Prevention of Heart Failure Induced by Doxorubicin With Early Administration of Dexrazoxane in Patients With Breast Cancer
Phase: PHASE1
Conditions: Degradation of Top2b and Top2a in Human by Dexrazoxane, Time Course and Degradation of Top2b in Human by Dexrazoxane, Effects of Dexrazoxane on Healthy Human
Sponsor: University of Arkansas

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Study Title: 
Prevention of Heart Failure Induced by Doxorubicin with 
Early Administration of Dexrazoxane (PHOENIX 1) 
 
Principal Investigator: 
Hui-Ming Chang, M.D., M.P.H. 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot 611 
Little Rock, AR 72205 
Email: HChang@uams.edu 
 
Co-Investigator: 
Edward Yeh, M.D. 
University of Arkansas for Medical Sciences 
4301 W. Markham Street 
Little Rock, AR 72205 
Email: EYeh@uams.edu 
 
Safety Officer: 
Jawahar Mehta, MD., PhD. 
University of Arkansas for Medical Sciences 
4301 W. Markham Street 
Little Rock, AR 72205  
Email: MehtaJL@uams.edu 
 
Sponsor: 
University of Arkansas for Medical Sciences 
 
Study location: 
University of Arkansas for Medical Sciences 
Winthrop P. Rockefeller Cancer Institute 

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Background and Rationale 
Doxorubicin, an inhibitor of DNA topoisomerase 2a (Top2a), is routinely used in the 
treatment of breast cancer, sarcoma, and pediatric leukemia. Long-term cancer survivors 
who were treated with doxorubicin often suffer from dose-dependent cardiotoxicity. Of the 
two topoisomerase 2 isozymes, Top2a is highly expressed in cancer cells and is required 
for cell division. However, adult cardiomyocytes express only topoisomerase 2b (Top2b). 
Studies from our laboratory showed that Top2a mediates doxorubicin’s tumoricidal 
activity, whereas Top2b mediates doxorubicin’s cardiotoxic effect. At present, 
dexrazoxane is the only FDA-approved drug for cardio-protection. The cardio- protective 
effect of dexrazoxane is due to its ability to bind to the ATPase domain of Top2b  to inhibit 
Top2b’s catalytic cycle. Currently, dexrazoxane is administered concurrently with 
doxorubicin. The FDA recommended dose of Dexrazoxane is 10 times the dose of 
Doxorubicin. Because dexrazoxane also binds to Top2a, it has the potential to interfere 
with doxorubicin’s tumoricidal effect. Thus, dexrazoxane has limited clinical utility as 
specified by FDA’s approved indication. In preliminary studies, dexrazoxane induced an 
ubiquitin/proteasome-mediated degradation of Top2b, but not Top2a. By 
administering dexrazoxane eight hours before doxorubicin, Top2b will be degraded 
to avoid cardiotoxicity, whereas Top2a will remain intact to preserve tumoricidal 
efficacy. Because the half-life of dexrazoxane is two hours, 93.75% of dexrazoxane will 
be eliminated eight hours (four half-lives) after administration. Indeed, dexrazoxane pre- 
treatment eight hours before doxorubicin provided complete protection against 
doxorubicin-induced cardiotoxicity in our animal model. We propose to conduct an 
investigator-initiated clinical trial to test this hypothesis. We will use the results from this 
study to design a pilot clinical trial on breast cancer patients. 
 
Objectives 
Primary Objective: To determine the effective dose of Dexrazoxane pre-treatment in 
degrading topoisomerase 2 b (Top2b) in human peripheral blood. 
Secondary Objectives: To determine the time course of Top2b degradation in healthy 
human volunteers. To determine topoisomerase 2 a (Top2a) in human peripheral blood 
will not be degraded by Dexrazoxane 
 
Study Design and Procedures 
This is a Phase 1 trial to determine time course and dose of dexrazoxane pre-treatment 
for optimal degradation of Topoisomerase 2 b (Top2b) in human volunteers. The FDA 
recommended dose of Dexrazoxane is 10 times the dose of Doxorubicin. All the doses in 
this protocol are in the FDA approved range and have been prescribed for many years. 
There will be 5 cohorts for different doses: 100mg/m2, 200 mg/m2, 300 mg/m2, 400 
mg/m2, or 500 mg/m2. Our plan is to enroll up to 5 subjects per cohort. We will start with 
100 mg/m2 and analyze the Top2 protein level from up to five subjects. Doses will 
escalate to

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200 mg/m2, 300 mg/m2, 400 mg/m2, and 500 mg/m2. If 100 mg/m2 dexrazoxane is 
insufficient, we will increase the dose to find the optimal dose. 
A blood sample will be obtained at screening to rule out anemia, pregnancy and to 
determine liver and kidney functions. If the serum pregnancy test is not performed at the 
time of the initial screening blood draw and another attempt is required in order to perform 
this test, a urine pregnancy test can be used as a substitute. A urine pregnancy test will 
be done on the day of the 12-hour infusion visit, prior to infusion. 
Subjects will be administered a dose of dexrazoxane by IV infusion over 15 (+/-5) minutes. 
Blood will be drawn to purify peripheral blood leukocytes for Top2b and Top2a 
assessment using Western blot analysis. 20 mL of blood will be drawn before 
dexrazoxane infusion. 10 mL of blood will be drawn hourly (+/- 5 minutes) after the start 
of infusion for 12 hours. The final lab draw of the 12-hour infusion day may occur at 6:30 
pm based on facility and staff availability.  The final blood draws occur at 24 hours (+/- 2 
hours); and 48 hours (+/- 2 hours) from the start of infusion. A total of 17 blood samples 
will be drawn for each subject.   
 
Subjects will be screened for COVID at each visit per institutional standards.  Subjects who 
do not pass the screening will not be permitted to continue with the study. 
 
Vital signs will be recorded at the following time points: 1) screening, 2) pre-infusion, 3) end 
of infusion, 4) 6 hours post-infusion, 5) 12-hours post infusion/discharge. Vital signs to be 
captured include: heartrate; respirations; blood pressure; temperature; pain (rate pain on 
scale of 1-10). Height and Weight will also be recorded at screening. 
 
A parking voucher will be provided for each visit. During the first 12 hours after infusion, 
meals and a parking voucher will be provided. 
 
Each subject will have a safety CBC one week (+/- 2 days) after dexrazoxane infusion to 
rule out myelosuppression. If the one-week post-study blood counts are below normal 
range, subject will have additional CBC two weeks post-infusion. 
Treatment failure and subject removal criteria includes: subject noncompliance with blood 
draw, or, subject develops rare hypersensitivity reactions to dexrazoxane infusion. 
 
Study Population 
Subjects will be healthy females, ages 18 to 65 years. Up to 50 subjects will be screened 
in order to enroll up to 25 subjects. 
Results from this protocol will be used to support future research with breast cancer 
patients; therefore, only women will be enrolled in the study. The protocol was approved 
by NIH review panel and program officer to study only female participants. 

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We plan to enroll 5 subjects to each of the 5 cohorts for a total of up to 25 subjects. 
Participants will be recruited using the UAMS Translational Research Institute (TRI) 
Research Participant Registry, ARresearch.org. After the list of potential participants is 
obtained from TRI, we will contact the individuals via email, if indicated as their 
communication preference. The email we will use when communicating with potential 
participants is included in the IRB submission. 
 
Participants will also be recruited using the Facebook pages of UAMS, TRI, and the 
Winthrop P. Rockefeller Cancer Institute. Participants may also be recruited at 
Community or University events, or from within UAMS via word of mouth. 
Subjects will be asked to self-report on the inclusion/exclusion criteria. However, a 
baseline blood sample will be obtained to rule out anemia and pregnancy and to 
determine liver and kidney function. 
 
Inclusion Criteria 
• Female 
• Age 18-65 years 
Exclusion Criteria 
• Women who are pregnant or breastfeeding 
• Presenting with an acute illness (may re-screen again in two weeks if illness has 
subsided) 
• Anemia (Hb < 12 g/dL for females) 
• Calculated Creatinine Clearance less than 60 mL/min 
• Liver function tests outside of normal range 
• Unwilling to refrain from alcohol consumption for 48 hours 
 
Participants with medical information suggestive of a chronic medical condition may be 
excluded from the research at the enrolling physician’s discretion. 
Repeat screening blood tests may be done at the discretion of the enrolling physician 
and/or principal investigator. All screening tests will be paid for by the research grant. 
 
Risks and Benefits 
Some subjects may experience discomforts, or pain on intravenous injection of 
dexrazoxane. We will minimize this risk by administering dexrazoxane as an IV infusion 

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over 15 (+/-5) minutes. If a participant reports pain during the infusion, the catheter will 
be checked to ensure it is properly inserted. If no problems are noted with the catheter, 
the  rate of the infusion will be slowed. There is a very low probability that a subject may 
develop subcutaneous and cutaneous necrosis. Subjects will be informed and instructed 
to report to study team if she develops this side effect. PI and study team members will 
arrange for medical care and expect full recovery on this. 
To reduce the risk of bruising and pain from multiple injections, the twelve hourly blood 
draws will be drawn from the IV catheter. If the initial IV line stops working for any reason, 
a new line will have to be placed. 
There is a very low probability that a subject may develop myelosuppression. Each 
subject will have screening CBC one week after dexrazoxane infusion to rule out 
myelosuppression. The study team will arrange for medical care and expect recovery if a 
subject develops myelosuppression. If the one-week post-study blood counts are not 
within normal range, subject will have additional CBC at 2 weeks post-infusion. 
The risk of allergic reaction is very low. In a rare situation, if the participant develops 
allergic reaction to dexrazoxane, the infusion will be stopped. 
Other adverse events may include: 
• Bluish color 
• changes in skin color 
• chest pain or tightness in the chest 
• chills 
• cold hands and feet 
• cough, sneezing, sore throat 
• difficult or labored breathing 
• fever 
• hoarseness 
• lower back or side pain 
• pain, redness, or swelling in the arm or leg 
• painful or difficult urination 
• swelling of the hands, ankles, feet, or lower legs 
• tenderness 
• unusual bleeding or bruising 
• unusual tiredness or weakness) 
All unanticipated problems or deviations should be reported immediately to principal 
investigator/sponsor. The immediate reports should be followed promptly by details 
written reports to investigator/sponsor. All reports will identify subjects by unique code 
numbers assigned rather than other identifiers. Unanticipated problems will be reported 
to IRB within 5 days of becoming aware of an event. 
A risk to study participants is the potential for loss of confidentiality of study data. 

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Measures to protect the confidentiality of study data will be implemented as described in 
the Data and Safety Monitoring Plan section below. 
There will be no direct benefits to the study participants; however, knowledge gained from 
the study could potentially benefit patients in the future. 
 
 
Subject Compensation 
Subjects completing all study visits will receive $400 compensation for their time. Subjects 
will be issued a Greenphire, Inc. ClinCard, which is a debit card that the stipends are 
loaded onto and can be used at their discretion. When a visit is completed, funds will be 
approved and loaded onto the card. Once approved to be released to the cards, the funds 
will be available for use. 
 
Subjects who partially complete the study will receive prorated compensation as 
described below.   
 
Screening - $50 
 Infusion – $80 
12-hr blood draws – $10 per blood draw (maximum of $120) 
24-hr blood draw – $50 
48-hr blood draw – $50 
1-week post infusion lab draw - $50 
 
A parking voucher will be provided for each visit.  Meals vouchers will also be provided to 
the subjects during the 12 hour infusion visit at visit 2. 
 
DATA AND SAFETY MONITORING PLAN 
Overall framework for safety monitoring and what information will be monitored. 
 
Plan for data management: A password-protected database will be used to manage all 
study data. To ensure confidentiality only subject ID numbers will be entered into the 
database. 
 
Paper records will be stored in the the PHOENIX 1 Clinical Trial office.  The records are 
stored in a double locked file cabinet, in the locked office. Only study staff will have 
access. Consent and HIPAA will have direct identifiers. Other paper source documents 
will be coded and the key to the code will be stored separately. Data from the de-identified 
source documents will also be stored on a password locked Microsoft Excel Spreadsheet 
located in a secure Box folder.  Only study staff will have access to this document.  
Records may be retained indefinitely, and at minimum, will be retained in accordance with 
institutional policy and applicable regulatory requirements. A UAMS approved vendor will 
be used to destroy documents. The key to the code will be destroyed at this time and 
thereby creating a de-identifiable data with the exception of the consent. 
 

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Participants will not be individually identified in any publication. Participants’ right to 
privacy will be protected. 
Plan for safety monitoring: The data and safety monitoring plan (DSMP) for this trial 
focuses on close monitoring by the PIs and the safety officer. QA monitoring will also be 
performed by independent Winthrop P. Rockefeller Cancer Institute staff. 
 
Frequency of monitoring: Monitoring will include enrollment, attrition, efficacy end- 
points, and adverse events. In addition to monitoring by the PIs, study coordinator, and 
safety officer monitoring, the University of Arkansas for Medical Sciences IRB monitors 
all aspects of the project on an annual basis. The frequency of the structured data  review 
for this study can be summarized below. 
 
Data type Frequency of review 
Subject accrual (adherence to protocol regarding demographics, inclusion/exclusion): At 
the end of each recruitment 
Adverse event rates (injuries): semi-annually 
Compliance to treatment: semi-annually 
Out of range laboratory data: semi-annually 
Stopping rules report regarding statistical power implications of dropouts and missing 
data: semi- annually 
IRB review: annually 
 
Process for Managing and Reporting Adverse Events, Serious Adverse Events and 
Unanticipated Problems: 
Unanticipated events will be reported to UAMS IRB, and both serious and non-serious 
adverse events will be reported to the Safety Officer. Adverse  events will be categorized 
and classified according to Common Terminology Criteria for Adverse Events Scale 
(CTCAE v5.0). Safety reports will be sent to the safety officer. Serious adverse events 
will be reported to the NIH Office of Biotechnology Activities, the  funding IC, and the FDA, 
in addition to UAMS IRB. The PI will be responsible for assembling the data and producing 
these reports, as well as assuring that  all parties obtain copies of these reports. 
 
Qualifications and responsibilities of the Safety Officer: 
The safety officer for this trial will be Jawahar (Jay) Mehta, MD., PhD. Dr. Mehta is a 
Distinguished Professor of Medicine, and Physiology and Biophysics, and the 
Stebbins Chair in Cardiology at UAMS. Dr. Mehta serves or has served on the editorial 
board of numerous journals including the American Journal of Cardiology; Circulation; 
Hypertension; Journal of the American College of Cardiology. Dr. Mehta has been funded 
numerous times by the Department of Veterans Affairs, the American Heart Association, 
and the National Institutes of Health. In 2017, he was ranked among the top 27 
cardiologists in the nation. As Safety Officer, Dr. Mehta will review eligibility criteria with 
Dr. Chang. He will review all reports sent by the study coordinator to determine whether 
there is any corrective action, trigger of an ad hoc review, or stopping rule violation that 
should be communicated to the UAMS IRB. In addition, the safety officer 

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may comment on whether the study PI needs to report any specific out- of-range 
laboratory data. 
 
 
Specimen Handling and Storage 
Specimens will be collected in the Winthrop P. Rockefeller Cancer Institute. Study staff 
will obtain the blood samples at the prescribed time intervals. Staff will label the tubes  with 
only the unique code and take them directly to the lab. Identifiers will not be included on 
the tubes. CTO staff will call  Dr. Jinn-Yuan Hsu or the assigned study staff to pick up the 
specimens. The specimens will be retrieved immediately and taken to the laboratory of 
the principal investigator to be processed and analyzed. Only the PI and study team will 
have access to the samples. After all the samples have been tested, the samples will be 
discarded. 
 
Data Analysis 
The goal of this protocol is to find the effective dose of dexrazoxane in degrading Top2b 
for the subsequent randomized clinical trial. We will select a dose of dexrazoxane, which 
reduces Top2b to less than 5% of baseline level in 8 hours in 5 volunteers. FDA 
recommended dose of dexrazoxane is 10 times the dose of doxorubicin. In the attached 
FDA approval documentation of dexrazoxane, 500mg/m2 is cited as a recommended 
dose. We will study dose levels 500mg/m2 or below. Healthy volunteers will be 
administered a dose of dexrazoxane. Blood will be drawn to purify peripheral blood 
leukocytes for Top2b and Top2a assessment using Western blot analysis. The following 
time points will be assessed: Pre-infusion,1,2,3,4,5,6,7,8,9,10,11,12,24, and 48 hours 
after start of dexrazoxane infusion. Each dose level will be administered to up to five 
subjects, starting with  an initial dose of 100 mg/m2, and escalating in 100 mg increments. 
 
Ethical Considerations 
This study will be conducted in accordance with all applicable government regulations 
and University of Arkansas for Medical Sciences research policies and procedures. This 
protocol and any amendments will be submitted and approved by the UAMS Institutional 
Review Board (IRB) to conduct the study. 
The formal consent of each subject, using the IRB-approved consent form, will be 
obtained before that subject is submitted to any study procedure. All subjects for this 
study will be provided a consent form describing this study and providing sufficient 

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information in language suitable for subjects to make an informed decision about their 
participation in this study. The person obtaining consent will thoroughly explain each 
element of the document and outline the risks and benefits, alternate treatment(s), and 
requirements of the study. The consent process will take place in a quiet and private 
room, and subjects may take as much time as needed to make a decision about their 
participation. Participant’s privacy will be maintained and questions regarding  
participation will be answered. No coercion or undue influence will be used in the consent 
process. This consent form must be signed by the subject and the person obtaining the 
consent. A copy of the signed consent will be given to the participant, and the informed 
consent process will be documented in the research record. 
 
Dissemination of Data 
Results of this study may be used for presentations, posters, or publications. The 
publications will not contain any identifiable information that could be linked to a 
participant. The study will be listed on clinicaltrials.gov in accordance with (journal or FDA) 
requirements. 

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