A Prospective Study to Evaluate Quantitative Non-Contrast Perfusion Using Arterial Spin Labeled MR Imaging for Assessment of Therapy Response in Metastatic Renal Cell Carcinoma
Phase: NA
Conditions: Renal Cell Carcinoma
Sponsor: University of Texas Southwestern Medical Center

 
Protocol.docx 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016 
 
STU 032018-078 
A Prospective Study to Evaluate Quantitative Non-Contrast Perfusion using Arterial Spin Labeled 
MR Imaging for Assessment of Therapy Response in Metastatic Renal Cell Carcinoma 
 
Principal Investigator: 
Ananth Madhuranthakam, PhD 
 
Director, MR Research 
 
Department of Radiology and 
 
Advanced Imaging Research Center 
 
UT Southwestern Medical Center 
 
5323 Harry Hines Blvd 
 
Dallas, TX – 75390-9061 
 
Phone: 214-648-7737 
 
Fax: 214-648-7783 
 
Ananth.Madhuranthakam@UTSouthwestern.edu  
 
Sub-Investigator(s): 
Ivan Pedrosa, MD, PhD 
 
Department of Radiology and 
 
Advanced Imaging Research Center 
 
 
James Brugarolas, MD, PhD 
 
Internal Medicine – Hematology/Oncology 
 
Simmons Comprehensive Cancer Center 
 
 
Hans Hammers, MD, PhD 
 
Internal Medicine – Hematology/Oncology 
 
Simmons Comprehensive Cancer Center 
 
 
Kevin Courtney, MD, PhD 
 
Internal Medicine – Hematology/Oncology 
 
Simmons Comprehensive Cancer Center 
 
 
 
 
 
Roderick McColl, PhD 
 
Department of Radiology  
 
 
Elena Vinogradov, PhD 
 
Department of Radiology and 
 
Advanced Imaging Research Center 
 
Biostatistician: 
Hong Zhu, PhD 
 
Department of Clinical Science 
 
Simmons Comprehensive Cancer Center 
 
UT Southwestern Medical Center 
 
5323 Harry Hines Blvd 
 
Dallas, TX – 75390-8551  
 
Phone: 214-648-7438 
 
Hong.Zhu@UTSouthwestern.edu 
 
Funding Source:  
NIH/NCI – U01CA207091 
 
Initial version: 
1.0 – March 30, 2018 
 
Amended: 
 
2.0 = August 27, 2019;  

 
Protocol.docx 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016 
 
 
 
3.0 = Feb. 26, 2021 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 

 
Protocol.docx 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: Ananth Madhuranthakam, PhD 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................ 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SUMMARY ......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE .............................................................................. 4 
1.1 Disease Background ...................................................................................................... 4 
1.2 Study Agent(s) Background and Associated Known Toxicities ..................................... 5 
1.3 Other Agents .................................................................................................................. 5 
1.4 Rationale ........................................................................................................................ 6 
1.5 Correlative Studies ........................................................................................................ 6 
2.0 
STUDY OBJECTIVES ................................................................................................... 6 
2.1 Primary Objectives ......................................................................................................... 6 
2.2 Secondary Objectives .................................................................................................... 6 
2.3 Exploratory Objectives ................................................................................................... 6 
2.4 Endpoints ....................................................................................................................... 6 
3.0 
Subject ELIGIBILITY ..................................................................................................... 6 
3.1 Inclusion Criteria ............................................................................................................ 7 
3.2 Exclusion Criteria ........................................................................................................... 7 
4.0 
TREATMENT PLAN ...................................................................................................... 7 
4.1 Treatment Dosage and Administration .......................................................................... 8 
4.2 Toxicities and Dosing Delays/Dose Modifications ......................................................... 8 
4.3 Concomitant Medications/Treatments ........................................................................... 8 
4.4 Other Modalities or Procedures ..................................................................................... 8 
4.5 Duration of Therapy ....................................................................................................... 8 
4.6 Duration of Follow Up .................................................................................................... 8 

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4.7 Removal of Subjects from Protocol Therapy ................................................................. 8 
4.8 Subject Replacement ..................................................................................................... 8 
5.0 
STUDY PROCEDURES ................................................................................................. 8 
5.1 Screening/Baseline Procedures .................................................................................... 8 
5.2 Procedures During Treatment ....................................................................................... 9 
5.3 Follow-up Procedures .................................................................................................... 9 
5.4 Time and Events Table ................................................................................................ 10 
5.5 Removal of Subjects from Study ................................................................................. 10 
6.0 
Measurement of Effect ............................................................................................... 11 
6.1 Antitumor Effect- Solid Tumors .................................................................................... 11 
6.2 Antitumor Effect - Hematologic Tumors ....................................................................... 13 
6.3 Safety/tolerability ......................................................................................................... 14 
7.0 
ADVERSE EVENTS ..................................................................................................... 14 
7.1 Experimental Therapy .................................................................................................. 14 
7.2 Adverse Event Monitoring ............................................................................................ 14 
7.3 Steps to Determine If an Adverse Event Requires Expedited Reporting ..................... 17 
7.4 Unblinding Procedures ................................................................................................ 17 
7.5 Stopping Rules ............................................................................................................ 17 
8.0 
DRUG/TREATMENT INFORMATION ......................................................................... 18 
9.0 
CORRELATIVES/SPECIAL STUDIES ........................................................................ 18 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................ 18 
10.1 Study Design/Study Endpoints .................................................................................... 18 
10.2 Sample Size and Accrual ............................................................................................. 18 
10.3 Data Analyses Plans .................................................................................................... 18 
11.0 
STUDY MANAGEMENT .............................................................................................. 19 
11.1 Conflict of Interest ........................................................................................................ 19 

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11.2 Institutional Review Board (IRB) Approval and Consent ............................................. 19 
11.3 Data Management and Monitoring/Auditing ................................................................ 20 
11.4 Adherence to the Protocol ........................................................................................... 20 
11.5 Amendments to the Protocol ....................................................................................... 21 
11.6 Record Retention ......................................................................................................... 21 
11.7 Obligations of Investigators ......................................................................................... 22 
12.0 
REFERENCES ............................................................................................................. 22 
13.0 
APPENDICES .............................................................................................................. 23 

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LIST OF ABBREVIATIONS  
ADC 
Apparent Diffusion Coefficient 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ASCO 
American Society of Clinical Oncology 
ASL 
Arterial Spin Labeled 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CEST 
Chemical Exchange Saturation Transfer 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCE 
Dynamic Contrast Enhanced 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSC 
Dynamic Susceptibility Contrast 
DSMB 
Data and Safety Monitoring Board 
DWI 
Diffusion Weighted Imaging 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IDE 
Investigational Device Exemption 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IV (or iv) 
Intravenously 
MGMT 
O6-methylguanine-DNA methyltransferase 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NSF 
Nephrogenic Systemic Fibrosis 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 

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p.o. 
peros/by mouth/orally 
PR 
Partial Response 
RANO 
Response Assessment in Neuro-Oncology 
RCB 
Residual Cancer Burden 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
Step 2: Baseline disease evaluation by MRI with and 
without IV contrast (T0) 
Step 5: Image interpretation 
Step 1: Patient registration 
Step 3: Initiation of anti-angiogenic 
therapy per standard clinical protocol 
or part of a clinical trial on Day 0 
Step 4: Disease evaluation by follow-up MRI with and without 
IV contrast at the following times: T1: 7±2 days, T2: 14±2 days, 
T3, T4, T5: along with the patient’s clinical imaging. 
Step 6: Patient follow-up per standard 
clinical protocol 
MRI including ASL will be performed before, 
during and after the treatment, in a total of 6 
MRI sessions, or when progression is 
clinically indicated. The baseline MRI will be 
performed up to 7 days before the treatment 
initiation. The first two follow-up MRIs will be 
performed on day 7±2 and day 14±2 after 
treatment initiation, with the option of 
participating at both time points. The last three 
time points (*) will be performed along with the 
patient’s clinical imaging. Thereafter, patients 
will be followed through standard clinical 
examinations for the next 3 years or until 
demise, whichever occurs first.  

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STUDY SUMMARY 
Title 
A Prospective Study to Evaluate Quantitative Non-Contrast Perfusion 
using Arterial Spin Labeled MR Imaging for Assessment of Therapy 
Response in Metastatic Renal Cell Carcinoma 
Short Title 
Quantitative MRI for therapy response assessment in metastatic RCC 
Protocol Number 
STU 032018-078 
Phase 
N/A 
Methodology 
Prospective study to evaluate quantitative MRI metrics for the 
assessment of treatment response  
Study Duration 
48 months 
Study Center(s) 
Single-center 
Objectives 
To prospectively determine whether ASL-measured perfusion can 
identify treatment response earlier than the currently used RECIST 
criteria. 
Number of Subjects 
90 (40 subjects with RCC and 50 healthy volunteers) 
Diagnosis and Main 
Inclusion Criteria 
Diagnosis: Locally advanced or metastatic renal cell carcinoma 
Main Inclusion Criteria: Patients with histologically proven clear cell 
RCC, scheduled to undergo anti-angiogenic treatment or immunotherapy 
(IO) who are 18 years of age and older and have no contraindication to 
MRI. 
Study Product(s), Dose, 
Route, Regimen 
N/A 
Duration of administration 
N/A 
Reference therapy 
N/A 
Statistical Methodology 
Primary end points for this study will include the absolute days of time to 
disease progression, progression free survival (PFS) and overall survival 
(OS) as well as disease status (progression versus not) at 7 months post 
treatment initiation. Progression will be determined according to the 
clinical RECIST criteria. One-sample correlation test will be used to 
determine the correlation between change in ASL measured tumor 
perfusion during and immediately after treatment and time to 
progression, and the correlation between change in ASL measured 
tumor perfusion and the corresponding tumor size change.  The 
correlations will be measured and compared using Pearson’s correlation 
coefficient along with 95% confidence interval. PFS and OS will be 
correlated with baseline perfusion and post-treatment changes at T1, T2 
and T3 compared to baseline using univariable and multivariable Cox 
regression models. Univariable and multivariable logistic regression 
models will be used to predict responders from non-responders 
(progression versus not at 7 months) with ASL measurements at 
baseline and at earlier time points (T1 and T2) alone, and in combination 
with other MR imaging metrics.  
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
The incidence of kidney cancer has steadily increased over the past three to four 
decades and is among the 10 most frequently diagnosed cancers in the US. 
Approximately 63,990 new cases of kidney cancer are estimated in 2017 and the 
prognosis has been historically poor (1). The current 5-year survival rates are estimated 
at 74% overall, decreasing to 53% among patients with locally advanced diseases (2).  
 
The most common form of kidney cancer, renal cell carcinoma (RCC), occurs in 90% of 
all kidney cancers. Among patients with localized RCC who are treated with 
nephrectomy, approximately one quarter have relapses in distant sites. Among patients 
with metastatic RCC, the 5-year survival rates are approximately 8%. With better 
understanding of the pathogenesis of the most common type of RCC, clear-cell renal cell 
carcinoma (ccRCC), newer treatment options with new agents are being developed to 
increase survival rates (3). 
 
The high cost and potential risks associated with human trials for the newly developed 
experimental therapies have emphasized the need for sensitive monitoring of tumor 
response. Imaging approaches can play an important role in the evaluation and selection 
of potential new therapies with non-invasive longitudinal monitoring of treatment 
response (4). Currently, the radiological assessment of treatment outcomes 
predominantly relies on morphological (i.e. size) changes using the Response Evaluation 
Criteria in Solid Tumors (RECIST) and other similar scores (5). This is a major limiting 
factor as the effects of many therapeutic agents at the microscopic level precede the 
eventual changes in tumor size. One such tumor property that has gained increased 
attention is angiogenesis (6), which has been shown to support tumor proliferation and 
infiltration. Increasing numbers of clinical trials have begun targeting tumor vascular 
supplies by directly inhibiting angiogenesis (e.g. antiangiogenic therapy) (7). Such clinical 
trials and the eventual clinical use of these therapies would be greatly assisted by the 
availability of robust imaging indicators of angiogenesis (i.e. tissue perfusion). 
 
Positron Emission Tomography (PET) using 15O-labeled water (15O-PET) is considered 
the gold standard for non-invasive measurement of tissue perfusion (8). However, the 
use of 15O-PET requires a cyclotron in close proximity to PET to produce short lived 15O-
water (half life 2.4 min), limiting its applicability in clinical settings (9). Alternative imaging 
techniques include ultrasound using microbubbles, perfusion computed tomography (CT) 
using iodinated contrast agent and perfusion MRI using gadolinium based contrast 
agents (10). All of these techniques require exogenous agents, restricting their use in 
longitudinal monitoring of treatment response. 
 
Arterial Spin Labeled (ASL) – MRI: 
ASL-MRI has recently emerged as a quantitative imaging (QI) method to measure 
perfusion (or capillary blood flow) without the administration of exogenous contrast 
agents (11). ASL magnetically “labels” the highly permeable water in the blood as a 
tracer and measures their accumulation in the tissue of interest, without injecting any 
exogeneous contrast. Various versions of ASL have been validated in animals using 
microspheres (12), and in humans using 15O-PET in the brain (13,14). ASL also has a 
number of advantages compared to dynamic contrast enhanced (DCE) and dynamic 
susceptibility contrast (DSC) based MR perfusion measurements. Specifically, ASL does 
not require exogenous agent alleviating the concerns of gadolinium accumulation (15,16) 
or nephrogenic systemic fibrosis (NSF) in patients with impaired renal function (17) and, 
unlike DCE/DSC, the contribution of vascular permeability to ASL measured perfusion is 

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negligible (18) enabling absolute perfusion quantification in physiological units 
(ml/100g/min).   
 
ASL-MRI consists of three distinct steps to achieve 
absolute quantification of tissue perfusion (Fig. 1). 
First, the acquisition of two images – a control 
image, where the blood and the static tissue is at its 
full magnetization and a label image, where only 
the inflowing blood is selectively inverted while the 
static tissue is maintained at its full magnetization. 
Second, the image reconstruction including the 
subtraction of labeled images from the control 
images to generate a perfusion-weighted image 
(PWI). Third, the perfusion quantification by 
modeling of PWI using a proton-density image and 
acquisition parameters to account for tissue 
characteristics to generate a quantitative perfusion 
map in physiological units of ml/100g/min. Both 
control and label images are acquired without 
administering any exogenous contrast agent, but 
using MR principles. The control image is acquired 
similar to other standard MR images. The label image is also acquired similar to other 
standard MR images, except that the inflowing blood such as the arterial blood in the 
abdominal aorta is selectively inverted using radiofrequency (RF) pulses and gradients 
(Fig. 2, yellow solid box). During the acquisition of control and label images, the subjects 
do not experience anything additional except the standard MR gradient noise and RF 
heating (that stays within the FDA guidelines) similar to any other standard MR 
examination. 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
This study will not investigate or focus on the role of any agents. 
 
Gadolinium-based contrast agent for MRI such as Gadavist (generic Gadobutrol) or 
Dotarem (generic Gadoterate acid), are FDA-approved contrast agents for the diagnostic 
study and will be used in this study.  
1.3 
Other Agents 
Not applicable (N/A). 
Figure 1. Schematic of an ASL acquired kidney perfusion. 
The acquisition includes a control image, where the 
magnetization is maintained at the equilibrium, and a label 
image, where the inflowing blood is selectively inverted. 
The subtraction between the control and the label image 
generates the perfusion-weighted image. Using a 
separately acquired proton-density image and the 
perfusion quantification model, absolute perfusion map in 
physiological values of ml/100g/min can be generated. 
Figure 2. The yellow box shows 
the ASL labeling plane, across 
the abdominal aorta. Using MR 
principles including selective RF 
pulses and gradients, the 
inflowing blood in the abdominal 
aorta at this labeling plane is 
selectively inverted with ASL. 

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1.4 
Rationale 
Recent discoveries in the biology of RCC have led to the development of targeted agents 
(e.g. vascular endothelial growth factor (VEGF)). Five of the FDA approved drugs for the 
treatment of metastatic RCC (bevacizumab, sunitinib, sorafenib, pazopanib, and axitinib) 
target either VEGF or its receptor. Clinically, these patients are followed every 2-3 
months after therapy initiation and treatment response is primarily evaluated using size 
changes (i.e. Response Evaluation Criteria In Solid Tumors (RECIST)) (5). However, 
rapid changes in ASL measured perfusion may predict tumor targeting better than size 
change, allowing better patient management. This study is targeted to demonstrate this 
capability in metastatic RCC patients. 
1.5 
Correlative Studies 
Standard clinical history including clinical histopathology will be collected and correlated. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1  
To determine whether ASL-measured perfusion can identify treatment response 
(time to progression) earlier than the currently used RECIST criteria in patients 
undergoing anti-angiogenic treatment. 
2.2 
Secondary Objectives 
 
2.2.1 
To determine the correlation between ASL-measured baseline perfusion and the 
treatment response  (PFS, OS). 
 
2.2.2     To determine the correlation between post-treatment changes in ASL-measured 
perfusion at T1, T2 and T3 compared to baseline and the treatment response 
(PFS, OS). 
 
2.2.3.  To predict responders from non-responders (progression versus not at 7 months) 
with measurements at baseline and at earlier time points (T1 and T2) using: 
a.  ASL-measured perfusion alone 
b.  ASL-measured perfusion in combination with other MR imaging metrics 
such as diffusion weighted imaging (DWI) derived apparent diffusion 
coefficient (ADC), and chemical exchange saturation transfer (CEST) 
measured CEST effect.  
2.3 
Exploratory Objectives 
2.3.1  
To determine whether ASL-measured perfusion can identify treatment response 
(time to progression) earlier than the currently used RECIST criteria in patients 
undergoing IO. 
2.4 
Endpoints 
Primary end points for this study will include the absolute days of progression free 
survival (PFS) and overall survival (OS). Additionally disease status (progression versus 
not) at 7 months and survival (dead or alive) at 24 months post-treatment initiation will 
also be documented. Progression will be determined based on the clinically accepted 
RECIST criteria. 
3.0 
Subject ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 

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3.1 
Inclusion Criteria (RCC Subjects) 
 
3.1.1 
Diagnosis/disease status: Patients with locally advanced or metastatic renal cell 
carcinoma. 
 
3.1.2 
Patients scheduled to undergo anti-angiogenic treatment or IO. 
 
3.1.3 
Age ≥ 18 years. 
 
3.1.4 
Performance status: ECOG Status 0, 1 and 2. 
 
 
3.1.5 
Women of child-bearing potential must agree to undergo a urine pregnancy 
screening per standard Radiology departmental protocol, in place to prevent 
imaging of pregnant patients. 
 
3.1.5.1 A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
3.1.6 
Ability to understand and the willingness to sign a written informed consent. 
 
Inclusion Criteria (healthy controls) 
 
3.1.7 
Age ≥ 18 years. 
 
3.1.8 
Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
Subjects may not be receiving any other anti-angiogenic agents, at the time of 
enrollment. 
 
3.2.2 
Subjects must not be pregnant since pregnancy is a contraindication to 
administration of gadolinium-based contrast agents. 
 
3.2.3 
Any contraindication to MRI per Radiology Department’s routine protocol, e.g. 
MRI-incompatible objects, including but not limited to medical devices (e.g. 
pacemakers, AICD, etc.) and other foreign bodies.  
 
3.2.4 
Known severe allergic reaction to Gadolinium-based contrast agents. 
 
3.2.5 
Patients with sickle cell disease and patients with other hemolytic anemias (low 
red blood count in body). 
 
3.2.6 
Patients with uncontrollable claustrophobia, sever lower back pain, and 
uncontrollable tremors, to the point that it would render them unable to tolerate 
an MRI study.  
 
4.0 
TREATMENT PLAN 

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4.1 
Treatment Dosage and Administration 
Not applicable. 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Not applicable. 
4.3 
Concomitant Medications/Treatments 
Not applicable.  
4.4 
Other Modalities or Procedures 
Subjects will undergo treatment, as determined by the referring physician. 
4.5 
Duration of Therapy 
Not applicable for this study. 
4.6 
Duration of Follow Up 
After the conclusion of the study, subjects will be followed through standard clinical 
examinations for the next 3 years or until demise, whichever occurs first.  
4.7 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from the study when any of the criteria listed in Section 5.5 
apply. Notify the Principal Investigator, and document the reason for study removal and 
the date the subject was removed in the Case Report Form. The subject should be 
followed-up per protocol.  
4.8 
Subject Replacement 
If a subject is withdrawn from the study based on any criteria listed in Section 5.5, prior to 
completion of T2 MRI session, another subject may replace them and should undergo the 
entire study protocol. 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 30 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history, specific history regarding infections, 
trauma, foreign bodies, medical devices, and implants. 
5.1.3 Demographics 
Age, gender, race, ethnicity 

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5.1.4 Review subject eligibility criteria (RCC Subjects only) 
Subjects will receive Group II gadolinium based contrast agents (GBCA) such as 
Gadavist (generic Gadobutrol) or Dotarem (generic Gadoterate acid) in this study. 
The risk of nephrogenic systemic fibrosis (NSF) for Group II GBCA is so low that 
the current clinical guidelines from the American College of Radiology (ACR) for 
use of these agents consider optional the screening of patient renal function – 
these were updated in 2017 (https://www.acr.org/Clinical-Resources/Contrast-
Manual). The concern for gadolinium deposition is also lower for Group II agents 
and not related to renal function (i.e. associated to multiple exposures). 
Accordingly, patients receiving group II GBCA for clinical MRI are no longer 
screened for renal function impairment at UT Southwestern. Hence, a strict 
threshold based on renal function will not be applied to avoid gadolinium 
administration in patients enrolled in this study. Patients will be informed of the 
risks of gadolinium administration and offered to participate in the non-contrast 
portion of the MRI exam if preferred. 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 Performance status (RCC Subjects only) 
Performance status evaluated prior to study entry. 
5.1.8 Adverse event assessment 
Baseline adverse events will be assessed. See section 7 for Adverse Event 
monitoring and reporting. 
5.1.9 Pregnancy test (for females of child bearing potential) 
See section 3.1.5.1 for definition.  
5.1.10 Tumor assessment (RCC Subjects only) 
Tumor measurements will be performed at baseline to identify metastatic tumors 
of ≥2.0 cm in at least one dimension on MRI.  
5.2 
Procedures During Treatment 
All MR imaging will be performed during treatment. 
5.3 
Follow-up Procedures 
After the conclusion of the study, subjects will be followed through standard clinical 
examinations for the next 3 years or until demise, whichever occurs first.  
 
 
 
 
 
 
 
 
 
 

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5.4 
Time and Events Table  
 
RCC Subjects 
 
 
Pre-
study 
Week 0 
(T0) before 
initiation of 
anti-
angiogenic 
therapy 
Day 
7±2 
(T1) 
Day 
14±2 
(T2) 
 T3 
 T4 
T5 
Follow-up 
(As indicated 
by clinical 
protocol) 
Assessment 
X 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
History and PE 
X 
 
 
 
 
 
 
 
Tumor 
Measurements 
X 
 
 
 
 
 
 
 
MRI* 
 
X 
X 
X 
X 
X 
X 
X 
*Clinically, metastatic RCC patients are imaged every 2-3 months after the initiation of anti-
angiogenic therapy, since morphological (i.e. size) changes are not anticipated earlier. However, 
our preliminary experience has shown functional changes including perfusion as early as 2-weeks 
after the initiation of the treatment (19). T0, T1, and T2 sessions will be performed for this proposal, 
while T3, T4, and T5 will be performed along with the clinical imaging sessions. The research MR 
imaging may take approximately an additional 15 minutes per each imaging session, when done 
in conjunction with the clinical imaging. The T0, T1, and T2 research MR imaging sessions will be 
performed additionally for the purpose of this study, with each taking approximately one hour.  
 
The ASL portion of the study does not require contrast. Clinically, the subjects will also receive 
gadolinium based contrast injection for the MRI study to measure the blood flow to the tumors. 
This is done at the clinical imaging time points of T3, T4, and T5. Similar to this, the contrast agent 
will also be administered during the research portion of the study at T0, T1 and T2 time points, to 
compare the blood flow measured with ASL-MRI. 
 
MRI including ASL will be performed before, during and after the treatment, in a total of 6 MRI 
sessions until 7 months after the first session, or when progression is clinically indicated. 
Thereafter, patients will be followed through standard clinical examinations for the next 3 years or 
until demise, whichever occurs first.  
 
Healthy Volunteers 
 
 
Pre-study 
Week 0  
Week  
3±1  
(T3) 
Assessment 
X 
 
 
Informed Consent 
X 
 
 
History and PE 
X 
 
 
Research MRI 
 
X 
X 
 
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation will be documented and may include: 
5.5.1 
Subject voluntarily withdraws from the study (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of study and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; 

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5.5.4 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.5 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event) AND pregnancy prevents the subject to undergo follow up 
studies, then subject will be removed from the study.  
5.5.6 
Development of second malignancy that requires treatment, which would 
interfere with this study; 
5.5.7 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented and 
approved by the Data Monitoring Committee. 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect- Solid Tumors 
 
This study is designed to monitor therapy response in metastatic RCC using MRI with 
both conventional methods and ASL. Hence, the standard clinical assessment will be 
performed using RECIST criteria with conventional MRI. The ASL defined therapy 
response is currently developmental and not yet defined. Based on prior studies, a 
coefficient of variance (COV) of 7% was observed in ASL measured perfusion within the 
same subject imaged at two different time points (21). Thus, we will use a threshold of 
>10% difference in ASL measured perfusion compared to baseline to define ASL 
measured therapy response.  
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
6.1.1 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm with MRI. All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters). 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with MRI), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal 
masses (not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions per organ 
and 6 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be 
used as reference by which to characterize the objective tumor response. 
 

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Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 6 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
6.1.2 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 28 days before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
MRI should be performed with cuts of 10 mm or less in slice thickness 
contiguously.  
6.1.3 
Response Criteria 
6.1.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the smallest sum LD recorded since 
the treatment started, or the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
6.1.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions 
6.1.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 

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treatment started). The subjects best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment. 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
6.1.4 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
6.1.5 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 
6.2 
Antitumor Effect - Hematologic Tumors 
Not applicable for this study. 

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6.3 
Safety/tolerability 
 
 Not applicable for this study. 
7.0 
ADVERSE EVENTS 
7.1 
Experimental Therapy 
Not applicable 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of subject safety 
and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
therapy, will be monitored until:  
Ø the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
Ø any abnormal laboratory values have returned to baseline;  
Ø there is a satisfactory explanation other than the study therapy for the changes 
observed; or 
Ø death. 
 
[Inserted from Adverse Event Definitions and Reporting Section – Appendix IB 
SCCC DSMC Plan] 
7.2.1 
Definition  
Adverse Events will be reported as indicated by the appropriate following table (see 
below).    
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, clinical event, or disease, temporarily 
associated with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 
specified in the protocol. Adverse events not specifically defined in the NCI CTCAE will 
be scored on the Adverse Event log according to the general guidelines provided by the 
NCI CTCAE and as outlined below.   
• 
Grade 1: Mild  

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• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Immediately life-threatening  
• 
Results in inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death which occurs during the protocol-specified period of monitoring 
for adverse and serious adverse events would be a serious adverse event, even if the 
event observed is a primary clinical endpoint of the study. 
7.2.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The term “unanticipated problem” is found, but not defined in the regulations for the 
Protection of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. 
Guidance from the regulatory agencies considers unanticipated problems to include any 
incident, experience, or outcome that meets each of the following criteria: 
• 
Unexpected (in terms of nature, severity or frequency) AND 
• 
Definitely or probably related to participation in the research AND  
• 
Serious or a possible unexpected problem in that the research places subjects or 
others at greater risk of harm than was previously known or recognized. Note: Any 
serious adverse event would always suggest a greater risk of harm. 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.2.3 
Reporting 
The UTSW IRB requires reporting of all UPIRSOs according to the guidance below. For 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. All SAEs occurring during the protocol-specified 
monitoring period should be submitted to the UTSW study team within 2 business days of 
the center learning of the event. 

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7.2.3.1 UPIRSOs occurring on the study require expedited reporting, and are submitted to the 
UTSW IRB through the UTSW eIRB by the UTSW study team and to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB report; FDA Form #3500A 
forms, or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be submitted to the UTSW study team and will be forwarded to the DSMC 
Coordinator.  The DSMC Coordinator forwards the information onto the DSMC Chairman 
who determines if immediate action is required.  Follow-up eIRB reports, and all 
subsequent SAE documentation that is available are also submitted to the DSMC Chair 
who determines if further action is required. (See Appendix IV of the SCCC DSMC Plan for 
a template Serious Adverse Event Form which may be utilized when a sponsor form is 
unavailable and SAE submission to the eIRB is not required). 
  
All serious adverse events which occur on research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. Hardcopies or electronic versions of the FDA Form #3500A forms, 
or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be forwarded to the DSMC Coordinator.   
 
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Cancer Center, the DOT Manager or lead coordinator ensures that all participating sites 
are notified of the event and resulting action, according to FDA guidance for expedited 
reporting. DSMC Chairperson reviews all serious adverse events upon receipt from the 
DSMC Coordinator.  The DSMC Chairperson determines whether action is required and 
either takes action immediately, convenes a special DSMC session (physical or 
electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
 
 
 
 
 
Telephone reports to: 
Ananth Madhuranthakam, PhD 
Phone: 214-645-1568 
 
Written reports to: 
Ananth Madhuranthakam, PhD 
UT Southwestern Medical Center 
Department of Radiology 
5323 Harry Hines Blvd, 
Dallas, TX 75390-9061 
Fax 214-648-7783 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
1. 
SAEs 
Serious adverse events (SAEs) for studies where the SCCC DSMC is the DSMC of 
record require reporting to the DSMC coordinator within 2 working days of PI awareness, 
 

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or as described in the protocol.   
2. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) 
Local Serious Adverse Event UPIRSOs require reporting to the UTSW IRB within 48 hours 
of PI awareness of the event (life threatening or fatal events experienced by subjects 
enrolled by the investigator(s) under UTSW IRB jurisdiction).   
Local UPIRSOs (non-serious events experienced by subjects enrolled by the 
investigator(s) under UTSW IRB jurisdiction) require reporting to the UTSW IRB within 5 
business days of PI awareness of the event. 
External UPIRSOs including those that occur as non-local events require reporting to the 
UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for INDs 
and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM227351.pdf 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
7.4 
Unblinding Procedures 
Patient information is not blinded and all information obtained from the imaging studies 
performed for the purposes of the study will be available to all clinics treating the patient.  
7.5 
Stopping Rules 
This study does not contain any stopping rules as it does not include treatment for 
patients.  

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8.0 
DRUG/TREATMENT INFORMATION 
Not applicable. 
9.0 
CORRELATIVES/SPECIAL STUDIES 
Standard clinical history including clinical histopathology will be collected and correlated. No 
additional correlative studies are collected. 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
 
This is a prospective, single-centered study, designed to address the following primary 
objective: 
1. To determine whether ASL-measured perfusion can identify treatment response (time 
to progression) earlier than the currently used RECIST criteria (tumor size). 
Hypothesis: Greater reduction in ASL measured tumor perfusion during and 
immediately after treatment is a marker of tumor responsiveness prior to size 
changes.  
 
Primary end points for this study will include the absolute days of time to disease 
progression, PFS and OS as well as disease status (progression versus not) at 7 months 
post treatment initiation. Progression will be determined based on clinically accepted 
RECIST criteria (20).  
10.2 
Sample Size and Accrual 
The sample size is calculated based on the primary objective. A significant correlation of 
0.75 was observed between one month ASL perfusion change and time to progression in 
our RCC patients, whereas the corresponding tumor size change was not correlated with 
time to progression (19). We expect approximately 50% of RCC patients to progress 
within 7 months of imaging protocol. Beyond this time point, patients will be followed 
according to their clinical scans for the next 3 years or until death. Using such 
information, we target 40 subjects for this study and anticipate approximately 20 subjects 
to progress within the 7 months period. This sample size would provide more than 95% 
power to detect a correlation of 0.75 between earlier perfusion changes (at T2 and T6) 
and time to progression, using two-sided correlation test at a significance level of 0.05.  
10.3 
Data Analyses Plans 
The perfusion difference images and the absolute quantified images will be converted to 
DICOM and transferred to a DICOM database (e.g. iPACS, OsiriX). A semi-automated 
segmentation algorithm and region of interest (ROI) based measures will be performed to 
extract perfusion measures. Percentage changes in perfusion within each ROI will be 
calculated at each follow-up MRI compared to the baseline image. The semi-automated 
tumor ROIs will be compared to expert segmentation by Dr. Pedrosa in all cases, who will 
also supervise the trainee (to be recruited) in the analysis. Additionally, morphological 
changes will also be calculated according to RECIST and 10% reduction in the sum of 
the largest diameters (20).  
 
Among patients with disease progression, one-sample correlation test will be used to 
determine the correlation between change in ASL measured tumor perfusion during and 
immediately after treatment and time to progression, and the correlation between change 
in ASL measured tumor perfusion during and immediately after treatment and the 
corresponding tumor size change.  The correlations will be measured and compared 
using Pearson’s correlation coefficient along with 95% confidence interval. PFS and OS 
will be correlated with baseline perfusion and post-treatment changes at T1 and T2 

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compared to baseline using univariable and multivariable Cox regression models. We 
used PFS at 7 months as a cutoff point to divide patients into “responders” versus “non-
responders” in this study. Univariable and multivariable logistic regression models will be 
used to predict responders from non-responders with ASL measurements at baseline and 
at earlier time points (T1 and T2) alone, and in combination with other MR imaging 
metrics. The statistical analysis will also be performed separately for male and female 
subjects to evaluate sex as a biological variable. 
 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
11.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject or legally authorized representative and by 
the person who conducted the informed consent discussion. 
11.3 
Registration Procedures 
 
All subjects must be registered with the Radiology Clinical Trials Office before enrollment 
to study. Prior to registration, eligibility criteria must be confirmed with the Radiology 
Clinical Trials Office Study Coordinator. To register a subject, call 214-645-1568 Monday 
through Friday, 9:00AM-5:00PM.  
 
New subjects will receive a number beginning with 001 upon study consent such that the 
first subject consented is numbered 001, the second subject consented receives the 
number 002, etc.  
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration code according to 
the numbering schema outlined above, which should then be entered as the patient study 
id in Velos upon updating the status to be enrolled. 
 

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The numbering schema should clearly identify the site number; the sequential number of 
the subject enrolled as well as the status of the subjects enrolled so that the number of 
subjects consented versus the number of subjects actually enrolled may be easily 
identified.   
11.4 
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, which 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.   
 
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.  
11.5 
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.  
11.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form 
must be completed within five (5) business days of making the change. 
11.5.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB. According to the IRB, a protocol deviation is 
any unplanned variance from an IRB approved protocol that:  
• 
Is generally noted or recognized after it occurs 

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• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, the guidelines below will be followed: 
 
Protocol Deviations: Deviations should be summarized and reported to the IRB 
at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within two (2) 
weeks of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.  
11.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 

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11.8 
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 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. 
12.0 
REFERENCES 
1. 
Cancer Stat Facts: Kidney and Renal Pelvis Cancer. April 2017. Accessed on April 11, 
2018. Available at: https://seer.cancer.gov/statfacts/html/kidrp.html.  
2. 
Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary C, Yu M, Ruhl J, Tatalovich 
Z, Mariotto A, Lewis D, Chen H, Feuer E, Cronin K. SEER Cancer Statistics Review, 1975-
2014, National Cancer Institute. Bethesda, MD. April 2017. Accessed on April 11, 2018. 
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13.0 
APPENDICES