Real-time MRI-Guided Stereotactic Body Radiation Therapy and Microwave Ablation for Non-Operable Renal Cell Carcinoma
Phase: PHASE1
Conditions: Carcinoma, Renal Cell
Sponsor: University of Wisconsin, Madison

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Phase IA/IB Trial of Real-time MRI-Guided Stereotactic Body 
Radiation Therapy and Microwave Ablation for Non-Operable Renal 
Cell Carcinoma 
 
NCT02782715 
 
 
PI:  
Michael Bassetti MD PhD 
Assistant Professor 
Department of Human Oncology 
University of Wisconsin Hospital and Clinics 
600 Highland Ave, K4/B100 
Madison, WI 53792 
 
bassetti@humonc.wisc.edu 
Phone: (608) 263 – 8500 
Fax: (608) 263 – 9167 
 
Co-Investigators:  
E. Jason Abel MD 
Assistant Professor 
Department of Urology 
University of Wisconsin Hospital and Clinics 
1685 Highland Ave 
Madison, WI 53705 
 
 
Sara Best MD 
Assistant Professor 
Department of Urology 
University of Wisconsin Hospital and Clinics 
1685 Highland Ave 
Madison, WI 53705 
 
 
Richard Chappell PhD 
Professor 
Department of Biostatistics & Medical Informatics and Department of Statistics 
University of Wisconsin Hospital and Clinics 
600 Highland Ave, K6/430 
Madison, WI 53792 
 
 
 
 

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Fred Lee MD 
Professor 
Departments of Radiology and Biomedical Engineering 
University of Wisconsin Hospital and Clinics 
600 Highland Ave, E3/366 
Madison, WI 53792 
 
Meghan Lubner MD 
Associate Professor 
Department of Radiology 
University of Wisconsin Hospital and Clinics 
600 Highland Ave, E3/366 
Madison, WI 53792 
 
 
Study Center: University of Wisconsin Hospital and Clinics 
 
 
 

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SYNOPSIS:  
Title 
Real-time MRI-Guided Stereotactic Body Radiation Therapy and Microwave 
Ablation for Non-Operable Renal Cell Carcinoma 
Short Title 
Microwave ablation with MRI-Guided SBRT Boost in Renal Cell Carcinoma 
Protocol Number/ 
Date 
UW15103 
Study Duration 
5 years 
Study Center(s) 
University of Wisconsin Hospital and Clinics  
Carbone Cancer Center, Madison, WI 
Objectives 
Primary Objective(s):  
The primary objective of this study is to determine the maximum tolerated 
dose (MTD) of stereotactic body radiation therapy followed by microwave 
ablation for non-operable renal cell carcinoma. 
Secondary Objective(s): 
The secondary objectives of this study include estimation of rates of local 
control, progression-free survival, overall survival, and tumor response on 
biopsy. 
Number of 
Subjects 
Based on the 3+3 dose-escalation design, between 9-18 patients will be 
enrolled in the initial Phase IA study, with an optional 10 patients enrolled on a 
Phase IB expansion cohort. 
Inclusion Criteria 
1. 
Histologically confirmed diagnosis of renal cell carcinoma 
2. 
Tumor size >4cm in largest dimension 
3. 
ECOG performance status of < 2 
4. 
Age > 18 years 
5. 
Signed informed consent document(s) 
6. 
Patients with metastatic disease will not be excluded 
Treatment 
summary 
The proposed study would be performed as a 3+3 dose-escalation study 
wherein three dose levels of SBRT would be evaluated:  
1. Dose level I: 6 Gy x 5 fractions 
2. Dose level II: 8 Gy x 5 fractions 
3. Dose level III: 10 Gy x 5 fractions 
 
Radiation treatments will be delivered two to three times a week, with five 
fractions completed over two weeks. 
 
Four to six weeks after radiation treatment, patients will undergo repeat CT or 
MRI imaging to assess tumor response and suitability for microwave ablation. 
 
Eight weeks after the conclusion of SBRT, patients will undergo microwave 
ablation (approximately 12 weeks after registration).   
 

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SCHEMA 
                
 
 
 
 
 
 
 
Registration in study, if eligibility criteria satisfied 
SBRT (week 1 and 2) 
Phase I: Microwave ablation with MRI-Guided SBRT Boost in  
Renal Cell Carcinoma 
Four weeks after SBRT completion: Assessment for ablation 
Microwave ablation 8 weeks  
from the completion of SBRT  
Dose-escalation levels (for Phase IA): 
•
Dose level I: 6 Gy x 5 fractions  
•
Dose level II: 8 Gy x 5 fractions 
•
Dose level III: 10 Gy x 5 fractions  
 
Dose-level for Phase IB will be based on the MTD from Phase IA 
Informed Consent 

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Table of Contents 
 
1.0 Protocol Summary  
2.0 Introduction 
3.0 Study Objectives 
4.0 Selection of Patients 
 
4.1 Inclusion 
 
4.2 Exclusion 
5.0 Registration Procedures 
6.0 Treatment Plan 
 
6.1 Overview 
 
6.2 Dose Escalation 
 
6.3 Pretreatment Workup 
 
6.4 Radiotherapy  
 
6.5 Microwave Ablation 
 
6.6 Pathology 
 
6.7 Other Therapy 
 
6.8 Duration of Therapy 
 
6.9 Follow-up 
6.10 Criteria for Removal from Treatment 
7.0 Measurement of Treatment 
 
7.1 Toxicity Assessment 
 
7.2 Local Control 
8.0 Study Parameters 
9.0 Statistical Analysis 
 
9.1 Number of Patients 
 
9.2 Study Endpoints 
 
9.3 Definition of endpoints 
 
9.4 Statistical Analysis 
 
9.5 Justification of Future Studies 
10.0 Pathology Review 
11.0 Data Collection 
12.0 Patient Consent 
13.0 Safety Monitoring 
 
13.1  SBRT 
 
13.2  Microwave Ablation 
 
13.3  Adverse Event Characteristics 
 
13.4  Adverse Event Reporting 
 
13.5 Stopping Rules 
References 
 
Appendix 1: Eligibility Checklist 
Appendix 2: UWCCC Data Safety Monitoring plan 
 
 
 

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1. 
Protocol Summary 
 
Renal cell carcinoma is traditionally managed via a surgical approach. Increasingly, local therapy with 
radiofrequency and microwave ablation is being utilized as an alternative for patients who may not 
tolerate a nephrectomy or who refuse one. Although local control rates for small lesions are excellent, 
they drop off precipitously for lesions over 4 cm. Furthermore, lesions in critical areas such as the renal 
hilum may be difficult to treat with this method. Stereotactic body radiation therapy (SBRT) has had a 
long record of treating patients with inoperable tumors in locations such as the lung and central nervous 
system, and there is increasing evidence that it may be useful for patients with renal cell carcinoma. The 
recent emergence of MRI-guided radiation therapy allows for direct visualization of tumors during 
treatment, and may potentially allow clinicians to treat tumors more precisely. This phase I study will 
treat renal cell carcinoma patients using a combination of MRI-guided stereotactic body radiation 
therapy and microwave ablation. 
 
The specific aims of this study are: 
1. To determine the safety and feasibility of treating patients with a combination of MRI-guided 
stereotactic body radiation therapy and microwave ablation. 
2. To assess short and long-term toxicity rates of patients treated with a combined modality 
approach. 
3. To assess local control, survival, and pathologic response to treatment 
 
2.  
Introduction 
 
The traditional management of renal cell carcinoma (RCC) has been total or partial nephrectomy. This 
has been shown to prevent long-term renal failure and cardiovascular disease, as well as decrease overall 
mortality[1]. Cytoreductive treatment has even been found to improve overall survival in the metastatic 
setting[2,3]. With the increasing numbers of renal masses found incidentally on routine imaging, focal 
therapies are being increasingly utilized as an alternative to partial nephrectomy for carefully selected 
patients who might not tolerate a nephrectomy or who refuse one. Studies of radiofrequency ablative 
treatments have reported disease-free survival, overall survival, and cause-specific survival rates of 
83.1-97%, 63-97.8%, and 96.4-100%, respectively[4]. More recently, microwave ablation has emerged 
as an alternative to radiofrequency ablation with promising early results[5,6]. Although thermal ablative 
strategies may be comparable to partial nephrectomy especially when balanced against the potential 
morbidity of surgery, they are less effective at controlling larger tumors. Three centimeters has emerged 
as a common threshold above which thermal ablative strategies are less commonly recommended, with 
5-year disease-free survival decreasing from 96% to 79%[7]. Microwave ablation is effective to 4cm; as 
with RFA, however, local control rates drop precipitously for tumors above 4cm[8]. 
 
The role of external beam radiation therapy in the treatment of RCC is less established, as it is typically 
considered a radioresistant entity. Radiation therapy is usually given in 30 or more doses of 2 Gy per 
fraction, delivered daily over several weeks. Stereotactic body radiation therapy (SBRT) differs from 
conventionally fractionated treatment, using radiation doses of up to 34 Gy in a single fraction. It is 
believed that at such high doses, radiation therapy is ablative[9]. Advances in physics, imaging, and 
motion management have made such treatment possible and it is considered standard of care in 

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medically inoperable non-small cell lung cancer [10]. Phase I studies utilizing SBRT in the treatment of 
renal cell carcinoma show promising results[11,12]. 
 
One challenge that exists when utilizing high doses of radiation therapy in the kidney is that of 
respiratory induced tumor motion. Respiratory gating techniques are utilized to minimize normal tissue 
irradiation. Nevertheless, any such technique is limited by the fact that it depends on the assumption that 
there is a good correlation between respiratory motion and tumor motion. 
 
The recent emergence of a radiation treatment system allowing real-time MRI imaging during treatment 
may obviate the dependence on respiratory gating techniques[13]. Tracking tumor motion in real time 
allows the potential for the delivery of safe and effective radiation treatment with the goal of improving 
control rates of ablative treatments for large, medically inoperable renal cell carcinomas. 
 
We propose a Phase I study to determine the feasibility of adding SBRT treatment for patients 
undergoing treatment for RCC. We hope to show that such treatment is feasible and safe. 
 
3.  
Study Objectives 
 
3.1 Working hypothesis – We hypothesize that the addition of SBRT treatment to microwave 
ablation is safe and can be delivered without undue toxicity. 
 
3.2 Primary Objective - The primary objective of this study is to determine the maximum tolerated 
dose (MTD) of stereotactic body radiation therapy followed by microwave ablation for non-
operable renal cell carcinoma. Toxicity will be evaluated via the CTCAE Criteria v5.0. Expected 
side effects of radiation treatment include potential fatigue, dermatitis, chest wall pain, nausea, 
and hematuria. Side effects of ablation may include hemorrhage, treatment site pain, urinary 
retention, and a decrease in glomerular filtration rate. 
 
3.3 Secondary Objective - The secondary objectives of this study include estimation of rates of local 
control, progression-free survival, overall survival, and tumor response on biopsy. 
 
3.4 Exploratory Objective – To assess pathologic response after stereotactic body radiation therapy 
and immune cell infiltrate. 
 
3.5 Study Duration – We estimate that approximately 40-50 potentially eligible patients are seen at 
UWCCC each year. With a 3+3 study design and an estimated 20% rate of enrollment, we 
estimate it will take 1-2 years for patient accrual, treatment, and followup for determination of 
acute toxicity of the initial 9-18 patient Phase IA cohort. This cohort will then be followed for a 
period of 3 years, giving an estimated study duration of 5 years. 
 
4. 
Selection of Patients 
 
4.1 Inclusion Criteria 
4.1.1 Patients with imaging findings consistent with renal cell carcinoma 
4.1.2 Deemed medically inoperable per urology evaluation 
4.1.3 Tumor size > 4cm in largest dimension 

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4.1.4 ECOG performance status of < 2 
4.1.5 Age > 18 years 
4.1.6 Signed informed consent document(s) 
4.1.7 Patients with metastatic disease will not be excluded 
 
4.2 Exclusion Criteria 
4.2.1 Patients who fail MRI screening 
4.2.2 Pregnant or nursing women 
4.2.3 History of prior radiation therapy to the upper abdomen 
4.2.4 History of invasive cancer in the last 3 years (except for appropriately treated low-risk 
prostate cancer, treated non-melanoma/melanoma skin cancer, appropriately treated ductal 
carcinoma in situ or early stage invasive carcinoma of breast and appropriately treated in-
situ/early stage cervical/endometrial cancer) 
4.2.5 Treatment with a non-approved or investigational drug within 28 days of study treatment 
 
 
5. 
Registration Procedures 
 
Patients may not begin protocol treatment prior to registration. All patients must meet eligibility 
criteria listed in Section 4 and provide written informed consent. The study coordinator will verify 
eligibility, assign a case number, and register the patient in the UWCCC ONCORE database prior 
to study treatment.  The following information will be recorded: 
 
5.1 
Protocol number 
5.2 
Patient’s name and initials 
5.3 
Patient’s medical record number 
5.4 
Patient demographic data including gender, birth date, race and zip code. 
5.5 
Signed patient consent form dates 
5.6 
Attending physician 
5.7 
HIPAA authorization form dates 
 
6. 
Treatment Plan/Overview 
 
6.1 
Overview 
 
Patients will be referred to the study by their treating urologist. The urologist will determine the 
appropriateness for patient referral and discuss the option of study participation with their 
patients. After biopsy, patients will be treated on study with a course of SBRT treatment by a 
radiation oncologist. A 3+3 dose escalation scheme will be used. Four to six weeks after 
treatment, patients will be evaluated for microwave ablation by the treating radiologist with 
repeat imaging to ensure microwave ablation remains feasible. Two months after treatment, 
patients will be referred to an interventional radiologist for treatment with microwave ablation as 
well as repeat biopsy for exploratory analysis. Both SBRT and MWA will be administered on an 
outpatient basis. Details of treatment are as described below. 
 
6.2 
Dose escalation 
 

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6.2.1. The proposed study will follow a phase IA-B dose-escalation design wherein three SBRT 
dose levels targeting the primary tumor will be evaluated; level I: 6 Gy x 5 fractions (a 
common palliative dose), level II: 8 Gy x 5 fractions and level III: 10 Gy x 5 fractions (a 
common definitive dose). 
 
6.2.2. Dose-limiting toxicity (DLT) will be defined as any grade 4 or higher toxicity that occurs 
within 30 days post MWA (approximately 90 days post SBRT) specifically: hemorrhage, 
hematoma, nephrotoxicity, gastric, duodenal or small bowel perforation or obstruction 
attributable to the radiation, the MWA or the combination of the treatment. Attributable 
DLT will be defined as that which is possibly, probably or definitely felt to be due to 
either radiation or ablation and occurring within the vicinity of the radiation treatment 
field (as reviewed by Drs. Bassetti/Wojcieszynski) or in the vicinity of the microwave 
ablation (as reviewed by Dr. Lee). Grade 3 toxicity is not considered a DLT as it may be 
seen in routine, standard of care treatment. If progressive disease is found at the time of 
interval imaging and the patient is deemed ineligibile for MWA, the patient will not be 
part of the cohort used for DLT analysis as his/her inclusion may falsely lower potential 
toxicity rates. 
 
6.2.3. A standard, traditional 3+3 design will be utilized for dose escalation (Figure). For each 
three patient cohort, DLT will be assessed. In the case of 0/3 DLTs, the dose will be 
escalated to the next level. In the case of 2/3 DLTs, the dose escalation will be halted 
with the previous level being the MTD. In the case of 1/3 DLTs, an additional three 
patients will be enrolled at the current dose level. If no additional DLTs are seen, the dose 
will be escalated to the next level. In the event of a total of 2 or more DLTs in 6 patients, 
the dose escalation will be halted with the previous dose level being the MTD. Once the 
MTD has been established, the MTD will be used for the subsequent Phase IB expansion 
cohort. 
 
6.2.4. Dose escalation/de-escalation will continue until a maximum of 18 patients are accrued 
or dose-level I is shown to exceed the MTD. To allow efficient conduct of the study 
without compromising patient safety, accrual in the phase-IA study will be done in 
groups of three patients, with subsequent dose level accrual only after the occurrence of 
DLT thirty days after ablation has been evaluated for all at the curret dose level. The 
phase-IB portion of the trial will consist of an additional ten patients (for a theoretical 
maximum of 28 total patients) to validate the results of phase-IA and provide a 
preliminary assessment of efficacy. 
 
 
 
 
 
 

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6.3 
 Pretreatment workup 
 
6.3.1. CT/MRI scan of the chest, abdomen, and pelvis 
6.3.2. Laboratory evaluation including complete blood count (CBC) with differential, basic 
metabolic panel (BMP) including creatinine 
6.3.3. A renal nuclear medicine scan may be obtained prior to radiation treatment or microwave 
ablation to estimate functional renal parenchymal volume if deemed necessary by the 
treating physicians. 
 
6.4 
Radiotherapy details 
 
6.4.1. Simulation 
 
All patients will be planned using MRI simulation on the MRIdian system (Viewray Inc., 
Mountain View, CA). Simulation scans will be performed with patients supine in the arms up 
or down position. MRI coils will be placed directly on the patient. Patients will be simulated 
with a breath hold technique. A standard-of-care computed-tomography (CT) planning scan 
will be obtained in the same position as the MRI planning scan in order to obtain density data 
for dose calculations. The MRI and CT planning scan will then be imported in to the 
Treatment Planning System (TPS) (Viewray Inc., Mountain View, CA) which will then be 
utilized to create SBRT treatment plans. 
 
6.4.2. Target Delineation 
 
Gross tumor volume (GTV) will be contoured with the help of co-registered pretreatment 
imaging. No expansion to a clinical tumor volume (CTV) will be performed. A planning 
tumor volume (PTV) will be customized for each patient at the time of simulation to account 

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for each patient’s ability to breath-hold, reproducible tumor motion, and estimated variation 
in daily setup. 
 
6.4.3. Radiation Dose 
 
The PTV will be treated to a dose of 6, 8, or 10 Gy for 5 fractions, for a total dose of 30, 40, 
and 50 Gy, respectively as per current dose cohort. 
  
6.4.4. Radiation fractionation 
 
Radiation treatments will be delivered on alternate days. Treatments will preferentially start 
on Mondays, although the start of therapy on Tuesday or Wednesday is also acceptable. 
  
6.4.5. SBRT Planning Process 
 
An inverse IMRT planning process will be performed using the treatment planning system to 
determine if the desired PTV dose is feasible to administer without exceeding a safe radiation 
dose to normal structures. 
 
6.4.6. Normal Tissue Constraints 
 
No volume outside of the PTV should receive more than 105% of the prescription dose. 
Planning dose-volume constraints (Table 1) are based on constraints used by Hong et al.[14] 
as well as Pham et al[12]. If dose constraints are unable to be met for a given patient at the 
current dose level, the dose per fraction will be decreased until acceptable constraints are met 
and the patient will continue off study. Of note, no specific dose constraints will be utilized 
for the involved kidney. This has been most extensively studied in a series of patients who 
underwent SBRT to a solitary kidney, with no reports of late toxicity noted[15]. As a result, 
the QUANTEC group guidelines recommend no specific dose constraints be applied to the 
involved kidney during SBRT[16]. 
 
Structure 
Dose Constraint 
Spinal Cord 
Dmax = 25 Gy 
Stomach 
D0.1cc < 32 Gy 
Bowel 
D0.1cc < 32 Gy 
Liver 
D700cc < 15 Gy 
Contralateral Kidney 
V13 < 30%, Mean < 10 Gy 
Table 1: SBRT Dose Constraint Table 
 
6.5 
Microwave ablation (MWA)details 
 
All procedures will be performed under sedation utilizing ultrasound and computed 
tomography (CT) guidance for percutaneous antenna placement and confirmation. A 
multidisciplinary team, consisting of a radiologist and a urologist experienced in tumor 
ablation, will perform each procedure. Depending on the size and location of the tumor, one 
to three antennas (Certus 140; NeuWave Medical, Madison, WI) will be used. The MW 

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system used for this study is the Certus 140 (NeuWave Medical, Inc., Madison, WI). The 
system is an FDA-approved, high-powered (140W in up to three channels) third-generation 
MW device that uses CO2 gas cooling to prevent shaft heating. The gas cooling also allows 
the probes to be stuck into tissue by creating a small ice ball at the tip using the Joule–
Thomson method, similar to the tissue cooling mechanism of cryoablation systems. The 
probes are 17-gauge, and several different ablation zone configurations are available 
depending on which probe is selected. The expected ablation diameter in ex vivo tissue is 
available on the manufacturer’s website (www.neuwave.com), but varies somewhat 
depending on the tissue type and tumor vascularity. If the tumor is in close proximity to 
adjacent structures, injectable grade dextrose 5% sterile water will be instilled through a 
spinal needle to increase the distance from the treatment zone (hydrodisplacement). For 
hydrodisplacement, the treatment team will consider the subjective proximity of structures as 
well as the expected ablation zone, which varies according to the manufacturer’s 
specifications for the individual probe types. An ablation protocol utilizing the 65W power 
setting for 5 minutes will be used in the majority of patients. Ultrasound will be used for real-
time monitoring of the extent of ablation to achieve a 5mm margin beyond the tumor, and 
immediate post-procedure imaging performed using contrast-enhanced CT (CECT) for all 
patients with adequate renal function. All patients will be admitted overnight for observation 
as per standard of care. 
 
6.6 
Tissue Sampling 
 
Clinical pathologic evaluation 
At the time of the initial diagnostic biopsy, a four quadrant biopsy will be performed per 
normal procedures.  All tissue from the four quadrant biopsy will be processed per normal 
UW pathology procedures.  
 
Research tissue sampling 
If a clinical biopsy confirming renal cell cancer has not yet been performed, at the time of the 
clinical biopsy, 3 additional core biopsy samples will be obtained for research purposes. The 
samples will allow for creation of paraffin embedded, cryo-embedded and fresh frozen 
sections for evaluation of SBRT treatment response prior to microwave ablation.  
 
During the microwave ablation procedure, 3 core biopsy samples will be obtained for 
research purposes. The primary tumor will be assessed for percent residual viable cells, the 
ratio of residual viable tumor to parenchyma, ratio of fibrotic stroma to tumor mass in the 
resected specimen, and immune cell infiltration, by the study team at a later date.   
 
The research samples will be obtained and stored by the University of Wisconsin Carbone Cancer 
Center Translational Science BioCore (TSB-BioBank, University of Wisconsin Hospital Carbone 
Cancer Center, 1111 Highland Ave, Madison, WI 53705).  The BioBank utilizes ONCORE for 
“registration” of the samples to the BioBank.  Actual samples study samples(research core samples) 
will be coded with the study number, case # assigned by Radiation Oncolgy staff, and timepoint: 1 
(pre-treatment) or 2 (post- XRT). All BioBank staff have undergone required human subjects 
training and HIPAA training. Actual specimens will be located within the BioBank in a room that is 
card access controlled with monitoring. 

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6.6.1. Permitted Supportive Therapy 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented 
on each site’s source documents as concomitant medication 
 
6.7 
Duration of Therapy 
 
Treatment with SBRT will be delivered over a period of two weeks, with radiation delivered 
two to three times per week. Four to six weeks after treatment, patients will be evaluated for 
microwave ablation by the treating radiologist with repeat CT or MRI imaging of the 
abdomen. Eight weeks after the conclusion of radiation treatment, patients will undergo 
microwave ablation, a single procedure. Adjuvant systemic treatment will be administered 
per institutional policies, physician recommendations, and patient preferences. Criteria for 
removal from study are described below. 
 
6.8 
Duration of Follow-Up: Refer to Table 2 
 
After study enrollment, patients will undergo SBRT over a period of approximately 2 weeks. 
After 8 weeks, patients will undergo microwave ablation. Post treatment, patients will be 
followed as per standard of care. This will include a clinical visit four weeks after ablation, 
three months after ablation, six months after ablation, followed by visits every 6 months for a 
period of 3 years. Imaging will include either contrast-enhanced CT or MRI imaging at 3 and 
6 months post therapy and every 6 months for 3 years. A BMP (including creatinine) will be 
obtained with imaging to evaluate renal function. Long term toxicity (specifically, 
nephrotoxicity, bowel obstruction, skin changes, and pain) will be assessed at these follow-
up visits. Follow-up visits will be conducted by one of the treating physicians (radiation 
oncologist, interventional radiologist, or urologist) who will document physical exam, 
laboratory, and imaging findings as well as evaluate for toxicity. Any other evaluations 
prompted by symptoms, laboratory evaluation, or at the treating physicians’ discretion may 
be performed as per standard of care. If a patient decides to withdraw from the study for non-
treatment related reasons, no additional study-specific information will be obtained from the 
patient’s future follow-up visit. 
 
6.9 
Criteria for Removal from Treatment 
 
A patient’s ongoing treatment on protocol will be temporarily or permanently withheld if any 
of the events below occur: 
 
6.9.1. Illness that prevents further administration of treatment 
6.9.2. Radiation dose constraints that are unable to be met at the current dose level. 
6.9.3. DLTs or other unacceptable adverse events 

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14
6.9.4. Patient decision to withdraw from study 
6.9.5. General or specific changes in patient’s condition render the patient unacceptable for 
further treatment in the judgment of the treating physician or the study investigators 
 
The reason for treatment stop/study removal and the date will be documented in a Case 
Report Form. 
 
7. 
Measurement of Treatment 
 
7.1 
Toxicity Assessment 
 
7.1.1. Dose-limiting toxicity (DLT) will be defined as  grade 4 non-hematologic/grade 5 
toxicity attributable to treatment , occurring until 30 days after ablation. Patients will be 
monitored and assessed for unexpected long-term toxicity during the post-treatment 
followup period. In the case of unexpected long-term toxicity, the dose level will be 
evaluated and potentially used to recalculate the MTD. Potential toxicities due to 
stereotactic body radiation therapy and microwave ablation are listed in Section 13.1 and 
13.2 respectively. The most likely acute side effects of treatment include fatigue, nausea, 
vomiting, and pain due to the procedure. Toxicities not caused by treatment, such as pain 
due to tumor progression, will be excluded from the assessment. 
 
7.2 
Local Control 
 
7.2.1. Imaging response will be measured as per the RECIST criteria[17] 
7.2.1.1. 
Complete Response (CR) – Disappearance of entire target lesion 
7.2.1.2. 
Partial Response (PR) – At least a 30% decrease in the sum of the diameters of 
the target lesion, taking as reference the baseline sum diameters. 
7.2.1.3. 
Progressive Disease (PD) - At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: 
the appearance of one or more new lesions is also considered progression)  
7.2.1.4. 
Stable Disease (SD) - Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study. 
 
7.3 
Progression free survival defined with follow-up radiological assessment with progression 
free survival (PFS) calculated from the point of start of SBRT to the point of recurrence or 
death. 
7.4 
Overall survival (OS) defined from the point of start of SBRT to the time of death or last 
follow-up if alive. 
7.5 
Tumor pathology: H&E staining and pathologic evaluation for percentage of viable tumor 
remaining as measured by the presence of necrosis, fibrosis, hyalinization, and/or 
calcification, compared to pre-SBRT pathology. 
 
 

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8. 
Study Parameters 
 
8.1 
Patients will be followed for a minimum of three years with standard-of-care clinical visits, 
laboratory studies, and imaging. A study calendar is provided below. After treatment, 
patients will be seen for clinical follow-up at 1 month after treatment and then every 3 
months until 6 months after treatment, at which point the visits will occur every 6 months 
until 3 years have passed, at which point further follow-up will be at the discretion of the 
treating physician. 
 

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Table 2: Study Calendar 
 
Pre-treatment 
(within 
6 
weeks of reg) 
Wk 1 
Wk 2 
4-6 wk  
post SBRT 
MWA 1 
1 month  
post MWA 
Follow 
up 
visits2 
Informed Consent 
X 
 
 
 
 
 
 
Biopsy4 
X 
 
 
 
 
 
 
MRI Clearance 
X 
 
 
 
 
 
 
Radiation planning  
X 
 
 
 
 
 
 
SBRT 
 
X 
X 
 
 
 
 
Microwave Ablation 
 
 
 
 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
X 
X 
Physical Examination 
X 
 
X 
X 
 
X 
X 
Vital Signs 
X 
 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
X 
X 
ECOG Performance status 
X 
X 
X 
X 
 
X 
X 
Complete blood count with 
differential count 
X 
 
X 
X 
 
 
 
Basic Metabolic Panel 
X 
 
 
X 
 
X 
X 
Adverse event evaluation 
 
X 
X 
X 
 
X 
X 
B-hCG for WOCBP 
X 
 
 
 
 
 
 
Research Biopsy3 
X 
 
 
 
X 
 
 
Radiological evaluation/CT or 
MRI of Chest, Abdomen and 
Pelvis 
X 
 
 
X5 
 
 
X5 
1:  MWA will be approximately 8 weeks post XRT 
2: Followup: 3 months and 6 months post MWA then every 6 month for 3 years, then annually 
3: Research biopsy sampling will be done at the time of the diagnositic biopsy (if not yet performed at 
time of consent) and at during the microwave ablation procedure 
4:  Clinical diagnostic biopsy does not have a “window”.  Patient must be treatment naïve for the renal 
cell carcinoma at time of study enrollment. 
5: 
Imaging post ablation therapy will be at MD discretion, and in accordance with NCCN guidelines  
 
 
9.0 Statistical Analysis 
 
9.1 Number of patients 
9.1.1 Phase IA – Nine (9) – eighteen (18) patients 
9.1.1.1 
We estimate that approximately 40-50 potentially eligible patients are 
seen at UWCCC each year. With a 3+3 study design and an estimated 
20% rate of enrollment, we estimate it will take 1-2 years for patient 
accrual, treatment, and followup for determination of toxicity of the 
initial 9-18 patient Phase IA cohort. 
9.1.2 Phase IB – Ten (10) patients 
9.1.2.1 
An additional ten patient, Phase IB expansion cohort will be accrued at 
the MTD at the conclusion of the Phase IA study to obtain further 
assessments of safety and provide preliminary estimates of local 
control rates to inform a potential Phase II study. 
 
9.2 Study Endpoint(s) 

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9.2.1 Primary Endpoint of Phase I study: 
9.2.1.1 
Dose-limiting toxicity with SBRT combined with microwave ablation 
for renal cell carcinoma. 
9.2.2 Secondary Endpoint(s) of Phase I study: 
9.2.2.1 
Local control rate 
9.2.2.2 
Progression free survival 
9.2.2.3 
Overall survival 
9.2.2.4 
Tumor pathology of post-SBRT specimen 
 
9.3 Definition of end-points 
 
9.3.1 Primary Endpoint of the Phase I study: 
 
Dose-limiting toxicity (DLT) will be defined as grade 4 or higher  non-hematologic 
toxicity attributable to treatment occurring until 30 days after ablation. This will exclude 
toxicities not caused by treatment, such as pain due to tumor progression. Toxicities will 
be defined per NCI CTCAE v5.0. 
 
9.3.2 Secondary endpoints of the Phase I study: 
9.3.2.1 
Local control: Radiologic response per RECIST criteria and 
volumetric measurements. 
9.3.2.2 
Progression free survival defined with follow-up radiological 
assessment with progression free survival (PFS) calculated from the 
point of start of SBRT to the point of recurrence or death. 
9.3.2.3 
Overall survival (OS) defined from the point of start of SBRT to the 
time of death or last follow-up if alive. 
9.3.2.4 
Tumor pathology: H&E staining and pathologic evaluation for 
percentage of viable tumor remaining as measured by the presence of 
necrosis, fibrosis, hyalinization, and/or calcification, compared to pre-
SBRT pathology. 
 
9.4 Statistical Analysis 
 
9.4.1 Primary objective of Phase I study: 
 
A 3+3 design will be utilized for dose escalation. For each three patient cohort, 
DLT will be assessed as above. In the case of 0/3 DLTs, the dose will be escalated 
to the next level. In the case of 2/3 DLTs, the trial will be terminated with the 
previous level being the MTD. In the case of 1/3 DLTs, an additional three 
patients will be enrolled at the current dose level. If no additional DLTs are seen, 
the dose will be escalated to the next level. In the event of a total of 2 or more 
DLTs in 6 patients, the trial will be terminated with the previous dose level being 
the MTD. Toxicities will be tabulated by type and grade. 
 
9.4.2 Secondary objectives of Phase I study: 

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18
 
9.4.2.1 
Local control will be reported actuarially as a percentage with an 
associated 95% exact confidence interval. 
9.4.2.2 
Progression free and overall survival will be estimated using the 
Kaplan-Meier method. For calculation of PFS, patients without 
recurrence and alive at last follow-up will be censored at the date of 
the last radiologic assessment. For calculation of OS, patients alive at 
last follow-up will be censored. Log-rank test and Cox regression 
analysis will be used for univariate and multivariate analyses, 
respectively. Chi-square and regression analysis will be performed to 
test association of categorical variables with treatment response. 
9.4.2.3 
Tumor response will be reported via rates of complete response, partial 
response, and no response. 
 
9.5 Justification for future studies 
 
9.5.1 After study accrual, patient safety data will be analyzed to ensure treatment was 
well tolerated. If found to be acceptable, a larger Phase II study powered to detect 
a 15% increase in local control rates as compared to historical control, with a 
power of 80% and alpha of 0.1 would be initiated. 
 
10.0 Pathology Review 
 
Post-stereotactic body radiation therapy pathology will be obtained at the time of microwave 
ablation and compared to the samples obtained prior to treatment. This will be obtained in order to 
complete the correlative studies described above and to determine tumor response to radiotherapy 
treatment. These pre-ablation samples are collected for research puposes only and no tissue will be 
submitted to the UW Pathology department for clinical use. 
 
Analysis of research samples 
-Samples will be processed and scored per standard institutional practices University of 
Wisconsin Carbone Cancer Center Translational Science BioCore (TSB-BioBank). Paraffin 
embedded, cryo-embedded, and fresh frozen sections will be stored. 
 
-Futrue analysis by the study team will include H&E staining and evaluation for percentage of 
viable tumor remaining as measured by the presence of necrosis, fibrosis, hyalinization, and/or 
calcification, and immune cell infiltration and compared to pre-SBRT pathology obtained at the 
time of original tumor diagnosis. 
 
Tumor samples will be sent to the TSB-BioBank, University of Wisconsin Hospital Carbone Cancer 
Center, 1111 Highland Ave, Madison, WI 53705 per standard procedures 
 
11.0 Data Collection/Storage/Confidentiality 
 
Clinical trial coordinators in the Department of Human Oncology will do baseline data 
collection for each patient accrued into the protocol. The PIs, with the support of co-

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investigators would collect specific disease, treatment and outcome related data, which 
will include: 
 
Medical history including basic patient demographics as collected during registration, co-
morbidities/habits and disease related variables including ECOG performance score, 
histological differentiation, tumor location, maximal tumor dimension as measured on 
diagnostic CT imaging, presence or absence of regional LN on diagnostic imaging, 
presence of metastatic disease at diagnosis, other pertinent findings on diagnostic 
imaging, stage, weight loss at presentation, baseline pain assessment, baseline laboratory 
parameters, treatment details, toxicity outcomes, treatment outcomes (clinical, 
radiological), and follow-up course.  
 
The information collected for this study will be protected by limiting access to the data 
sheet to the study researchers. To ensure patient confidentiality information collected in 
this study will be kept on a secure computer within the Department of Radiation 
Oncology network, which is protected by a firewall that ensures the privacy of the 
network. Access to the information is limited to those listed in the protocol, all of whom 
have completed the requisite human subjects/HIPAA training and been given valid 
clinical access to this information. 
 
Each subject will be assigned a research subject number, which is a code that can link the 
medical record number to the study data in the subject log. The subject log will be 
maintained on a secure password protected computer in the Department of Human 
Oncology. In addition to the principal investigators, the co-investigators will have access 
to the subject log. 
 
12.0 Patient Consent and Peer Judgment 
 
Current FDA, NCI, state, federal, and institutional regulations regarding informed consent will 
be followed. 
 
13.0 Safety Monitoring 
 
13.1 Adverse Event List for SBRT 
Likely 
Gastritis 
Nausea and vomiting 
Diarrhea 
Fatigue 
Loss of appetite and weight loss 
Mild radiation dermatitis 
Less likely 
Pigmentation changes and fibrosis in the cutaneous, subcutaneous and deep visceral tissues 
in the radiation field 
Musculo-skeletal aches in the treatment fields. 

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Decrease in blood counts resulting in increased risk of infection, weakness, and/ or in 
bleeding and bruising easily 
Hematuria 
Rare but serious late effects 
Bowel obstruction 
Gastric, duodenal or small-bowel ulceration or perforation 
Hepatotoxicity 
Chronic Kidney Injury 
Renal Hemorrhage 
Transient myelopathy 
Second malignancy 
 
13.2 Adverse Event List for Microwave Ablation/Biopsy 
Likely 
Pain 
Paresthesia 
Post-ablation syndrome 
Nausea 
Vomiting 
Malaise 
Fever 
Hematuria 
Acute Kidney Injury 
Less Likely 
Hemorrhage 
Hematoma 
Rare but serious late effects 
Bladder outlet obstruction 
Bowel perforation or ulceration 
Nephrotoxicity 
Myelopathy 
Chronic Kidney Injury 
Ureteral damage 
Tumor seeding 
13.25 Adverse Event List for Biospy 
 Likely 
Pain 
Infection 
A general feeling of discomfort 
Blood in urine 
Less Likely 
Bleeding that requires a transfusion 
Blood clot in the kidney 
Rare but serious late effects 
Difficulty passing urine due to damage to the kidneys and ureters 
Permanent tingling/numbness in the area treated due to nerve damage 

4/16/19 
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13.3 Adverse events characteristics 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  A copy of the CTCAE 
can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes only. 
 
 
Attribution of the AE: 
 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
13.4 Adverse Event Reporting 
 
Adverse events (AEs) and serious adverse events (SAEs) will be recorded in study database. All 
SAEs will be reported to the GU DOWG, UWCCC, and UW HS-IRB per policy. Reporting 
criteria are summarized in Table 3. 
 
An AE is an undesirable medical occurrence (sign, symptom, or diagnosis) or worsening of a 
pre-existing medical condition (diabetes, congestive heart failure, rheumatoid arthritis) that 
occurs after initiation of the investigational product whether or not it is considered to be 
investigational product related.  A worsening of an existing medical condition is one that was 
present at baseline (e.g., cancer, diabetes, migraine headaches, gout) and became more 
severe, more frequent, or increased in duration during investigational product treatment.  
 
Expected events - Expected events are those that have been previously identified as resulting 
from treatment of renal cell cancer with radiation and MWA. These are defined above for acute and 
late toxicities (section 13.1). For purposes of this study, reporting requirements are determined 
by the assessment of the following adverse event characteristics: the type or nature of the 
event; the severity (grade); the relationship to the study therapy (unrelated, not likely, possibly, 
likely, or definitely related), and whether the event is expected or unexpected. 
 
Recommended assessment steps include: 
• Identification of adverse event. 
• Determine whether the adverse event is expected or unexpected. 
• Grading the severity of the adverse event using the appropriate set of criteria; CTCAE v5.0 
(General, unexpected). 
• Determination as to whether the adverse event is related to the study therapy using the 
following categories: Unrelated, Possible, Probable, and Definite 
 
For the purpose of this study adverse event information will be collected through 30 day post MWA 
visit.  After the 30 day visit only events specific late treatment effects will be collected. 

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We will continue to collect information on gastric, duodenal bowel and bladder  ulcerations, 
perforations and obstructions, nephrotoxicity, myelopathy, ureteral damage tumor seeding and second 
malignancy’s 
 
An SAE is defined by regulatory agencies as one that suggests a significant hazard or side 
effect, regardless of the investigator or sponsor’s opinion on the relationship to 
investigational product.  This includes, but may not be limited to, any event that (at any 
dose): 
 
1. Is fatal 
2. Is life threatening (places the subject at immediate risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
4. Is a persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. Any event that does not exactly meet this definition yet, in the investigator’s opinion 
represents a significant hazard can be assigned the “other significant hazard” regulatory 
reporting serious criteria 
7. Additionally, important medical events that may not be immediately life threatening or 
result in death or hospitalization but that may jeopardize the subject or require 
intervention to prevent one of the outcomes listed above, or result in urgent investigation, 
may be considered serious.  Examples include allergic bronchospasm, convulsions, and 
blood dyscrasias. 
 
Note: All deaths on treatment require both routine and expedited reporting regardless of 
causality. Attribution to treatment or other cause must be provided. “On treatment” is 
defined as during or within 30 days of completing protocol treatment (MWA). 
 
 
All serious adverse events deemed to be related by the investigator to the SBRT or MWA (as 
listed in section 13.) will be collected and recorded throughout the study period beginning 
with the signing of the informed consent through the day patient is removed from the study 
or the date of death or three years after completion of the MWA (or the last SBRT treatment 
if surgery is not performed), whichever is earlier.   
 
All serious adverse events that occur after the subject has signed the informed consent form 
must be reported to University of Wisconsin Carbone Cancer Center Data Safety and 
Monitoring Board and other regulatory agencies. 
 
Serious adverse events occurring after conclusion of the study AND thought to be possibly 
related to the investigational study will be collected and reported within 10 working days of 
discovery or notification of the event via the same mechanism. 
 
Table 3. Expedited reporting requirements for adverse events that occur within 30 days of the last protocol 
intervention. 
 
FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 

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NOTE: Investigators MUST immediately report to the PI, UWCCC and UW IRB per policy ANY Serious 
Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 
CFR 312.64). FDA Med Watch (3500A) will be submitted for grade 4 and 5 events at the discretion of the 
sponsor-investigator. 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 
2) A life-threatening adverse event. 
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria* MUST be immediately reported to the 
UWCCC within the timeframes detailed in the table below:  With the exception of a 24 hr hospitalization for 
MWA procedure 
Hospitalization 
Grade 1 and Grade 2 
Timeframes 
Grade 3 
Time Frames 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization  ≥ 
24 hrs 
Not required 
 
10 Calendar Days 
24 Hour; 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 
hrs 
Not required 
 
10 Calendar Days 
• 
See section 13.0 for listing of toxicities 
• 
Grade 3 toxicities during the 24hr hospitalization for MWA are exemption from SAE reporting 
 
Expedited AE reporting timelines are defined as: 
• 
24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
• 
10 Calendar Days – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
intervention and have an attribution of possible, probable, or definite require reporting as follows: 
 
Expedited 24-hour notification followed by complete report within 10 working days for: 
• 
All Grade 4, and 5 AEs 
 
 
13.5 Stopping Rules 
 
13.5.1 As described above, the study will use a standard 3+3 dose escalation design. For each 
three patient cohort, DLT will be assessed as above. In the case of 2/3 DLTs, the trial will 
be terminated with the previous level being the MTD. In the case of 1/3 DLTs, an 
additional three patients will be enrolled at the current dose level. In the event of a total 

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of 2 or more DLTs in 6 patients, the trial will be terminated with the previous dose level 
being the MTD. 
 
13.6 Patient withdrawal 
If a patient withdraws for any reason, a Case Report Form will be generated and filed. 
 
 
 

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14 References 
 
1. Zini L, Perrotte P, Capitanio U, Jeldres C, Shariat SF, Antebi E, Saad F, Patard JJ, Montorsi F, 
Karakiewicz PI. Radical versus partial nephrectomy: Effect on overall and noncancer 
mortality. Cancer 2009;115:1465-1471. 
2. Mathieu R, Pignot G, Ingles A, Crepel M, Bigot P, Bernhard JC, Joly F, Guy L, Ravaud A, Azzouzi 
AR, Gravis G, Chevreau C, Zini L, Lang H, Pfister C, Lechevallier E, Fais PO, Berger J, Vayleux 
B, Roupret M, Audenet F, Descazeaud A, Rigaud J, Machiels JP, Staehler M, Salomon L, 
Ferriere JM, Kleinclauss F, Bensalah K, Patard JJ. Nephrectomy improves overall survival in 
patients with metastatic renal cell carcinoma in cases of favorable mskcc or ecog 
prognostic features. Urologic oncology 2015. 
3. Sun M, de Velasco G, Trinh QD, Choueiri TK. Assessing the contemporary role of cytoreductive 
nephrectomy in metastatic renal cell carcinoma: Another step in the right direction. 
European urology 2015. 
4. Wagstaff P, Ingels A, Zondervan P, de la Rosette JJ, Laguna MP. Thermal ablation in renal cell 
carcinoma management: A comprehensive review. Current opinion in urology 2014;24:474-
482. 
5. Yu J, Liang P, Yu XL, Cheng ZG, Han ZY, Zhang X, Dong J, Mu MJ, Li X, Wang XH. Us-guided 
percutaneous microwave ablation versus open radical nephrectomy for small renal cell 
carcinoma: Intermediate-term results. Radiology 2014;270:880-887. 
6. Moreland AJ, Ziemlewicz TJ, Best SL, Hinshaw JL, Lubner MG, Alexander ML, Brace CL, Kitchin 
DR, Hedican SP, Nakada SY, Lee FT, Jr., Abel EJ. High-powered microwave ablation of t1a 
renal cell carcinoma: Safety and initial clinical evaluation. Journal of endourology / 
Endourological Society 2014;28:1046-1052. 
7. Best SL, Park SK, Youssef RF, Olweny EO, Tan YK, Trimmer C, Cadeddu JA. Long-term outcomes 
of renal tumor radio frequency ablation stratified by tumor diameter: Size matters. The 
Journal of urology 2012;187:1183-1189. 
8. Yu J, Liang P, Yu XL, Cheng ZG, Han ZY, Mu MJ, Wang XH. Us-guided percutaneous microwave 
ablation of renal cell carcinoma: Intermediate-term results. Radiology 2012;263:900-908. 
9. Guerrero M, Li XA. Extending the linear-quadratic model for large fraction doses pertinent to 
stereotactic radiotherapy. Physics in medicine and biology 2004;49:4825-4835. 
10. Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, Cheney RT, Chirieac 
LR, D'Amico TA, Demmy TL, Dilling TJ, Govindan R, Grannis FW, Jr., Horn L, Jahan TM, 
Komaki R, Kris MG, Krug LM, Lackner RP, Lanuti M, Lilenbaum R, Lin J, Loo BW, Jr., Martins 
R, Otterson GA, Patel JD, Pisters KM, Reckamp K, Riely GJ, Rohren E, Schild S, Shapiro TA, 
Swanson SJ, Tauer K, Yang SC, Gregory K, Hughes M. Non-small cell lung cancer, version 
1.2015. Journal of the National Comprehensive Cancer Network : JNCCN 2014;12:1738-1761. 
11. Siva S, Pham D, Gill S, Corcoran NM, Foroudi F. A systematic review of stereotactic 
radiotherapy ablation for primary renal cell carcinoma. BJU international 2012;110:E737-
743. 
12. Pham D, Thompson A, Kron T, Foroudi F, Kolsky MS, Devereux T, Lim A, Siva S. Stereotactic 
ablative body radiation therapy for primary kidney cancer: A 3-dimensional conformal 
technique associated with low rates of early toxicity. International journal of radiation 
oncology, biology, physics 2014;90:1061-1068. 

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13. Lamey M, Yun J, Burke B, Rathee S, Fallone BG. Radio frequency noise from an mlc: A feasibility 
study of the use of an mlc for linac-mr systems. Physics in medicine and biology 
2010;55:981-994. 
14. Hong TS, Ryan DP, Blaszkowsky LS, Mamon HJ, Kwak EL, Mino-Kenudson M, Adams J, Yeap B, 
Winrich B, DeLaney TF, Fernandez-Del Castillo C. Phase i study of preoperative short-
course chemoradiation with proton beam therapy and capecitabine for resectable 
pancreatic ductal adenocarcinoma of the head. International journal of radiation oncology, 
biology, physics 2011;79:151-157. 
15. Svedman C, Karlsson K, Rutkowska E, Sandstrom P, Blomgren H, Lax I, Wersall P. Stereotactic 
body radiotherapy of primary and metastatic renal lesions for patients with only one 
functioning kidney. Acta oncologica 2008;47:1578-1583. 
16. Dawson LA, Kavanagh BD, Paulino AC, Das SK, Miften M, Li XA, Pan C, Ten Haken RK, 
Schultheiss TE. Radiation-associated kidney injury. International journal of radiation 
oncology, biology, physics 2010;76:S108-115. 
17. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: Revised recist guideline (version 1.1). 
European journal of cancer 2009;45:228-247. 
 
 
 

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ELIGIBILITY CHECKLIST –  
--------(Y)  1. Does the patient have a pathologically-confirmed diagnosis of renal cell carcinoma? 
--------(Y)  2. Has the patient been deemed medically inoperable by his/her urologist?  
--------(Y)  3. Is the tumor greater than 4 cm in greatest dimension per imaging? 
--------(Y)  4.  Is the patient over the age of 18? 
--------(Y)  5.  Has the patient provided written inform consent for study participation? 
--------(Y)  6.  Has the patient undergone complete pre-treatment work-up as listed in the protocol 
document (section 6.3)? 
--------(N)  7.  Does the patient have a history of any prior invasive cancer in the last 5 years 
(except for a diagnosis of low-risk prostate cancer post appropriate therapy, treated 
non- melanoma/melanoma skin cancer, appropriately treated ductal carcinoma in situ 
or early stage invasive carcinoma of breast and appropriately treated in-situ or early 
stage cervical/endometrial cancer), OR any prior radiation therapy to the upper 
abdomen? 
--------(N) 8.  Is the patient a pregnant or nursing woman?  
--------(Y) 9.  If the patient is a woman of childbearing potential, are they agreeable to the use of 
contraceptive methods (hormonal or barrier method of birth control; abstinence) from 
the point of study entry and for the duration of completion of all active treatments? 
Should a woman become pregnant or suspect she is pregnant while 
participating in this study, is she willing to inform her treating physician 
immediately? 
--------(N) 10.  Has the patient received any treatment with a non-approved or investigational drug 
within 28 days of study treatment? 
--------(N) 11.  Is the patient’s ECOG performance score < 2?  
--------(Y) 12.  Has the patient passed the MRI screening process?  
 
 
 
 
 

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The following questions will be asked at Study Registration:   
--------(Y).  Has the Eligibility Checklist (above) been completed? Is the patient eligible for this 
study? 
---------------------Date the study-specific Consent signed  
---------------------Patient’s Name  
---------------------Patient’s UWHC MRN 
--------------------- Patient’s Date of Birth 
--------------------- Patient’s zip code 
 
The Eligibility Checklist will be completed in its entirety prior to enrollment on study. The 
completed, signed, and dated Checklist used at study entry must be retained in the patient’s 
study file.  
 
 
Completed by 
Date 
 
 
Verified by 
Date 
 
 
 
 
 

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UWCCC Data Safety Monitoring Plan 
 
Oversight And Monitoring Plan  
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the regular review and 
monitoring of all ongoing clinical research in the UWCCC. A summary of DSMC activities are as follows:  
 
• Reviews all clinical trials conducted at the UWCCC for subject safety, protocol  
 
 
compliance, and data integrity.  
 
• Reviews all Serious Adverse Events (SAE) requiring expedited reporting, as  
 
 
defined in the protocol, for all clinical trials conducted at the UWCCC, and   
 
studies 
conducted at external sites for which UWCCC acts as an oversight  
 
 
body.  
 
• Reviews all reports generated through the UWCCC DSMS elements (Internal  
 
 
Audits, Quality Assurance Reviews, Response Reviews, Compliance   
 
 
Reviews, and Protocol Summary Reports) described in Section II of this  
 
 
document.  
 
• Notifies the protocol Principal Investigator of DSMC decisions and, if applicable,   
 
any requirements for corrective action related to data or safety issues.  
 
• Notifies the CRC of DSMC decisions and any correspondence from the DSMC to   
 
the protocol Principal Investigator.  
 
• Works in conjunction with the UW Health Sciences IRB in the review of relevant   
 
safety information as well as protocol deviations, non-compliance, and  
 
 
unanticipated problems reported by the UWCCC research staff.  
 
• Ensures that notification is of SAEs requiring expedited reporting is provided   
 
to external sites participating in multi-institutional clinical trials   
 
 
coordinated by the UWCCC. 
 
Monitoring And Reporting Guidelines  
UWCCC quality assurance and monitoring activities are determined by study sponsorship and risk 
level of the protocol as determined by the PRMC. All protocols (including Intervention Trials, Non-
Intervention Trials, Behavioral and Nutritional Studies, and trials conducted under a Training Grant) 
are evaluated by the PRMC at the time of committee review. UWCC monitoring requirements for trials 
without an acceptable external DSMB are as follows: 
 
Intermediate Monitoring 
Protocols subject to intermediate monitoring generally include UW Institutional Phase I/II and Phase 
II Trials.  These protocols undergo review of subject safety at regularly scheduled DOWG meetings 
where the results of each subject’s treatment are discussed and the discussion is documented in the 
DOWG meeting minutes.  The discussion includes the number of subjects enrolled, significant 
toxicities, dose adjustments, and responses observed.  Protocol Summary Reports are submitted on a 
semi-annual basis by the study team for review by the DSMC. 
 
 
Review and Oversight Requirements 
Serious Adverse Events requiring reporting within 24 hours (as described in the protocol) must also be 
reported to the Data and Safety Monitoring Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu within one business day. The OnCore SAE Details Report must be 
submitted along with other report materials as appropriate (NCI AdEERS form or FDA Medwatch Form 
#3500 and/or any other documentation available at that time of initial reporting). The DSMC Chair will 
review the information and determine if immediate action is required. Within 10 working days, all available 

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subsequent SAE documentation must be submitted electronically along with a 24 hour follow-up SAE 
Details Report and a completed UWCCC SAE Routing Form to saenotify@uwcarbone.wisc.edu. All 
information is entered and tracked in the UWCCC database. 
 
The Principal Investigator notifies all investigators involved with the study at the UWCCC, the IRB, the 
sponsor, and the funding agency and provides documentation of these notifications to the DSMC.  
 
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor-investigator, the PI reviews the 
event to determine whether the SAE requires reporting to the FDA and other participating investigators.  
 
For a multiple-institutional clinical trial the PI is responsible for ensuring SAEs are reported to the FDA as 
well as to all participating investigators 
 
Serious Adverse Event-Reported within 10 Days 
Serious Adverse Events requiring reporting within 10 days (as described in the protocol) must also be 
reported to the Data and Safety Monitoring Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu. The OnCore SAE Details Report must be submitted along with other report 
materials as appropriate (NCI AdEERS form or FDA Medwatch Form #3500 and/or any other 
documentation available at that time of initial reporting). The DSMC Chair will review the information and 
determine if further action is required. All information is entered and tracked in the UWCCC database.  
 
The Principal Investigator notifies all investigators involved with the study at the UWCCC, the IRB, the 
sponsor, and the funding agency and provides documentation of these notifications to the DSMC.  
 
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor-investigator, the PI reviews the 
event to determine whether the SAE requires reporting to the FDA and other participating investigators.  
 
For a multiple-institutional clinical trial the PI is responsible for ensuring SAEs are reported to the FDA as 
well as to all participating investigators. 
 
Sponsor-Investigator Responsibilities for SAE Review 
In the event the UWCCC Principal Investigator is acting as the Sponsor-Investigator (i.e., the PI holds the 
IND), the PI assumes responsibilities of the study sponsor in accordance with FDA 21 CFR 312.32. In this 
capacity, the UWCCC PI reviews all reports of serious adverse events occurring on the study at the UWCCC 
and participating external sites and makes a determination of 1) suspectedness (i.e., whether there is a 
reasonable possibility 
That the drug caused the AE); and 2) unexpectedness in the context of theis study.  SAE with suspected 
causality to study intervention deemed unexpected are reported as IND safety Reports by the UWCCC PI to 
the FDA, all participating investigators on the study, within 15 calendar days.  All fatal or life-threatening 
SAE that are unexpected and have suspected causality to the study intervention will be reported by the 
UWCCC PI to the FDA, all participating investigators on the study within 7 calendar days. 
 
 
Study Progress Review 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC in the timeframe determined by 
the risk level of the study (quarterly; semi-annually; or annually). The PSR provides a cumulative report of 
SAEs, as well as instances of non-compliance, protocol deviations, and unanticipated problems, toxicities 
and responses that have occurred on the protocol in the timeframe specified. PSRs for those protocols 
scheduled for review are reviewed at each DSMC meeting. 

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Protocol Summary Reports enable DSMC committee members to assess whether significant benefits or risks 
are occurring that would warrant study suspension or closure. This information is evaluated by the DSMC in 
conjunction with other reports of quality assurance activities (e.g., reports from Internal Audits, Quality 
Assurance Reviews, etc.) occurring since the prior review of the protocol by the DSMC. Additionally, the 
DSMC requires the study team to submit external DSMB or DSMC reports, external monitoring findings for 
industry-sponsored studies, and any other pertinent study-related information. 
 
In the event that there is significant risk warranting study suspension or closure, the DSMC will notify the PI 
of the DSMC findings and ensure the appropriate action is taken for the protocol (e.g., suspension or 
closure). The DSMC ensures that the PI reports any temporary or permanent suspension of a clinical trial to 
the sponsor (e.g., NCI Program Director, Industry Sponsor Medical Monitor, Cooperative Group Study 
Chair, etc.) and other appropriate agencies. DSMC findings and requirements for follow-up action are 
submitted to the CRC 
 
EXPEDITED REPORTING OF SERIOUS ADVERSE EVENTS 
Depending on the nature, severity, and attribution of the serious adverse event an SAE report will be phoned 
in, submitted in writing, or both according to Table  below. All serious adverse events must also be reported 
to the UWCCC Data and Safety Monitoring Committee Chair. All serious adverse events must also be 
reported to the UW IRB (if applicable), and any sponsor/funding agency not already included in the list. 
 
Determine the reporting time line for the SAE in question by using the following table. Then refer to sections 
A and B below if the SAE occurred at the UWCCC or sections C and D if the SAE occurred at 1 South Park, 
Johnson Creek, or a WON Site. 
 
SAE Requiring [24] Hour Reporting Occurs at UWCCC: 
 
1. Report to the UWCCC:  
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting Workflow for DOWGs 
on the UWCCC website (http://www.uwccc.wisc.edu) for specific instructions on how and what to report to 
the UWCCC for [24] hour initial and follow-up reports. A follow-up report is required to be submitted 
within 5 days of the initial [24] hour report.  
For this protocol, the following UWCCC entities are required to be notified:  
a) saenotify@uwcarbone.wisc.edu  
b) Dr. Mike Bassetti, UWCCC PI  
c) Diana Trask, UWCCC Radiotherapy PM  
d) Any other appropriate parties listed on the SAE Routing Form (for follow-up reports only)  
 
2. Report to the IRB:  
Consult the UW-IRB website for reporting guidelines 
 
SAE Requiring [10] Day Reporting Occurs at UWCCC:  
1. Report to the UWCCC:  
Reference the SAE SOP and the SAE Reporting Workflow for DOWGs on the UWCCC website 
(http://www.uwccc.wisc.edu) for specific instructions on how and what to report to the UWCCC for 
[10] day reports.  
 
For this protocol, the following entities are required to be notified: 

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a) saenotify@uwcarbone.wisc.edu  
b) Any appropriate parties listed on SAE Routing Form  
 
2. Report to the IRB:  
Consult the UW-IRB website for reporting guidelines. 
 
 
Other Reporting Requirements  
Reporting to the FDA  
Serious Adverse Events occurring on studies on which a UW PI is acting as sponsor-investigator must be 
reported to the FDA within the appropriate time frame. Mandatory and voluntary reporting guidelines and 
instructions are outlined on the FDA website: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
 
 

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33
Expedited reporting requirements for adverse events that occur within 30 days of the last dose of 
radiation therapy1 
 
FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 
NOTE: Investigators MUST immediately report to the PI, UWCCC and UW IRB per policy ANY Serious 
Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 
CFR 312.64). FDA Med Watch (3500A) will be submitted for grade 4 and 5 events at the discretion of the 
sponsor-investigator. 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
7) Death. 
8) A life-threatening adverse event. 
9) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours. 
10) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
11) A congenital anomaly/birth defect. 
12) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria* MUST be immediately reported to the 
UWCCC within the timeframes detailed in the table below:  With the exception of a 24 hr hospitalization for 
MWA procedure 
Hospitalization 
Grade 1 and Grade 2 
Timeframes 
Grade 3 
Time Frames 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization  ≥ 
24 hrs 
Not required 
 
10 Calendar Days 
24 Hour; 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 
hrs 
Not required 
 
10 Calendar Days 
 
• 
See section 13.0 for listing of toxicities 
• 
Grade 3 toxicities during the 24hr hospitalization for MWA are exemption from SAE reporting 
 
Expedited AE reporting timelines are defined as: 
• 
24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of learning of the 
AE, followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
• 
10 Calendar Days – A complete expedited report on the AE must be submitted within 5 calendar 
days of learning of the AE 
 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
intervention and have an attribution of possible, probable, or definite require reporting as follows: 
 
Expedited 24-hour notification followed by complete report within 10 working days for: 
• 
All Grade 4, and 5 AEs