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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 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 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.
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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 5bromo-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 3**H-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, 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, Dualantibody 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; proinflammatory 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 premade gradient 4% to 12% Bis-Tris gels (Invitrogen, Burlington, ON, Canada) and transferred to nitrocellulose. Patient sera/plasma will be diluted 1/500 in Blotto (5% dry milk powder; 0.1% Tween 20; 50 mmol/L Tris; 150 mmol/L NaCl) and incubated with nitrocellulose membranes for 1 h at room temperature using a multichannel immuoblotting device (Mini Protean II Multiscreen, Bio-Rad, Missassauga, ON, Canada). The membrane will then incubated for 1 h at room temperature with horseradish peroxidase–conjugated goat anti-human IgG (H+L;
Jackson ImmunoResearch, West Grove, PA) diluted 1/10,000 in Blotto and visualized by enhanced chemiluminescence.  
9.3 **Specimen Banking**
Subject samples collected for this study will be retained at the department of pathology and at the lab of Dr. Hannan (NC7. 208). 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
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10.0 quality of life and

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 IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 51 of 79 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].
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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.  
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.
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10.2.1 projection model and sensitivity

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.
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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
(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.
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12.0 study management 12.1 conflict

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.
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11.2 institutional review board (irb)

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.
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12.3 required documentation (for multi-site

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 IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 54 of 79 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.
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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 SCCCDSMC, 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.  
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 IRBapproved 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 IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 56 of 79 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.
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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.  
2. Kavanagh, B.D., R.C. McGarry, and R.D. Timmerman, Extracranial radiosurgery
(stereotactic body radiation therapy) for oligometastases. Semin Radiat Oncol, 2006. 16(2): p. 77-84.  
3. Milano, M.T., et al., *Oligometastases treated with stereotactic body radiotherapy: longterm follow-up of prospective study.* Int J Radiat Oncol Biol Phys, 2012. 83(3): p. 878-86.  
4. Salama, J.K., et al., Stereotactic body radiotherapy for multisite extracranial oligometastases: Final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease. Cancer, 2012. 118(11): p. 2962-70.  
5. Finkelstein, S.E., et al., *The confluence of stereotactic ablative radiotherapy and tumor* immunology. Clin Dev Immunol, 2011. **2011**: p. 439752.  
6. Corso, C.D., A.N. Ali, and R. Diaz, *Radiation-induced tumor neoantigens: imaging and* therapeutic implications. Am J Cancer Res, 2011. 1(3): p. 390-412.  
7. Rubner, Y., et al., How does ionizing irradiation contribute to the induction of anti-tumor immunity? Front Oncol, 2012. 2: p. 75.  
8. Ma, Y., et al., *Chemotherapy and radiotherapy: cryptic anticancer vaccines.* Semin Immunol, 2010. 22(3): p. 113-24.  
9. Apetoh, L., et al., *Toll-like receptor 4-dependent contribution of the immune system to* anticancer chemotherapy and radiotherapy. Nat Med, 2007. 13(9): p. 1050-9.  
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signature page version 11
14.0 appendices 14.1 appendix a

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
0 Dead  
| 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                                |  
14.2 Appendix B: High Dose Interleukin-2 Bolus Administration Algorithm  
  
UNIVERSITY HOSPITALS & CLINICS
St. Paul / Zale Lipshy Physician Orders High Dose Interleukin-2 Bolus Administration Algorithm To be completed prior to each dose at 6.00 am 2.00 pm and 8.00 pm  
| To be completed prior to each dose at 6.00 am 2.00 pm and 8.00 pm   |                                                          |                                                     |                                                |
|---------------------------------------------------------------------|----------------------------------------------------------|-----------------------------------------------------|------------------------------------------------|
| Sinus tach greater than 130 (persists after correcting              |                                                          |                                                     |                                                |
| System                                                              | Relative Criteria                                        |                                                     |                                                |
| Cardiac                                                             | ❏ Sinus tach 120-130                                     | o                                                   | hypotention, fever, stopping dopamine)         |
| EKG changes of Ischemia                                             |                                                          |                                                     |                                                |
| Atrial fibrillation                                                 |                                                          |                                                     |                                                |
| Supraventricular tachycardia                                        |                                                          |                                                     |                                                |
| L                                                                   | Ventricular armythmias (frequent PVCs, bigeminy, V-tach) |                                                     |                                                |
| o                                                                   | Elevated CK-MB                                           |                                                     |                                                |
| Dermatologic                                                        | L                                                        | Moist desquamation                                  |                                                |
| Gastrointestinal                                                    |                                                          | Diarrhea, 1000 milshift x 2                         |                                                |
| ❏ Billrubin > 7 mg/dL                                               | c                                                        | Vomiting not responsive to medication               |                                                |
|                                                                     | Severe abdominal distention affecting breathing          |                                                     |                                                |
| Severe abdominal pain, unrelenting                                  |                                                          |                                                     |                                                |
| Homodynamic                                                         | ❏ Max. phenylephrine of 1.5 mog/kg/min                   | o                                                   | Max. phenylephrine greater than 1.5 mcg/kg/min |
| ❏ Min. phenylephrine greater than 0.5 moglikg/min                   | Min. phenylephrine greater than 0.8 mcg/kg/min           |                                                     |                                                |
| ❏ Gualac + sputum, emesis                                           |                                                          |                                                     |                                                |
| Homorrhagic                                                         | Frank blood in sputum, emesis, stoo                      |                                                     |                                                |
| ❏ Platelets 30-50,000/mm²                                           | Platelets less than 30,000/mm                            |                                                     |                                                |
| Infections                                                          | Clinical suspicion                                       | Strong clinical suspicion or documented Infection   |                                                |
| □ Vivid dreams                                                      |                                                          |                                                     |                                                |
| Neurologic                                                          | Mental status changes not reversible in 2 hours          |                                                     |                                                |
| □ Emotional lability                                                | Disonentation                                            |                                                     |                                                |
| Hallucinations                                                      |                                                          |                                                     |                                                |
| Pulmonary                                                           | ❏ Resting shortness of breath                            | More than 4 L O2 to maintain sats greater than 95%  |                                                |
| □ 3 to 4 L O, by NC for sats greater than 95%                       | c                                                        | Endotracheal intubation                             |                                                |
| ❏ Rales 1/3 up chest                                                | Rales 1/2 up chest                                       |                                                     |                                                |
| Pleural effusion requiring tap or chest tube while on therapy       |                                                          |                                                     |                                                |
| □ Urine 80 to 160 mi/8 hour                                         |                                                          |                                                     |                                                |
| Ronal                                                               | Urine less than 80 ml/8 hour                             |                                                     |                                                |
| Urine 10 to 20 mi/hour                                              | Utine less than 10 ml/hour                               |                                                     |                                                |
| □ Creatinine 2.5 to 2.9 mg/dL                                       | Creatinine equal to or greater than 3.0 mg/dL            |                                                     |                                                |
| Weight gain                                                         | □ 15% weight gain over baseline                          |                                                     |                                                |
| Fever                                                               | - greater than 40° C but responsive to antipyretics      | │ greater than 40° C (104.0°F) for more than 24 hrs |                                                |
| Total Relative Criteria:                                            | Total Absolute Criteria:                                 |                                                     |                                                |  
Check one option below: Does not have any relative and absolute criteria:
❏ Give this scheduled dose.  
Has no absolute criteria but 1 or 2 relative criteria:
- Hold this scheduled dose (if corrective measures are effective, may continue after delay of up to 1 hour).  
Has any of the following
- 3 or more relative criteria
- Or any absolute criteria - Or on hold for over 24 hours
❏ Discontinue interieukin-2 therapy.  
Oncology Fellow Signature and ID\#
_Date/Time:  
| Oncology Fellow Name (PRINTED):   |
|-----------------------------------|
| Oncology Attending:               |
| Nurse Signature:                  |  
Pager \#:
Pager \#: Date/Time:
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 14.3
appendix c high dose interleukin-2
14.0 appendices 14.1 appendix a

UNIVERSITY HOSPITALS & CLINICS
St. Paul / Zale Lipshy Physician Orders High Dose Interleukin-2 Bolus DRG 492 Height:  
  
BSA:
r - actual weight
◾ ideal weight
🙂 adjusted weight  
  
Ideal Body Weight Calculations:
Males (kg) = 50+ (2.3 x \# inch > 5ft) Females (kg) = 45.5 + (2.3 x \# inch > 5ft)
Course Attending Physician:
Fellow/Resident:
Pager:
Admit to Unit Diagnosis: - Renal Cell Carcinoma - Metastatic Melanoma Metastatic Disease Sites: - Lung - Liver - Spleen - Soft Tissue/Sub-Q - Adrenal - Lymph Node Other:
Allergies:
Labs:
Admission: CBC, differential, Comp12, LDH, CPK, PT, PTT, magnesium, phosphorus, urinalysis, uric acid,
→
TSH, CK
Daily AM: CBC, differential, Comp12, LDH, magnesium, phosphorus, CK, PT, PTT, ionized Ca 10 Obtain baseline EKG
■
Procedures:
◾
- Chest x-ray after insertion of central venous catheter Nursing:
- Diet:  Regular, as tolerated
- Vital Signs with pulse ox: Before each dose of IL-2 and every 4 hours around the clock
◄ No IM injections
🙂 No powder to skin Pulse ox monitoring: ↑ Continuous
♦ Prn
❏ Continuous cardiac monitoring for SBP less than 90 mm Hg and HR greater than 120 beats per min. Daily EKG
while on continuous cardiac monitoring.  
◾
- Foley catheter (if unable to comply with strict I and Os) ◾ Strict intake and output Q 8 hours ◾  Daily weight BID (using the same scale) Contact physician with the following:
◾  urine output less than 30 ml/hr I temp greater than 38.5°C
- HR greater than 120 beats per minute
SBP less than 90 mm Hg pulse oximetry reading less than 95%
□
- alteration of mental status, including confusion and personality changes Medications:
Page I of 3 Physician Signature & ID\#:
Date/Time :  
| Date/Time:   |
|--------------|  
Pager\#:
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19  
| Physician name (PRINTED):   |
|-----------------------------|
| Nurse Signature:            |
ut southwestern medical center
high dose interleukin-2 bolus drg

◾
◾
hour and preferably 4 hours prior to first dose of IL-2. Continue until 8h after the last dose of IL-2.  
- Cephalexin (Keflex®) 250 mg PO BID after central line/PICC placement Pre-medications for IL-2:
❏ Ondansetron (Zofran®) 16 mg IV, 30 minutes prior to first dose of IL-2 and then daily until 12 hours after last dose of IL2
◾ ❏ Acetaminophen (Tylenol®) 650mg PO/PR 30 minutes prior to first dose of IL-2 then every 6 hours around the clock until 12 hours after last dose of IL-2
- Indomethacin (Indocin®) 25 mg PO 30 minutes prior to first dose of IL-2 then every 6 hours around the clock until 12 hours after last dose of IL-2
❏ Esomeprazole (Nexium®) 40 mg PO 30 minutes prior to first dose of IL-2 then daily until 12 hours after last dose of IL-2 Interleukin-2:
- Complete "High Dose Interleukin-2 Bolus Administration Algorithm" and call doctor on call at 0700, 1500 and 2300 to obtain permission to administer the next scheduled dose and notify pharmacy of decision. Each dose should be administered within one hour of the scheduled times (if the patient does not meet criteria for administration during that time, the dose should be held).  
- Interleukin-2 (Proleukin®) 600,000 IU/kg/dose =
international units total dose in D5W 50 ml to be infused IV over 15 minutes Q 8 Hours x 14 doses. Starts at 15:00 on solution.  
PRN medications:
◾
◾ ◾
❏ Lorazepam (Ativan®) 1 mg PO/IV Q 8 hours PRN for anxiety/nausear
◾
◾
◾
◾
Blood Pressure Management:
- NS 500 ml IV over 30 minutes for urine output less than 30 ml in 3 hours or SBP less than 90 mm Hg (or more than 20 mm Hg below baseline SBP); may repeat times 2 (total fluid bolus 1.5 L)
◾◾◾
mcg/kg/min to maintain SBP equal to or greater than 90 mm Hg (or equal to or greater than 20 mm Hg below baseline SBP).  
 Phenylephrine 20 mg/500 ml NS at 1 mcg/kg/min for SBP still less than 90 mm Hg (or more than 20 mm Hg below baseline SBP) after NS bolus and dopamine. Titrate to keep SBP above 90 mm Hg. If SBP remains less than 90 with Phenylephrine at 1.5 mcg/kg/min., notify physician and anticipate holding next dose of IL-2.  
Page 2 of 3  
| Physician Signature & ID#:                            | Date/Time:   |
|-------------------------------------------------------|--------------|
| Physician name (PRINTED):                             | Pager#:      |
| Nurse Signature:                                      | Date/Time:   |
| IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 |              |  
  
UNIVERSITY HOSPITALS & CLINICS
St. Paul / Zale Lipshy Physician Orders
ut southwestern medical center
high dose interleukin-2 bolus drg

Electrolyte Management:  
◾◾ KCl 40 mEq in NS 100 ml IVPB infuse over 4 hrs pm potassium less than 3.5 via central venous catheter ◾◾
creatinine less than 2 Other: Avoid contrast material unless strictly necessary. If patient to be readmitted for a second cycle a week from discharge, PICC line may be kept in place but patient should be discharged on Cephalexin (Keflex®) 250 mg PO BID.  
Patient's will typically need diuretics on discharge (+/- potassium supplements) and may resume outpatient antihypertensives.  
14.4 **Appendix D: US EQ-5D-3L**
Health Questionnaire English version for the US  
  
By placing a checkmark in one box in each group below, please indicate which statements best describe your own health state today.
ut southwestern medical center
mobility

I have no problems in walking about I have some problems in walking about I am confined to bed
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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
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pain/discomfort

I have no pain or discomfort I have moderate pain or discomfort  
I have extreme pain or discomfort
ut southwestern medical center
anxiety/depression

I am not anxious or depressed  
I am moderately anxious or depressed I am extremely anxious or depressed Best imaginable health state 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.
ut southwestern medical center
14.5 appendix e fact-g

Below is a list of statements that other people with your illness have said are important. Please circl or mark one number per line to indicate your response as it applies to the past 7 days.  
GP1 GP2 GP3 GP4 GPS
GPS GP7 GS! GS2 GS3 GS4 GSS
GSS
Q1 GS7  
| Not                                                            | A little   | Some-    | Very   |       |      |
|----------------------------------------------------------------|------------|----------|--------|-------|------|
| PHYSICAL WELL-BEING                                            | Quite      |          |        |       |      |
| at all                                                         | bit        | what     | a bit  | much  |      |
| I have a lack of energy                                        | 0          | 2        | 3      | 4     |      |
| l                                                              |            |          |        |       |      |
| I have nausea                                                  | 2          | 3        |        |       |      |
| 0                                                              | 1          | 4        |        |       |      |
| Because of my physical condition, I have trouble               |            |          |        |       |      |
| meeting the needs of my family .                               | 0          | l        | 2      | 3     | 4    |
| I have pain                                                    | 0          | l        | 2      | 3     | 4    |
| I am bothered by side effects of treatment .                   | l          | 2        | 3      |       |      |
| 0                                                              | 4          |          |        |       |      |
| 2                                                              |            |          |        |       |      |
| I feel ill                                                     | 0          | l        | 3      | 4     |      |
| I am forced to spend time in bed .                             | 0          | l        | 2      | 3     | 4    |
| SOCIAL/FAMILY WELL-BEING                                       | Not        | A little | Some-  | Quite | Very |
| at all                                                         | bit        | what     | a bit  | much  |      |
| I feel close to my friends .                                   | 0          | l        | 2      | 3     | 4    |
| I get emotional support from my family                         | l          | 2        | 3      |       |      |
| 0                                                              | 4          |          |        |       |      |
| I get support from my friends.                                 | 2          | 3        |        |       |      |
| 0                                                              | l          | 4        |        |       |      |
| My family has accepted my illness                              | 0          | 1        | 2      | 3     | 4    |
| I am satisfied with family communication about my              |            |          |        |       |      |
| illness                                                        | 0          | 1        | 2      | 3     | 4    |
| I feel close to my partner (or the person who is my main       | 2          | 3        |        |       |      |
| support) .                                                     | 0          | l        | 4      |       |      |
| Regardless of your current level of sexual activity, please    |            |          |        |       |      |
| answer the following question. If you prefer not to answer it, |            |          |        |       |      |
| please mark this box and go to the next section.               |            |          |        |       |      |
| I am satisfied with my sex life .                              | 0          | l        | 2      | 3     | 4    |  
| GEI   |
|-------|
| GE2   |
| GE3   |
| GE4   |
| ges   |
| GE6   |  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| FUNCTIONAL WELL-BEING                                                  | Not   | A little   | Some-   |
|------------------------------------------------------------------------|-------|------------|---------|
| at all                                                                 | bit   | what       |         |
| I am able to work (include work at home) ............................  | 0     | 2          |         |
| l                                                                      |       |            |         |
| My work (include work at home) is fulfilling.........................  | 0     | 2          |         |
| l                                                                      |       |            |         |
| I am able to enjoy life.                                               | 2     |            |         |
| 0                                                                      | l     | 2          |         |
| I have accepted my illness                                             | 0     | l          |         |
| I am sleeping well .                                                   | 0     | l          | 2       |
| I am enjoying the things I usually do for fun ........................ | 0     | 1          | 2       |
| I am content with the quality of my life right now..............       | 0     | l          | 2       |  
| Quite   | Very   |
|---------|--------|
| a bit   | much   |
| 3       | 4      |
| 3       | 4      |
| 3       | 4      |
| 3       | 4      |
| 3       | 4      |
| 3       | 4      |
| 3       | 4      |  
| GF1   |
|-------|
| GF2   |
| GF3   |
| GF4   |
| gfs   |
| GF6   |
| GF7   |  
| EMOTIONAL WELL-BEING                                                | Not   | A little   | Some-   | Quite   | Very   |
|---------------------------------------------------------------------|-------|------------|---------|---------|--------|
| at all                                                              | bit   | what       | a bit   | much    |        |
| I feel sad                                                          | 2     |            |         |         |        |
| 0                                                                   | l     | 3          | 4       |         |        |
| I am satisfied with how I am coping with my illness..........       | 0     | l          | 2       | 3       | 4      |
| I am losing hope in the fight against my illness................... | 0     | l          | 2       | 3       | 4      |
| I feel nervous .                                                    | 0     | 1          | 2       | 3       | 4      |
| I worry about dying                                                 | 0     | 2          | 3       |         |        |
| l                                                                   | 4     |            |         |         |        |
| 2                                                                   | 3     |            |         |         |        |
| I worry that my condition will get worse .                          | 0     | l          | 4       |         |        |  
14.6
ut southwestern medical center
appendix f fksi

Below is a list of statements that other people with your illness have said are important. Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
GP1 GPS GP4 C 2 BPI
H17 GF3 B 1 GE6 CC L 2 B
GF1 ROC2 gfs  
| Not                                            | A little   | Some-   | Quite   | Very   |    |
|------------------------------------------------|------------|---------|---------|--------|----|
| at all                                         | bit        | what    | a bit   | much   |    |
| I have a lack of energy                        | 0          | 2       |         |        |    |
| l                                              | 3          | 4       |         |        |    |
| I am bothered by side effects of treatment .   | 0          | 2       |         |        |    |
| l                                              | 3          | 4       |         |        |    |
| I have pain                                    | 0          | 2       | 3       |        |    |
| l                                              | 4          |         |         |        |    |
| I am losing weight .                           | 2          |         |         |        |    |
| 0                                              | 1          | 3       | 4       |        |    |
| I have bone pain .                             | 2          |         |         |        |    |
| 0                                              | 1          | 3       | 4       |        |    |
| I feel fatigued                                | 2          |         |         |        |    |
| 0                                              | 1          | 3       | 4       |        |    |
| I am able to enjoy life.                       | 2          |         |         |        |    |
| 0                                              | 1          | 3       | 4       |        |    |
| I have been short of breath                    | 2          |         |         |        |    |
| 0                                              | l          | 3       | 4       |        |    |
| I worry that my condition will get worse .     | 2          | 3       |         |        |    |
| 0                                              | l          | 4       |         |        |    |
| I have a good appetite .                       | 2          |         |         |        |    |
| 0                                              | 1          | 3       | 4       |        |    |
| I have been coughing .                         | 2          |         |         |        |    |
| 0                                              | l          | 3       | 4       |        |    |
| I am bothered by fevers (episodes of high body |            |         |         |        |    |
| temperature) .                                 | 0          | 1       | 2       | 3      | 4  |
| I am able to work (include work at home) .     | 0          | l       | 2       | 3      | 4  |
| I have had blood in my urine                   | 0          | 2       | 3       |        |    |
| 1                                              | 4          |         |         |        |    |
| I am sleeping well .                           | 0          | 1       | 2       | 3      | 4  |
ut southwestern medical center
14.7 appendix g - patient

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
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if you do not have

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.)  
| Don't                                                                                                                                                                                                                                                                                                                                                                                                              | Not   | Partial   | Full    |          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------|------------|----------|----------|
| TYPE OF SERVICE                                                                                                                                                                                                                                                                                                                                                                                                     | Know   | Covered    | Coverage | 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  
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*.  
| 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            | Paid for by           |
|----------------------------------------------------------------------|---------------------------------------------------------|--------------------------------------------------------|-----------------------|-----------------------|
| Fare                                                                 | Insurance/ Government  (circle one)                     |                                                        |                       |                       |
| Cancer Clinic/ Radiation  Facility Type of Visit                     |                                                         | 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)  
  
yourself paid by private insurance  paid by government
Amount (if known):
$ ____________ N/A N/A
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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 Amount (if known):
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 78 of 79  
$ ______________ $ _______________ $ _____________  
  
  
  
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):
$ ______________ $ _______________ $ _____________
ut southwestern medical center
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):
$ ______________ $ _______________ $ _____________
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g) family care (child or

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):
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 79 of 79  
$ ______________ $ _______________ $ _____________
ut southwestern medical center
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.  
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 80 of 79 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:
Widowed  Separated  Divorced  
$$\begin{array}{r l}{\square}&{{}{\mathrm{Married}}}\end{array}$$
$$\square\,\mathrm{C}$$  
Married  Common Law  Single (never married)
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 _____________________________
IL-2 STU012013-041, Hannan, Form A3, Mod_49, 05-20-19 81 of 79 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 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
_____________________________________________________________________________________________ _____________________________________________________________________________________________ _____________________________________________________________________________________________
___________________________________________________________________________________- ____________________________
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