR) for Patients with Metastatic Clear Cell Renal Cell
Cancer (mRCC)
NCT number: NCT01896271
Document date: May 20, 2019