Clinical trial NCT04625517
Conditions: Breast Cancer
Keywords: mammography contrast enhanced spectral mammography
Sponsor: University of Texas Southwestern Medical Center
Start date: 2020-01-22; Completion date: 2022-06-15
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to investigate the diagnostic accuracy of Contrast Enhanced Spectral Mammography (CEDM) in predicting early neoadjuvant therapy response and pathologic complete response (pCR) compared to mammography.

Patients diagnosed with invasive breast cancer with available mammography and ultrasound imaging are eligible for the study.

Eligible patients will be imaged at baseline (before initiation of neoadjuvant chemotherapy or endocrine therapy), early (2-4 cycles of neoadjuvant therapy) and late (after completion of neoadjuvant chemotherapy or endocrine therapy) timepoints with mammography. CEDM will be done within 2 weeks of the specified timepoint. Additionally, a survey of subject experience with CEDM and other pre-operative imaging will be collected after CEDM is performed.

Detailed description:
The use of neoadjuvant systemic therapy in the treatment of breast cancer patients is increasing beyond the scope of locally advanced disease. Imaging provides important information in assessing response to therapy as a complement to conventional tumor measurements via physical examination. Tumor response to neoadjuvant therapy can also provide prognostic information. The attainment of pCR after completion of neoadjuvant therapy and surgical resection is associated with improved disease-free survival. This correlation is especially strong for Triple-receptor negative and human epidermal growth factor receptor 2 (HER-2) positive breast cancer. Studies of neoadjuvant therapy have used a variety of methods for assessing tumor response. Currently, there are no established clinical practice guidelines for how best to assess tumor response to neoadjuvant therapy. Typically, patients undergo conventional breast imaging such as mammography and ultrasonography (US) and physical examination, and dynamic contrast-enhanced breast magnetic resonance imaging (DCR-MRI) in selected cases.

Contrast Enhanced Digital Mammography (CEDM) is a novel imaging technique, which allows digital mammography to be used with contrast enhancement to depict cancers that would otherwise be occult on standard unenhanced mammography. CEDM is performed with and without intravenous iodine contrast, using the dual energy subtraction technique. Compared with mammography and US, CEDM improves the sensitivity for breast cancer detection without decreasing specificity. CEDM digital detector has higher spatial resolution than MRI, revealing details that are approximately 10 times better. In contrast to the rapid washout in MRI, enhancement on CEDM in fact persists for at least 10 min after contrast agent infusion. Today CEDM is available commercially for clinical use. It is estimated that over 200,000 CEDM examinations have been performed to date in both research and clinical settings. CEDM costs significantly less compared to MRI. Furthermore, longer time delays between contrast injection and CEDM exposure could result in stronger enhancement and hence better visibility compared to MRI, especially given the much higher spatial resolution of digital mammography. It is unknown whether CEDM can improve the sensitivity of mammography in the early assessment of neoadjuvant therapy response. We hypothesize that CEDM is superior to mammography and ultrasound in assessing early response, and pre-surgical residual cancer after neoadjuvant therapy, and when performed, non-inferior to MRI in assessing the residual disease using the metrics of pCR and residual cancer burden (RCB).

Arms: arm 1: Patients with ipsilateral intact biopsy-proven breast cancer
Interventions: intervention 1: Digital Mammography intervention 2: Low Osmolar Contrast Material, 300-399 Mg/Ml Iodine Concentration, Per Ml
Intervention descriptions: intervention 1: Digital Mammography enhanced with an iodinated contrast agent intervention 2: Injection of low osmolar contrast material during the digital mammography exam

Protocol documents:
Prot_SAP_000.pdf: 
 
STU2019-0529, Dogan, FormA3-ResearchProtocol, Mod_6, 04-12-21 
 
 
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, 12/2018 
 
PROTOCOL NUMBER 
Performance of contrast-enhanced spectral mammography to assess neoadjuvant chemotherapy 
response 
[Phase III, Prospective, Single-Arm, Single-Center, Contrast-Enhanced Spectral Mammography, Breast 
Cancer] 
 
Principal Investigator:  
Basak Dogan, MD 
 
 
 
 
UT Southwestern 
 
 
 
 
5323 Harry Hines Blvd. Dallas, TX 75390 
 
 
 
 
(214) 645-3290  
 
 
 
 
Basak.Dogan@UTSouthwestern.edu 
 
 
Co-Principal Investigators or Lead Sub-Investigator(s): 
 
 
 
 
 
 
Jennifer Schopp 
 
 
 
 
Assistant Professor, Diagnostic Radiology 
 
Biostatistician: 
 
Yin Xi 
 
 
 
 
UT Southwestern 
 
 
 
 
5323 Harry Hines Blvd. Dallas, TX 75390 
 
 
 
 
(214) 648-7755  
 
 
 
 
(214) 648-7784 
 
 
 
 
Yin.Xi@UTSouthwestern.edu 
 
Funding Source:  
UTSW Radiology 
 
Initial version: 
[Version 1.0, 10/24/2019] 
Amended: 
 
04/01/2021 
 
 
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 
 


 
STU2019-0529, Dogan, FormA3-ResearchProtocol, Mod_6, 04-12-21 
 
 
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, 12/2018 
 
 
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. 
 
Amendment/Version #_V4.0________________________ 
PROTOCOL NUMBER 
Performance of contrast-enhanced spectral mammography to assess neoadjuvant chemotherapy 
response 
[Exploratory, Prospective, Single Arm, Single Center, Contrast-Enhanced Spectral Mammography, Breast 
Cancer] 
 
 
Principal Investigator (PI) Name: ___BASAK DOGAN, M.D.___________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS (EXAMPLES) ...............................................................................1 
STUDY SCHEMA ...................................................................................................................3 
STUDY SUMMARY ................................................................................................................4 
1.0 BACKGROUND AND RATIONALE ...................................................................................5 
1.1 
Disease Background........................................................................................................ 5 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities ................. 5 
1.3 
Other Agents .................................................................................................................... 6 
1.4 
Rationale .......................................................................................................................... 7 
2.0 STUDY OBJECTIVES .......................................................................................................7 
2.1 
Primary Objectives ........................................................................................................... 7 
2.2 
Secondary Objectives ...................................................................................................... 7 
2.3 
Exploratory Objectives ..................................................................................................... 7 
2.4 
Endpoints ......................................................................................................................... 8 
3.0 PATIENT ELIGIBILITY ......................................................................................................8 
3.1 
Inclusion Criteria .............................................................................................................. 8 
3.2 
Exclusion Criteria ............................................................................................................. 8 
4.0 CEDM RESPONSE ASSESSMENT PLAN .........................................................................9 
4.1 
CEDM .............................................................................................................................. 9 
4.2 
Other Modalities or Procedures ..................................................................................... 10 
4.3 
Duration of Follow Up .................................................................................................... 10 
4.4 
Removal of Subjects from Protocol Therapy ................................................................. 10 
4.5 
Subject Replacement..................................................................................................... 10 
5.0 STUDY PROCEDURES ..................................................................................................10 


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5.1 
Screening/Baseline Procedures .................................................................................... 10 
5.2 
Procedures During CEDM ............................................................................................. 10 
5.3 
Follow-up Procedures .................................................................................................... 11 
5.4 
Time and Events Table .................................................................................................. 11 
5.5 
Removal of Subjects from Study ................................................................................... 11 
6.0 Measurement of Effect ..................................................................................................11 
6.1 
Response Evaluation Criteria ........................................................................................ 11 
6.2 
Safety/tolerability ........................................................................................................... 12 
6.3 
Pathology ....................................................................................................................... 12 
7.0 ADVERSE EVENTS ........................................................................................................12 
7.1 
Adverse Event Monitoring ............................................................................................. 13 
7.2 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the SCCC 
DSMC and/or HRPP ................................................................................................................... 15 
7.3 
Unblinding Procedures .................................................................................................. 16 
8.0 STATISTICAL CONSIDERATIONS .................................................................................16 
8.1 
Study Design/Study Endpoints ...................................................................................... 17 
8.2 
Sample Size and Accrual .............................................................................................. 17 
8.3 
Data Analyses ................................................................................................................ 17 
9.0 STUDY MANAGEMENT..................................................................................................18 
9.1 
Conflict of Interest .......................................................................................................... 18 
9.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 18 
9.3 
Registration/Randomization Procedures ....................................................................... 18 
9.4 
Data Management and Monitoring/Auditing .................................................................. 19 
9.5 
Adherence to the Protocol ............................................................................................. 19 
9.6 
Amendments to the Protocol ......................................................................................... 20 
9.7 
Record Retention ........................................................................................................... 20 


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9.8 
Obligations of Investigators ........................................................................................... 21 
10.0 REFERENCES .............................................................................................................21 
11.0 APPENDICES ..............................................................................................................23 


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LIST OF ABBREVIATIONS (EXAMPLES) 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CEDM 
Contrast enhanced digital mammography 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
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 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
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 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 


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SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 
 
 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligible patients 
Baseline US, Mammography ± MRI 
 BASELINE  CEDM (at 90 seconds, 5 min and 10 min) 
EARLY-TO –MID CHEMOTHERAPY ASSESSMENT: 
1. CEDM  (at 90 seconds, 5 min and 10 min) 
2. Clinical Exam 
 
POST-CHEMOTHERAPY, PRE-SURGERY : 
1. CEDM  (at 90 seconds, 5 min and 10 min) 
2. Clinical exam 
 


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STUDY SUMMARY 
Title 
Performance of contrast-enhanced spectral mammography to assess 
neoadjuvant therapy response 
Short Title 
Contrast-enhanced mammography Assessment of Breast Cancer  
Neoadjuvant Therapy response 
Protocol Number 
The standard protocol number used to identify this study 
Phase 
III 
Methodology 
Prospective, Single Arm, Unblinded 
Study Duration 
24 months 
Study Center(s) 
Single-Center, UTSW Breast Center & Parkland Moody Center for 
Breast Health 
Objectives 
Primary Objectives 
1. To investigate the diagnostic accuracy of Contrast Enhanced Spectral 
Mammography (CEDM) in predicting early neoadjuvant therapy 
response and pCR compared to mammography. 
  2. To investigate the correlation accuracy of CEDM pre-operative lesion 
size and final pathological size,compared to mammography.  
 
 
 
Number of Subjects 
100 
Diagnosis and Main 
Inclusion Criteria 
1. 18 years and older male or female patients 
2. Ipsilateral intact biopsy-proven breast cancer clinical T1-T4 (by 
imaging)  
3. Available mammography and ultrasound imaging of the existing index 
cancer, with orthogonal measurements 
4. Prior history of ipsilateral or contralateral breast cancer, presenting 
with a new primary or recurrent disease. 
5. Patients who were determined to be candidates for either neoadjuvant 
chemotherapy or neoadjuvant endocrine therapy by the treating 
physician. 
6. Women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, 
and for days following completion of study participation. Should a woman 
become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately. 
Study Product(s), Dose, 
Route, Regimen 
Contrast-Enhanced Digital Mammography 
Duration of administration 
N/A 
Reference therapy 
 
Statistical Methodology 
Descriptive Statistics will be produced. Spearman rank correlation will be 
used to measure the agreement between final pathologic and imaging 
tumor size data. ROC analysis will be used to assess the diagnostic 
performance of CEDM. 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
The use of neoadjuvant systemic therapy in the treatment of breast cancer patients is 
increasing beyond the scope of locally advanced disease. Imaging provides important 
information in assessing response to therapy as a complement to conventional tumor 
measurements via physical examination. Tumor response to neoadjuvant therapy can 
also provide prognostic information. The attainment of pathologic complete response 
(pCR) after completion of neoadjuvant therapy and surgical resection is associated with 
improved disease-free survival (1-3). This correlation is especially strong for Triple-
receptor negative (ER, PR negative and HER-2 non amplified), and HER-2 positive 
breast cancer. Studies of neoadjuvant therapy have used a variety of methods for 
assessing tumor response. Currently, there are no established clinical practice guidelines 
for how best to assess tumor response to neoadjuvant therapy. Typically, patients 
undergo conventional breast imaging (mammography and ultrasonography [US]) and 
physical examination, and dynamic contrast-enhanced breast MRI (DCR-MRI) in selected 
cases. 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
Studies of neoadjuvant therapy have used a variety of methods for assessing breast 
cancer response to neoadjuvant therapy. Physical measurement of tumor size with 
calipers is typically performed prior to each chemotherapy cycle or monthly if neoadjuvant 
endocrine therapy is used (4). The accuracy of clinical breast examination for determining 
pCR in patients with locally advanced breast cancer after neoadjuvant hormonal or 
chemotherapy is 57%, which is inferior to mammography (74%) and US (79%)  
(5,6).Mammography has been shown to be more sensitive than physical examination for 
detecting presence of residual tumor after therapy but is less specific and may 
underestimate the degree of treatment response (7,8). The mammographic lesion type, 
such as architectural distortion, and margin impact its accuracy for size measurement, 
with decreased accuracy when margins are indistinct or spiculated and due to masking 
from adjacent normal tissue (9). Additional challenges with mammography include the 
presence of microcalcifications, which do not correlate with presence of viable tumor (10-
12). US has been shown to be a better predictor for pathologic tumor size than 
mammography after treatment with neoadjuvant therapy (13-15). The sensitivity and 
specificity of mammography in predicting pathologic complete response were 54.2% and 
86.3%, respectively. The sensitivity and specificity of breast ultrasound in predicting 
pathologic complete response were 45.8% and 93.8%, respectively. The best method for 
predicting complete pathologic response (pCR) appears to be the combination of 
mammography with US (80% likelihood when findings of both modalities are negative) 
(14,16). Standard imaging methods used to monitor response to neoadjuvant 
therapy are summarized in Table 1.  
 
 
 
 
 
 
 
 
 
 
 


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Table 1. Standard imaging methods used to monitor response to neoadjuvant 
therapy 
 
 
Table 2. Meta-analyses depicting MRI sensitivity in achieving pCR (from Fowler et 
al Radiology 2017 Nov) 
 
 
DCE-breast MRI sensitivity and specificity in predicting pCR ranges from 63-88% and 55-
91%, heavily depending on the imaging cut off criteria used to define imaging  complete 
response on MRI interpretation.  As demonstrated by a recent meta-analysis (Table 2) 
MRI can significantly underestimate residual disease. This is likely due in part because 
initial tumor enhancement and visibility on MRI peaks at 2 minutes, however with 
chemotherapy contrast delivery to the tumor may be significantly delayed due to the 
disruption of neovasculature.   
1.3 
Other Agents 
Contrast Enhanced Digital Mammography (CEDM) is a novel imaging technique, which 
allows digital mammography to be used with contrast enhancement to depict cancers that 
would otherwise be occult on standard unenhanced mammography. CEDM is performed 
with and without i.v. iodine contrast, using the dual energy subtraction technique (20-25). 
Compared with mammography and US, CEDM improves the sensitivity for breast cancer 
detection without decreasing specificity (20,21). CEDM digital detector has higher spatial 
resolution than MRI (i.e. typically pixel sizes 100 μm and 1 mm, respectively), revealing 


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details that are approximately 10 times better. In contrast to the rapid washout in MRI, 
enhancement on CEDM in fact persists for at least 10 min after contrast agent infusion. 
Today CEDM is available commercially for clinical use.  It is estimated that over 200,000 
CEDM examinations have been performed to date in both research and clinical settings. 
CEDM costs significantly less compared to MRI. (26). Furthermore, longer time delays 
between contrast injection and CEDM exposure could result in stronger enhancement 
and hence better visibility compared to MRI, especially given the much higher spatial 
resolution of digital mammography. It is unknown whether CEDM can improve the 
sensitivity of mammography in the early assessment of neoadjuvant therapy response. 
We hypothesize that CEDM is superior to mammography and ultrasound in assessing 
early response, and pre-surgical residual cancer after neoadjuvant therapy, and when 
performed, non-inferior to MRI in assessing the residual disease using the metrics of pCR 
and RCB.   
1.4 
Rationale 
The use of neoadjuvant systemic therapy in the treatment of breast cancer patients is 
increasing beyond the scope of locally advanced disease. Imaging provides important 
information in assessing response to therapy as a complement to conventional tumor 
measurements via physical examination. Tumor response to neoadjuvant therapy can 
also provide prognostic information. The attainment of pathologic complete response 
(pCR) after completion of neoadjuvant therapy and surgical resection is associated with 
improved disease-free survival (1-3). This correlation is especially strong for Triple-
receptor negative (ER, PR negative and HER-2 non amplified), and HER-2 positive 
breast cancer. Studies of neoadjuvant therapy have used a variety of methods for 
assessing tumor response. Currently, there are no established clinical practice guidelines 
for how best to assess tumor response to neoadjuvant therapy. Typically, patients 
undergo conventional breast imaging (mammography and ultrasonography [US]) and 
physical examination, and dynamic contrast-enhanced breast MRI (DCR-MRI) in selected 
cases. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To investigate the diagnostic accuracy of Contrast Enhanced Spectral 
Mammography (CEDM) in predicting early neoadjuvant therapy response and 
pCR.    
2.2 
Secondary Objectives 
2.2.1 
To investigate the correlation of CEDM pre-operative lesion size and final 
pathological size. 
 
2.2.2  
To determine additional sites of disease in the ipsilateral or contralateral breast 
identified by CEDM. 
2.3 
Exploratory Objectives 
 
To determine the optimal post neoadjuvant therapy CEDM timing which 
helps demonstrate the residual disease extent. 
2.3.2. To identify any patient preference differences between CEDM and breast MRI 


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2.4 
Endpoints 
2.4.1  Primary: Diagnostic performance (sensitivity and specificity) measured as area 
under the curve (AUC) in the response assessment by varying metrics including pCR and 
RCB classification. 
 
2.4.2 Secondary: Correlative statistic for CEDM lesion sizing vs pathologic lesions sizing, 
frequency of finding additional sites of disease in ipsilateral or contralateral breasts by 
CEDM and number of such new lesions. 
 
2.4.3 Exploratory: AUC of CEDM using varying time points for CEDM, survey scores for 
patient experience with CEDM 
3.0 
Subject ELIGIBILITY 
3.1 
Inclusion Criteria 
 
18 years and older male or female patients 
 
Ipsilateral intact biopsy-proven invasive breast cancer clinical T1-T4 (by imaging)  
 
Available mammography and ultrasound imaging of the existing index cancer, 
with orthogonal measurements 
 
Prior history of ipsilateral or contralateral breast cancer, presenting with a new 
primary or recurrent disease 
 
Patients who were determined to be candidates for either neoadjuvant 
chemotherapy or neoadjuvant endocrine therapy by the treating physician  
3.2 
Exclusion Criteria 
 
History of ipsilateral mastectomy. 
 
Women who already started neoadjuvant chemotherapy or endocrine therapy.  
 
Woman who may be pregnant. 
 
Prior history of anaphylactic or anaphylactoid reaction to any contrast.  
 
Prior allergy to iodine or iodinated contrast.    
Imaging Services will practice safe contrast administration through the evaluation of the 
patients’ history via the electronic medical record and/or patient questionnaire. 
Individualized, patient centric protocol planning, medication review, and contrast dosage 
will be utilized to reduce adverse events. Renal function testing is not routinely required 
for every patient receiving contrast. Creatinine and Estimated Glomerular Filtration Rate 
(eGFR) testing will be performed on patients at risk for contrast induced nephrotoxicity 
(CIN). Patients with reduced eGFR may be given intravenous (IV) iodinated contrast 
safely in many circumstances. Clinically significant nephrotoxicity after iodinated contrast 
media administration is highly unusual in patients with normal or mildly reduced renal 
function GFR is tested in patients with a risk factor for decreased renal function.  
Patients with one or more of the following conditions are considered to be at high risk for 
contrast induced nephropathy (CIN). These patients will be required to have renal 
function testing (eGFR) within 30 days before receiving intravenous iodinated contrast. 
 
 
 
i) Kidney problems 


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ii) Kidney surgery 
iii) Gout 
iv) Hypertension 
v) Diabetes mellitus 
vi) Age > 60 
 
Patients with known distant metastasis. 
4.0 
CEDM RESPONSE ASSESSMENT PLAN 
 
Patients diagnosed with invasive breast cancer with available mammography and ultrasound imaging are 
eligible for the study. 
 
Eligible patients will be imaged at baseline (before initiation of neoadjuvant chemotherapy or endocrine 
therapy), early (2-4 cycles of neoadjuvant therapy) and late (after completion of neoadjuvant 
chemotherapy or endocrine therapy) timepoints with mammography.CEDM will be done within 2 weeks of 
the specified timepoint.  Three dimensional orthogonal measurements will be obtained in all timepoints. 
Additional sites of disease in the ipsilateral or contralateral breast identified by CEDM will be recorded 
and reported. ACR BI-RADS MRI lexicon will be used for reporting. 
4.1 
CEDM 
To perform a CEDM examination, an IV is placed in the forearm or antecubital vein and a 
low osmolar iodinated contrast agent is administered at approximately 3ml/s using a 
power injector.  Contrast agents with iodine concentration between 300 mg/ml and 370 
mg/ml are typically used.  The volume of contrast is similar to that used for a CT scan, 
approximately 1.5 ml/kg body weight, typically around 90-150 ml.  After a delay of at least 
90 seconds from the end of the injection, the patient is positioned for 2 standard 
mammography views (craniocaudal and mediolateral oblique) of each breast.  Rather 
than a standard single energy mammogram, however, the CEDM device acquires dual-
energy image pairs in each projection.   Since there is less than 1 second between the 
low-energy and high energy images, the imaging time is the same as that needed for a 
standard mammogram.  Additional projections may be obtained since optimally enhanced 
images can typically be obtained up to 7-10 minutes following injection.  Following image 
acquisition, contrast-enhanced subtraction images are produced using a weighted 
logarithmic subtraction of the low energy image from the high energy image. Because the 
difference in iodine absorption between the images is larger than the difference in tissue 
absorption, this dual energy subtraction technique has the effect of increasing the 
visibility of the iodine while almost completely eliminating the visibility of background 
tissue. The resulting images will be sent to a review workstation or PACS for 
interpretation by the radiologist. The low energy images, which are identical to standard 
unenhanced mammograms, will also be used in the interpretation. 
 
The risks of CEDM include the risks of contrast administration including allergic 
reactions and renal function abnormalities. Just as with CT, patients will be screened 
for allergy history and possible renal function abnormalities. Allergic or physiologic 
reaction are reported to occur in less than 1% of patients when using low osmolar 
contrast agents although this increases in patients with prior reactions (11,12).  
Severe acute reactions occur in 4/10,000 (0.04%) of patients (13). Any contrast 
reaction will be handled in accordance with the Radiology Department’s Contrast-
Reaction Guidelines 
https://hs.swmed.edu/communities_collaboration/radpoint/clinicaloperations/Practice%
20Guidelines%20%20Procedures/Contrast%20Reactions%20-


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%20Pocket%20Guide.pdf#search=contrast%20reaction)Concomitant 
Medications/Treatments 
4.2 
Other Modalities or Procedures 
Every effort will be made to perform any additional imaging such as ultrasound and 
contrast-enhanced breast MRI at the same timepoint with CEDM, however patients will 
not be excluded based on inability to perform these imaging.  
4.3 
Duration of Follow Up 
Adverse reactions to contrast will be monitored according to institutional guidelines. 
Patients will be observed for at least 30 minutes after contrast administration for any 
immediate side effects of contrast. Only contrast-specific side effects will be recorded, 
including moderate to severe allergic reactions to contrast, laryngospasm, angioedema, 
hypotension, bradycardia, diffuse hives.  
Overall study duration is expected to be approximately 4-6 months from initiation of 
neoadjuvant therapy until final surgery in which negative margins are achieved.   
4.4 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator and document the reason for treatment discontinuation 
and the date of discontinuation. The subject should be followed-up per protocol.  
4.5 
Subject Replacement 
Loss of any subjects before second timepoint CEDM occurs will result in subject 
replacement. 
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: 
 
Medical history, and reviewing subject eligibility criteria previous and 
concomitant medications 
 
Informed Consent 
5.2 
Procedures During CEDM 
CEDM will be performed using UTSW Imaging Protocol (attached, Appendix A), 
including monitoring for immediate contrast reactions. 
 
Discussion of additional findings: All breast imaging findings are routinely discussed with 
the patient by the radiologist immediately after imaging in our clinical practice. Additional 
findings identified on CEDM will be addressed similar to additional disease noted on 
ultrasound or breast MRI per standard of care.  
 


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Survey of patient experience with CEDM and other pre-operative imaging such as MRI 
will be collected after CEDM is performed, optimally at pre-operative time point 
(Appendix B).  
5.3 
Follow-up Procedures 
Patients’ medical records will be followed 30 days after completion of definitive surgery to 
collect final pathology outcomes, or if they develop progressive disease.  
5.4 
Time and Events Table  
 
 
Baseline 
Mid chemotherapy 
Pre-Operative 
Informed Consent 
x 
 
 
History and allergies 
X 
X 
X 
CEDM 
X 
X 
X 
QUESTIONNAIRE 
 
 
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 treatment (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.5.9 
Patient develops moderate to severe reaction to contrast (as defined by the 
Department’s guidelines for iodinated contrast) over the course of neoadjuvant 
therapy follow-up. Mild reactions will be considered for pre-medication and 
decided on a case by case basis.  
6.0 
Measurement of Effect 
Response assessments will be performed in early and late (post chemotherapy and pre-surgery) 
timepoints. Every effort will be made to obtain CEDM during within 2 weeks of .  
 
 
 
Response to therapy will be assessed for each patient as follows: 
 
6.1 
Response Evaluation Criteria 
 
Response evaluation criteria in solid tumors (RECIST) 1.1 criteria, considering 
the sum of the largest dimension of malignancies at baseline and its variation at 
subsequent measurements . Clinical response is classified as follows: complete 
response (CR, disappearance of all lesions); partial response (PR, ≥ 30% 
dimensional reduction), stable disease (SD, < 30% dimensional reduction/< 20% 


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dimensional increase) and progressive disease (PD, ≥ 20% dimensional 
increase). 
 
For pathologic response, RCB index is assessed routinely per standard of 
care, where a complete pathologic response has an RCB of zero, and 
residual disease is classified into three categories (RCB-I, RCB-II, and RCB-
III)  
http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert
3 
 
This is not a treatment study. Patients will be treated either as per standard of 
care neoadjuvant protocol or as part of ongoing treatment trials in the UT 
Southwestern Medical Center.  
 
Percent change in tumor volume using the following formula for 
ellipsoidal/spherical volume derived from mid-dynamic sequence subtraction 
series:  V (cm3) = (4/3 π) x length/2 x width/2 x height/2 
 
Pre-surgery lesion size on CEDM, on 90 to120 second, 5 minute and 10 
minute time points will be assessed using three maximal dimensions.  
 
On pre-surgery CEDM, association of any residual calcifications with 
enhancement will be recorded 
 
The largest single focus of enhancement will be recorded, as well as an 
overall residual tumor volume (single maximal dimension) 
 
The association of post biopsy clip with the enhancement will be recorded.  
6.2 
Safety/tolerability 
Analyses will be performed for all patients having undergone at least one baseline and 
one mid or post therapy CEDM. We will perform standard of care pre and post CEDM 
monitoring in the immediate post CEDM phase, record and grade any reactions.   
We will also ask patients to fill out a survey regarding their comfort level with CEDM 
(APPENDIX B) before their surgery.  
6.3 
Pathology  
Final histopathology for correlation will include the size of residual tumor (ypT), tumor cellularity (%) and 
amount of DCIS (%).Per AJCC8th edition [Amin MB, Edge SB, Greene FL, et al, eds.AJCC Cancer 
Staging Manual. 8th ed. New York: Springer; 2017] (ypT) is based on the largest continuous focus of 
residual invasive cancer, if present. Treatment-related fibrosis adjacent to residual invasive carcinoma or 
between foci of residual cancer is not included in the ypT maximum dimension. When multiple foci of 
residual tumor are present, the (m) modifier is included. 
In addition, we will record ki67 index pre and post therapy and its potential correlation with the degree of 
tumor response seen on CEDM. 
 
The agreement between pre-operative CEDM measurements  and mammography in categorizing tumor 
response RCB0-I/ RCBII/RCBIII will be assessed using weighed kappa.  
7.0 
ADVERSE EVENTS 


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7.1 
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. 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:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline or is stable in the opinion of the investigator;  
 there is a satisfactory explanation other than the study therapy for the changes 
observed; or 
 death. 
 
Definitions  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam, imaging finding or clinically significant laboratory finding), symptom, 
clinical event, or disease, temporarily associated with the subject’s participation in the 
research, whether or not it is considered related to the subject’s participation in the 
research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Acute Adverse Events  
Iodine contrast is known to only have immediate side effects within the first 30 minutes of 
contrast injection. All subjects experiencing an adverse event will be monitored in Breast 
Imaging center for the first 30 minutes:   
 
Type and severity of contrast reaction or extravasation will be recorded.   
 
We will monitor the patient until the adverse event resolves or the 
symptoms or signs that constitute the adverse event return to baseline; 
 
Extravasation will be managed according to the Department of Radiology 
Standard operating procedures.  
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Adverse 
events not specifically defined in the NCI CTCAE will be scored on the Adverse Event log 
according to the general guidelines provided by the NCI CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 


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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 hospitalization1,2 or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring >24 hour inpatient admission to the hospital would be a serious 
adverse event for any research participant; likewise, in a study investigating end-stage 
cancer care, any hospitalization or death which occurs during the protocol-specified 
period of monitoring for adverse and serious adverse events would be a serious adverse 
event, even if the event observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay. Hospitalization is used as an indicator of the seriousness of the adverse event and 
should only be used for situations where the AE truly fits this definition and NOT for 
hospitalizations associated with less serious events. For example: a hospital visit where a 
patient is admitted for observation or minor treatment (e.g. hydration) and released in 
less than 24 hours. Furthermore, hospitalization for pharmacokinetic sampling is not an 
AE and therefore is not to be reported either as a routine AE or in an expedited report. 
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
 
 
 
 
AND 


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• 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.2 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the 
SCCC DSMC and/or HRPP 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 minutes of the last dose of protocol 
treatment. Any event that occurs more than 30 minutes after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
as indicated in the sections below. 
 
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 treatment. 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 (if applicable); 
 
the drug package insert (if applicable); 
 
the current Investigator’s Brochure (if applicable) 
 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
 
 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer 
Center (SCCC) Data Safety Monitoring Committee (DSMC) 
 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs/UPIRSOs occurring during the protocol-specified 
monitoring period should be submitted to the SCCC DSMC within 5 business days of the 
PI or delegated study team members awareness of the event(s). In addition, for 


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participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. 
 
The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC 
DSMC Coordinator.  Hardcopies or electronic versions of the eIRB Reportable 
Event report; FDA Form #3500A forms, or other sponsor forms, if applicable; 
and/or any other supporting documentation available should be submitted to the 
DSMC Coordinator.  The DSMC Coordinator forwards the information onto the 
DSMC Chairman who determines if immediate action is required.  Follow-up eIRB 
reports, and all subsequent SAE/UPIRSO documentation that is available are also 
submitted to the DSMC Chair who determines if further action is required. (See 
Appendix III of the SCCC DSMC Plan for a template Serious Adverse Event Form 
which may be utilized when a sponsor form is unavailable and SAE submission to 
the eIRB is not required). 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP/IRB 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, outcomes, 
etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
subject’s underlying condition or not expected as a risk of the study; therefore, not 
included in the investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  Note: According to OHRP, if the adverse event is serious, it 
would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of 
PI awareness. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, 
and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-administration/irb/assets/policies-
combined.pdf. 
7.3 
Unblinding Procedures 
N/A. There is no blinding in this study. 
8.0 
STATISTICAL CONSIDERATIONS 


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8.1 
Study Design/Study Endpoints 
The primary endpoint of this study is diagnostic performance (sensitivity and specificity) 
measured as area under the curve (AUC) in the response assessment. Key secondary 
and exploratory endpoints include correlation between pre-operative CEDM lesion size 
and final pathology and assessment of timing of CEDM for best performance in predicting 
pathologic response. 
 
8.2 
Sample Size and Accrual 
Due to the exploratory nature of the study and lack of reliable prior information, a formal 
sample size calculation was not done. We are proposing to accrue 100 patients for 
enhanced certainty of our descriptive statistics. We assume 40% prevalence of pCR. A 
sample of 100 patients will provide 95% confidence intervals of at most (maximum) ± 
0.17 (for sensitivities), ± 0.14 (for specificities) and ± 0.12 (for AUC). Simple asymptotic 
with continuity correction and normal approximation was used for calculation for 
sensitivity and specificity. Binormal approximation was used for the calculation for AUC. 
Assuming one lesion per patient, 100 patients will provide 95% confidence interval of 
spearman rank correlation of lesion size with a width no larger than 0.39. Fisher’s 
transformation followed by a normal approximation was used for calculation. Results from 
this study would help us design a multi-institutional study allowing comparison to other 
imaging modalities with a larger patient cohort. 
 
8.3 
Data Analyses 
 
Descriptive statistics will be produced for all patients; frequencies and percentages for 
categorical measures and means, medians, standard deviations, and ranges for 
continuous measures. The number of cancer foci identified by each imaging modality will 
be compared. Tumors will be categorized according to immunohistochemical 
approximated molecular profiles (Luminal A, Luminal B, Triple-negative and HER-2 
amplified).  Additional exploratory analyses will be performed as needed. 
 
1. Sensitivity of CEDM versus mammography 
  
Histopathological assessment will be used as the reference standard. 
For categorical measurements of tumor response (CR/PR/SD/PD or RCB0-I /RCB II 
/RCB III): 
1. 
Sensitivities and specificities in predicting pCR (or RCB0) will be 
calculated for CEDM and mammography respectively.  
2. 
The agreement between CEDM and mammography in categorizing 
tumor response (CR/PR/SD/PD or RCB0-I/ RCBII/RCBIII) will be assessed using 
weighed kappa. 
 
2. For continuous measurements of tumor response (RECIST, percent change in tumor 
volume and pre-surgery lesion size): 
1. 
ROC analysis will be used to assess the diagnostic performance of 
CEDM and mammography. The Area under the ROC curve (AUC) will be 
compared. A leave-one-out cross validation algorithm will be used to reduce bias 
from overfitting. 
2. 
The agreement between CEDM and mammography in RECIST, percent 
change in volume and pre-surgery lesion size will be assessed using intraclass 
correlation (ICC). 
3. Spearman’s rank correlation will be used to measure the association between final 
pathologic and imaging tumor size.  


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9.0 
STUDY MANAGEMENT 
9.1 
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. 
9.2 
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 and by the person who conducted the 
informed consent discussion. 
9.3 
Registration/Randomization 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/randomization code 
according to the numbering schema outlined above, which should then be entered as the 
patient study id in Velos upon updating the status to enrolled. 
 
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.   
 


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9.4 
Data Management and Monitoring/Auditing 
 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic 
case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements, as appropriate for the project 
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. This review 
includes but is not limited to accuracy of case report forms, protocol compliance, timeless 
and accuracy of Velos entries and AE/SAE management and reporting. Documentation 
of trial monitoring will be maintained along with other protocol related documents and will 
be reviewed during internal audit.   
 
For further information, refer to the UTSW SCCC IIT Management Manual. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and UPIRSOs in real time as they are reported and reviews 
adverse events on a quarterly basis.  The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure 
data integrity and regulatory compliance.  A copy of the DSMC plan is available upon 
request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC works as part 
of the DSMC to conduct regular audits based on the level of risk. Audit findings are 
reviewed at the next available DSMC meeting.  In this way, frequency of DSMC 
monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of 
investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles.  
9.5 
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.  
 
Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
 intentional on part of the investigator; or 
 in the investigator’s control; or 
 not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
 Reporting requirement: Exceptions are non-emergency deviations that 
require prospective IRB approval before being implemented. Call the IRB if 
your request is urgent. If IRB approval is not obtained beforehand, this 
constitutes a major deviation. 


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Emergency Deviations: include any departure from IRB-approved research 
that is necessary to:  
 
Avoid immediate apparent harm, or 
 
Protect the life or physical well-being of subjects or others 
 Reporting requirement: Emergency deviations must be promptly 
reported to the IRB within 5 working days of occurrence. 
 
 
Major Deviations (also called violations): include any departure from IRB-
approved research that: 
 
Harmed or placed subject(s) or others at risk of harm (i.e., did or has the 
potential to negatively affect the safety, rights, or welfare of subjects or 
others), or 
 
Affect data quality (e.g., the completeness, accuracy, reliability, or validity of 
the data) or the science of the research (e.g., the primary outcome/endpoint of 
the study) 
 Reporting requirement: Major deviations must be promptly reported to  
the IRB within 5 working days of PI awareness. 
 
 
Minor Deviations: include any departure from IRB-approved research that: 
 
Did not harm or place subject(s) or others at risk of harm (i.e., did not or did 
not have the potential to negatively affect the safety, rights, or welfare of 
subjects or others), or 
 
Did not affect data quality (e.g., the completeness, accuracy, reliability, or 
validity of the data) or the science of the research (e.g., the primary 
outcome/endpoint of the study) 
 Reporting requirement: Minor deviations should be tracked and 
summarized in the progress report at the next IRB continuing review.
 
9.6 
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.  
9.7 
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. 
 


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Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
9.8 
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 is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
10.0 
REFERENCES 
 
List all protocol references. 
1. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in 
patients with triple-negative breast cancer. J Clin Oncol 2008;26(8):1275–1281. Crossref, 
Medline,  
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chemotherapy. Anticancer Res 2000;20(1B):553–558. Medline 


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10.  Weiss A, Lee KC, Romero Y, et al. Calcifications on mammogram do not correlate with tumor 
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residual mammographic microcalcifications after neoadjuvant chemotherapy for locally advanced 
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neoadjuvant chemotherapy. Ann Surg 2006;243(2):257–264. Crossref, Medline 
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ultrasonography and mammography in predicting pathologic response after neoadjuvant 
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17. Mariscotti G, Houssami N, Durando M, et al. Accuracy of mammography, digital breast 
tomosynthesis, ultrasound and MR imaging in preoperative assessment of breast cancer. 
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18. Lobbes MB, Prevos R, Smidt M, et al. The role of magnetic resonance imaging in assessing 
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19. Fowler AM, Mankoff DA, Joe BN Radiology. 2017;285(2):358-375.  
20. Lewin JM, Isaacs PK, Vance V, Larke FJ. Dual-energy contrast enhanced digital subtraction 
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21. Jochelson MS, Dershaw DD, Sung JS, Heerdt AS, Thornton C, Moskowitz CS, Ferrara J, Morris 
EA. Bilateral contrast-enhanced dual-energy digital mammography: feasibility and comparison 
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22. Dromain C, Balleyguier C, Muller S, Mathieu MC, Rochard F, Opolon P, Sigal R. Evaluation of 
tumor angiogenesis of breast carcinoma using contrast-enhanced digital mammography. AJR Am 
J Roentgenol. 2006;187(5):W528–37.  
23. Dromain C, Thibault F, Muller S, Rimareix F, Delaloge S, Tardivon A, Balleyguier C. Dual-energy 
contrast enhanced digital mammography: initial clinical results. Eur Radiol. 2011;21(3):565–74.  
24. Dromain C, Thibault F, Diekmann F, Fallenberg EM, Jong RA, Koomen M, Hendrick RE, Tardivon 
A, Toledano A. Dual-energy contrast-enhanced digital mammography: initial clinical results of a 
multireader, multicase study. Breast Cancer Res. 2012;14(3):R94.  
25. Luczyńska E, Heinze-Paluchowska S, Hendrick E, Dyczek S, Ryś J, Herman K, Blecharz P, 
Jakubowicz J. Comparison between breast MRI and contrast-enhanced spectral mammography. 
Med Sci Monit. 2015;21:1358–67 
26. Patel BK, Gray RJ, Pockaj BA. Potential Cost Savings of Contrast-Enhanced Digital 
Mammography. AJR Am J Roentgenol. 2017 Jun;208(6):W231-W237. 
 
 
 
 
 


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11.0 
APPENDICES 
Please list all relevant appendices in alphabetical order, e.g., Appendix A, Appendix B, etc. 
 
Forms, questionnaires, performance scales, inclusion/exclusion checklists may be included in an 
appendix. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A. CEDM IMAGING PROTOCOL 
 
CONTRAST-ENHANCED DIGITAL MAMMOGRAPHY (CEDM)  
1. Indications  
• 
Screening Mammogram (with Contrast):  
o High-risk screening in patients who have previously been screened with breast MRI.  
o Supplemental screening for patients with known dense breast tissue  
• 
Diagnostic Mammogram (with Contrast):  
o Evaluation of extent of disease of a recently diagnosed breast cancer  
o Assessment of response to neoadjuvant therapy  
o Axillary metastasis from a mammographically and clinically occult breast primary  
o Evaluation of a callback finding seen on screening mammography  
o Evaluation of mammographically OR clinically evident areas of concern without an ultrasound 
correlate  
o Unilateral pathological nipple discharge with no mammographic and ultrasound correlate  
  
2. Pregnancy and Breastfeeding  
• 
All women of childbearing age should complete the ‘Pregnancy Status Consent Form.’  
• 
The policy regarding imaging pregnant or potentially pregnant patients is UHISAD 108.00.  
• 
There is no medical indication to stop breastfeeding after IV iodinated contrast administration. If a 
mother chooses, she can pump and discard breast milk for 12-24 hours before resuming normal breast 
feeding. Ultimately, an informed decision to temporarily stop breast feeding should be left up to the 
mother.  
 
3. Kidney Function  
• 
The mammography technologist will review the electronic medical records of all patients to 
determine whether there are renal function test results available for review. Estimated glomerular 
filtration rate (eGFR), in mL/min/1.73m2, is used as a marker for renal function.  
 •       Patients with one or more of the following conditions are considered to be at high risk for contrast  
 
induced nephropathy (CIN). These patients will be required to have renal function testing (eGFR) 
within 30 days before receiving intravenous iodinated contrast. o Age > 60  
 
o Hypertension (High blood pressure)  
 
o Diabetes mellitus  
 
o Kidney problems  
 
o Kidney surgery  
 
o Gout  
 
o Patients taking metformin-containing medications (see Item 4)  
 
 
•       For patients with eGFR > 60 30, proceed with the procedure.  
 
•       For patients with eGFR ≤ 60 30 mL/min/1.73m2, the procedure should be aborted. DO NOT 
PERFORM THE PROCEDURE. Alternative imaging techniques will be explored.  
 
4. Metformin-containing medications  
• 
Metformin-containing medications include, but are not limited to, the following:  
 
Brand Name  
Active ingredient(s)  
 
 
Actoplus Met  
metformin and 
pioglitazone  
Actoplus Met XR  
metformin extended 
release and 
pioglitazone  


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Avandamet  
metformin and 
rosiglitazone  
Fortamet  
metformin extended 
release  
Glucophage  
metformin  
Glucophage XR  
metformin extended 
release  
Glucovance  
metformin and 
glyburide  
Glumetza  
metformin extended 
release  
Invokamet  
metformin and 
canagliflozin  
Invokamet XR  
metformin extended 
release and 
canagliflozin  
Janumet  
metformin and 
sitagliptin  
Janumet XR  
metformin extended 
release and sitagliptin  
Jentadueto  
metformin and 
linagliptin  
Jentadueto XR  
metformin extended 
release and linagliptin  
Kazano  
metformin and 
alogliptin  
Kombiglyze XR  
metformin extended 
release and saxagliptin  
Prandimet  
metformin and 
repaglinide  
Riomet  
metformin  
Synjardy  
metformin and 
empagliflozin  
Synjardy XR  
metformin extended 
release and 
empagliflozin  
Xigduo XR  
metformin extended 
release and 
dapagliflozin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A. Please rate your comfort 
level during Breast MRI 
(please leave blank if not 
performed) 
D. Study time for Contrast-
Enhanced Mammmography 
 
Extremely          Relatively    Neither short    Long        Extremely Long 
  Short                    Short          Nor Long 
         5                       4                    3                           2                   1            
Extremely          Relatively    Neither short    Long        Extremely Long 
  Short                    Short          Nor Long 
         5                       4                    3                           2                      1         
Scan Time 
Comfort level and tolerance 
C. Study time for Standard 
Breast MRI (please leave 
blank if not performed) 
 Extremely       Relatively     Neither comfortable     Somewhat             Extremely 
Comfortable     Comfortable   Nor Uncomfortable   Uncomfortable    Uncomfortable 
         5                       4                               3                           2                                     1       
B. Please rate your comfort 
level during Contrast-
enhanced Mammography 
Extremely       Relatively     Neither comfortable     Somewhat          Extremely 
Comfortable     Comfortable   Nor Uncomfortable   Uncomfortable   Uncomfortable 
         5                       4                               3                              2                                     
1
 
APPENDIX B. CEDM PATIENT SURVEY/QUESTIONNAIRE 
 
 
 


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F. Overall satisfaction level 
with Contrast enhanced 
mammography 
G. Assuming they are equally 
accurate, how likely are you to 
choose contrast enhanced 
mammography over breast MRI 
as test of choice to measure 
your response ? 
 
H. How likely are you to 
choose contrast enhanced 
mammography over breast MRI 
for your annual routine 
screening in the future  ? 
 
Extremely          Relatively    Neither Satisfied    Somewhat      Extremely  
  Satisfied            Satisfied      Nor Dissatisfied   Dissatisfied      Dissatisfied 
         5                       4                    3                                2                           1         
Disease Monitoring  Preference- Please only respond if you also underwent breast MRI 
Extremely      Relatively    Neither Likely    Somewhat         Extremely  
  Likely            Likely          Nor Unlikely            Unlikely            Unlikely 
         5                       4                    3                                2                           1         
Extremely      Relatively    Neither Likely    Somewhat         Extremely  
  Likely            Likely          Nor Unlikely            Unlikely            Unlikely 
         5                       4                    3                                2                           1         
E. Overall satisfaction level 
with Standard Breast MRI 
(please leave blank if not 
performed) 
 
Extremely          Relatively    Neither Satisfied    Somewhat      Extremely  
  Satisfied            Satisfied      Nor Dissatisfied   Dissatisfied      Dissatisfied 
         5                       4                    3                                2                           1         
Overall Satisfaction 
 
 
 
Other Comments:  


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Appendix C. AJCC 8th edition pre- and post neoadjuvant therapy staging (see attached file).  
 
  


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Appendix D. ACR Contrast Manual, 2018 (excerpt) 
 
ADMINISTRATION OF CONTRAST MEDIA TO WOMEN WHO ARE BREASTFEEDING  
 
Imaging studies requiring either iodinated or gadolinium-based contrast media are occasionally required 
in patients who are breast feeding. Both the patient and the patient’s physician may have concerns 
regarding potential toxicity to the infant from contrast media that is excreted into the breast milk. The 
literature on the excretion into breast milk of iodinated and gadolinium-based contrast media and the 
gastrointestinal absorption of these agents from breast milk is very limited; however, several studies have 
shown that the expected dose of contrast medium absorbed by an infant from ingested breast milk is 
extremely low. 
 
Iodinated X-ray Contrast Media (Ionic and Nonionic) Background  
 
The plasma half-life of intravenously administered iodinated contrast medium is approximately 2 hours, 
with nearly 100% of the media cleared from the bloodstream in patients with normal renal function within 
24 hours. Because of its low lipid solubility, less than 1% of the administered maternal dose of iodinated 
contrast medium is excreted into the breast milk in the first 24 hours [1,2]. In addition, less than 1% of the 
contrast medium ingested by the infant is absorbed from its gastrointestinal tract [3]. Therefore, the 
expected systemic dose absorbed by the infant from the breast milk is less than 0.01% of the 
intravascular dose given to the mother. This amount represents less than 1% of the recommended dose 
for an infant being prescribed iodinated contrast material related to an imaging study (usually 1.5 to 2 
mL/kg).  
 
The potential risks to the infant include direct toxicity and allergic sensitization or reaction, which are 
theoretical concerns but have not been reported. The likelihood of either direct toxic or allergic-like 
manifestations resulting from ingested iodinated contrast material in the infant is extremely low. As with 
other medications in milk, the taste of the milk may be altered if it contains contrast medium [1-4].  
 
Recommendation  
Because of the very small percentage of iodinated contrast medium that is excreted into the 
breast milk and absorbed by the infant’s gut, we believe that the available data suggest that it is 
safe for the mother and infant to continue breast-feeding after receiving such an agent. Ultimately, 
an informed decision to temporarily stop breast-feeding should be left up to the mother after these facts 
are communicated. If the mother remains concerned about any potential ill effects to the infant, she may 
abstain from breast-feeding from the time of contrast administration for a period of 12 to 24 hours.  
 
There is no value to stop breast feeding beyond 24 hours. The mother should be told to express and 
discard breast milk from both breasts during that period. In anticipation of this, she may wish to use a 
breast pump to obtain milk before the contrast-enhanced study to feed the infant during the 24-hour 
period following the examination.