A Phase I/II Study of Dermaprazole For Radiation Dermatitis in Post-Mastectomy Breast Cancer Patients.
Phase: PHASE1
Conditions: Radiation Dermatitis, Breast Cancer
Sponsor: Baylor College of Medicine

Study Title:  A PHASE I/II STUDY OF DERMAPRAZOLE FOR RADIATION DERMATITIS IN 
POST-MASTECTOMY BREAST CANCER PATIENTS (TOPAZ) 
 
NCT #:  NCT05269160 
 
Document Date: 09Dec2024 

 
 
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A PHASE I/II STUDY OF DERMAPRAZOLE FOR RADIATION DERMATITIS IN 
POST-MASTECTOMY BREAST CANCER PATIENTS (TOPAZ) 
Version 9.0 
Date:  12/09/2024 
 
Coordinating 
Center: 
Dan L Duncan Comprehensive Cancer Center  
Baylor College of Medicine 
 
 
 
Principal 
Investigator: 
Michelle S. Ludwig, MD, PhD 
Radiation Oncology 
7200 Cambridge, MS BCM 711 
Houston, TX 77030 
713-724-4440 (phone) 
Michelle.Ludwig@bcm.edu 
 
 
Co-
Investigators: 
Daniel Hamstra, MD, PhD 
Radiation Oncology 
7200 Cambridge, MS BCM 711 
Houston, TX 77030 
713-798-6385 (office) 
Daniel.Hamstra@bcm.edu    
 
Pavan M. Jhaveri, MD 
Radiation Oncology 
7200 Cambridge, MS BCM 711 
Houston, TX 77030 
713-873-9685 (office) 
pavan.jhaveri@bcm.edu    
 
Alfredo Echeverria, MD 
Radiation Oncology 
7200 Cambridge, MS BCM 711 
Houston, TX 77030 
713-873-9685 (office) 
alfredo.echeverria@bcm.edu   
 
Shelly Sharma, MD 
Radiation Oncology 
7200 Cambridge, MS BCM 711 
Houston, TX 77030 
713-873-9685 (office) 
Shelly.Sharma@bcm.edu   
 
 

 
 
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Alex Hanania, MD, MPH 
Radiation Oncology 
7200 Cambridge, MS BCM 711 
Houston, TX 77030 
713-873-9685 (office) 
alexander.hanania@bcm.edu  
 
Krystal Morales, MD, PhD 
Radiation Oncology 
7200 Cambridge, MS BCM 711 
Houston, TX 77030 
Krystal.moralesrivera@bcm.edu 
 
Soo Jung Kim, MD, PhD 
Dermatology 
One Baylor Plaza 
Houston, TX 77030 
713-798-6131 (office) 
soojungk@bcm.edu  
 
Christina Chapman, MD 
Radiation Oncology 
7200 Cambridge, MS BCM 711 
Houston, TX 77030 
832-355-7118 
Christina.chapman@bcm.edu 
 
Snehal Desai, MD 
Radiation Oncology 
7200 Cambridge, MS BCM 711 
Houston, TX  77030 
832-355-7118 
Snehal.Desai@bcm.edu 
 
 
Study 
Statistician: 
Eunji Jo 
One Baylor Plaza 
Houston, TX 77030 
713-798-4923 (office)  
ejo@bcm.edu 
 
 
 
 

 
 
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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ............................................................................................5 
2. 
STUDY SCHEMA .......................................................................................................6 
3. 
OBJECTIVES ...............................................................................................................7 
3.1. 
Primary Objective .........................................................................................................7 
3.1.1 
Phase I - Safety .............................................................................................................7 
3.1.2 
Phase II - Efficacy ........................................................................................................7 
3.2. 
Secondary Objectives ...................................................................................................7 
4. 
BACKGROUND AND RATIONALE .........................................................................7 
4.1. 
Study Disease ................................................................................................................7 
4.2. 
Rationale for Dermaprazole  .........................................................................................8 
5. 
PATIENT SELECTION .............................................................................................11 
5.1. 
Inclusion Criteria (BC arm) ........................................................................................11 
5.2. 
Exclusion Criteria (BC arm) .......................................................................................11 
. 
 
 
 
6. 
STUDY DRUG ...........................................................................................................13 
6.1. 
Formulation and Preparation ......................................................................................13 
6.2. 
Stability .......................................................................................................................13 
6.3. 
Packing, Shipping and labeling by Compounding Pharmacy ....................................13 
6.4. 
Drug Storage, Disposal, Dispensation and use ...........................................................14 
7. 
TREATMENT/INTERVENTION PLAN ..................................................................14 
7.1. 
Radiotherapy Administration......................................................................................14 
7.1.1 
Breast Cancer ..............................................................................................................14 
7.2. 
Study Intervention ......................................................................................................15 
7.2.1. 
Application prior to Radiaton (Patch Test) .................................................................15 
7.2.2. 
Application During and After Radiation Treatment ...................................................15 
7.3. 
Prohibited Medication or Therapies ...........................................................................16 
7.4. 
Assessment and Procedures ........................................................................................16 
7.4.1 
Baseline and Screening Evaluations ...........................................................................16 
7.4.2 
CT Simulation .............................................................................................................17 
7.4.3 
On Treatment: weekly during radiation treatment ......................................................17 
7.4.4 
Two weeks post radiation treatment ...........................................................................17 
7.4.5 
Post-Treatment follow up ...........................................................................................18 
7.4.6 
Table 1 ........................................................................................................................19 
7.4.7 
Criteria for Removal from study Intervention (Dermaprazole) ..................................21 
8. 
TREATMENT EVALUATION .................................................................................21 
9. 
MEASUREMENT OF EFFECT ................................................................................21 
10. 
STATISTICAL CONSIDERATIONS .......................................................................22 
10.1. 
Study Design ...............................................................................................................22 
10.2. 
Sample Size/ Accrual Rate .........................................................................................22 

 
 
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10.3. 
Statistical Analysis ......................................................................................................24 
11. 
DATA  MANAGEMENT ..........................................................................................25 
12. 
QUALITY ASSURANCE ..........................................................................................25 
13. 
DATA AND SAFETY MONITORING .....................................................................26 
14. 
PROTECTION OF HUMAN SUBJECTS .................................................................26 
15. 
ADVERSE EVENTS..................................................................................................26 
15.1. 
Adverse Event (AE) Definition ..................................................................................26 
15.2. 
Serious Adverse Event (SAE) Definition ...................................................................26 
15.3. 
Relationship of Adverse Events to the Study Intervention .........................................27 
15.4. 
Adverse Event (AE) Grading scale .............................................................................27 
15.4.1. 
Rash Maculo-Papular (outside the radiation field) .....................................................27 
15.4.2. 
Adverse events inside the Radiation field ..................................................................28 
15.5. 
Dose Limiting Toxicity (DLT) ...................................................................................29 
15.6 
Potential Risks/Discomforts .......................................................................................29 
15.7. 
Adverse Event Reporting Requirements ....................................................................30 
15.8. 
Management of AEs and Impact on Treatment ..........................................................31 
16. 
PREGNANCY ............................................................................................................31 
APPENDIX 1. SKINDEX16 FORMS IN ENGLISH & SPANISH ...........................................32 
17. 
REFERENCES ...........................................................................................................36 
 
 
 
 
              

 
 
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1. 
PROTOCOL SUMMARY 
Radiotherapy is a mainstay of treatment in breast cancer treatment, in the adjuvant setting. 
Radiation dermatitis occurs in up to 65% of these patients; currently, there is no standard of care 
for this treatment-related toxicity. The aim of this study is to investigate the safety and 
tolerability (Phase I) and preliminary efficacy (Phase II) of prophylactic esomeprazole cream ( 
termed “Dermaprazole”) in patients who require radiation for  breast cancer in the adjuvant 
setting.   
All study participants will begin using Dermaprazole for 1-2 weeks prior to receiving radiation.  
During the CT Simulation, study participants will be instructed to apply Dermaprazole in a 
“patch test” area - an area of the chest outside of the field of radiation.  This is to assess for 
immediate skin reactions including itching, irritation and allergy.  If there are no immediate 
allergic reactions at the conclusion of the simulation visit, the study participant will be instructed 
to apply the cream in the patch test for 2-4 days to assess for contact dermatitis and if no itching 
or rash at that time (evaluation will be conducted via phone call). Patients will be questioned 
regarding any visible skin changes or irritation (itching, peeling, scaling), and patients 
responding in the affirmative will be asked to present for clinic visit or send photographs for 
visual classification according to the scale outlines in Table 1 below. Skin reactions matching a 
score of 3 will be evaluated with a second clinic visit between 2 to 7 days after initial 
application. Any skin reactions of score 4 or 5 at final assessment will be deemed to be positive 
for allergic contact dermatitis, and patients will be deemed positive for allergic contact 
dermatitis. 
 If no concern for allergic or contact dermatitis, patients will be advised to begin application in 
the area that will be irradiated in addition to the patch test area for 1-2 weeks until the radiation 
starts. Patients will be instructed to discontinue use immediately if any local skin reactions occur. 
 
Table 1:  
Grading System for Patch Test Reactions (immediate allergic reactions and delayed 
contact dermatitis) 
Score 
Description 
1 
Negative reaction 
2 
Doubtful reaction, faint macular erythema 
3 
Weak, non-vesicular reaction with erythema, infiltration, and papules 
4 
Strong vesicular reaction with erythema, infiltration, and papules 
5 
Spreading bullous reaction 
 
For the subset of patients determined to have allergic reactions or contact dermatitis, a second patch test 
will be conducted to determine whether the allergy is to dermaprazole itself or the vehicle used in the 
topical formulation. A topical application of the vehicle without the active ingredient (dermaprazole) will 
be applied to the patient’s forearm. Similar to the above protocol, patients will be assessed at 30 minutes 
and 2-4 days after topical application (in clinic for first assessment, phone call for second). Patients with 
skin reactions will send photos or present for clinic follow up and reactions greater than 3 in the scale 
above will be interpreted to mean the patient has an allergic reaction to the vehicle rather than 
dermaprazole. Alternative formulations with different carrier vehicles will be considered in the future, but 
for the purposes of this phase I/II study, such patients will be excluded. 

 
 
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After allergic reaction testing/contact dermatitis evaluation is complete, patients begin radiation 
and will continue daily application both in the patch test area and in the radiation field during 
radiotherapy, and for 2 weeks after they complete their radiation treatment.  During the entire 
time while using the Dermaprazole, study participants will be evaluated for adverse events such 
as contact dermatitis in the patch test area as well as radiation dermatitis within the treatment 
field.  All participants will be followed for 1 month after the final Dermaprazole application. 
 
Two dose levels of Dermaprazole (1% and 2%) will be evaluated in the combination Phase I/II 
dose escalation/de-escalation BOIN design study evaluating preliminary efficacy at the 
Maximum Feasible Dose (MFD).  The Dermaprazole will be initiated at a dose of 1% and 
escalated to 2% as appropriate based on the number of adverse events.  A Dose Limiting 
Toxicity (DLT) will be any of the following: a) any greater than Grade 2 skin toxicity outside 
the radiation field (Macules/ papules covering 10-30% of the area with or without symptoms of 
pruritus, burning, tightness) b) any greater than Grade 2 radiation dermatitis (Moderate to brisk 
erythema; patchy moist desquamation, mostly confined to skin folds and creases; moderate 
edema) within the treatment field that is probably or definitely related to Dermaprazole.  
Dermatitis will be evaluated by a radiation oncologist on a weekly basis using the Common 
Terminology Criteria for Adverse Events (CTCAE) V5.0 criteria.  Patient reported quality of life 
will be evaluated using a validated survey instrument called SkinDex16.   

 
 
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2. 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After Radiation, 
application of 
Dermaprazole continues 
twice daily to irradiated 
area  and patch test area 
for two weeks.  
Follow up visit at 1 
and 6 weeks 
Allergic reactions/ 
unacceptable AE’s 
present. Subject taken 
oﬀ study and proceeds 
with radiation  
Dermaprazole 
application on 
patch test 
area  
Eligible. 
Register onto 
study  
Assess for 
allergic 
reactions 
(immediate) 
and contact 
ermatitis (2-
4 days)   by 
Radiation 
Oncologist  
No allergic 
reactions/ contact 
dermatitis  
present. Subject 
remains on study. 
Proceed cream in 
patch test and 
radiation ﬁeld until  
radiation start 
Subject signs consent 
Eligibility 
review 
Ineligible- 
Screen 
fail.  
CT simulation with 
investigator 
marking patch test 
area, area of 
radiation ﬁeld and 
providing 
instructions for 
Dermaprazole 
application 
During Radiation (3- 
7 weeks for BC 
subjects  ), 
application of 
Dermaprazole 
continues twice 
daily to patch test 
area and to 
irradiated area. 
Radiation oncologist 
will assess for 
dermatitis and AE’s 
on a weekly basis.  
Pre-screen  breast 
cancer patients 

 
 
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3. 
OBJECTIVES 
3.1. 
Primary Objective 
3.1.1. 
Phase I - Safety 
To define the safety and maximum feasible dose (MFD) of Dermaprazole in preventing radiation 
dermatitis for breast cancer patients. This will be evaluated by application of the cream:  
1. Prior to, during and after radiation via patch testing to assess for baseline irritant or 
contact dermatitis.  
2. Prior to, during and after radiation via monitoring treatment field receiving prophylactic 
Dermaprazole to assess for adverse events.  
3.1.2  
Phase II Efficacy 
      1.  To evaluate clinically bothersome radiation dermatitis rate for breast  
            cancer patients at maximum feasible dose.  
 
3.2. 
Secondary Objective 
1. To assess the rate of grade 2 or higher acute radiation dermatitis. 
2. To assess time to occurrence of grade 2 or higher acute radiation dermatitis. 
3. To assess the time to healing if grade 2 or higher acute radiation dermatitis develops. 
4. To assess patient-reported quality of life outcomes using SkinDex16. 
5.  To assess radiation adherence;  defined as the number of missed radiation treatments due 
to skin toxicity.  Dose over time, i.e., total days from start of treatment to end of 
treatment will be recorded. 
4. 
BACKGROUND AND RATIONALE 
4.1. 
Study Disease 
Radiation therapy (RT) is a mainstay of treatment in breast cancer (BC).  Quantitatively, up to 
95% of patients receiving RT experience some degree of acute radiation-induced dermatitis 
(RD).  About  20-25% of patients develop severe skin reaction including: moist desquamation, 
ulceration, necrosis and scarring. About 65% of patients with breast cancer experience clinically 
significant radiation dermatitis (Grade II or higher) during treatment.i  There is no gold standard 
treatment for RD and the use of corticosteroids is associated with considerable side effects 
including skin atrophy, further breakdown of skin integrity and possible superinfection. 
Currently, the recommendation regarding RD is to use alcohol-free and fragrance-free water 
emollients (such as Aquaphor) after radiotherapy is administered to protect the skin barrier, 
though this has not been proven to be effective in preventing RD toxicity. Open wounds are 
often treated with Silvadene or other antibiotic cream due to concern of superinfection. If 
infection develops, topical and/or oral antibiotics are considered; if itching develops, 

 
 
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corticosteroids or antihistamines are considered. No topical ointments are allowed at least 2 
hours prior to radiation due to theoretical increase in skin dose due to “bolus effect”, or the dose 
distribution being brought higher onto the epidermis due to unaccounted for tissue-equivalent 
material. However, there is no data to substantiate these common practices and RD is often 
thought to be an unavoidable consequence of radiotherapy. 
Given the unmet medical need for therapies to address radiation dermatitis, our basic science 
team has been investigating candidate drugs to mitigate the problem. After screening a library of 
130,000 compounds, we found that proton pump inhibitors (PPIs) have previously unrecognized 
yet potent effect in modulating inflammation and fibrosis induced by chemotherapy and ionizing 
radiation.  
Radiation-induced dermatitis occurs in most patients following radiotherapy. According to the 
NCI-CTCAE and the RTOG toxicity scoring system, mild dermatitis (Grade I) is characterized 
by mild redness (erythema), epidermal thickening (hyperkeratosis) or dry desquamation and 
appears shortly after initiation of RT. ii iii iv Moderate dermatitis (Grade II) occurs within two 
weeks of radiotherapy and manifests painful and intense erythema, loss of hair from the root 
(epilation), blisters and edema. Of note, the presence of grade II toxicity is generally regarded as 
clinically significant toxicity. In severe dermatitis (Grade III and IV), moist desquamation occurs 
excessively and may lead to persistent inflammation, full-thickness skin necrosis and severely 
painful ulceration that is prone to infection. The acute effects occur almost immediately at 
radiation doses between 2 and 40 Gray (2-40 Gy) whereas chronic effects occur several months-
to-years after exposure to high radiation doses (>45 Gy) and typical skin changes include 
atrophy, scarring and spider veins (telangiectasia).v 
The effect of radiation on the skin is in part due to its effect in promoting the production of 
highly reactive free radicals that are involved in DNA damage.vi vii viii In addition, radiation 
upregulates inflammatory cytokines (e.g. TNFα, IL1β, IL6, VCAM1 and ICAM1) that can 
exacerbate sustained injury and compromise skin integrity. ix x xi About one third of breast cancer 
patients are profoundly affected by clinically relevant dermatitis (Grade II or higher) due to the 
development of serious skin reactions described above. The predictive risk factors for prolonged 
effect of severe dermatitis include age, sex, body mass index (BMI), site and volume of the body 
exposed to radiation, use of concurrent radiosensitizing drugs or chemotherapeutic regimen and 
presence of diabetes, autoimmune disorders, or genetic mutations.xii xiii xiv Severe dermatitis can 
result in discontinuation of the radiotherapy before completion of the prescribed dose and 
threatens the relapse of underlying cancer. xv xvi xvii 
4.2. 
Rationale for Dermaprazole 
Several non-pharmacological and pharmacological approaches have been evaluated for the 
prevention, treatment or management of severe radiation dermatitis. xviii - xix However, the use of 
many of these agents is not recommended either due to lack of efficacy or insufficient clinical 
data. Meanwhile, various pharmacological agents have been developed to mitigate radiation 
dermatitis. Of these, topical corticosteroids are the archetype. Among the steroid-based products, 
mometasone furoate (0.1%), betamethasone (0.1%) and hydrocortisone (1%) are extensively 
studied in clinical trials.xx - xxiHowever, the use of topical corticosteroid for radiation dermatitis 
is limited due to the risk of cutaneous atrophy, stretch marks (striae), allergy, secondary skin 
infection (e.g. cellulitis, candidiasis). In obese and diabetic patients (as in our population), the 

 
 
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prophylactic use of corticosteroids leads to increased rates of candida infection with risk of 
bacterial superinfection if open wound develops during radiotherapy. Accordingly, there is an 
unmet clinical need to develop safe and effective products. 
Our earlier research discovered that PPIs directly regulate the nitric oxide synthase (NOS) 
pathway via inhibition of the inducible isoform (iNOS) which is significantly expressed in skin 
cells in response to inflammatory stimuli as in radiation or chemotherapy.
xxiii
xxii - 
 The nitric 
oxide (NO) catalyzed by iNOS is short-lived and rapidly oxidizes to peroxynitrite (OONO-); a 
highly reactive molecule that is involved in the generation of nitrotyrosine; a more stable product 
that is involved in tissue inflammation. Additionally, a number of inflammatory cytokines 
released during chemoRT are known to enhance NO production. We found that regulation of the 
iNOS pathway by PPIs is due to their direct interaction with dimethylarginine 
dimethylaminohydrolase (DDAH), an enzyme that breaks down asymmetric dimethylarginine 
(ADMA, the endogenous and competitive NOS inhibitor). Subsequently, we showed that 
esomeprazole is the most potent PPI that controls the pro-inflammatory enzyme DDAH and 
many classic pro-inflammatory cytokines (such as NFKB, TNFα, IL1β, IL6, VCAM1, and 
ICAM1) that are reported to be pathologically upregulated in radiation dermatitis.xxiv 
Recently, supported by Dan L Duncan Comprehensive Cancer Center Pilot Grant, we 
reformulated esomeprazole sodium powder into a Lipoderm®-based equivalent to 2% active 
esomeprazole cream (Dermaprazole) that retained the inherent biologic antioxidant, anti-
inflammatory, and anti-fibrotic effects of esomeprazole. This was executed by mixing 
esomeprazole powder with propylene glycol, and Lipoderm as a transdermal base. Notably, our 
LC-MS study showed that a relatively low strength of Dermaprazole (1-2%) was highly stable 
and biologically active in modulating esomeprazole target genes. 
Accordingly, we evaluated the efficacy of this formulation in a mouse model of RD in a 
prophylactic and therapeutic settings in the presence of corticosteroid control. Remarkably, our 
study showed that while 90% of the animals in the corticosteroid group had grade II or higher 
dermatitis, topical PPI mitigated the radiation dermatitis in most of the animals with only 20% 
showing grade II or higher radiation dermatitis (Figure 1). We evaluated 1% and 2% strengths 
further after our efficacy studies showed lack of superiority at >2% Dermaprazole strengths.   
Figure 1: 
Mouse Model of RD: Representative Digital photography Data 
 
Topical application of Dermaprazole improves skin appearance in a model of radiation-induced dermal 
inflammation and fibrosis. Mice were irradiated (2 x 15Gy) on Days 0 and Day 7. Dermaprazole, vehicle (base) 
cream, or the corticosteroid hydrocortisone were applied once a day on the indicated days (D1-D30 for prophylactic 

 
 
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group and D10-D30 for therapeutic group). Representative images from the same animals are shown (n=10 
animals/group). 
 
We also observed that Dermaprazole use led to significantly lower ulceration, necrosis, 
inflammation, and fibrosis (Figure 2). Overall, most Dermaprazole treated animals showed 
complete or nearly complete closure of the wounds within 4 weeks following exposure to 
ionizing radiation. 
 
Figure 2: 
Mouse Model of RD: Representative Histological Data 
 
Panel A: H&E stained irradiated skin tissue from an animal model of RD treated with vehicle cream, Dermaprazole 
or hydrocortisone once daily on the indicated days.  
Panel B: Masson’s trichrome stain was used to assess the degree of dermal fibrosis in the animal model of RD. 
Increased collagen deposition (blue stain) is observed in the vehicle and steroid groups. Treatment with 
Dermaprazole inhibited collagen deposition. Representative images are shown at 20X magnification. The scale bar 
shown in the vehicle group at day 16 is 50 um and applies to all the images. 
 

 
 
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5. 
PATIENT SELECTION 
5.1. 
Inclusion Criteria 
 
a) Women with breast cancer, treated with ipsilateral*. 
____ i) 
Simple (total) mastectomy OR 
____ ii) Modified radical mastectomy, OR 
____ iii) Radical mastectomy 
____ iv) Segmental mastectomy 
____ v) Skin Sparing/nipple sparing mastectomy 
*tissue expanders or implants or tissue flaps are acceptable 
 
b) Histological diagnosis of invasive ductal or lobular carcinoma (diagnosed within 2 years of 
enrollment). 
 
c) Planned to receive adjuvant chest wall radiation of at least 40Gy or higher biologically 
equivalent dose (BED). 
 
d) Age 18 years or older. 
 
e) Women of childbearing potential (any woman with menses in the last 12 months) must agree 
to pregnancy testing and contraceptive use throughout the study period. Testing consists of 
human chorionic gonadotropin (HCG) urine testing, which if suspected to be falsely positive 
may be confirmed by ultrasound. If ultrasound is negative, patient is considered not pregnant 
and eligible for inclusion in the study. In addition to routine contraception method such as 
barrier devices, hormonal methods, and intrauterine devices, heterosexual celibacy, and 
surgical sterility (hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or a partner 
with history of vasectomy) is considered acceptable. If a celibate patient chooses to become 
sexually active during the study period, she must use one of the listed methods of 
contraception throughout the study period. 
 
f) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. 
 
g) Written Informed Consent. 
 
h) History and Physical within 12 weeks of enrollment. 
5.2. 
Exclusion Criteria  
 
a) Prior chest wall radiotherapy. 
 
b) Any serious medical condition or illness that would preclude the safe administration of the 
study drug including, but not limited to: active infection, symptomatic heart failure, unstable 
angina, psychiatric illness or social situations that would limit compliance with treatment. 
 
c) Concurrent chemotherapy. 
 
d) Biopsy-proven skin (epidermal) involvement or positive margins after surgery. 
 

 
 
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e) Open wound at time of consultation, or delayed surgical wound healing as defined as open 
wound >8 weeks post-op. 
 
f) Known active collagen vascular disease such as systemic lupus erythematous, scleroderma or 
dermatomyositis. 
 
g) Allergy or sensitivity to proton pump inhibitors. 
 
h) Pregnancy or breast feeding. 
 
i) Use of clopidrogrel, St. John’s Wort, rifampin, or methotrexate. 
d)   

 
 
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6. 
STUDY DRUG  
Dermaprazole is a repurposed drug derived from esomeprazole powder and compounded into a 
topical formulation.  The parent compound, esomeprazole is a widely available, safe and 
tolerable FDA-approved prescription (since 2001) and over-the-counter antacid medication 
(since 2014).  Esomeprazole is not chemically modified in any form, and the excipients are 
compliant with the standards of the Professional Compounding Centers of America (PCCA).  
6.1. 
Formulation and Preparation  
Dermaprazole will be formulated at a strength equivalent to either 1% or 2% active 
esomeprazole powder in a topical liposomal-based cream in collaboration with a compounding 
Pharmacy.   The compounding pharmacy is accredited by the Pharmacy Compounding 
Accreditation Board (PCAB) and fully compliant with USP <795>, USP <797> and USP <71> 
compounding standards.  The name, address and contact information of the compounding 
pharmacy is: 
Village Compounding Pharmacy 
975 Corbindale Rd,  
Houston TX,  77024  
P: 713-464-5069 
F: 713-464-5099  
email bpylant@villagecompounding.com 
 
6.2. 
Stability 
Timetable studies performed in a standard container unit dose system indicate that under 
refrigerated conditions (2°C to 8°C), potency as well as total aerobic microbial, yeast, and mold 
counts are maintained within USP method specifications for at least 45 days.  For purposes of 
this study, product must be used within 60 days of compounding.  Dermaprazole cream is stable 
for at least one week at controlled temperature (36-46̊F) after it has been opened. However, in 
order to facilitate correct patient utilization of the product and to eliminate oxidation, we plan to 
utilize single-use syringes. 
6.3. 
Packing, Shipping and Labeling by Compounding Pharmacy 
Once the subject is registered onto the study, the study PI will notify the study biostatistician to 
ascertain the dose level needed and to verify the order.  The compounding pharmacy will be 
notified of the dose level by the study PI and will then compound the cream at either 1% or 2% 
strength.  Once compounded, Dermaprazole will be packaged into prefilled 5 mL single use 
syringes by the Compounding pharmacy.  Each syringe will be labeled with the date it was 
compounded and the strength.  The Compounding pharmacy will ship the Dermaprazole cream 
in syringes to the Investigational Pharmacy for dispensation to the study subject.  Orders can 
only be shipped on a Tuesday from the compounding pharmacy and will be received by the 
Investigational pharmacy on a Wednesday.  
 

 
 
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6.4. 
Drug Storage, Disposal, Dispensation and use 
The study drug should be stored under refrigerated conditions (36-46̊F).   
Prescription paper orders with patient instructions have been created for the main site and the 
affiliate site.  After the order is signed by the ordering physician, it will be sent via fax and/or 
email to the Investigational Pharmacy.   
The Investigational Pharmacy will label the syringes received from the Compounding pharmacy 
for the subjects.  Study participants will be given syringes in a cold bag or on ice.  Subjects will 
be  instructed to store the cream under refrigerated conditions (36-46̊F) and will be instructed to 
return all used and unused syringes at each visit.   All syringes will be disposed of in the medical 
waste bins at either Baylor St Luke’s or Smith Clinic after accountability is done.  For any 
unused syringes that are not dispensed to the subject, the investigational pharmacist will perform 
IP accountability, generate certificates of disposal, and dispose of the syringes in the pharmacy 
biohazard waste bin.  Dermaprazole syringes will be dispensed at the CT simulation visit for use 
until first radiation treatment, again at the beginning of external beam, and at the end of 
treatment for two additional weeks of Dermaprazole application after radiation treatment is over.  
One syringe is enough for one application and subjects will need to apply dermaprazole twice a 
day.  Since two syringes will be used in a day, sufficient number syringes will be dispensed at 
the first weekly visit for use during radiation treatment (depending on the number of planned 
radiation treatments), and twenty eight syringes will be dispensed on the last day/week of 
radiation treatment for the additional two weeks of Dermaprazole application post radiation 
treatment.  
7. 
TREATMENT/INTERVENTION PLAN 
7.1. 
Radiotherapy Administration 
Radiation treatment will be given per standard of care. The treatments outlined below reflect 
current clinic/hospital practices. Deviations from these treatments should be minimized but are at 
the discretion of the treating investigator, and do not constitute a protocol violation. Any delay in 
radiotherapy after simulation past 16 days will lead to removal from the study and 
discontinuation of the cream. 
Dose, Prescription, and Planning: Breast radiation will be given as per standard of care. 
Ipsilateral chest wall radiation of 40- 50 Gy will be permitted with or without boost up to 66 Gy. 
Radiation is to be delivered at 1.8-3Gy per day, 5 days per week, for 3 to 7 weeks using three-
dimensional technique. Intensity modulated radiotherapy (IMRT) or other experimental skin-
sparing techniques are not permitted. Chest wall radiation must be delivered using medial and 
lateral tangential fields. Separate posterior axillary boost, supraclavicular field, and internal 
mammary field are permitted as long as all “hot spots” on skin are as per standard guidelines. All 
beams must be matched exactly at field edge. 
Definition of “Chest Wall”: Per RTOG Breast Atlas, the chest wall or breast to be covered by 
tangential fields is defined cranially as the caudal border of the clavicular head, caudally as loss 
of radiographically apparent contralateral breast, anteriorly by the skin, posteriorly by the rib-
pleural surface, laterally by the mid axillary line, and medially as the sternal-rib junction. 

 
 
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Simulation and Treatment: CT-based simulation and planning must precede treatment. Tissue-
equivalent bolus is permitted on protocol per discretion of consulting radiation oncologist. CT-
based simulation must be used for treatment planning and weekly x-ray portal images are 
required to confirm accurate delivery.  
7.2. 
Study Intervention 
The sole intervention for this study is prophylactic Dermaprazole cream with monitoring as 
described below.  The radiation and chemotherapy are standard of care.  Additional research 
related components for the study include Quality of Life Survey, and treatment compliance 
survey which is done during routine visits.   
7.2.1. 
Application prior to Radiation (Patch Test)  
At consultation and prior to radiation therapy, patients will be screened for allergy and/or contact 
reactions using repeat open application (“patch”) testing in the contralateral infraclavicular area.  
The patch test will be outside of the area to be irradiated.  A 2x2 cm “patch” area will be marked 
by the treating physician at the time of CT simulation. The patient will be advised to apply a thin 
layer of Dermaprazole in the patch area at the time of CT simulation and assessed for immediate 
allergic reactions.  If no allergic reactions occur upon this initial application, the subject will 
continue to apply the cream for 2 – 4 days in the patch area. The coordinator or treating 
physician will then call the patient to ask if any itching/rash in the patch area, and if not then the 
patient will be advised to begin the cream in the patch area and in the planned radiation field 
until the start of their radiation therapy. Patients will be instructed to discontinue use 
immediately if any local skin reactions occur.  
If a patient experiences a local skin reaction to the initial application of dermaprazole, the agent 
will be applied a second time to the contralateral chest wall followed by assessment of the skin at 
30 mins (to assess for immediate/anaphylactic reactions), and 2-4 days after application (for 
delayed hypersensitivity reactions). The first assessment will be conducted at the time of clinic 
visit, the latter assessment will be conducted via phone call. Patients will be questioned regarding 
any visible skin changes or irritation (itching, peeling, scaling), and patients responding in the 
affirmative will be asked to present for clinic visit or send photographs for visual classification 
according to the scale outlines in table 1 below. Skin reactions matching a score of 3 will be 
evaluated with a second clinic visit between 2 to 7 days after initial application. Any skin 
reactions of score 4 or 5 at final assessment will be deemed to be positive for allergic contact 
dermatitis, and patients will be deemed positive for allergic contact dermatitis. 
 
Table 1:  
Grading System for Patch Test Reactions (immediate allergic reactions and delayed 
contact dermatitis) 
Score 
Description 
1 
Negative reaction 
2 
Doubtful reaction, faint macular erythema 
3 
Weak, non-vesicular reaction with erythema, infiltration, and papules 
4 
Strong vesicular reaction with erythema, infiltration, and papules 
5 
Spreading bullous reaction 

 
 
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For the subset of patients determined to have allergic reactions or contact dermatitis, a second patch test 
will be conducted to determine whether the allergy is to dermaprazole itself or the vehicle used in the 
topical formulation. A topical application of the vehicle without the active ingredient (dermaprazole) will 
be applied to the patient’s forearm. Similar to the above protocol, patients will be assessed at 30 minutes 
and 2-4 days after topical application (in clinic for first assessment, phone call for second). Patients with 
skin reactions will send photos or present for clinic follow up and reactions greater than 3 in the scale 
above will be interpreted to mean the patient has an allergic reaction to the vehicle rather than 
dermaprazole. Alternative formulations with different carrier vehicles will be considered in the future, but 
for the purposes of this phase I/II study, such patients will be excluded. 
During the entire time while using the Dermaprazole, study participants will be evaluated for 
adverse events such as contact dermatitis in the patch test area as well as radiation dermatitis 
within the treatment field.  All participants will be followed for 1 month after the final 
Dermaprazole application. 
The study PI or co-Investigator (radiation oncologist)  will document the patch area at CT 
simulation.  Subjects will be evaluated weekly for adverse  events by the study PI or Co-I 
(radiation oncologist) who will determine if the subject can continue to receive the Dermaprazole 
cream.  Subjects found to have an AE in the radiation field prior to starting treatment will cease 
dermaprazole and the start of radiation therapy will be delayed to allow for healing.  See Section 
15.4 for details. 
7.2.2. 
Application During And after Radiation Treatment 
All radiation will follow standard practice. Variations (dose adjustments, delays, etc.) that follow 
standard clinical practice are allowed and are not considered deviations, though these will be 
recorded to assess for interference. Radiation details such as dose modality, fractionation, as well 
as total treatment time in days will be recorded in the electronic medical record as per routine 
practice.  
Patients will apply Dermaprazole twice daily to assess the effect on  radiation dermatitis. Patients 
will be instructed to apply a thin layer of the cream along the area exposed to chest wall 
irradiation (i.e., borders as specified above, plus a one to two inch margin around the irradiated 
area), starting from the day of simulation, throughout the radiation treatment period, and for two 
weeks after completion of radiation. Patients will  also continue to apply Dermaprazole cream to 
the contralateral patch test area (for control) during the radiation treatment (RT) period and for 
the 2 weeks after radiation. Patients who develop open wounds may be prescribed topical or oral 
antibiotic if indicated per usual practices.   
During adjuvant radiation, patients are assessed once every 5 treatments (i.e. weekly, for the 
duration of radiation treatment [up to 7 weeks]). Using CTCAE v5 criteria, the grade of radiation 
dermatitis is recorded in the area of radiation treatment by a radiation oncologist. Patients will 
continue to be clinically monitored in the control area of patch testing for contact/irritant 
reactions.  If severe radiation dermatitis develops, it will be managed per usual care (sterile 
wound dressings, antibiotics) as per treating physician’s discretion. 

 
 
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7.3. 
Prohibited Medications or Therapies 
Prior to entry into the study, subjects must not use the medications and/or procedures specified 
in Section 5.2. 
During the study, subjects must not use the following products: 
• clopidrogrel 
• St. John’s Wort 
• rifampin 
• methotrexate 
7.4. 
Assessments and Procedures 
7.4.1  
Baseline and Screening Evaluations 
• Written Informed consent 
• Review of inclusion/exclusion criteria 
• Comprehensive History and Physical Exam  
• ECOG Performance Status 
• Outside Radiation Field Dermatitis form 
• SkinDex16 questionnaire at consultation 
• Other tests may be obtained at the investigator’s discretion. Invasive interventions or 
procedures will be minimized and will only be performed with the approval of the 
principal investigator. 
 
7.4.2  
CT Simulation 
• Radiation Oncologist will mark the patch test area, area of radiation field, and provide 
instructions to study participant about applying Dermaprazole to these areas prior to 
radiation treatment. 
• Patient will apply Dermaprazole cream to the patch test area at CT simulation and the 
Radiation Oncologist will check for immediate allergic reactions (development of 
prutitis, urticarial, or rash after application)  at the time of first application. 
• Distribution of Dermaprazole syringes for two weeks 
Application of Dermaprazole to patch test area (BID) by study participant for 2-4 days.  
Patient will be called by study coordinator or treating physician to ask if any itching or 
rash in the patch test area. If not, patient will be advised to begin the application of 
Dermaprazole to irradiated area (BID) by study participant until the start of radiation. 
 

 
 
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7.4.3 
On  Treatment: weekly during radiation treatment (i.e. one visit per 5 
treatments), up to 7 weeks 
• Evaluation for delayed type hypersensitivity reaction prior to start of radiation 
• Focused exam by Radiation Oncologist 
• Outside Radiation Field Dermatitis Form 
• Weekly Evaluation questionnaire 
• SkinDex 16 questionnaire 
• Adverse event evaluation and DLT evaluation, including evaluation of radiation 
dermatitis with note of components (erythema, epilation, fibrosis, etc.,) 
• Radiation dermatitis assessment done weekly by Radiation Oncologist 
• Distribution of Dermaprazole syringes (Week 1) 
• Application of Dermaprazole to patch test area (BID) by study participant 
• Application of Dermaprazole to irradiated area (BID) by study participant 
7.4.4 Two weeks post radiation treatment  
• Application of Dermaprazole to patch test area (BID) by study participant 
• Application of Dermaprazole to irradiated area (BID) by study participant 
• Distribution of Dermaprazole syringes (on last day of radiation) 
 
7.4.5 Post-Treatment follow-up 
Subjects will be followed for a total of 6 weeks after completion of radiation  to assess 
intervention-related safety.  
Follow up Visit (6 weeks after completion of all radiation therapy, +/- 7 days) 
• Focused exam 
• Outside Radiation Field Dermatitis Form 
• Weekly Evaluation questionnaire 
• SkinDex 16 questionnaire 
• Adverse event and DLT evaluation, including evaluation of radiation dermatitis with note 
of components (erythema, epilation, fibrosis, etc.,) 
• Radiation dermatitis assessment by Radiation Oncologist  

 
 
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7.4.6 
Table 1: Calendar of Study Assessments & Testing  
 
 
Screening/ 
Baseline 
CT 
simulation 
Phone Call 
to 
document 
no delayed 
type 
allergic 
reaction 
Before 
First 
Radiation 
Treatment 
(can be on 
start day of 
radiation) 
Weekly 
During 
radiation 
treatment  
Follow/ up 
 
6 weeks after 
radiation 
treatment b 
SCREENING 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
Eligibility (Inclusion/Exclusion Criteria) 
X 
 
 
 
 
 
CLINICAL  
 
 
 
 
 
 
Comprehensive History and Physical Exam c 
X 
 
 
 
 
 
Focused Exam (Radiation Oncologist) 
 
 
 
X 
X 
X 
ECOG Performance Status 
X 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
ASSESSMENTS 
 
 
 
 
 
 
Outside Radiation Field Dermatitis Form  
X 
 
 
X 
X 
X 
Allergic reaction evaluation 
 
X 
X 
X 
X 
 
Weekly evaluation questionnaire  
 
 
 
X 
X 
X  
SkinDex16 questionnaire 
X 
 
 
X 
X 
X 
Adverse Events d 
 
 
 
X 
X 
X 
DLT assessment d 
 
 
 
X 
X 
X 
CTCAE Version 5  
Dermatitis (Radiation Oncologist)  
 
 
 
 
X 
X 
X 
CTCAE Version 5  
 
 
 
 
 
 
 
X 
EXPERIMENTAL TREATMENT 
 
 
 
 
 
 
Distribution of Dermaprazole syringes e 
 
X 
 
X 
 
 
Dermaprazole Patch Test (applied BID) 
 
X 
 
X 
X 
 

 
 
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Dermaprazole in Irradiated Area (applied BID) 
 
X 
 
X 
X 
 
(a) Radiation treatment may be anywhere from 3 to 7 weeks for a study participant. Weekly assessments to be performed within +/- 3 days. 
(b) Weekly assessments to be completed within +/- 7 days during the 1 month follow-up period. 
(c) Comprehensive history and physical exam to be completed within 12 weeks of enrollment. 
(d) Adverse events will be assessed by the Radiation Oncologist.  If a DLT occurs, the DLT form will be filled out.  
(e) Dermaprazole syringes will be dispensed at the CT simulation visit  to be applied during radiation treatment, and at the end of treatment for two additional weeks of 
Dermaprazole application after radiation treatment is over.  One syringe is enough for one application and subjects would need to apply dermaprazole twice a day.  
Two syringes will be used in a day, so sufficient syringes will be dispensed at the CT simulation for two weeks, then at the beginning of radiation for the duration of 
radiation treatment, and twenty eight syringes will be dispensed on the last day/week of radiation treatment for the additional two weeks of Dermaprazole application 
post radiation treatment.  
 

 
 
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7.4.7. 
Criteria for Removal from Study Intervention (Dermaprazole) 
Intervention is defined as Dermaprazole cream but not the radiotherapy itself.  Subjects may be 
removed from study treatment (Dermaprazole) for any of the following:  
a. Inter-current illness that prevents further administration of treatment,  
b. Unacceptable adverse event(s), DLT, or suspected allergy, 
c. Patient’s decision to withdraw from the study treatment, 
d. Deterioration in the patient’s condition rendering the patient unacceptable for further 
treatment in the judgment of the investigator. This may include, but is not limited to: 
progression in comorbid diseases that become more life threatening, deterioration of 
performance status unrelated to the trial, or any other situation in which continuation 
of treatment on this study would be detrimental to the health of the patient at the 
discretion of the treating physician. 
e. Any delay in radiotherapy after simulation past 16 days  
Subjects should complete the post-treatment visits if they are removed from study treatment 
before completion.  
8. 
TREATMENT EVALUATION 
A general history and physical examination must be done within 12 weeks prior to registration.  
Pathologic diagnosis of the tumor must be within 2 years prior to registration. 
After completion of adjuvant radiation, patients will be seen at one month for a toxicity check 
and clinical evaluation of skin by a radiation oncologist. 
9. 
MEASUREMENT OF EFFECT 
Rates and severity of radiation dermatitis will be determined by the radiation oncologist and 
defined using NCI Common Terminology Criteria for Adverse Events (CTCAE version 5) for 
dermatitis radiation.  In particular, the individual components of radiation dermatitis will be 
recorded: erythema, desquamation, edema, bleeding, skin necrosis and skin ulceration.  These 
will be used in assessment weekly by the treating radiation oncologist as well as during review 
by the dermatologist after completion of treatment (i.e. the dermatologist will not know where 
the patient is in their treatment course). 
Compliance to intervention and use of other topical agents will be documented qualitatively 
during weekly assessments. The effect of the intervention on quality of life will be evaluated 
using SkinDex 16 (Appendix 1). 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
 Study Design 
This is a combination Phase I/II trial of Dermaprazole to determine the maximum feasible dose 
(MFD) among two dose levels (topical intervention at 1% and 2%), and to evaluate the disease 

 
 
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response rate at the MFD.  Dose-limiting toxicity will be ascertained using the Common 
Terminology Criteria for Adverse Events v5.0 (See Appendix 2). The primary outcome for the 
phase II component will be the rate of clinically bothersome radiation dermatitis. No individual 
dose modifications will be made.  If a patient develops toxicity, the study drug will be 
discontinued. 
This study will use Bayesian Optimal Interval (BOIN) design to provide monitoring of toxicity 
beyond the Phase I cohort.  BOIN design has algorithmic escalation/de-escalation rules easy to 
implement like a traditional 3+3 design but allows for specification of the target DLT rate, 
different size cohorts, is more likely to correctly select the MFD and allocate more patients to the 
MFD and expands consistent toxicity monitoring to the entire cohort. BOIN design with a target 
DLT rate of 0.3 and cohort size of 3 begins exactly in the same fashion as the “3+3” allowing for 
the implemented design change in early stages. Calculations were done using R package 
BOIN.xxv  
10.2. 
Sample Size/Accrual Rate 
Phase I component considerations. 
The study is designed to escalate the dose if the observed toxicity rate at the current dose is <= 
0.2365, and de-escalate the dose if the observed toxicity rate at the current dose is >= 0.3585. If 
the observed toxicity rate is between 0.2365 and 0.3585, additional patients will be treated at the 
current dose. For cohorts of size 3, the decision boundaries are shown in Tables 2a and 2b. Two 
doses levels of Dermaprazole (1% and 2%) are evaluated, beginning with the lower dose for each 
disease site.* 
 
 
 
Table 2a: DLT Regulation of Dose Escalation and De-Escalation:  
 
Number of 
patients treated 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36+1 
Escalate*** if 
number of DLT 
<= 
0 
1 
2 
2 
3 
4 
4 
5 
6 
7 
8 
9 
Treat additional 
3 pts on current 
dose if number 
of DLT= 
1 
2 
3 
3,4 
4,5 
5,6 
5-7 
6-8 
7-9 
8-10 
9-11 
10-12 
Deescalate* if 
number of DLT 
>= 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Eliminate** if 
number of DLT 
>= 
3 
4 
5 
7 
8 
9 
10 
11 
12 
13 
14 
15 
* At the lowest dose level, if the recommendation is to de-escalate AND the dose level has not been 
eliminated from consideration, 3 additional pts will be accrued at the same dose level; otherwise, the trial 
will stop. Last cohorts have 5 and 4 patients to reach the required sample sizes. 

 
 
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** Eliminate dose level and all higher doses from further use.  
*** At the time of the design change the study escalated to the highest dose and will continue enrolling 
additional patients at this dose unless de-escalation is recommended. 
 
Phase II component considerations. 
Sample size was estimated using historical rates of radiation dermatitis which are well 
established in the literature based on dose and target. Relevant to our study, the rate of clinically 
bothersome radiation dermatitis in our historical breast cancer patients is 65%. Based on our 
preclinical study with animal and human skin models, we expect a 20% absolute reduction in the 
proportion of patients with clinically meaningful radiation dermatitis from historical controls (i.e. 
we expect to see 45% of the patients in the breast cancer arm with clinically meaningful radiation 
dermatitis To attain the power of 80%, with a one-sided test, alpha (α) of 0.05, and assuming no 
attrition, our final sample size has to be 37 patients in the breast cancer cohort. The treatment is 
considered effective if 25 or more of breast cancer patients are responding to therapy as defined 
as not having grade 2 or greater radiation dermatitis (i.e <25 of 37 breast cancer patients having 
grade 2 or higher skin toxicity). 
 
Total study sample size. 
This study will enroll at least 3 patients at each dose level and 37 breast cancer patients at the 
MFD level.  Each time a cohort of 3 DLT evaluable subjects in the Breast group (or sooner if 
there are safety concerns) is complete, the study statistician will be notified and will review the 
data and make a recommendation as to whether to escalate, de-escalate or keep them at the same 
dose level.  Participants will continue to be enrolled and monitored for toxicity according to the 
rules specified above until all efficacy evaluable participants have been enrolled to any single 
dose level. For the purposes of this intent-to-treat analysis, a subject is considered evaluable for 
the primary endpoint after completing at least one day of Dermaprazole treatment with 
radiotherapy.  It is expected that all dose levels will be safe and assuming that even the highest 
dose level has a DLT rate substantially lower than the target (i.e. <10%), which is what we 
expect. We will have more than 99% chance of selecting the top dose level at the end of the trial. 
In this case the total number of patients enrolled would be 40 (3+37). Per our current database, 
the clinic is treating approximately 40 eligible patients per year. As such, accrual should take no 
longer than 12 months with planned completion of follow up within 6 months of completion. 
This is a conservative estimate given that some patients may decline to partake in a study for an 
investigational drug. These calculations are based on assumption that clinic is treating 40 eligible 
patients per year. Assuming this is overestimating true availability by 20% and this study would 
require an additional 6 months to complete enrollment for a total study duration of 24 months. 
10.3. 
 Statistical Analysis 
Primary Analysis: The primary objective is to determine the safety and MFD of topical 
Dermaprazole cream in preventing radiation dermatitis.  This will be evaluated in two ways: by 
assessment of baseline irritant (as described in section 15.1) or contact dermatitis as part of the 
patch test (outside of the irradiated field) to before/during radiation.   
Evaluation of DLT (as described in section 15.1.4) of Dermaprazole when in the field of radiotherapy.  
The dose enrolling according to rules described in Table 2b will be determined to be the MFD. The 
posterior DLT rate and 95% confidence interval will be estimated using all toxicity evaluable cases. 

 
 
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The rates of clinically bothersome radiation dermatitis in our historical breast cancer patients will be 
calculated along with 95% confidence intervals and compared with historical rates using One Sample Test 
of Proportions. 
 
Secondary Analysis:  The proportion of patients with maximum observed acute grade 2, 3, and 4 
skin reactions (as described in Section 9) will be expressed in percentage. Time to develop grade 
2, 3, and 4 radiation reactions and time to healing if grade 2 or higher acute radiation dermatitis 
develops will be described using Kaplan Meier curves. The median of the peak score of each 
QOL component will be reported. Radiation compliance will be reported in terms of number of 
missed treatments due to skin toxicity.  Descriptive and summary statistics will be computed for 
demographic and clinical data of all subjects enrolled in the study considering other factors that 
could potentially affect the severity of radiation dermatitis, such as age, radiation technique, 
concurrent chemotherapy, smoking or tobacco use, body mass index, comorbidities, and ECOG 
performance status, will be reported 
11. 
DATA  MANAGEMENT  
 All subject data will be abstracted from the electronic medical record available for each enrolled patient 
and documented in an electronic database created for this study using OnCore, the proprietary, HIPAA-
compliant software used by Dan L Duncan Comprehensive Cancer Center for these purposes. Each 
subject will be assigned a study code to facilitate subsequent coding of the data set once complete. This 
number will be used to link any primary source data stored in the HIPAA-compliant electronic database 
used for this study.  
12. 
QUALITY ASSURANCE 
All Dan L Duncan Comprehensive Cancer Center treatment studies conducted at BCM-affiliated 
institutions are subject to a formal, comprehensive source document review through the Quality 
Assurance program. The primary purpose of Quality Assurance (QA) activity is to evaluate and 
ensure that the conduct of clinical trials complies with all federal regulations and International 
Conference on Harmonization Good Clinical Practices. A secondary purpose of QA activity is to 
ensure that standard operating procedures (SOPs) establishing the processes used for conduct of 
clinical trials, and data collection and management related to clinical trials are appropriately 
defined, implemented, and being followed, and to improve and refine the processes established 
in the SOPs when necessary. Adherence to protocol compliance, eligibility verification, informed 
consent verification, and data accuracy will be evaluated by the PI. The PI will provide radiation 
therapy quality control. All cases will be discussed and reviewed by a group of board certified 
radiation oncologists within the department.  
All handling and storage once delivered from the compounding pharmacy will be shipped to the 
investigational pharmacies at Smith Clinic and Baylor St. Luke’s respectively and will be 
dispensed by the investigational pharmacies.  Airtight and light-protected syringes have been 
chosen to minimize product oxidation and contamination. Please note the compounding 
pharmacy will ship Dermaprazole on ice, and the investigational pharmacy will maintain the 
drug in a refrigerated environment.  Additional information is provided in Section 6 of the 
protocol.  

 
 
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13. 
DATA AND SAFETY MONITORING 
 This study will be reviewed regularly by the Data Review Committee (DRC) of the Dan L Duncan 
Comprehensive Cancer Center.  The DRC will monitor the study for progress and enrollment, toxicities, 
adverse events, and soundness of data, in accordance with the DDLCCC Data and Safety Monitoring Plan 
and the DRC SOP. 
The frequency of data review by the DRC is determined by the Protocol Review and Monitoring 
Committee at the time of initial review and is based on the level of risk to the study subjects.  Review will 
occur at a minimum of once each year after activation.   
Data Quality Assurance 
This study will be monitored by the DLDCCC Quality Assurance program for study conduct and quality 
of data, according to CTSU policy.  Protocol compliance, eligibility verification, informed consent 
procedure verification, and data accuracy will be monitored. 
14. 
PROTECTION OF HUMAN SUBJECTS 
This study will protect the rights of human subjects. No additional financial cost will be incurred 
by the patients.  Efforts will be made to protect patient confidentiality.  The study is completely 
voluntary and patients will be able to withdraw at any time.   
The study will be conducted in compliance with Food and Drug Administration (FDA) 
regulations, the ethical principles of the Declaration of Helsinki concerning medical research in 
humans (Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects, Helsinki 1964 and amendments 2013), the International Council for Harmonization 
(ICH) – Good Clinical Practice (GCP) Guidelines as currently amended, and all applicable 
standard operating procedures (SOPs) of the Baylor College of Medicine. 
15. 
ADVERSE EVENTS 
15.1. 
Adverse Event (AE) Definition 
An adverse event is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study.   
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
15.2. 
Serious adverse event (SAE) Definition 
A serious adverse event is an undesirable sign, symptom, or medical condition which: 
• 
is fatal; 
• 
is life-threatening (immediate risk of death); 
• 
requires or prolongs inpatient hospitalization for ≥24 hours; 
• 
results in persistent or significant disability/incapacity to conduct normal life functions; 
• 
constitutes a congenital anomaly or birth defect; or 

 
 
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• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. 
Events not considered to be serious adverse events are hospitalizations for: 
• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• 
elective or pre-planned treatment for a pre-existing condition that did not worsen, or that is 
required per protocol 
• 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission 
• 
respite care 
• 
Death due to disease progression unless attributable to the study drug(s). 
 
Events listed above may be reported to a participating site’s local IRB, if required per local 
regulations. 
15.3. 
Relationship of Adverse Events to the Study Intervention 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment.  The Investigator is to classify the drug relationship of an AE according to the 
definitions outlined below:  
Definitely: The AE is clearly related to the study treatment. 
Probably:  The AE is likely related to the study treatment. 
Possibly: The AE may be related to the study treatment.  
Unlikely:  The AE is doubtfully related to the study treatment.  
Unrelated: The AE is clearly NOT related to the study treatment. 
15.4. 
Adverse Event (AE) Grading scale 
15.4.1. 
Rash Maculo-Papular outside the radiated field 
• Grade 1: Macules/papules covering <10% BSA with or without symptoms (e.g., 
pruritus, burning, tightness) 
• Grade 2: Macules/papules covering 10 - 30% BSA with or without symptoms (e.g., 
pruritus, burning, tightness); limiting instrumental ADL; rash covering > 30% BSA with 
or without mild symptoms 
• Grade 3: Macules/papules covering >30% BSA with moderate or severe symptoms; 
limiting self care ADL 
• Grade 4: n/a 
Any reaction outside the radiated field ≥Grade 2 at any point will lead to immediate halting of 
Dermaprazole use in that patient and reported as an adverse event and a dose limiting toxicity.  

 
 
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The patch test area will be used to assist in deciding the likelihood of Dermaprazole causing the 
adverse event. 
15.4.2. 
Adverse events inside the Radiation Field:  
Adverse events are at the discretion of the managing radiation oncologist.  All adverse events 
must state if they are definitely, probably, possibly, unlikely, or unrelated to the Dermaprazole 
intervention.  All adverse events are in terms of CTCAE V 5.0 .  
The following definitions will be used for radiation dermatitis:  
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
− Faint erythema or dry desquamation 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
− Moderate to brisk erythema; patchy moist desquamation, mostly confined to skin 
folds and creases; moderate edema 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL  
− Moist desquamation in areas other than skin folds and creases; bleeding induced 
by minor trauma or abrasion 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
− Skin necrosis or ulceration of full thickness dermis; spontaneous bleeding from 
involved site; skin graft indicated 
• Grade 5: Death related to radiation dermatitis.  
 
AEs will be graded in accordance with the NCI Common Terminology Criteria for Adverse 
Events v 5. (CTCAE) http://ctep.cancer.gov/reporting/ctc.html.   If not described in the NCI-
CTCAE, AEs will be graded according to their severity using the following criteria (38).  
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Symptoms 
or Signs 
Asymptomatic 
or mild 
Moderate 
limiting age 
appropriate 
instrumental 
ADLs 
Severe, not 
immediately 
life 
threatening. 
Disabling, 
limiting self-
care ADLs 
Life 
threatening 
Death 
related to 
AE 

 
 
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Page 29 of 37 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Intervention 
Observation 
Local or 
non-
invasive 
intervention 
Hospitalization 
Urgent/ 
emergent 
intervention 
Death 
related to 
intervention 
 
The AE collection/reporting period will begin with the first day of application of Dermaprazole 
and will end 30 days after radiation. AEs after study registration but prior to the first day of study 
treatment will be captured as baseline symptoms present at the start of study. 
Acute and late designations will be defined by the timing of occurrence from treatment.  
• Acute toxicity will be defined as events occurring during or within 30 days of 
treatment completion.  
• Late toxicity will be defined as events occurring or persisting ≥30 days from 
treatment completion.  
15.5. 
Dose Limiting Toxicity (DLT):  
A DLT is defined as any of the following: 
1. Any  >Grade 2 skin toxicity events outside the radiation field. 
2. Any >Grade 2 radiation dermatitis inside the radiation field that is probably or definitely 
related to Dermaprazole. (AE Attribution will be at the discretion of the study PI/Co-I). 
3. Any Grade greater than or equal to 4 radiation dermatitis inside the radiation field. 
4. A DLT will be detected from the first day of treatment to 1 month after the end of 
radiation. Any skin reaction ≥Grade 2 will lead to immediate halting of Dermaprazole use 
in that patient and reported as an adverse event and a dose limiting toxicity. The patch 
test area will be used to assist in deciding the likelihood of Dermaprazole causing the 
adverse event. Patients not completing the evaluation period for acute toxicity will be 
considered not evaluable and be replaced. 
Note: All patients will be followed for safety until the end of the trial; in an unlikely event of 
detecting a late Grade 4 skin toxicity, the study will be halted to consider dose de-escalation or 
may be stopped. 
15.6. 
Potential Risks/Discomforts 
Dermaprazole: The interventional cream is not yet tested in humans and reactions in vivo 
(especially in patients experiencing radiation dermatitis) are not yet known. Possible side effects 
include allergy or infection. Given the efficacy and lack of toxicity in pre-clinical studies, it is 
unlikely that the interventional cream would lead to worsened rates of radiation dermatitis and 
skin integrity, though this is a possibility. Please also refer to the Investigator’s Brochure for 
Dermaprazole.   
Adverse events of Special Interest: 

 
 
H-45698                        
 
 
Page 30 of 37 
The systemic exposure of Dermaprazole is not yet known; therefore, weekly monitoring for 
clinical signs or symptoms that may be evident of systemic toxicity (e.g., acute interstitial 
nephritis, C. dificile associated diarrhea, bone fracture, new onset cutaneous and systemic lupus 
erythematosus) will be required. 
15.7. 
Adverse Event Reporting Requirements: 
The AE collection/reporting period will begin with the first day of treatment with Dermaprazole.  
New AEs and SAEs that are ongoing at the end of the radiation will be followed for 30 days, 
unless they have resolved earlier.   
All adverse events will be recorded on the appropriate study-specific case report form (CRFs). 
15.7.1. 
The AE description will include the nature of the experience, the date of onset, the 
resolution date, the severity of each sign or symptom reported using the NCI-CTCAE 
(version 5.0), the seriousness of the event, the potential relationship to study 
treatment, the course of action taken, and the outcome of the experience.   
15.7.2 
If an adverse event meets all of the elements below, it should be reported to the IRB 
within 5 working days of the event: 
 
a) suggests that the research places one or more participants or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized; and 
 
b) is unexpected/unanticipated (in terms of nature, severity, or frequency); and 
 
c) is possibly, probably or definitely related to the participation in the research 
procedures (an event is “related to the research procedures” if in the opinion of the 
principal investigator, it was more likely than not to be caused by the research 
procedures or if it is more likely than not that the event affects the rights and welfare 
of current participants).  
15.7.3  
Any Adverse event that is unexpected, serious, and possibly/probably/definitely 
related to the study should be reported to the review committee (DRC) within 15 
calendar days of knowledge of event. Adverse events that are reported should be sent 
to the DLDCCC Patient Safety Officer (PSO) at dldcc-pso@bcm.edu by the PI and 
study team. The PSO will review and distribute the report to the DRC Chairs and 
members and send any correspondence back to the PI. 
15.7.4 
For studies in which the IND is held by a DLDCCC investigator, any event that is reported to 
the FDA should also be reported to the DRC at the same time.  
 
15.7.5 
All serious adverse events should be communicated to the principal investigator within 24-48 
hours.  
 
15.7.6 
Unexpected serious adverse events believed to be definitely, probably, or possibly related to 
the medications will be reported to the Food and Drug Administration via MedWatch within 7 
days of the Investigator becoming aware of the occurrence of the event.   
 
15.7.7 
Serious adverse events that are an unanticipated problem should be reported to the IRB within 
5 days of knowledge 

 
 
H-45698                        
 
 
Page 31 of 37 
 
15.7.8 
Follow up information pertaining to a previously submitted IND Safety Report will be 
submitted as soon as available and no later than 15 calendar days after sponsor’s awareness of 
the information.  
15.8. 
Management of AEs and Impact on Treatment 
 
15.8.1 
Expected mild/moderate Grade 1 adverse events inside or outside the radiation field 
that are either possibly related or unrelated to the investigational product will be 
managed conservatively by the treating physician.   
15.8.2 
Unexpected or serious adverse events will be managed on a case by case basis at the 
discretion of the treating Investigator in coordination with the study team. Emergent 
face-to-face evaluation within 48 hours will be sought for each suspected 
intervention-related serious adverse effect.   
15.8.3  
Adverse events possibly, probably, or definitely related to Dermaprazole will prompt  
 
 
result in discontinuation of the study treatment (Dermaprazole cream).  If the AE 
occurs within the planned radiation field prior to the start of radiation, the start of  
radiation will be held until the AE resolves (~2 weeks).  If the AE occurs after the  
start of radiation, the radiation will continue as scheduled unless Grade 4 toxicity  
occurs, in which case delay to allow for healing is permitted.  Any changes to  
radiation treatment will be per routine clinical care.   If severe (≥Grade 3) radiation 
dermatitis develops it will be managed per usual care (sterile wound dressings,  
antibiotics) as per treating physician’s discretion. 
16.0   
Pregnancy 
Pregnancy testing will be performed at screening/baseline prior to study enrollment for women 
of childbearing age as part of the standard of care procedure for receiving radiation therapy and 
to ensure the subject meets study eligibility.  Pregnant patients will be excluded from the study 
since they will not be able to receive radiation and will meet one of the exclusion criterions. 
 
 
 

 
 
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Page 32 of 37 
APPENDIX 1. SKINDEX16 FORMS IN ENGLISH & SPANISH 
 
 
THESE QUESTIONS CONCERN THE SKIN CONDITION 
WHICH HAS BOTHERED YOU THE MOST DURING THE 
PAST WEEK 
 
 
 
During the past week, how often 
have you been bothered by: 
 
 
 
  
Never 
Bothered 
 
Always 
Bothered 
 
 
  
______________________________ 
 
1. 
Your skin condition itching .
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
2. 
Your skin condition burning or stinging 
 
  0     1     2      3     4      5     6 
 
 
 
3. 
Your skin condition hurting .
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
4. 
Your skin condition being irritated 
.
 
 
  0     1     2      3     4      5     6 
 
 
 
5. 
The persistence / reoccurrence of your 
skin condition .
.
.
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
6. 
Worry about your skin condition  
(For example: that it will spread, get worse, scar, be 
unpredictable, etc).
.
.
.
.
.
.
.
.
 
  0     1     2      3     4      5     6 
 
 
 
7. 
The appearance of your skin condition 
 
  0     1     2      3     4      5     6 
 
 
 
8. 
Frustration about your skin condition 
 
  0     1     2      3     4      5     6 
 
 
 
9. 
Embarrassment about your skin condition  
  0     1     2      3     4      5     6 
 
 
 
10. 
Being annoyed about your skin condition  
  0     1     2      3     4      5     6 
 
 
 
11. 
Feeling depressed about your skin 
condition .
.
.
.
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
12. 
The effects of your skin condition on your 
interactions with others ........................... 
(For example: interactions with family, friends, 
close relationships, etc) 
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
13. 
The effects of your skin condition on your 
desire to be with people .
.
.
.
 
 
  0     1     2      3     4      5     6 

 
 
H-45698                        
 
 
Page 33 of 37 
 
 
 
14. 
Your skin condition making it hard to show 
affection .
.
.
.
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
15. 
The effects of your skin condition on your 
daily activities .
.
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
16. 
Your skin condition making it hard to work 
or do what you enjoy .
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
 
Have you answered every item? 
Yes  
No  

 
 
H-45698 
 
Page 34 of 37 
 
 
ESTAS PREGUNTAS SE RELACIONAN CON LA AFECCIÓN EN LA PIEL  
QUE MÁS LE HA MOLESTADO DURANTE LOS ÚLTIMOS 7 DÍAS 
 
 
 
Durante los últimos 7 días, ¿con 
qué frecuencia le ha 
molestado…? 
 
 
 
  
Nunca me 
molestó 
 
Siempre 
me 
molestó 
 
 
  
______________________________  
1. 
La picazón en la afección en la piel .
.
  
  0     1     2      3     4      5     6 
 
 
 
2. 
El ardor o escozor en la afección en la piel 
  0     1     2      3     4      5     6 
 
 
 
3. 
El dolor en la afección en la piel .
.
.
  
  0     1     2      3     4      5     6 
 
 
 
4. 
La irritación en la afección en la piel 
.
  
  0     1     2      3     4      5     6 
 
 
 
5. 
La persistencia / recurrencia de la 
afección en la piel .
.
.
.
.
.
.
  
  0     1     2      3     4      5     6 
 
 
 
6. 
La preocupación por la afección en la piel  
(Por ejemplo: de que se extenderá, empeorará, 
dejará cicatriz, sea impredecible, etc.) 
.
.
  
  0     1     2      3     4      5     6 
 
 
 
7. 
El aspecto de la afección en la piel .
.
  
  0     1     2      3     4      5     6 
 
 
 
8. 
La frustración por la afección en la piel .
  
  0     1     2      3     4      5     6 
 
 
 
9. 
La vergüenza por la afección en la piel .
  
  0     1     2      3     4      5     6 
 
 
 
10. 
Sentirse fastidiado por la afección en la 
piel .
.
.
.
.
.
.
.
.
.
.
.
  
  0     1     2      3     4      5     6 
 
 
 
11. 
Sentirse deprimido por la afección en la 
piel .
.
.
.
.
.
.
.
.
.
.
.
  
  0     1     2      3     4      5     6 
 
 
 
12. 
Los efectos de la afección en la piel en sus 
relaciones con los demás (Por ejemplo: 
relaciones con su familia, amigos, relaciones 
cercanas, etc.) .
.
.
.
.
.
.
.
.
  
  0     1     2      3     4      5     6 
 
 
 
13. 
Los efectos de la afección en la piel en su 
deseo de estar con otras personas 
.
  
  0     1     2      3     4      5     6 
 
 
 

 
 
H-45698 
 
Page 35 of 37 
 
14. 
Que la afección en la piel le dificulte 
demostrar afecto .
.
.
.
.
.
.
  
  0     1     2      3     4      5     6 
 
 
 
15. 
Los efectos de la afección en la piel en sus 
actividades diarias .
.
.
.
.
.
.
  
  0     1     2      3     4      5     6 
 
 
 
16. 
Que la afección en la piel le dificulte 
trabajar o hacer lo que disfruta .
.
.
  
  0     1     2      3     4      5     6 
 
 
 
 
¿Ha respondido cada pregunta? 
Sí  
No  
 

 
 
H-45698 
 
Page 36 of 37 
 
17.0  
REFERENCES 
 
i Chan, R.J., J. Webster, B. Chung, L. Marquart, M. Ahmed, and S. Garantziotis, Prevention and treatment of acute 
radiation-induced skin reactions: a systematic review and meta-analysis of randomized controlled trials. BMC 
Cancer, 2014. 14: p. 53. 
ii U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES. Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0. National Cancer Institute, 2009. 
iii Cox, J.D., J. Stetz, and T.F. Pajak, Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the 
European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys, 1995. 31(5): 
p. 1341-6. 
iv Trotti, A., R. Byhardt, J. Stetz, C. Gwede, B. Corn, K. Fu, L. Gunderson, B. McCormick, M. Morrisintegral, T. 
Rich, W. Shipley, and W. Curran, Common toxicity criteria: version 2.0. an improved reference for grading the acute 
effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys, 2000. 47(1): p. 13-47. 
v Brown, K.R. and E. Rzucidlo, Acute and chronic radiation injury. J Vasc Surg, 2011. 53(1 Suppl): p. 15S-21S. 
vi Lopez E, Guerrero R, Nunez MI, del Moral R, Villalobos M, Martinez-Galan J, Valenzuela MT, MunozGamez JA, 
Oliver FJ, Martin-Oliva D, Ruiz de Almodovar JM. Early and late skin reactions to radiotherapy for breast cancer 
and their correlation with radiation-induced DNA damage in lymphocytes. Breast cancer research: BCR. 
2005;7:R690-698 
vii Gamulin M, Garaj-Vrhovac V, Kopjar N. Evaluation of DNA damage in radiotherapy-treated cancer patients using 
the alkaline comet assay. Collegium antropologicum. 2007;31:837-845 
viii Lomax ME, Folkes LK, O'Neill P. Biological consequences of radiation-induced DNA damage: Relevance to 
radiotherapy. Clinical oncology. 2013;25:578-585 
ix Brach MA, Gruss HJ, Kaisho T, Asano Y, Hirano T, Herrmann F. Ionizing radiation induces expression of 
interleukin 6 by human fibroblasts involving activation of nuclear factor-kappa b. J Biol Chem. 1993;268:8466-8472 
x Muller K, Meineke V. Radiation-induced alterations in cytokine production by skin cells. Experimental 
hematology. 2007;35:96-104 
xi Mukherjee D, Coates PJ, Lorimore SA, Wright EG. Responses to ionizing radiation mediated by inflammatory 
mechanisms. J Pathol. 2014;232:289-299 
xii Chen MF, Chen WC, Lai CH, Hung CH, Liu KC, Cheng YH. Predictive factors of radiation-induced skin toxicity 
in breast cancer patients. BMC cancer. 2010;10:508 
xiii Hymes SR, Strom EA, Fife C. Radiation dermatitis: Clinical presentation, pathophysiology, and treatment 2006. 
Journal of the American Academy of Dermatology. 2006;54:28-46 
xiv Meyer F, Fortin A, Wang CS, Liu G, Bairati I. Predictors of severe acute and late toxicities in patients with 
localized head-and-neck cancer treated with radiation therapy. International journal of radiation oncology, biology, 
physics. 2012;82:1454-1462 
xv Chen YP, Tsang NM, Tseng CK, Lin SY. Causes of interruption of radiotherapy in nasopharyngeal carcinoma 
patients in taiwan. Japanese journal of clinical oncology. 2000;30:230-234 
xvi McCloskey SA, Jaggernauth W, Rigual NR, Hicks WL, Jr., Popat SR, Sullivan M, Mashtare TL, Jr., Khan MK, 
Loree TR, Singh AK. Radiation treatment interruptions greater than one week and low hemoglobin levels (12 g/dl) 
are predictors of local regional failure after definitive concurrent chemotherapy and intensity-modulated radiation 
therapy for squamous cell carcinoma of the head and neck. American journal of clinical oncology. 2009;32:587-591 
xvii Putora PM, Schmuecking M, Aebersold D, Plasswilm L. Compensability index for compensation radiotherapy 
after treatment interruptions. Radiation oncology. 2012;7:208 
xviii Sitton E. Early and late radiation-induced skin alterations. Part ii: Nursing care of irradiated skin. Oncology 
nursing forum. 1992;19:907-912 
xix Macmillan MS, Wells M, MacBride S, Raab GM, Munro A, MacDougall H. Randomized comparison of dry 
dressings versus hydrogel in management of radiation-induced moist desquamation. International journal of 
radiation oncology, biology, physics. 2007;68:864-872 
xx Bostrom A, Lindman H, Swartling C, Berne B, Bergh J. Potent corticosteroid cream (mometasone furoate) 
significantly reduces acute radiation dermatitis: Results from a double-blind, randomized study. Radiotherapy and 
oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2001;59:257-265 
xxi Ulff E, Maroti M, Serup J, Falkmer U. A potent steroid cream is superior to emollients in reducing acute radiation 
dermatitis in breast cancer patients treated with adjuvant radiotherapy. A randomised study of betamethasone versus 

 
 
H-45698 
 
Page 37 of 37 
 
 
two moisturizing creams. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology 
and Oncology. 2013;108:287-292 
xxii Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, Leiper J, Cooke JP. Unexpected 
effect of proton pump inhibitors: Elevation of the cardiovascular risk factor asymmetric dimethylarginine. 
Circulation. 2013;128:845-853 
xxiii Hirst D, Robson T. Nitric oxide in cancer therapeutics: Interaction with cytotoxic chemotherapy. Current 
pharmaceutical design. 2010;16:411-420 
xxiv Pham, N., Ludwig, M. S., Wang, M., Ebrahimpour, A., Bonnen, M. D., Diwan, A. H., ... & Donovan, D. T. 
(2019). Topical Esomeprazole Mitigates Radiation-Induced Dermal Inflammation and Fibrosis. Radiation 
research, 192(5), 473-482. 
xxv R package BOIN [software on the Internet] 2016 May 29; [cited 2016 May 11]. Available from: https://cran.r-
project.org/web/packages/BOIN/index.html.