Conditions: Mammographically Dense Breast
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 194
Healthy volunteers: yes

Brief summary:
This randomized phase II trial studies how well afimoxifene works in reducing the risk of breast cancer in women with mammographically dense breast. Estrogen can cause the growth of breast cancer cells. Hormone therapy using afimoxifene may fight breast cancer by blocking the use of estrogen by the tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate and compare the percent change in mammographic breast density (using Cumulus software) from baseline to month 12 in women applying 4mg afimoxifene (4-hydroxytamoxifen \[4-OHT\]) gel per breast versus placebo.

SECONDARY OBJECTIVES:

I. To compare the Cumulus versus (vs.) Volpara breast density measurement methods to estimate percent change in mammographic breast density from baseline to month 12 in women applying 4mg of 4-OHT gel per breast vs. placebo.

II. To compare the percentage of women who underwent a change in Breast Imaging Reporting and Data System (BIRADS) category, comparing pre-and post- treatment measurements, for recipients of active agent versus placebo.

III. To estimate percentage of women with \>= 10% absolute decrease in quantitative mammographic density percentage between baseline and 12 months, comparing between treated group 4mg per breast 4-OHT gel to placebo.

IV. To describe symptoms assessed by breast cancer prevention trial (BCPT) eight symptom scale (BESS) questionnaire and laboratory toxicity assessment (factor VIII \[F VIII\], Von Willebrand \[vWB\] factor, sex hormone-binding globulin \[SHBG\], lipid profile).

V. To evaluate serum measurements of 4-OHT and related metabolite levels and factors related to tamoxifen exposures, such as insulin-like growth factor (IGF) pathway members, C-reactive protein (CRP), estradiol.

VI. To evaluate tissue biomarkers (among women undergoing optional pre- and post-treatment biopsies): terminal duct lobular unit (TDLU) involution; collagen structural changes; SETER/PR index: estrogen related transcription, Ki-67, COX-2, p16, CD68.

VII. To examine whether any reductions in mammographic density seen after 1 year of 4-OHT vs. placebo gel application persist at 24 months, one year after gel application has stopped.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients apply placebo gel topically to each breast once daily (QD) for up to 52 weeks.

ARM B: Patients apply afimoxifene gel topically to each breast QD for up to 52 weeks.

After completion of study treatment, patients are followed up at 24 months.

Arms:
arm 1: Patients apply placebo gel topically to each breast QD for up to 52 weeks. arm 2: Patients apply afimoxifene gel topically to each breast QD for up to 52 weeks.

Interventions: intervention 1: Afimoxifene intervention 2: Laboratory Biomarker Analysis intervention 3: Placebo intervention 4: Questionnaire Administration
Intervention descriptions: intervention 1: Applied topically intervention 2: Correlative studies intervention 3: Applied topically intervention 4: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
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COVER PAGE 
DCP Protocol #: 
MDA2016-07-02 
Local Protocol #: MDACC: 2017-0328; DFCI: 17-745; Moffitt: MCC 19296; NWU: STU00205571; 
University of Arizona Cancer Center: 1908915872; University of Minnesota: 
00004641; University of Wisconsin: 2019-0861.  
A Randomized, Double-blind, Placebo-controlled Study of 4-hydroxytamoxifen Topical Gel in 
Women with Mammographically Dense Breast 
Consortium Name: 
University of Texas MD Anderson Early Phase Clinical Research 
Consortium 
Name of Consortium Principal 
Powel H. Brown, MD, PhD 
Investigator: 
Professor and Chair, Department of Clinical Cancer Prevention 
University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 1360 
Houston, TX 77030-4009 
Telephone: (713) 792-4509 
Fax: (713) 794-4679 
phbrown@mdanderson.org 
MD Anderson Consortium 
Lana A. Vornik, MHA, MS 
Administrative Director: 
Director, Research Planning and Development 
Department of Clinical Cancer Prevention 
University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 1360 
Houston, TX 77030-4009 
Telephone: (713) 792-9594 
Fax: (713) 745-4230 
lavornik@mdanderson.org 
Organization Name: 
University of Texas MD Anderson Cancer Center 
Protocol Principal Investigator: 
Banu Arun, M.D. 
Professor 
Department of Breast Medical Oncology 
1515 Holcombe Blvd. 
Unit 1354 
Houston, TX  77030 
Telephone: (713) 792-2817 
Fax: (713) 563-0910 
barun@mdanderson.org 
Investigator: 
Marion E. Scoggins, M.D. 
Associate Professor 
Diagnostic Radiology 
1515 Holcombe Blvd. 
Unit 1350 
Houston, TX 77030 
Telephone: (713) 792-3337 
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Fax: (713) 563-9779 
MEScoggins@mdanderson.org  
 
Organization:  
 
Dana Farber Cancer Institute 
Investigator: 
 
Judy E. Garber, MD, MPH 
 
 
Medical Oncology 
 
 
450 Brookline Ave  
 
 
Boston, MA 02215  
 
 
Telephone: (617) 632-5770  
 
 
Fax: (617) 632-4088 
 
 
Judy_Garber@dfci.harvard.edu  
 
Investigator: 
Sughra Raza, M.D. 
Physician 
Brigham & Women’s Hospital 
Department of Radiology 
75 Francis St. 
Boston, MA 02115 
Telephone: (617) 732-6269 
Fax: (617) 713-3023 
sraza1@partners.org 
 
Organization  
Moffitt Cancer Center, University of South Florida 
Investigator:  
Nagi B. Kumar, Ph.D., R.D., FADA 
Cancer Epidemiology 
12902 Magnolia Drive  
Tampa, FL 33612  
Tel (813) 745-6885  
Fax (813) 745-7183  
nagi.kumar@moffitt.org  
 
Investigator: 
Richard Roetzheim, MD, MSPH 
Senior Member, Cancer Epidemiology Program &  
Breast Oncology Department 
Moffitt Cancer Center 
Professor, Family Medicine,  
University of South Florida 
Richard.Roetzheim@moffitt.org  
Phone: (813)-745-4673 
 
 
Investigator: 
John Heine, PhD 
Cancer Epidemiology Program / Physicist / Breast Imaging 
12902 Magnolia Drive 
Tampa, FL 33612 
Tel: (813) 745-6719 
Fax: (813) 745-6525 
John.Heine@moffitt.org  
 
 
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Investigator: 
Bethany Niell, MD, PhD 
Department of Diagnostic Imaging 
12902 Magnolia Drive 
Tampa, FL 33612 
Tel: (813) 745-4183 
Fax: (813) 745-5762 
Bethany.niell@moffitt.org  
 
Organization:  
Northwestern University 
Investigator:  
Seema Khan, MD 
Surgery, Breast Surgery Division; Feinberg School of Medicine 
303 East Superior, Lurie 4th floor 
Chicago, IL 60611 
Tel 312 503-4236 
s-khan2@northwestern.edu 
 
Investigator:  
Sandra S Rao, MD 
Department of Radiology 
676 N. St. Clair, Suite 800 
Chicago, IL. 60611 
Tel: (312) 472-0436 
Fax: (312) 472-0480 
Sandra.Rao@nm.org  
 
Organization:  
University of Arizona Cancer Center 
Investigator:  
Pavani Chalasani, MD, MPH 
Department of Medicine 
1515 N Campbell Ave, PO Box 245024 
Tucson, AZ 85724 
Tel: (520) 626-0191 
Fax: (520) 626-2225 
PChalasani@uacc.arizona.edu  
 
Investigator:  
Kimberly Fitzpatrick, MD 
Department of Radiology 
4291 N Campbell Ave 
Tucson, AZ 85719 
Tel: (520) 694-8217 
kfitzpat@radiology.arizona.edu  
 
Organization:  
 
University of Minnesota 
Investigator: 
 
Heather C Beckwith, MD 
Department of Hematology, Oncology and Transplant 
420 Delaware St SE 
MMC 480 Mayo  
8480A  
Minneapolis, MN 55455 
Telephone: (612) 625-4918 
Fax: (612) 625-6919 
einho003@umn.edu  
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Jessica E Kuehn-Hajder, MD 
Department of Radiology 
420 Delaware St SE 
MMC 292 Mayo 
8292A  
Minneapolis, MN 55455 
Telephone: (612) 626-4510 
Fax: (612) 642-3188 
kueh0094@umn.edu 
 
Organization:  
University of Wisconsin 
Investigator:  
Lee G. Wilke, MD 
Department of Surgery 
600 Highland Ave, K3/705 
Madison, WI 53792 
Tel: (608) 263-1164 
Fax: (608) 252-0942 
wilke@surgery.wisc.edu  
 
Investigator:  
Amy Fowler, MD, PhD 
Department of Radiology 
600 Highland Ave, MC-3252 
Madison, WI 53792-3252 
Phone: (608) 262-9186 
Email: afowler@uwhealth.org 
 
Organization:  
National Cancer Institute * 
Investigator:  
Gretchen Gierach, PhD, MPH 
Investigator, Metabolic Epidemiology Branch 
Division of Epidemiology and Genetics 
9609 Medical Center Drive, Rm. 7-E108, MSC 9774 
Bethesda, MD 20892-9774 
Phone:  (240) 276-7299 
Fax:  (240) 276-7838 
gierachg@mail.nih.gov  
 
Medical Monitor 
 
Marjorie Perloff, MD 
Chemopreventive Agent Development Research Group 
Division of Cancer Prevention 
9609 Medical, Rm 5E544 
Rockville, MD 200850 
Office Tel (240)276-7097 
Cell (240)731-1772 
FAX (240)276-7847 
Email: perloffm@mail.nih.gov  
 
Scientific Monitor: 
 
Brandy Heckman-Stoddard, PhD, MPH 
 
 
Breast and Gynecologic Cancer Research Group 
 
 
Division of Cancer Prevention 
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9609 Medical Center Dr. 
 
 
Bethesda, MD 20892-9783 
 
 
Phone number: (240)276-7048 
 
 
Fax number: (240)276-7828 
 
 
Email: heckmanbm@mail.nih.gov  
 
Organization: 
 
University of Texas MD Anderson Cancer Center 
Statistician: 
 
J. Jack Lee, Ph.D. 
 
 
1515 Holcombe Boulevard, Unit 447 
Houston, TX 77230 
 
 
Telephone: (713) 794-4158 
 
 
Fax: (713) 563-4242 
 
jjlee@mdanderson.org  
 
* Non-Accruing; mammographic images review only 
 
 
IND Sponsor:  
BHR Pharma, LLC  
 
IND#  
 
# 59,081 
 
Agent(s)/Supplier: 
4-hydroxytamoxifen gel/ BHR Pharma, LLC 
 
NCI Contract # 
HHSN261201200034I 
 
Protocol Version Date: 10/20/2022 
 
Protocol Revision or   
Amendment #  
Version 20 
 
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SCHEMA 
 
A Randomized, Double-blind, Placebo-controlled Study of 4-hydroxytamoxifen Topical Gel in Women with 
Mammographically Dense Breast 
 
 
Women age 40-69 years, or less than 40 years if Gail risk is greater than 1.66%. 
All participants will have mammographically dense breast (heterogeneously dense or extremely dense based on 
ACR BIRADS 4th or 5th edition classification) 
 
 
Baseline measures: Mammographic density and eligibility labs, BESS2 questionnaire, 4-OHT1 metabolites, research 
labs: estradiol, IGF3 related markers, CRP4, SHBG5, vWB6 Factor, Factor VIII, lipid profile 
Optional breast biopsy: Tissue biomarkers: 4-OHT1 metabolites, TDLU7 involution, collagen structural changes, 
estrogen related transcription (SET index), Ki-67, COX-2, p16, CD68 
 
 
Randomization 1:1  
Stratified by study site and baseline breast density (heterogeneously dense (C) or extremely dense (D)) 
 
 
Intervention: 2mg per breast topical 4-OHT gel versus topical placebo gel applied to both breasts per day for 12 
months 
 
Phone call at Day 7-14 and at Month 3; 
Clinic visit at 6 months (May be a telephone visit for participants affected by COVID-19 closures);  
Phone call at Month 9  
 
 
Final clinic visit at 12 months  
(For participants affected by COVID-19 closures - Month 12 visit will be conducted by telephone. Participants will 
be reconsented for extended gel application with mammogram performed within 6 months) 
 
Optional breast biopsy (For participants affected by COVID-19 closures can occur at the time of the final 
mammogram if gel application was extended) 
 
 
Post-intervention follow-up at 24 months (up to 32 months for participants affected by COVID-19 closures): 
standard of care bilateral mammogram 
 
Primary endpoint:  To estimate and compare the percent change in mammographic breast density (using Cumulus software) from baseline to Month 
12 [or Month 13-18 under the COVID-19 Contingency Plan] in women applying 2mg 4-OHT gel per breast versus placebo based on tomosynthesis 
imaging using the 2D synthetic image. 
 
Secondary endpoints:  
1. To estimate and compare the percent change in mammographic breast density (using Volpara) from Baseline to Month 12 in women applying 
2mg 4-OHT gel per breast versus placebo.  
2. To estimate and compare the percent change in mammographic breast density (using LIBRA) from Baseline to Month 12 in women applying 
2mg 4-OHT gel per breast versus placebo.  
3. To compare the percentage of women who underwent a change in BIRADS category, comparing pre-and post- treatment measurements, for 
recipients of active agent versus placebo.  
4. To conduct subgroup analyses including BIRAD category, menopausal status, cup size, and total breast volume. 
5. To estimate percentage of women with ≥ 10% absolute decrease in quantitative mammographic density percentage between baseline and 12 
months, comparing between treated group 2mg per breast 4-OHT gel to placebo based on Cumulus method.  
6. To describe symptoms assessed by BCPT Eight Symptom Scale (BESS) questionnaire and laboratory toxicity assessment (Factor VIII (F VIII), 
Von Willebrand (vWB) factor, Sex Hormone-Binding Globulin (SHBG), lipid profile). 
7. To evaluate plasma measurements of 4-OHT and related metabolite levels and factors related to tamoxifen exposure. 
8. To evaluate tissue measurements of 4-OHT and related metabolite levels and factors related to tamoxifen exposure. 
 
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Exploratory endpoints:  
1. To compare the Cumulus vs. Volpara vs. LIBRA breast density measurement methods to estimate percent change in mammographic breast 
density from baseline to Month 12 in women applying 2mg of 4-OHT gel per breast vs. placebo. 
2. To perform correlation of drug concentrations in the plasma and the tissue. 
3. To evaluate plasma measurements of Insulin-like growth factor (IGF) pathway members, C-reactive protein (CRP), and estradiol. 
4. To compare the 2D natural vs. 2D synthetic breast density measurement using the Cumulus method to estimate percent change in mammographic 
breast density from baseline to Month 12 in women applying 2mg of 4-OHT gel per breast vs. placebo. 
5. To evaluate tissue biomarkers (among women undergoing optional pre- and post-treatment biopsies): 
Terminal duct lobular unit (TDLU) Involution  
Collagen structural changes  
SETER/PR index: estrogen related transcription 
Ki-67, COX-2, p16, CD68.  
6. To examine whether any reductions in mammographic density seen after 1 year of 4-OHT vs. placebo gel application persist at 24 months (or 
longer under the COVID-19 Contingency Plan), one year after gel application has stopped. 
 
1 4-hydroxytamoxifen (4-OHT), 2 BCPT Eight Symptom Scale (BESS), 3Insulin-like growth factor (IGF), 4 C-reactive protein (CRP+), 5 Sex 
hormone-binding globulin (SHBG), 6 Von Willebrand factor (vWB), 7 Terminal duct lobular unit (TDLU)  
 
 
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TABLE OF CONTENTS 
 
COVER PAGE.............................................................................................................................................. 1 
SCHEMA ...................................................................................................................................................... 6 
1. 
OBJECTIVES ................................................................................................................................... 10 
1.1 
Primary Objectives .................................................................................................................................... 10 
1.2 
Secondary Objectives ................................................................................................................................ 10 
1.3 
Exploratory Objectives .............................................................................................................................. 10 
2. 
BACKGROUND............................................................................................................................... 11 
2.1 
Breast Cancer Risk Reduction ................................................................................................................... 11 
2.2 
Study Agent ............................................................................................................................................... 11 
2.3 
Rationale for Study Agent and Primary Endpoint Marker ......................................................................... 11 
3. 
SUMMARY OF STUDY PLAN ...................................................................................................... 16 
4. 
PARTICIPANT SELECTION .......................................................................................................... 17 
4.1 
Inclusion Criteria ....................................................................................................................................... 17 
4.2 
Exclusion Criteria ...................................................................................................................................... 18 
4.3 
Inclusion of Women and Minorities .......................................................................................................... 18 
4.4 
Recruitment and Retention Plan ................................................................................................................ 18 
5. 
AGENT ADMINISTRATION .......................................................................................................... 19 
5.1 
Dose Regimen and Dose Groups/Gel Application..................................................................................... 19 
5.2 
Run-in Procedures ..................................................................................................................................... 19 
5.3 
Contraindications ....................................................................................................................................... 19 
5.4 
Concomitant Medications .......................................................................................................................... 20 
5.5 
Dose Modification ..................................................................................................................................... 20 
5.6 
Adherence/Compliance .............................................................................................................................. 20 
6. 
PHARMACEUTICAL INFORMATION ......................................................................................... 20 
6.1 
Study Agent (IND # 59,081, BHR Pharma, LLC) ..................................................................................... 20 
6.2 
Reported Adverse Events and Potential Risks ........................................................................................... 21 
6.3  
Availability ................................................................................................................................................ 22 
6.4 
Agent Distribution ..................................................................................................................................... 22 
6.5  
Agent Accountability ................................................................................................................................. 22 
6.6 
Packaging and Labeling ............................................................................................................................. 23 
6.7 
Storage ....................................................................................................................................................... 23 
6.8 
Registration/Randomization ...................................................................................................................... 23 
6.9 
Blinding and Unblinding Methods ............................................................................................................. 24 
6.10 Agent Destruction/Disposal ....................................................................................................................... 25 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ...................................................................... 26 
7.1 
Schedule of Events .................................................................................................................................... 26 
7.2 
Baseline Testing/Prestudy Evaluation ....................................................................................................... 30 
7.3 
Evaluation During Study Intervention ....................................................................................................... 32 
7.4 
Evaluation at Completion of Study Intervention ....................................................................................... 33 
7.5 
Post-intervention Follow-up Period ........................................................................................................... 33 
7.6 
Methods for Clinical Procedures ............................................................................................................... 36 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION............................................... 36 
8.1 
Primary Endpoint ....................................................................................................................................... 36 
8.2 
Secondary Endpoints ................................................................................................................................. 36 
8.3 
Exploratory Endpoints ............................................................................................................................... 37 
8.4 
Off-Agent Criteria ..................................................................................................................................... 38 
8.5 
Off-Study Criteria ...................................................................................................................................... 38 
8.6 
Study Termination ..................................................................................................................................... 38 
9. 
CORRELATIVE/SPECIAL STUDIES ............................................................................................ 38 
9.1 
Rationale for Methodology Selection ........................................................................................................ 38 
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9.2 
Comparable Methods ................................................................................................................................. 39 
10. 
SPECIMEN MANAGEMENT ......................................................................................................... 39 
10.1 Laboratories ............................................................................................................................................... 39 
10.2 Collection and Handling Procedures ......................................................................................................... 39 
10.3 Shipping Instructions ................................................................................................................................. 41 
10.4 Tissue Banking .......................................................................................................................................... 41 
11. 
REPORTING ADVERSE EVENTS ................................................................................................. 42 
11.1 Adverse Events .......................................................................................................................................... 42 
11.2 Serious Adverse Events ............................................................................................................................. 43 
12. 
STUDY MONITORING ................................................................................................................... 45 
12.1 Data Management ...................................................................................................................................... 45 
12.2 Case Report Forms .................................................................................................................................... 45 
12.3 Source Documents ..................................................................................................................................... 45 
12.4 Data and Safety Monitoring Plan ............................................................................................................... 46 
12.5 Sponsor or FDA Monitoring ...................................................................................................................... 46 
12.6 Record Retention ....................................................................................................................................... 46 
12.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ......... 47 
13. 
STATISTICAL CONSIDERATIONS .............................................................................................. 48 
13.1 Study Design/Description .......................................................................................................................... 48 
13.2 Randomization/Stratification ..................................................................................................................... 48 
13.3 Accrual and Feasibility .............................................................................................................................. 49 
13.4 Primary Objective, Endpoint(s), Analysis Plan ......................................................................................... 49 
13.5 Secondary Objectives, Endpoints, Analysis Plans ..................................................................................... 50 
13.6 Reporting and Exclusions .......................................................................................................................... 52 
13.7 Evaluation of Toxicity ............................................................................................................................... 52 
13.8 Evaluation of Response ............................................................................................................................. 52 
13.9 Interim Analysis......................................................................................................................................... 53 
13.10 Ancillary Studies ....................................................................................................................................... 53 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................ 53 
14.1 Form FDA 1572 ......................................................................................................................................... 53 
14.2 Other Required Documents ....................................................................................................................... 53 
14.3 Institutional Review Board Approval ........................................................................................................ 54 
14.4 Informed Consent ...................................................................................................................................... 54 
14.5 Submission of Regulatory Documents ....................................................................................................... 54 
14.6 Other .......................................................................................................................................................... 55 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE ...................................................................... 55 
REFERENCES ........................................................................................................................................... 56 
 
APPENDIX A: Performance Status Criteria 
APPENDIX B: Gel Application Instructions 
APPENDIX C: Compliance Drug Labels 
APPENDIX D: 4-OHT Diary 
APPENDIX E:  BESS Questionnaire 
APPENDIX F: Alcohol and Tobacco Use Assessment Questionnaires – Baseline 
APPENDIX G: Alcohol and Tobacco Use Assessment Questionnaires – Month 12 
APPENDIX H: Resources for tobacco and alcohol quitting 
APPENDIX I: Specimen Inventory Form 
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1. 
OBJECTIVES 
 
The overall objective is to evaluate whether daily application of 2mg (2mL) per breast of 4- 
hydroxytamoxifen (4-OHT) topical gel versus placebo lowers breast density in women with 
mammographically dense breast, based on the intent-to-treat principle, i.e., all participants who have MD 
measurements from both baseline and 52 weeks, regardless of compliance, will be included in the primary 
analysis. 
 
 
1.1 
Primary Objectives  
 
To estimate and compare the percent change in mammographic breast density (using Cumulus software) 
from baseline to Month 12 [or Month 13-18 under the COVID-19 Contingency Plan] in women applying 
2mg 4-OHT gel per breast versus placebo based on tomosynthesis imaging using the 2D synthetic image.  
 
1.2 
Secondary Objectives  
 
Note: data from Month 13-18 visit instead of Month 12 will be used if participants were seen under the 
COVID-19 Contingency Plan. 
 
1. To estimate and compare the percent change in mammographic breast density (using Volpara) 
from Baseline to Month 12 in women applying 2mg 4-OHT gel per breast versus placebo.  
2. To estimate and compare the percent change in mammographic breast density (using LIBRA) 
from Baseline to Month 12 in women applying 2mg 4-OHT gel per breast versus placebo.  
3. To compare the percentage of women who underwent a change in BIRADS category, 
comparing pre-and post- treatment measurements, for recipients of active agent versus placebo.  
4. To conduct subgroup analyses including BIRAD category, menopausal status, cup size, and 
total breast volume. 
5. To estimate percentage of women with ≥ 10% absolute decrease in quantitative mammographic 
density percentage between baseline and 12 months, comparing between treated group 2mg 
per breast 4-OHT gel to placebo based on Cumulus method.  
6. To describe symptoms assessed by BCPT Eight Symptom Scale (BESS) questionnaire and 
laboratory toxicity assessment (Factor VIII (F VIII), Von Willebrand (vWB) factor, Sex 
Hormone-Binding Globulin (SHBG), lipid profile). 
7. To evaluate plasma measurements of 4-OHT and related metabolite levels and factors related 
to tamoxifen exposure. 
8. To evaluate tissue measurements of 4-OHT and related metabolite levels and factors related to 
tamoxifen exposure. 
 
1.3 
Exploratory Objectives  
 
1. To compare the Cumulus vs. Volpara vs. LIBRA breast density measurement methods to 
estimate percent change in mammographic breast density from baseline to Month 12 in women 
applying 2mg of 4-OHT gel per breast vs. placebo. 
2. To perform correlation of drug concentrations in the plasma and the tissue. 
3. To evaluate plasma measurements of Insulin-like growth factor (IGF) pathway members, C-
reactive protein (CRP), and estradiol. 
4. To compare the 2D natural vs. 2D synthetic breast density measurement using the Cumulus 
method to estimate percent change in mammographic breast density from baseline to Month 
12 in women applying 2mg of 4-OHT gel per breast vs. placebo. 
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5. To evaluate tissue biomarkers (among women undergoing optional pre- and post-treatment 
biopsies): 
Terminal duct lobular unit (TDLU) Involution  
Collagen structural changes  
SETER/PR index: estrogen related transcription 
Ki-67, COX-2, p16, CD68.  
6. To examine whether any reductions in mammographic density seen after 1 year of 4-OHT vs. 
placebo gel application persist at 24 months (or longer under the COVID-19 Contingency 
Plan), one year after gel application has stopped. 
 
 
2. 
BACKGROUND 
 
2.1 
Breast Cancer Risk Reduction 
 
Tamoxifen oral tablet at 20 mg/day for 5 years is currently FDA approved for the use of breast cancer risk 
reduction. However, despite the known fact that it can reduce breast cancer risk by 50%, less than 20% of 
high risk women choose to take Tamoxifen for risk reduction; mostly because of the low, but still slight 
increased risk of endometrial cancer, thromboembolic events (TEE), arthralgia and menopausal side effects 
(hot flushes, weight gain, hair thinning).  These systemic side effects unfortunately cause underutilization 
of this effective breast cancer chemoprevention agent. One approach to improve the benefit/ risk ratio might 
be to consider an innovative way to administer the agent where the preventive effects remains, but systemic 
side effects are not present (or minimal).  
 
 
2.2 
Study Agent 
 
4- hydroxytamoxifen topical gel ( 4-OHT gel) is a local (breast) transdermal administered agent and has 
been initially evaluated in clinical trials for cyclical breast pain and has been shown to be well tolerated 1  
Further, 4-OHT and oral tamoxifen was studied in the neoadjuvant setting in 55 patients with invasive 
breast cancer; Ki-67 decreased with both applications (gel and oral) 2.   In a very recent study, funded 
through the NCI-DCP-Prevention Consortium; a regimen of 6-10 weeks of 4-OHT gel at 4mg/day was 
compared to 20 mg/day oral tamoxifen in patients with ductal carcinoma in situ 3. Compared with oral 
tamoxifen, a recent DCP sponsored study found that 4-OHT gel did not result in statistically significantly 
lower breast parenchymal drug concentrations or reductions in Ki-67. Furthermore, risk factors for TEE 
increased in the oral Tamoxifen group, but not in the 4-OHT gel group (factor VIII, von Willebrand factor 
and SHBG). While the toxicity profile is safer, it will be also important to show that the gel form achieves 
the ultimate desired endpoint; reduction in breast cancer incidence. Currently, there are no prospective 
studies evaluating the preventive effect of 4-OHT gel in high risk women.  Therefore, a pilot study 
evaluating 4-OHTs effect in breast tissue of high risk women is needed. However, such a study would 
ideally require a validated risk marker. 
 
 
2.3 
Rationale for Study Agent and Primary Endpoint Marker 
 
Mammographic density (MD) is one of the strongest independent predictors of breast cancer risk among 
women, apart from older age and BRCA1/2 mutation 4. It is estimated that women with the highest MD 
have a two- to sixfold increased risk of developing breast cancer 5.  MD is determined by the differential 
ability of X-rays to permeate the different cell types and components of human breast tissue. In this regard, 
there are two main components of the breast: fibroglandular tissue and adipose tissue. Mammographically 
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dense breast tissue represents fibroglandular breast tissue, which includes the epithelial ducts and glands as 
well as interlobular connective tissue.  In contrast, adipose tissue easily allows passage of x-rays, yielding 
low density on a mammogram MD is heavily influenced and inversely proportional to age, reflecting the 
relative decrease in glandular breast tissue and increase in fatty breast tissue associated with aging 6. A 
recent meta-analysis of 42 studies evaluating MD and breast cancer risk showed no differences observed 
by age/menopausal status at mammography or by ethnicity, however significantly and progressively 
increasing risk parallel to increasing MD among women undergoing mammographic screening 7.  
 
Studies of tamoxifen in the adjuvant and preventive setting have demonstrated that a decline in MD of 
approximately 10% is consistently associated with better outcomes 8, 9. In a case-control analysis nested 
within the IBIS-I breast cancer prevention trial, Cuzick et al., observed that approximately 46% of 
tamoxifen-treated women experienced a ≥10% reduction in MD at 12−18 months and these women had a 
63% reduction in breast cancer risk (odds ratio [OR] =0.37, 95% confidence interval [CI] =0.20‒0.69, 
p=0.002) as compared with all women on placebo (regardless of MD) 8. In contrast, tamoxifen-treated 
women with <10% reduction in MD did not experience risk reduction compared to all women on placebo 
(OR=1.13, 95% CI 0.72‒1.77, p=0.60).  Further, several other retrospective analyses have reported that 
among women with ER-positive breast cancer treated with tamoxifen, those whose MD declined in the 
unaffected breast 10, 11, 12, had better outcomes (reduced risk of recurrence 10, 13 or death from breast cancer 
11, 12). In contrast, other agents that have shown chemopreventive efficacy, including raloxifene and 
exemestane, have not been reported to consistently reduce MD 14.  
 
The original corporate sponsor completed a 6-month study of 4-OHT gel for breast density reduction using 
0.05% (w/v) 4-OHT, a less concentrated gel than currently available (0.2% (w/v) gel). Though overall 
results of this study were nonsignificant, post-hoc analysis of patients with baseline breast density ≥80% 
(n=19; 4-OHT=9; placebo=10) revealed a −4% vs. a +0.7% (p=0.024) change in baseline density following 
6 months of treatment for 4-OHT gel 1mg/d per breast vs. placebo, respectively (source NCI TORF FF-
2015 document). 
 
Taken together, changes in MD would be an ideal “biomarker” to be evaluated as the primary endpoint in 
this short-term prevention using 4-OHT gel in high risk women.  The duration of 12 months was chosen 
because most studies referenced above reported mammographic data at least 12 months. 
 
Preliminary information gained from this study will enable us to plan a prospective, large, national study 
using 4-OHT gel for breast cancer risk reduction that can be easily performed not only at academic but also 
non-academic institutions.  Therefore, it is very important that we choose endpoints that are validated, easily 
measurable and do not require special and expensive technology. This future possibility was already 
discussed with and is supported and welcomed by the SWOG Cancer Prevention and Epidemiology Group.  
 
Potential Surrogate Biomarkers 
This study will also enable us to evaluate other potential surrogate biomarkers in the context of early phase 
prevention studies. As an exploratory endpoint, our proposed laboratory correlates and biomarkers are 
discussed below: 
 
Tissue Biomarkers  
Overview: Tissue biomarkers have been selected to interrogate the following targets that represent: 
a) Structure-function activity of terminal ductal lobular units (TLDUs) by counting acinar 
density 
b) Breast tissue density by assessing the patterns of collagen matrix 
c) Hormone-mediated cellular activity by measuring the transcriptional expression levels of 
ER-alpha and ER-associated genes (SETER/PR index) 
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d) Pharmacogenomic response to endocrine therapy by measuring Ki67 protein by 
immunohistochemistry and aurora kinase-alpha gene expression  
e) Inflammatory response to 4-OHT therapy by measuring COX2 and p16 proteins, and 
recruitment of CD68 monocytes.  
All biomarkers will be compared in biopsies obtained before and after exposure to the 4-OHT gel, in order 
to explore pharmacodynamic responses of interest. That said, the baseline measures will also be evaluated, 
particularly for items a-c (above) that might be less likely to change in response to short-term exposure, but 
combine to provide the cellular, matrix and targeted molecular context of the tissues in each participant 
prior to exposure to treatment.   
a) TDLU Involution: TDLU involution is characterized by a reduction in the number and size of TDLUs 
and their secretory acinar units  15.  Reduced involution in TDLUs has been associated with increased risk 
of breast cancer in several studies of women with benign breast disease 16, 17. Furthermore, a recent study 
showed that, especially amongst premenopausal women, reduced TDLU involution was associated with 
higher area and volumetric MD; indicating that TDLU involution and MD are correlated markers of breast 
cancer risk. In continuation of this, there is also data suggesting that increased MD and reduced TDLU 
involution are actually independent risk factors for breast cancer 18. Taken all these together, in our proposal, 
as an exploratory endpoint, our aim is to assess TDLU involution, correlate with MD and evaluate whether 
baseline TDLU involution correlates/predicts change in MD induced by 4-OHT gel. The TDLU density 
(acini per TDLU) is readily determined from pathologic review of the same routine H&E stained tissue 
sections that are usually used for diagnosis using image analysis tools for area-based quantitation.  
b) Collagen structural changes: Increased breast density is associated with an increase in the deposition of 
extracellular matrix (ECM) components, especially collagen. Several studies have shown the link between 
breast cancer, breast density and increased deposition of stromal collagen 19, 20.  Interestingly, Keely and 
co-workers have shown in an in vitro model that increasing the density of collagen in the matrix is sufficient 
to disrupt breast epithelial differentiation, suggesting that matrix density is itself an important regulator of 
cellular behavior 21, 22, 23.  Keely et al found evidence for a collagen "signature" of parallel fibril alignment 
that is present even before a tumor is palpable.  This signature could be potentially used to identify high 
risk areas in the breast tissue. These investigators 21 first introduced the tumor associated collagen signature 
(TACS) nomenclature to describe collagen alignment patterns. The TACS phenotypes are currently 
classified into three groups. TACS-1 describes the standard desmoplastic response of increased collagen 
deposition surrounding initiating tumor cells. TACS-2 is observed as straightened fibers aligned 
tangentially around developing tumors, while TAC-3 is seen as radially aligned fibers that facilitate local 
invasion 24. The assessment is based on pattern, rather than intensity, and the authors qualitatively searched 
for these patterns in a tissue microarray of samples from human breast cancers and this exploratory analysis 
suggested that the presence of the TACS-3 collagen alignment pattern in invasive breast cancers may be a 
risk factor or disease free and disease specific survival (DFS and DSS respectively) for patients who had 
ER-positive breast cancer that measured more than 1.35 cm in diameter 25. Clearly, there is risk of statistical 
over fitting to the outcomes, but the observations are intriguing because of the novelty of collagen pattern 
assessments and the known relevance of mammographic breast density to risk of developing ER+ breast 
cancer.  
While increased deposition of stromal collagen is associated with breast density and breast cancer risk, 
there is no data related to collagen structural changes as a predictor to changes in MD induced by 4- OHT 
gel, and it is not known whether the time it takes to remodel collagen fibers (weeks to months in a healing 
wound) would be relevant to a short duration of exposure to the transdermal agent, or whether the existing 
patterns of collagen deposition influence the susceptibility of breast epithelial and stromal cells to this agent. 
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However, an important issue is the method used to evaluate collagen deposition patterns in the biopsies of 
benign breast tissues. Indeed, the high-energy photon transmission that was used in the research literature 
describing TACS collagen patterns is too complicated and distant from routine diagnostic practice to be 
broadly applicable. But the Masson’s trichrome stain is routine, cheap, ubiquitous in pathology labs (for 
example, we use it to assess patterns of early fibrosis in liver biopsies), and can be combined with 
polarization light microscopy to clearly identify the birefringence of aligned collagen fibers (as we 
frequently observe when looking for amyloid proteins). Masson’s trichrome staining of collagen fibers 
would be readily generalizable to diagnostic practice.  
c) SETER/PR index: We have previously published a gene expression index for estrogen receptor-related gene 
expression that was theragnostic for prognosis following endocrine therapy for early (node-negative), and 
following chemo-endocrine therapy for higher-risk (node-positive) hormone receptor-positive and HER2-
negative HR+/HER2- breast cancers.26 However, it is only recently that we have been able to measure the 
SET index from formalin-fixed and paraffin-embedded tumor tissues from residual disease. This SETER/PR 
index measures 18 transcripts that are strongly correlated with both ER and PR expression, and are not 
related to proliferation. The SETER/PR index compares the expression of those 18 transcripts to 10 reference 
transcripts within the assay, and also includes probes to measure the expression levels of ESR1, PGR, 
ERBB2, and AURKA (aurora kinase A) transcripts. The reproducibility of the SETER/PR index exceeds 99% 
across batches and technicians, and the assay is performed on a single 10µm tissue section from FFPE 
blocks of biopsies from breast cancers. We expect that the less cellular samples from benign breast tissues 
would require at least 10 TDLUs (usually obtained from 3 x 10µm sections from core biopsies). 
Furthermore, the SETER/PR index is independently prognostic following endocrine therapy in metastatic 
breast cancer samples, and in primary tumor samples from node-positive or node-negative breast cancers. 
In an exploratory in silico analysis, we observed no change in SET index values measured from sequential 
core biopsies of invasive HR+/HER2- cancers taken before and after a 2-week exposure to neoadjuvant 
endocrine therapy. That result was different from the pharmacodynamic reduction in the proliferation-
related signature of genomic grade index that was reported in the same samples. However, the observed 
stability of the SET index during short-term endocrine therapy might be consistent with a long-term 
treatment that continues to have efficacy over a long time.  Otherwise, rapid suppression would probably 
render the treatment ineffective over the longer term. We do not know whether this will also be the case 
with non-malignant tissues – perhaps shorter-term suppression of endocrine capacity may be possible.  
The SETER/PR index assay is technically feasible using sections from 20-gauge core biopsy samples from 
metastatic sites (2-3 cores), whereas many mammotome core biopsy samples of proliferative benign 
histologic lesions are of 11-gauge or 9-gauge and contain considerably more epithelial tissue. In our limiting 
dilution study using purified RNA, this assay provided accurate measurement down to 30 ng of RNA, and 
that is considerably less than we typically obtain from core biopsy sections. This project will be the first to 
evaluate the SETER/PR index in the setting of endocrine therapy in benign tissues (and is therefore innovative) 
so the rationale is based on the index as a measure of ER-related transcription, a biological process that is 
known to be important in benign breast disease, and is central to the pharmacology of the prevention 
strategy to be tested.  We will also analyze the ratio of fatty/non-fatty tissue. Our analysis will explore two 
hypotheses: i) whether pharmacodynamic responses to exposure of tissues to 4-OHT (e.g. reduction in 
proliferation or TLDU density) will be greater when the tissues have higher SETER/PR index; and ii) whether 
exposure to 4-OH decreases the SETER/PR index.  
 
d) Markers of proliferation and inflammation: Ki-67 has been widely evaluated in previous phase I and II 
prevention trials that have revealed conflicting data 27, 28, 29, 30. In one study, a reduction in Ki-67 was seen 
with 6 months of letrozole therapy; whereas another study did not show any changes with 6 months of 
letrozole therapy28, 27. In another  study of arzoxifene, no changes in Ki-67 were seen 31.  A separate study 
was done in premenopausal women using 12 months of lignans and a reduction in Ki-67 was observed 30. 
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It is possible that the mechanism of action for Ki-67 reduction is different for tamoxifen and indeed a 
reduction in Ki-67 in patients with DCIS has been shown with oral as well as 4-OHT 3. However, the effect 
in breast tissue of high risk women is not known. Therefore, we would like to evaluate changes in Ki-67 
induced by 4-OHT in our study.   
As other exploratory endpoints, we will evaluate changes in COX-2, p16, and CD68 with 4-OHT treatment. 
The inducible COX-2 gene is the master switch that activates the inflammatory response. Induction of 
COX-2 by any inflammatory stimulus (e.g., tobacco, alcohol, ischemia, trauma, pressure, foreign bodies, 
toxins, bacteria, viruses, lipopolysaccharides, etc.) quickly results in the biosynthesis of prostaglandins of 
the E-series, particularly prostaglandin E2 (PGE-2), and these prostaglandins in turn on  the inflammatory 
response 32 . Molecular studies show the role of COX-2 in the progression of breast cancer 33,  and meta-
analysis of epidemiologic studies show impact of selective and non-selective agents that reduce breast 
cancer risk by inhibition of COX-2 34. Currently there is no data evaluating 4-OHT effect on COX-2 
expression in high risk women.  
Among cell cycle check points, p16 serves as a negative regulator of cell cycle 35. An alteration in the cell 
cycle check points is one of the most common abnormalities encountered in the molecular basis of human 
cancer  and unrestricted cellular proliferation due to deregulation of cell cycle is the key feature of 
malignancy.  Altered expressions of p16 and the correlation with clinical and pathologic factors in breast 
cancer have been reported,  mostly showing correlation with poor prognostic features 36. Given its important 
role in breast carcinogenesis, our aim is to evaluate if 4-OHT can reduce expression of p16 in high risk 
breast tissue and whether p16 could serve as a potential surrogate biomarker in future phase I, II prevention 
trials. 
CD68 (marker of Tumor Associated Macrophages: Tumor-associated macrophage (TAM) represent the 
major inflammatory component of the stroma of many tumors, including breast cancer that can express 
several protumoral functions, including secretion of growth factors and matrix-proteases, promotion of 
angiogenesis and suppression of adaptive immunity37.  The protumoral role of TAM in cancer is further 
supported by clinical studies that found a correlation between the high macrophage content of tumors and 
poor patient prognosis and also by evidence showing that long-term use of non-steroidal anti-inflammatory 
drugs reduces the risk of several cancers  37. Currently, there is no data related to the role of TAM related 
inflammation and its reversal with a preventive agent. Therefore, in our current study we will evaluate 
CD68 (marker of TAM) in high risk breast tissue of women treated with 4-OHT. 
Plasma Biomarkers: IGF Pathway: 
Studies have shown that dysregulation of the IGF pathway and an increase in insulin-like growth factor 1 
(IGF-1) can result in increased risk of breast cancer38.  A previous study has shown that 2 months use 
tamoxifen can reduce IGF-1/IGFBP-3 39 and another study showed the same with raloxifene 40 . We have 
previously shown an increase in IGFBP-1 with 6 months use of anastrozole 41. Currently, there is no data 
related to the modulation of the IGF pathway, therefore we aim to study modulation of this pathway induced 
by 4-OHT treatment. 
 
Rationale for including Alcohol and Tobacco Assessment Questionnaires 
Increasing evidence suggests that tobacco and alcohol use are risk factors in the development of 
intraepithelial neoplasia and cancer. In addition, tobacco and alcohol use may adversely affect agent 
intervention, for example by altering the safety profile or metabolism of a drug. Standardized assessments 
of tobacco and alcohol use during clinical trials will aid in understanding the potential relationship between 
the use of these products and clinical endpoints or cancer prevention biomarkers. Therefore, NCI, DCP is 
including assessment of tobacco and alcohol use at baseline and Month 12 to determine the potential impact 
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of tobacco and alcohol use on 1) treatment toxicity and symptom burden, and 2) the efficacy of treatment 
intervention. 
 
In summary, the overall objective is to evaluate whether daily application of 4 mg of 4-OHT topical gel (2 
mg per breast) versus placebo lowers breast density in women with mammographically dense breast.  
 
 
3. 
SUMMARY OF STUDY PLAN 
 
We will conduct a prospective, randomized, double-blind, placebo-controlled phase II study of 4-
hydroxytamoxifen topical gel in women with mammographically dense breast.  
 
Women age 40-69 years, or less than 40 years if Gail risk is greater than 1.66% will be eligible.  All 
participants will have mammographically dense breast (heterogeneously dense or extremely dense based 
on ACR BIRADS 4th or 5th edition classification).   
 
Women with prior annual mammograms showing heterogeneously dense or extremely dense breasts will 
be approached for enrollment into the study prior to their next annual mammogram. Informed consent must 
be obtained prior to starting any further study procedures.  Consenting should be done prior to next annual 
mammogram (the baseline study mammogram).  Once the participant has signed consent, the 
mammography center should be alerted not to delete the raw images. In centers where raw images are 
stored, consent can occur after the annual mammogram that will serve as the baseline mammogram for the 
study.  The mammogram must be within 3 months of randomization.  Raw images must be obtained from 
the Baseline, 12-Months and 24-Months mammograms.  Mammography reports from the previous annual 
mammography visit should also be obtained.  If it is not possible to see a participant in person for the Month 
12 visit during the COVID-19 pandemic, the visit will be rescheduled per the COVID-19 Contingency Plan 
(see Section 7 for details) and mammograms will be rescheduled accordingly and corresponding raw images 
from that mammogram will be obtained.  
 
158 women with confirmed eligibility will be randomized 1:1 to 2 arms. Participants in Arm A will receive 
4-OHT, participants in Arm B will receive placebo. The daily dose of gel application is 4 mg (2 mg per 
breast).  The 4-OHT gel or placebo will be applied topically in 1 pump actuation to each breast. Women 
will undergo baseline toxicity assessment, blood draw and instructions on how to apply the gel and an 
optional breast core biopsy. While women will not be stratified by menstrual cycle (as there is minimal, if 
any, effect of the menstrual cycle on our primary endpoint of mammographic density), their menstrual cycle 
will be recorded.  Randomization will be performed stratified by study site and baseline breast density 
category (heterogeneously dense (C) or extremely dense (D)).  The research nurse/coordinator will call the 
participants at Day 7-14 to verify the start of study agent, and at months 3 and 9 for toxicity assessment. 
The participants will return to the clinic at 6 months for toxicity assessments, physical exam and vital signs, 
lab tests and plasma biomarker blood draws, collection of unused study agent, and to receive additional 
study agent. At 12 months, the participants will return to clinic for toxicity assessment, collection of unused 
study agent, collection of blood for plasma biomarkers, standard of care mammogram, and the optional 
breast core biopsy, if she opted to participate in this part of the study.  At 24 months the research staff will 
collect the standard of care bilateral mammogram images; the participants will not be approached.  For the 
period of the COVID-19 pandemic, if participants cannot be seen in person at Months 6 and/or 12, the 
COVID-19 contingency plan will be followed (see Section 7 for details).  
 
 
 
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4. 
PARTICIPANT SELECTION 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Women age 40-69 years, or less than 40 years if 5-year breast cancer Gail risk is ≥ 1.66%. 
 
4.1.2 
Mammographically dense breast (heterogeneously dense (C) or extremely dense (D), based on 
ACR BIRADS© fifth edition classification or heterogeneously dense (3) or extremely dense (4), 
based on ACR BIRADS© fourth edition classification) in either breast.    
 
4.1.3 
ECOG performance status ≤1 (Karnofsky ≥70%; see Appendix A) 
 
4.1.4 
Participants must have normal organ and marrow function defined as ALL of the below: 
 
White Blood Cells 
≥3,000/microliter 
Platelets 
 
≥100,000/microliter 
Total bilirubin  
≤1.5 × institutional upper limit of normal (ULN) 
AST (SGOT)/ALT (SGPT) 
≤1.5 × institutional upper limit of normal (ULN) 
 
4.1.5 
Participant must have a gynecology examination within the last 5 years (gynecology examination 
is not required if participant had a hysterectomy). 
 
4.1.6 
Premenopausal women using a hormonal or non-hormonal Intra-Uterine Device (IUD) birth 
control method will be eligible, if they have been on the same IUD for at least 3 months prior to 
enrollment and plan to continue using the same method throughout the study.   
 
4.1.7 
Women who are using postmenopausal hormones, and are planning to continue the same regimen 
through the study intervention are eligible to participate.  
 
4.1.8 
Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e. tanning beds) for the 
duration of the study. 
 
4.1.9 
Ability to understand and the willingness to sign a written informed consent document. 
 
 
4.2 
Exclusion Criteria 
 
4.2.1 
History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to 4-OHT gel. 
 
4.2.2 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
thromboembolic disease, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
 
4.2.3 
Pregnant, unwilling to use adequate contraception during study treatment duration, had given birth, 
or nursed at any time during the last 12 months (see footnote 1 below). 
 
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4.2.4 
Women with a previous history of invasive breast cancer or bilateral DCIS or current untreated 
DCIS. Women with a history of cancer within the last 3 years, except for non-melanoma skin 
cancer. Women with unilateral DCIS (with or without radiation therapy) are eligible as long as they 
have an unaffected breast. 
 
4.2.5 
Prior bilateral breast surgery (mastectomy, segmental mastectomy, or breast augmentation surgery 
including breast implants or breast reductions). 
 
4.2.6 
Women with “mosaic mammographic screening views”, i.e., whose larger breast size precludes 
being imaged within a single mammographic screening view. 
 
4.2.7 
Women with active liver disease. 
 
4.2.8 
Women with a uterus and abnormal uterine bleeding, or prior diagnosis of endometrial 
hyperplasia, endometrial polyps, or endometrial cancer. 
 
4.2.9 
Prior use of SERMS and AIs, except for a maximum of 3 months and at least 12 months prior. 
 
4.2.10 Skin lesions on the breast that disrupt the stratum corneum (e.g., eczema, ulceration). 
 
4.2.11 Treatment with any investigational drug or investigational biologic within 30 days of initiating 
study treatment or during the study. 
 
1  The effects of 4-OHT gel on the developing human fetus at the recommended dose are unknown. For this reason 
and because tamoxifen is known to be teratogenic, all heterosexually active women who may become pregnant must 
agree to use a reliable non-hormonal contraceptive method or a hormonal IUD during the study and for 2 months 
after completing study medications. Reliable nonhormonal methods of contraception include barrier contraception 
and an Intra-Uterine Device (IUD). Hormonal IUDs are also allowable methods of birth control. [Note: Women 
who had tubal ligation or had a partner who had undergone a vasectomy (and are monogamous) are eligible for the 
study and are not required to use barrier contraception. 
 
 
4.3 
Inclusion of Women and Minorities 
 
Men and women less than 40, unless they have sufficient breast cancer risk that they would be undergoing 
mammography screening, are excluded because these populations are not routinely screened using 
mammography.  Women of all races and ethnic groups are eligible for this trial.   
 
 
4.4 
Recruitment and Retention Plan 
 
Participants will be recruited for enrollment on this trial from mammographic screening units and breast 
clinics at participating institutions, with particular attention to enhancing racial, ethnic and socioeconomic 
diversity. Prior to enrollment, the study will be discussed in detail with the participant, and possible 
toxicities will be presented. The informed consent document will be reviewed with the participant by the 
study physician or other medical staff authorized by the participating institution to obtain Informed Consent. 
To facilitate accrual, information about the trial will be advertised, for example, on the websites of 
participating institutions.   
 
Refer to the study-specific Recruitment and Retention Plan for more details.  
 
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5. 
AGENT ADMINISTRATION 
 
Intervention will be administered on an outpatient basis. Reported AEs and potential risks are described in 
Section 6.2.  
 
 
5.1 
Dose Regimen and Dose Groups/Gel Application 
 
Participants will self-administer the 4-OHT/ placebo gel.  The participants will be instructed to apply the 
gel daily to both breasts, freshly washed, either by washcloth, shower, or bath, preferably in the morning 
(in order to minimize potential transfer to the partner at night). If morning shower is not possible, the 
participant will wash the breasts with a washcloth before gel application, to remove the prior day’s dose. If 
a morning swim is planned, application should be after the swim. No washing or immersion in water should 
occur for at least 4 hours following gel application. The gel should not be used near fire, flame or while 
smoking since it is flammable due to alcohol. Once dry, the gel is no longer flammable. Detailed instructions 
regarding application are in Appendix B and a demonstration of gel application will occur during the 
Randomization visit. A model bust may be used to demonstrate to the patient how to apply the gel if such 
a model is available.  The treated breasts should be covered at all times to avoid transfer to other people 
and protect from natural or artificial sunlight; contact is permitted after the treated area has been washed 
with soap and water and washing is allowable after a minimum of 4 hours post-application. 
 
Each 4-OHT/placebo gel canister will contain ~100 mL gel product and will be metered to dispense 2 mg 
of 4-OHT/placebo gel per pump.  There will be 200 mg of 4-OHT in 100 mL of 4-OHT gel.  Because there 
are 80 reliable doses per canister, each canister will provide 40 days of therapy at 2 mg/day/per breast. 
Daily dose of 4-OHT/placebo gel application is 4 mg (2 mg per breast). Five gel canisters will be given to 
the participant at the time of randomization and should be returned at Month 6 visit. One (1) ml (one 
actuation of the pump) should be applied each day per breast. At Month 6 visit five additional canisters will 
be provided to the participant and the containers provided at the time of randomization will be collected. 
All containers will be collected at the Month 12 visit. 
 
COVID-19 Contingency Plan: 
During the COVID-19 pandemic, if a participant is not able come for an in person visit at Month 6, instruct 
the participant during the phone visit to keep all used canisters and to bring the canisters to the 
next in person clinic visit. Five additional canisters will be provided to the participant (via mail or picked 
up in person).  At Month 12, participants will be telephone consented to extend the gel application and 
instructed to keep using the gel until their mammogram can be rescheduled up to 18 Months. In addition 
they will be provided five additional canisters (via mail or picked up in person) and all canisters will be 
collected at the mammogram visit. 
 
 
5.2 
Run-in Procedures  
N/A 
 
 
5.3 
Contraindications 
 
Participants are to avoid exposure of the treated breast skin to natural or artificial sunlight. This includes 
sunbathing or the use of tanning beds with the breasts exposed. Also, women who have dermatologic 
conditions causing the breakdown of skin in the area of gel application should not use 4-OHT gel.  
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5.4 
Concomitant Medications 
 
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken 
by the participant will be documented on the concomitant medication CRF and will include: 1) start and 
stop date, if known; if unknown, mark “unknown” in the database, 2) dose and route of administration, and 
3) indication.  
 
 
5.5 
Dose Modification 
 
For grade 1-2 toxicities, no dose modifications will be made. If a grade 2 toxicity possibly, probably, or 
definitely related to study drug re-occurs, the gel application will be stopped until the adverse event 
resolves, then full dose will be reintroduced. If the toxicity re-occurs for a 3rd time, the participant will be 
taken off study drug. For grade 3 toxicity possibly, probably, or definitely related to study drug, gel 
application will be stopped until the adverse event resolves, then full dose will be reintroduced. If the 
adverse event re-occurs, the participant will be taken off study drug. Participants experiencing Grade 4 
toxicities of any attribution will be taken off study drug. 
 
 
5.6 
Adherence/Compliance 
 
5.6.1 
The interval from initiation of drug to end of treatment and final mammogram may vary. If a 
participant has used the gel at least 9 months and 75% of days during that interval, she will be 
considered compliant.  
 
5.6.2 
The following method will be used to monitor each participant’s agent compliance: 
1) Participants will be given a 4-OHT diary and instructed to complete an entry each time a dose is 
taken (see Appendix D, 4-OHT diary). 
2) Canisters will be weighed when released and also upon return. 
 
If there are discrepancies between the two measures of compliance, the lower compliance value 
will be used as a conservative estimate of compliance.  If the canister weight is the lower of the two 
compliance values any discarded doses will be considered in the calculation of compliance.  
 
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1 
Study Agent (IND # 59,081, BHR Pharma, LLC)   
 
The study agent, 4-OHT, is being provided as a topical hydroalcoholic gel for transdermal administration 
to the breasts for localized treatment. 4-OHT is a highly active metabolite of tamoxifen, a selective estrogen-
receptor modulator (SERM) which is approved as an oral tablet for the prevention and treatment of estrogen 
receptor positive breast cancer. 4-OHT and its related metabolite, endoxifen, are thought to provide the 
bulk of the pharmacological activity of tamoxifen since they are ~100 times more active than tamoxifen, 
which is now viewed as a prodrug.  
4-OHT (Z:E 1:1 racemic mixture) is provided as a 0.2% (w/v, 200 mg/mL) hydroalcoholic gel in a pump. 
Each pump action expels 1 mL of gel containing 2 mg of 4-OHT. Participants are to be advised to pump 
one time to expel 1 mL of gel for application to each breast for a total daily dose of 4 mg 4-OHT. Gel 
excipients are alcohol (~75%), isopropyl myristate, hydroxypropyl cellulose, and potassium phosphate 
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buffer pH 7. Matching placebo gel is the same composition without 4-OHT. Due to the high concentration 
of alcohol (~75%), participants are advised to not apply the gel while near fire, flame, heat, or while 
smoking; the gel is not flammable once it has dried.   
 
 
6.2 
Reported Adverse Events and Potential Risks 
 
4-OHT has undergone preclinical animal testing to support human clinical studies. In pharmacokinetic (PK) 
and toxicokinetic studies, dermal (topical, rats) and subcutanous (injection, rats and dogs) dosing of 4-OHT 
resulted in dose-proportional increases in drug bioavailability with elimination primarily by the fecal route. 
4-OHT has been evaluated in toxicology studies in rats (dermal, subcutaneous) and dogs (subcutaneous). 
Topical 4-OHT up to 200 g/kg/day was generally well tolerated by rats, while subcutaneous doses of up 
to 150 g/kg/day were well tolerated by dogs. There were no clinical signs of toxicity; however, decreases 
in body weight, reduced uterus and ovary size, and changes in the genital tract were observed. Dermal 
irritation studies in rabbits of 4-OHT vs. placebo gel induced comparable skin reactions, consisting of none 
or slight to moderate edema or erythema, on scarified and non-scarified flanks.  
 
4-OHT was not mutagenic or genotoxic in the Ames test (with and without metabolic activation), the HPRT 
gene mutation assay in Chinese hamster cells, and the in vivo mouse micronucleus test. Additionally, no 
chromosomal abnormalities were seen in human lymphocytes treated with 4-OHT, with or without 
metabolic activation. Consistent with these results, topical 4-OHT was not carcinogenic in rats treated with 
up to 1000 g/kg/day for 101 weeks. Finally, the reproductive toxicity of 4-OHT was evaluated in seven 
studies with rats and three studies with rabbits. Repeated doses of up to 200 g/kg/day of dermal or 
subcutaneous administration of 4-OHT were well tolerated by rats and rabbits. High doses of topical 4-
OHT led to impaired female fertility and retardation in fetal body weight, increased incidence of 
resorptions, and wavy ribs in some fetuses.  
 
Topical 4-OHT in alcohol solution or gel has been administered to >450 pre- and postmenopausal women. 
In phase 1 safety and PK studies, topical 4-OHT was provided to women at doses ranging from 0.25–1 
mg/breast/day for three weeks up to three months. Topical 4-OHT was well tolerated with only drug-related 
mild pruritus being observed in a few patients. Additionally, topical 4-OHT resulted in substantial breast 
tissue uptake with minimal metabolism and very low systemic plasma concentrations.  
 
Multiple phase 2 pharmacodynamic studies have been completed in pre- and postmenopausal women with 
treatment durations of up to six months and doses up to 4 mg/day. Topical 4-OHT has been shown to be 
well-tolerated, absorbed, and pharmacologically active in breasts for reducing breast pain (mastalgia), 
breast density, and breast cancer cell proliferation in women with ductal carcinoma in situ (DCIS) and 
locally advanced breast cancer. In a placebo-controlled, six-month phase 2 study of 4-OHT topical gel in 
premenopausal women with cyclical breast pain, the most common AEs seen in 4-OHT- vs. placebo-treated 
women (4 mg/day) were: headache (20% vs. 10%), nasopharyngitis (11% vs. 12%), application site reaction 
(4% vs. 0%), and pharyngitis (4% vs. 0%)1. These events were all mild to moderate and some headaches 
and application site reactions (application site burning, itching) were deemed drug-related. Additional drug-
related AEs seen in 4-OHT-treated women were decreased appetite, exfoliative dermatitis, and hypotension. 
No significant changes in hematologic parameters, liver function, renal function, electrolytes, or serum 
glucose were observed. 
 
In a recent NCI, DCP-sponsored presurgical study of women with DCIS, 6–10 weeks of topical 4-OHT gel 
at 4 mg/day (2 mg to each breast) or oral tamoxifen at 20 mg/day resulted in similar 4-OHT breast levels 
and similar reductions in breast tumor cell proliferation3. Systemic levels of 4-OHT were markedly lower 
(five-fold) with topical 4-OHT gel compared with oral tamoxifen. 4-OHT topical gel was well-tolerated 
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and the most common AEs that were either similar or less frequent in 4-OHT- vs. tamoxifen-treated women 
were: hot flush (50% vs. 50%), breast pain (42% vs. 64%), fatigue (33% vs. 29%), and hyperhydrosis (25% 
vs. 43%). Only three AEs were elevated in 4-OHT-treated women compared with tamoxifen-treated 
women: pruritis (17% vs. 0%), vulvovaginal dryness (17% vs. 0%), and weight increased (17% vs. 0%). 
 
 
6.3  
Availability 
 
4-OHT and matching placebo gel are provided by the NCI, DCP Repository. Each gel canister will contain 
~100 mL gel product (200 mg of 4-OHT in 100 mL of gel) and will be metered to dispense 2 mg of active 
agent per pump. Because there are 80 reliable doses per canister, each canister will provide 40 days of 
therapy at 2 mg/day/per breast. Placebo canisters will contain an equal weight of placebo gel.  
 
 
6.4 
Agent Distribution 
 
Agents will only be released by NCI, DCP after documentation of IRB approval of the DCP-approved 
protocol and consent is provided to DCP and the collection of all Essential Documents is complete (see 
DCP website for description of Essential Documents).  
 
NCI, DCP-supplied agents may be requested by the Investigator (or their authorized designees) at each 
Organization. DCP guidelines require that the agent be shipped directly to the institution or site where the 
agent will be prepared and administered. DCP does not permit the transfer of agents between institutions 
(unless prior approval from DCP is obtained). DCP does not automatically ship agents; the site must make 
a request. Agents are requested by completing the DCP Clinical Drug Request form (NIH-986) (to include 
complete shipping contact information) and faxing or mailing the form to the DCP agent repository 
contractor: 
 
John Cookinham 
MRIGlobal 
DCP Repository 
1222 Ozark Street 
North Kansas City, MO 64116 
Phone: (816) 360-3805 
FAX: (816) 753-5359 
Emergency Telephone: (816) 360-3800 
 
 
6.5  
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of 
the inventory and disposition of all agents received from DCP using the NCI Drug Accountability Record 
Form (DARF) or an institutionally-approved accountability system. The Investigator is required to maintain 
adequate records of receipt, dispensing and final disposition of study agent. This responsibility may be 
delegated to the site coordinator, institutional pharmacist or their designees.  Include on receipt record from 
whom the agent was received and to whom study agent was shipped, date, quantity and batch or lot number. 
On dispensing record, note quantities and dates study agent was dispensed to and returned by each 
participant. Drs. Arun, Garber, Khan, Kumar, Chalasani, Beckwith and Wilke or their representatives will 
be responsible for study agent accountability for participants at UT MD Anderson Cancer Center, Dana 
Farber Cancer Institute, Northwestern University and Moffitt Cancer Center, University of Arizona Cancer 
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Center, University of Minnesota, and University of Wisconsin, respectively. DCP requirements for agent 
accountability and the required forms are available on the DCP website.  
 
 
6.6 
Packaging and Labeling 
 
4-OHT will be packaged by the Besins Healthcare, Inc.  Labeling and distribution to the sites will be done 
by NCI, DCP or its authorized designee. 
 
Transdermal 4-OHT or placebo gel will be packaged into canisters.  A dispensing pump system that allows 
the administration of the correct amount of topical gel will be used. Each canister will have a label printed 
with the treatment kit number, volume and concentration of gel, lot number, protocol number and “placebo 
or 4-OHT gel” along with the statement “Caution: New Drug- Limited by Federal law (US) to 
investigational use only”. Detailed instruction for gel application will be provided. Each participant will be 
provided with 5 canisters at initial dispensing, and another 5 canisters at Month 6 Visit. Under the COVID-
19 Contingency Plan 5 additional canisters will be provided at Month 12 (see Section 5.1 for more details).  
 
Canisters will be packaged into kits, 5 canisters per kit. A three-part label will be attached to each kit.  The 
fixed part of the label will remain attached to the kit.  The first tear-off portion of the label (the middle 
portion) will be removed from the kit at the time of dispensing and will be affixed to the Compliance Drug 
Labels form (Appendix C). This portion of the label will be identical to the first portion of the label, except 
that it will contain a scratch off area with the unblinding information should the PI need to be unblinded in 
case of emergency (See Section 6.9).  The second tear-off portion of the label will be removed from the kit 
by the pharmacist at the time of dispensing. This portion of the label will contain unblinded information 
and will be maintained by the pharmacist following institutional guidelines or maybe discarded if this 
portion of the label is not needed for drug accountability purposes due to the use of electronic capture. 
 
Placebo gel will be packaged into canisters for the purpose of demonstration.  These canisters are labeled 
“For demonstration purposes only” and provided to study coordinators to show consented participants 
how to pump the canister and what the gel looks like.”  Participants are allowed to touch the gel and are 
asked to wash their hands after the demonstration. 
 
 
6.7 
Storage 
 
All study drug must be stored in a secure limited-access area, at controlled room temperature (20 – 25ºC 
[68° to 77°F]; excursions are permitted to 15° to 30°C [59° to 86°F]) in accordance with labeled storage 
requirements. Participants will be instructed to store the study drug at home at room temperature, and to 
avoid extreme heat or cold during transportation from the clinic to home. Investigational labeling will 
include instructions to keep the product out of the reach of children. 
 
 
6.8 
Registration/Randomization 
 
Screening and Registration into the DMI Database:  
Once informed consent has been signed, participants will be registered into the DMI database.  The DMI 
database will assign a participant’s PID upon completion of the registration process. 
 
Randomization:  
Participants will be assigned a randomization number once the following has been accomplished: eligibility 
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has been verified at the site level, eligibility has been confirmed by the site PI, and eligibility CRF has been 
entered into the DMI web application.  The randomization number will be generated by the database and 
assigned to the participant. Randomization will be performed stratified by study site and baseline breast 
density category (heterogeneously dense (C) or extremely dense (D)).  Refer to Section 13.2 for details of 
randomization.  
 
Screening/Registration/Randomization into site-specific databases: 
The DMI is the database of record for the study. Registration and randomization should occur per the 
procedures outlined above. If the site staff needs to enter study data into site-specific electronic databases 
per their institutional requirements, they should do so in accordance with their institutional policies and 
procedures. 
 
Appropriate CRFs must be completed for any participant who signs an informed consent. If a consented 
participant is a screen failure and deemed ineligible, the following CRFs must be completed: 1) the 
Registration CRF; 2) the Randomization CRF with the eligibility box checked “no”, 3) the Inclusion and 
Exclusion CRFs showing why the participant is ineligible, 4) the Off-Study CRF, 5) the Adverse Event 
CRF, 6) the Concomitant Medication CRF and 7) the Verification CRF. If no Adverse Event and/or 
Concomitant Medications were assessed by the time the participant is deemed ineligible, check the 
appropriate boxes on the Off Study eCRF.  All participants who sign an informed consent must formally 
go off study. All participant registration information will be entered into DMI. If a participant experiences 
a serious Adverse Event during the screening process, a Serious Adverse Event (SAE) form must be 
completed. 
 
 
6.9 
Blinding and Unblinding Methods 
 
• 
Participants will be blinded to 4-OHT topical gel or placebo. 
• 
The Statistician and the Study Pharmacist will not be blinded to 4-OHT topical gel or placebo. 
• 
All other Investigators will be blinded to 4-OHT topical gel or placebo. 
• 
The MDACC Data and Safety Monitoring Board will also be blinded unless unblinding is 
warranted (the reasons for unblinding are outlined below). 
• 
All participants will self-administer the gel by pump actuation.  Participants in the placebo and 
treatment group will administer daily 1 pump worth of gel to each breast.  
• 
Study assignments will be unblinded to the Study Investigators and Site Coordinators after all of 
the data are collected and the study database has been locked. Unblinding will also occur if the 
participant’s physician deems that unblinding is necessary, such as in the case of unacceptable 
toxicity thought to be related to the study agent or progressive disease, or if the participant becomes 
pregnant. 
• 
Unblinding will only take place after consultation with the NCI, DCP Medical Monitor Marjorie 
Perloff, MD. 
• 
If unblinding is indicated prior to the completion of the study, it will be conducted as follows: 
o The Site Investigator contacts the Protocol Principal Investigator (Dr. Arun) and requests 
the participant’s treatment status be unblinded. 
o The Protocol Principal Investigator (Dr. Arun) contacts the NCI, DCP Medical Monitor 
and requests the participant’s treatment status be unblinded. The Protocol Principal 
Investigator then conveys the Medical Monitor’s decision to the Site Investigator. The Site 
Investigator or their designee then proceeds with unblinding as written out below.  
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o If the NCI, DCP Medical Monitor cannot be reached and the participant requires 
emergency care, the Protocol Principal Investigator may authorize the site Investigator to 
break the blind. 
o If the Site Investigator is unable to reach the Protocol Principal Investigator and the 
participant requires emergency care, then the Site Investigator must proceed with 
unblinding as written out below.  
o The Site Investigator requests the participant’s treatment status be unblinded by the 
research pharmacist (or designated individual responsible for dispensing drug). 
o The Site Investigator officially takes the participant off-study.  
o The date and reason for breaking the blind must be submitted by the Site Investigator to 
the Protocol Principal Investigator as soon as possible.  
o It is the responsibility of the Study Principal Investigator to report the date and reason for 
breaking the blind to the NCI, DCP Medical Monitor, Marjorie Perloff, MD, as soon as 
possible. 
o The date and reason for breaking the blind must be submitted by the Study Principal 
Investigator to the MD Anderson Consortium Principal Investigator, Powel H. Brown, MD, 
PhD, or designee as soon as possible via email to phbrown@mdanderson.org or phone at 
(713) 792-4509. 
o The date and the reason for breaking the blind will be reported by the MD Anderson 
Consortium Principal Investigator or designee to the MD Anderson DSMB as soon as 
possible. 
 
 
6.10 
Agent Destruction/Disposal  
 
At the completion of investigation, all undispensed study agent will be returned to NCI, DCP Repository 
according to the DCP “Guidelines for AGENT RETURNS” and using the DCP form “Return Drug List”.  
The Guidelines and form are available on the DCP website. Unused drug, that has been dispensed to 
participants, but that is returned unused by the participants, will be disposed of by each institution following 
institutional guidelines after canisters have been weighed and the weights have been recorded. Record the 
weight to the nearest hundredth. 
 
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7. 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1.1 
Schedule of Events  
 
Evaluation/ 
Procedure 
Baseline 
Testing/ 
Prestudy 
Evaluation/ 
Randomization
a 
Breas
t core 
biops
y 
(Opti
onal) 
Start of 
Interven
tion 
Day 
7-14c 
Month 3c 
Month 
6 
Month 
9c or 
Early 
Termina
tion 
Month 
12 
Month 
24 
 
<60 days of 
Day 1 
 
Day 1b 
 
Day 90 ± 
14 days 
Day 
180 ± 
14 
days 
Day 270 
± 14 
days 
Day 
365 ± 
30 
days 
Day 
730 ± 
30 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Assess Eligibility 
X 
 
 
 
 
 
 
 
 
Confirm 
Eligibility 
X 
 
 
 
 
 
 
 
 
Registration 
X 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical Exam  
Xd 
 
 
 
 
Xd 
 
Xd 
 
Vital 
Signs/ 
Height and Weight 
e 
X 
 
 
 
 
Xe 
 
Xe 
 
Laboratory Tests f 
Xf 
 
 
 
 
 
 
Xf 
 
Pregnancy Test 
Xg 
Xg 
 
 
 
X 
 
X 
 
Mammogram 
Xh 
 
 
 
 
 
 
X 
X 
Breast core biopsy 
(Optional)i 
 
Xi 
 
 
 
 
 
X 
 
Blood 
for 
Biomarkers j 
X 
 
 
 
 
X 
 
X 
 
Concomitant 
Medications 
X 
 
 
X 
X 
X 
X 
X 
 
Adverse Events 
 
 
 
X 
X 
X 
X 
X 
 
Dispense 
Study 
Agent 
X* 
 
 
 
 
X 
 
 
 
Collect 
Unused 
Study Agent 
 
 
 
 
 
X 
 
X 
 
Demonstration of 
gel application 
X* 
 
 
 
 
 
 
 
 
Start Study Agent 
 
 
X 
 
 
 
 
 
 
Review 
Agent 
Diary 
l / Drug 
compliance 
X* 
 
 
Xk 
X 
X 
X 
X 
 
Telephone Contact 
 
 
 
Xk 
X 
 
X 
 
 
BESS 
Questionnaire m 
X 
 
 
 
 
X 
 
X 
 
Tobacco 
and 
Alcohol 
Use 
Assessment n,o 
X n 
 
 
 
 
 
 
Xo 
 
 
a Baseline Testing/ Prestudy Evaluation may be done on the same day as Randomization. 
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b Participants will start treatment within 7 days of dispensing drug.  
c Telephone contact.  The telephone call can be replaced with alternate forms of communication preferred by the 
participant – text, email, health portal message or other where local policy allows, as long as all required information 
is collected. 
d At Baseline the physical exam should include a clinical breast exam, nodal, if not performed within the last 12 
months. At Months 6 and 12 the physical exam should include a breast exam.  
e  Do not repeat height measurement after Baseline Testing. 
f CBC (hemoglobin, hematocrit, RBC, WBC, platelet count), total bilirubin, AST (SGOT)/ALT (SGPT). In 
premenopausal women: FSH, LH, estradiol. H&H are not part of the eligibility criteria.  Results from outside (i.e., 
non-study site) CLIA approved laboratories drawn < 60 days of Day 1 may be used to confirm eligibility. The outside 
labs must show normal values for each result. 
g A urine or serum pregnancy test < 14 days before starting study agent for women of child-bearing potential.  Results 
must be known prior to randomization and drug dispensing. If the pregnancy test result is positive at Baseline (any 
time before randomization), the participant is a Screen Failure.  For participants who agree to the optional biopsy the 
pregnancy test will be repeated if needed to satisfy the requirement of having a negative pregnancy test within 14 days 
of starting study agent.   
h Obtain previous annual mammography report.  Once the participant has signed consent, the mammography center 
should be alerted not to delete the raw images. In centers where raw images are stored, consent can occur after the 
annual mammogram that will serve as the baseline mammogram for the study.  The mammogram must be within 3 
months of randomization.   
i The optional biopsy will be done after randomization (may be done on the day of randomization, but before start of 
intervention). 
j Refer to sections 8.2 and 10.1 for a description of blood biomarkers. 
k Confirm start of gel application. 
l Refer to Appendix D. 
m Refer to Appendix E. 
n See Appendix F “Alcohol and Tobacco Use Assessment Questionnaires – Baseline” 
o See Appendix G “Alcohol and Tobacco Use Assessment Questionnaires – Month 12”. Assessed in person or on the 
phone.  
 
* Dispense study drug after randomization.  Dispensing of study agent does not have to be on the same day as 
randomization. Prescriptions should be written/signed after the participant is randomized. Randomization number 
must be confirmed prior to dispensing.  For women who agree to the optional biopsy – dispensing study agent, 
demonstrating of gel application, and reviewing the agent diary and drug compliance will occur on the day of the 
biopsy. 
 
 
 
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7.1.2 
Schedule of Events  
COVID-19 Contingency Plan: assumes that the participants have to miss in person visits at either Mo 6 or 12, or both 
Evaluation/ 
Procedure 
Baseline Testing/ 
Prestudy 
Evaluation/ 
Randomizationa 
Breast 
core 
biopsy 
(Optio
nal) 
Start of 
Interventi
on 
Day 
7-14c 
Month 3c 
Month 6 
Month 9c 
or Early 
Terminat
ion 
Month 
12 
Month 
13-18 
Month 
24 + 8 
Months 
 
<60 days of Day 
1 
 
Day 1b 
 
Day 90 ± 
14 days 
Day 180 
± 14 
days 
Day 270 ± 
14 days 
Day 365 
± 30 
days 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
X 
(Note 
5) 
 
Assess Eligibility 
X 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X 
 
 
 
 
 
 
 
 
 
Registration 
X 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical Exam  
Xd 
 
 
 
 
 
 
 
Xd 
 
Vital Signs/ Height 
and Weight e 
X 
 
 
 
 
 
 
 
Xe 
 
Laboratory Tests f 
Xf 
 
 
 
 
 
 
 
Xf 
 
Pregnancy Test 
Xg 
Xg 
 
 
 
 (Note 1) 
 
(Note 1) 
X 
 
Mammogram 
Xh 
 
 
 
 
 
 
 
X 
X 
Breast core biopsy 
(Optional)i 
 
Xi 
 
 
 
 
 
 
X 
 
Blood 
for 
Biomarkers j 
X 
 
 
 
 
 
 
 
X 
 
Concomitant 
Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
 
 
X 
X 
X 
X 
X 
X 
 
Dispense 
Study 
Agent 
X* 
 
 
 
 
X 
(Note 2) 
 
X (Note 
2) 
 
 
Collect 
Unused 
Study Agent 
 
 
 
 
 
 (Note 3) 
 
 (Note 3) 
X 
 
Demonstration of gel 
application 
X* 
 
 
 
 
 
 
 
 
 
Start Study Agent 
 
 
X 
 
 
 
 
 
 
 
Review Agent Diary 
l / Drug compliance 
X* 
 
 
Xk 
X 
X 
X 
X 
X 
 
Telephone Contact 
 
 
 
Xk 
X 
X 
X 
X 
 
 
BESS Questionnaire 
m 
X 
 
 
 
 
X 
(Note 4) 
 
X 
(Note 4) 
X 
 
Tobacco 
and 
Alcohol 
Use 
Assessment n,o 
X n 
 
 
 
 
 
 
  
Xo 
(Note 6) 
 
 
a Baseline Testing/ Prestudy Evaluation may be done on the same day as Randomization. 
b Participants will start treatment within 7 days of dispensing drug.  
c Telephone contact.  The telephone call can be replaced with alternate forms of communication preferred by the participant – 
text, email, health portal message or other where local policy allows, as long as all required information is collected. 
d At Baseline the physical exam should include a clinical breast exam, nodal, if not performed within the last 12 months. At 
Month 13-18 the physical exam should include a breast exam.  
e  Do not repeat height measurement after Baseline Testing. 
f CBC (hemoglobin, hematocrit, RBC, WBC, platelet count), total bilirubin, AST (SGOT)/ALT (SGPT). In premenopausal 
women: FSH, LH, estradiol. H&H are not part of the eligibility criteria.  Results from outside (i.e., non-study site) CLIA approved 
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laboratories drawn < 60 days of Day 1 may be used to confirm eligibility. The outside labs must show normal values for each 
result. 
g A urine or serum pregnancy test < 14 days before starting study agent for women of child-bearing potential.  Results must be 
known prior to randomization and drug dispensing. If the pregnancy test result is positive at Baseline (any time before 
randomization), the participant is a Screen Failure.  For participants who agree to the optional biopsy the pregnancy test will be 
repeated if needed to satisfy the requirement of having a negative pregnancy test within 14 days of starting study agent.   
h Obtain previous annual mammography report.  Once the participant has signed consent, the mammography center should be 
alerted not to delete the raw images. In centers where raw images are stored, consent can occur after the annual mammogram that 
will serve as the baseline mammogram for the study.  The mammogram must be within 3 months of randomization.   
i The optional biopsy will be done after randomization (may be done on the day of randomization, but before start of 
intervention). 
j Refer to sections 8.2 and 10.1 for a description of blood biomarkers. 
k Confirm start of gel application. 
l Refer to Appendix D. 
m Refer to Appendix E. 
n See Appendix F “Alcohol and Tobacco Use Assessment Questionnaires – Baseline” 
o See Appendix G “Alcohol and Tobacco Use Assessment Questionnaires – Month 12”. Assessed in person or on the phone.  
 
* Dispense study drug after randomization.  Dispensing of study agent does not have to be on the same day as randomization. 
Prescriptions should be written/signed after the participant is randomized. Randomization number must be confirmed prior to 
dispensing.    For women who agree to the optional biopsy – dispensing study agent, demonstrating of gel application, and 
reviewing the agent diary and drug compliance will occur on the day of the biopsy. 
 
Note 1: Premenopausal women should be reminded that they are strongly advised not to become pregnant while on study and 
should continue using appropriate contraceptive methods. 
 
Note 2: Mail or email the 4-OHT Diary to the participant. Ship a new 6-month supply of the study agent to the participant, if you 
can do so.  Ask the participant to record their daily use of agent on the 4-OHT Diary; using a new Diary for each Canister. Instruct 
the participant to bring their completed Diaries to the next in person clinic visit.  Instruct the participant to keep all used 
canisters and to bring the canisters with ALL of their completed Diaries to the next in person clinic visit.  Follow other 
Contingency Plan instructions from Section 7.2 below. 
 
Note 3: Instruct the participant to keep all used canisters and to bring the canisters with ALL of their completed Diaries to the 
next in person clinic visit. 
 
Note 4: Mail or email the BESS QUESTIONNAIRE to the participant ahead of the telephone visit, if possible. Ask the 
participant to fill it out ahead of the visit, to sign and date the form at the time of completion, and keep it. Collect the information 
during the visit, if allowed by the institution and if the participant feels comfortable to discuss the responses over the phone. 
Participants should return the BESS QUESTIONNAIRE at their next in person visit.  If you were not able to mail/email the 
BESS QUESTIONNAIRE ahead of the telephone visit, collect the information over the phone, if possible. Record the answers. 
 
Note 5: Participants that are asked to extend their gel application will be reconsented following the CIRB remote consent 
procedure for the extended gel application.  
 
Note 6: ALCOHOL and TOBACCO ASSESSMENTs will be done in clinic when participants return for their mammogram. 
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7.2 Baseline Testing/Prestudy Evaluation  
 
Baseline Testing/Prestudy Evaluation/Randomization (< 60 days of Day 1) 
 
Baseline Testing/Prestudy Evaluation interventions will be conducted < 60 days of Day 1, may require 
multiple visits or may be done on the day of randomization and will consist of the following procedures:  
 
o Women with prior annual mammograms showing heterogeneously dense or dense breast/s will be 
approached for enrollment into the study prior to their next annual mammogram. Informed consent 
must be obtained prior to starting any further study procedures.  Consenting should be done prior 
to next annual mammogram, that will serve as the baseline study mammogram.  Once the 
participant has signed consent, the mammography center should be alerted not to delete the raw 
images.  Raw images must be obtained for study purposes (see instructions in Section 8.1).  In 
centers where raw images are stored, consent can occur after the annual mammogram (the baseline 
mammogram for this study).  The mammogram must be within 3 months of randomization.  
Mammography report from the previous annual visit should also be obtained.   
 
o Registration: Once informed consent has been signed, participants will be registered into the DMI 
database.  The DMI database will assign a participant’s PID upon completion of the registration 
process. Participants will also be registered into site-specific registry databases as applicable.  
 
o Data collection including race, height, weight, cancer family history, reproductive history, previous 
breast biopsy results (if applicable), hormonal medication use (HRT, OCP, SERM, aromatase 
inhibitors), BRCA status (if available), cup size, BIRADs for each site and medication assessment 
for drugs known to inhibit 4-OHT gel or tamoxifen action. 
 
o Limited physical examination must be done < 60 days of Day 1. IInclude a clinical breast exam if 
not performed within the last 12 months. If a breast mass is found on initial examination, the 
participant will receive standard evaluation and will not participate until the mass has been 
classified as benign. 
 
o Laboratory tests will include the following: 
o CBC (hemoglobin, hematocrit, RBC, WBC, platelet count)  
o Total bilirubin 
o AST (SGOT)/ALT (SGPT) 
 
o Staging of reproductive age. All women will be asked for the date of their last menstrual cycle. In 
premenopausal women: FSH, LH, estradiol. 
 
o A urine or serum pregnancy test within 14 days of starting study agent for women of child-bearing 
potential.  Results must be known prior to randomization and drug dispensing. The urine pregnancy 
test must be done in the clinic. The pregnancy test will be repeated at 6 months and 12 months 
visits.  
o If the pregnancy test result is positive at Baseline (any time before randomization), the 
participant is a Screen Failure. 
o For participants with the optional biopsy the pregnancy test will be repeated if needed to satisfy 
the requirement of having a negative pregnancy test within 14 days of starting study agent. 
 
o Concomitant medications will be documented. 
 
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Once registration is complete, eligibility has been confirmed and eligibility CRF is entered into the web 
application, participants will be assigned a randomization number pre-generated by the database.  
 
o Randomization will be performed stratified by study site and baseline breast density 
(heterogeneously dense (C) or extremely dense (D)). 
 
o Dispense study drug after randomization.  Dispensing of study agent does not have to be on the 
same day as randomization. Prescriptions should be written/signed after the participant is 
randomized. Randomization number must be confirmed prior to dispensing.     
 
o Participants will be provided with the gel kit with a 6 months’ supply and an agent diary (see 
Appendix D). The agent diary will be reviewed with the participant.  Demonstration of gel 
application will be done. Instructions on how to apply gel will be provided. See Appendix B.  
Participants who agree to the option biopsy will receive their gel kit on the day of the biopsy. 
 
o Blood draw for research biomarkers.  
 
o BESS Questionnaire (refer to Appendix E). 
 
o Tobacco and Alcohol Use Assessment, using the Baseline questionnaires. See Appendix F 
“Alcohol and Tobacco Use Assessment Questionnaires – Baseline”. Refer to Appendix H for 
resources for alcohol and tobacco quitting. These resources can be given to individuals if there is 
concern about alcohol or tobacco dependence. It is not expected that investigators will refer 
individuals for assistance or that they will undertake the care of individuals for alcohol or tobacco 
dependence. 
 
 
Optional Breast Core Biopsy 
 
o Breast core biopsy for participants who agreed to the optional procedure. The optional biopsy will 
be done after randomization. It may be done on the day of randomization, but before start of 
intervention.  If the participant is on aspirin, non-steroidal anti-inflammatory drugs or Vitamin E, 
she will be instructed to discontinue these and return in 7-10 days for the biopsy.  The participant 
will start to apply the gel at least 24 hours after the biopsy. If the biopsy has been performed in the 
morning, the participant can start applying the gel the next morning, after 24 hours.   If the biopsy 
was performed in the afternoon, and the participant wishes to apply the gel in the mornings for the 
duration of the study, then the participant can start applying the get on the morning of the 2nd day 
after the biopsy.   Remind the participant to start treatment within 7 days of dispensing drug. 
 
o For women who agree to the optional biopsy – dispensing study agent, demonstrating of gel 
application, and reviewing the agent diary and drug compliance will occur on the day of the biopsy. 
See instructions above. 
 
 
Start of Intervention (Day 1) 
 
o Participants will start treatment within 7 days of dispensing drug. 
 
o A telephone contact is scheduled for 7-14 days post Day 1. 
 
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7.3 
Evaluation During Study Intervention 
 
Day 7-14: Telephone Contact   
The following will be performed: 
o Verification of the start date of gel application. 
o Concomitant medications.  
o Adverse events. 
o Participants will be reminded of the need to complete the agent diary daily.  
The telephone call can be replaced with alternate forms of communication preferred by the participant – 
text, email, health portal message or other where local policy allows, as long as all required information is 
collected. 
 
Month 3 [Day 90 ± 14 days]: Telephone Contact 
The following will be performed: 
o Adverse events.  
o Concomitant medications.  
o Drug compliance and agent diary review.  
The telephone call can be replaced with alternate forms of communication preferred by the participant – 
text, email, health portal message or other where local policy allows, as long as all required information is 
collected. 
 
Month 6 [Day 180 ± 14 days]  
At month 6 the participant will return to clinic as per standard of care breast high risk screening follow-up. 
The following will be performed: 
o Physical exam, including a breast examination. 
o Vital signs, weight. 
o A urine or serum pregnancy test will be performed. The urine pregnancy test must be done in the 
clinic.  If the pregnancy test result is positive at the 6 Months visit, do not dispense study agent, 
follow the pregnancy to term and complete the Outcome of Pregnancy CRF. Take the participant 
off study at the completion of the pregnancy when the outcome of pregnancy is known.  
o Blood draw for research biomarkers. 
o Concomitant medication. 
o Adverse events.  
o Collect unused study agent. 
o Compliance check will be performed by evaluating the participant’s agent diary.  
o Participant will be provided with a 6 months’ supply of study agent (gel kit) and a new agent diary.  
o BESS Questionnaire (refer to Appendix E). 
 
Month 9 [Day 270 ± 14 days]: Telephone Contact 
 
The following will be performed: 
o Adverse events. 
o Concomitant medications.  
o Drug compliance and agent diary review. 
The telephone call can be replaced with alternate forms of communication preferred by the participant – 
text, email, health portal message or other where local policy allows, as long as all required information is 
collected. 
 
 
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7.4 
Evaluation at Completion of Study Intervention 
 
Month 12 [Day 365 ± 30 days] 
 
Month 12 clinic visit is a standard high risk evaluation.  
The following will be performed: 
o Physical exam, including a breast examination. 
o Vital signs, weight. 
o Laboratory tests will include the following: 
o CBC (hemoglobin, hematocrit, RBC, WBC, platelet count)  
o Total bilirubin 
o AST (SGOT)/ALT (SGPT) 
o In women who were considered premenopausal at baseline: FSH, LH, estradiol. 
o A urine or serum pregnancy test will be performed. The urine pregnancy test must be done in the 
clinic.  If the pregnancy test result is positive at the 12 Months visit, follow the pregnancy to term 
and complete the Outcome of Pregnancy CRF. Take the participant off study at the completion of 
the pregnancy when the outcome of pregnancy is known. 
o Bilateral mammogram. The raw images must be obtained (see instructions in Section 8.1) for study 
purposes.   
o For participants who underwent the baseline breast biopsy, the biopsy will be repeated. 
o Blood draw for research biomarkers 
o Adverse events.  
o Concomitant medication.  
o Collect unused study agent. 
o Compliance check will be performed by evaluating the participant’s agent diary.  
o BESS Questionnaire (refer to Appendix E). 
o Tobacco and Alcohol use assessment will be performed at Month 12, using the Month 12 
questionnaires (see Appendix G “Alcohol and Tobacco Use Assessment Questionnaires – Month 
12”).   
o Participants will be reminded of the need to return for their Month 24 visit, which is their standard 
clinical high risk follow-up visit.  
 
 
7.5 
Post-intervention Follow-up Period 
 
Month 24 [Day 730 ± 30 days] 
o Standard of care bilateral mammogram. Raw images must be obtained for study purposes (see 
instructions in Section 8.1).   
 
 
 
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COVID-19 Contingency Plan 
 
The Contingency assumes that the participants have to miss in person visits at Mo 6 and/or.  If the 
participants are able to come in person for Mo 6 and 12 Visits, proceed per protocol during the 
pandemic.  
 
Month 6 [Day 180 ± 14 days]: Telephone Contact  
The following will be performed: 
o Concomitant medication. 
o Adverse events.  
o Premenopausal women should be reminded that they are strongly advised not to become pregnant 
while on study and should continue using appropriate contraceptive methods. 
o Mail or email the 4-OHT Diary to the participant. Ask the participant to record their daily use of 
agent on the 4-OHT Diary; using a new Diary for each Canister.  
o Ship or have participant pickup a new 6-month supply of the study agent.   
o Instruct the participant to keep all used canisters and to bring the canisters with all of their 
completed Diaries to the next in person clinic visit. 
o 
Drug compliance and agent diary review.  
o Mail or email the BESS QUESTIONNAIRE to the participant ahead of the telephone visit, if 
possible. Ask the participant to fill it out ahead of the visit and collect the information during the 
visit, if allowed by the institution and if the participant feels comfortable to discuss the responses 
over the phone. Participants should return the BESS QUESTIONNAIRE, at their next in person 
visit.  If you were not able to mail/email the BESS QUESTIONNAIRE ahead of the telephone 
visit, collect the information over the phone, if possible. Record the answers. 
 
Month 9 [Day 270 ± 14 days]: Telephone Contact 
 
The following will be performed: 
o Adverse events. 
o Concomitant medications.  
o Drug compliance and agent diary review. 
The telephone call can be replaced with alternate forms of communication preferred by the participant – 
text, email, health portal message or other where local policy allows, as long as all required information is 
collected. 
 
Month 12 [Day 365 ± 30 days]: Telephone Contact 
The following will be performed: 
o Adverse events.  
o Concomitant medication.  
o Premenopausal women should be reminded that they are strongly advised not to become pregnant 
while on study and should continue using appropriate contraceptive methods. 
o Mail or email the 4-OHT Diary to the participant. Ask the participant to record their daily use of 
agent on the 4-OHT Diary; using a new Diary for each Canister.  
o Participants will be asked to extend their gel application and will be reconsented following the 
CIRB remote consent procedure for the extended gel application.  
o Ship or have the participant pickup a new 6-month supply of the study agent.   
o Instruct the participant to keep all used canisters and to bring the canisters with all of their 
completed Diaries to the next in person clinic visit. 
o Drug compliance and agent diary review.  
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o Mail or email the BESS QUESTIONNAIRE to the participant ahead of the telephone visit, if 
possible. Ask the participant to fill it out ahead of the visit, to sign and date the form at the time of 
completion, and keep it. Collect the information during the visit, if allowed by the institution and 
if the participant feels comfortable to discuss the responses over the phone. Participants should 
return the BESS QUESTIONNAIRE at their next in person visit.  If you were not able to 
mail/email the BESS QUESTIONNAIRE ahead of the telephone visit, collect the information 
over the phone, if possible. Record the answers. 
o Participants will be reminded of the need to reschedule their mammogram within the next 6 months.  
o Participants that do not want to extend their gel application should be taken off agent and asked to 
allow the collection of their next available mammogram for study purposes.  
 
 
7.4 
Evaluation at Completion of Study Intervention 
 
Month 13-18 
 
The following will be performed: 
o Physical exam, including a breast examination. 
o Vital signs, weight. 
o Laboratory tests will include the following: 
o CBC (hemoglobin, hematocrit, RBC, WBC, platelet count)  
o Total bilirubin 
o AST (SGOT)/ALT (SGPT) 
o In women who were considered premenopausal at baseline: FSH, LH, estradiol. 
o A urine or serum pregnancy test will be performed. The urine pregnancy test must be done in the 
clinic.  If the pregnancy test result is positive at the 13-18 Month visit, follow the pregnancy to term 
and complete the Outcome of Pregnancy CRF. Do not take the participant off study until the 
completion of the pregnancy when the outcome of pregnancy is known. 
o Bilateral mammogram. The raw images must be obtained (see instructions in Section 8.1) for study 
purposes.   
o For participants who underwent the baseline breast biopsy, the biopsy will be repeated if participant 
extended their gel application. 
o Blood draw for research biomarkers 
o Adverse events.  
o Concomitant medication.  
o Collect unused study agent. 
o Compliance check will be performed by evaluating the participant’s agent diary.  
o BESS Questionnaire (refer to Appendix E). 
o Tobacco and Alcohol use assessment will be performed at Month 12, using the Month 12 
questionnaires (see Appendix G “Alcohol and Tobacco Use Assessment Questionnaires – Month 
12”).   
o Participants will be reminded of the need to return for their next annual mammogram (Month 24 + 
8 Months), which is their standard clinical high risk follow-up visit.  
 
7.5 
Post-intervention Follow-up Period 
 
Month 24 + 8 Months  
o Collection of the standard of care bilateral mammogram images. Raw images must be obtained for 
study purposes (see instructions in Section 8.1).   
 
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7.6 
Methods for Clinical Procedures 
 
Breast core biopsy (see also Section 10.2):  
The breast core biopsy (image guided) is optional. A 14-gauge needle will be used. Every effort will be 
made to collect 4 cores of tissue, with the minimum of 2 cores per participant. 
 
Tissue will be considered adequate for research assays if the H&E stained slide from the block demonstrates 
at least one TDLU in every tissue core. One H&E slide will be prepared for adequacy and histological 
assessment. Usually each terminal duct lobular unit contains 200 to 2500 cells. If no terminal duct lobular 
units are seen, deeper sections will be obtained. Subsequent slides will be used for biomarker analysis.    
Refer to Section 10.2 for tissue collection and handling procedures.  
 
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
8.1 
Primary Endpoint 
 
The primary objective of this study is to evaluate mammographic density (MD) changes induced by 4-OHT 
gel versus placebo in women with mammographically dense breast. Our hypothesis is that 4-OHT will 
reduce MD. Baseline and 12 months mammogram [or mammograms from Month 13-18 under the COVID-
19 contingency plan] will be evaluated for 4-OHT effect using Cumulus software for the primary endpoint 
evaluation. Analysis will be based on tomosynthesis imaging using the 2D synthetic image. 
 
MD will be classified using BIRADS descriptions on mammographic reports (i.e: predominantly adipose 
tissue, scattered fibroglandular densities, heterogeneously dense or extremely dense). BIRADS MD 
assessment is a consistently utilized measure of breast fibroglandular tissue volume, which can be 
universally followed and reproduced. BIRADS is a scheme for putting the findings from mammogram 
screening into a small number of well-defined categories.  In addition to BIRADS, baseline and follow up 
MD will be quantified and recorded using semi-automated software, Cumulus, which has been utilized in 
earlier density assessment studies 10, 11, 12 .  Cumulus reading will be centralized with the reader blinded to 
the timepoint and treatment group.  
 
For the primary endpoint, the densest breast will be used. 
 
At each institution mammographic images will be collected by a study specific data coordinator who will 
be overseen by the site Investigator. This data coordinator will also ensure that images are collected in 
usable format with appropriate de-identification. Follow the instructions in Section 10.2 for Collection and 
Handling of images. 
 
In summary, the effect of utilized software on the density percent assessment is estimated to be minimal. 
Based on this, we will use:  
 
a) Downgrading of the baseline reported BIRADS breast density. 
 
b) Decrease in breast fibroglandular density by 10% or more as assessed by semi- and automated 
Breast Density software. 
 
 
8.2 
Secondary Endpoints 
 
Note: data from Month 13-18 visit instead of Month 12 visit will be used if participants were seen under 
the COVID-19 Contingency Plan. If data were not collected at Month 6 under the COVID-19, such 
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participants will have missing data. 
 
Breast biopsy for secondary and exploratory endpoints will be performed in the opposite (non-target) breast.   
 
8.2.1 
We will estimate and compare the percent change in mammographic breast density (using Volpara) 
from Baseline to Month 12 in women applying 2mg 4-OHT gel per breast versus placebo.   
 
8.2.2 
We will estimate and compare the percent change in mammographic breast density (using LIBRA) 
from Baseline to Month 12 in women applying 2mg 4-OHT gel per breast versus placebo.  
 
8.2.3 
We will compare the percentage of women who underwent a change in BIRADS category, 
comparing pre-and post- treatment measurements, for recipients of 4-OHT gel versus placebo.  
 
8.2.4 
We will conduct subgroup analyses including BIRAD category, menopausal status, cup size, and 
total breast volume.  
 
8.2.5 
We will estimate the percentage of women with ≥ 10% absolute decrease in quantitative 
mammographic density percentage between baseline and 12 months, comparing between treated group 2mg 
per breast 4-OHT gel versus placebo based on Cumulus method.  
 
8.2.6 
Markers of Toxicity: Baseline, 6 and 12 months BESS questionnaire will be used. Further blood 
based toxicity markers will be also evaluated at baseline and again at months 6 and 12 (F VIII, vWB factor, 
SHBG, lipid profile). 
 
8.2.7 
Markers of Tamoxifen exposure (in plasma): Plasma measurements of 4-OHT and related 
metabolite levels and factors related to tamoxifen exposures will be measured at baseline and again at 
months 6 and 12. (If baseline drug metabolite levels are low; other plasma biomarkers will not be measured 
at baseline and month 12. Further, the second analysis of 4-OHT and metabolites at 6 and 12 months will 
also not be performed). 
 
8.2.8 
Markers of Tamoxifen exposure (in tissue): Tissue measurements of 4-OHT and related metabolite 
levels and factors related to tamoxifen exposures will be measured at baseline and again at month 12. (If 
baseline drug metabolite levels are low; other tissue biomarkers will not be measured at baseline and month 
12. Further, the second analysis of 4-OHT and metabolites at 12 months will also not be performed). 
 
 
8.3 
Exploratory Endpoints 
 
8.3.1 
To compare the Cumulus vs. Volpara vs. LIBRA breast density measurement methods to estimate 
percent change in mammographic breast density from baseline to Month 12 in women applying 2mg of 4-
OHT gel per breast vs. placebo. 
 
8.3.2 
To perform correlation of drug concentrations in the plasma and the tissue. 
 
8.3.3 
To evaluate plasma measurements of Insulin-like growth factor (IGF) pathway members, C-
reactive protein (CRP), and estradiol. 
 
8.3.4 
To compare the 2D natural vs. 2D synthetic breast density measurement using the Cumulus method 
to estimate percent change in mammographic breast density from baseline to Month 12 in women applying 
2mg of 4-OHT gel per breast vs. placebo. 
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8.3.5 
To evaluate tissue biomarkers (among women undergoing optional pre- and post-treatment 
biopsies): 
• 
Structure-function activity of TLDUs will be evaluated by counting acinar density. 
• 
Breast tissue density will be evaluated by assessing the patterns of collagen matrix. 
• 
Hormone-mediated cellular activity will be evaluated by measuring the transcriptional expression 
levels of ER-alpha and ER-associated genes (SETER/PR index). 
• 
Pharmacogenomic response to 4-OHT will be evaluated by measuring Ki67 protein by 
immunohistochemistry and aurora kinase-alpha gene expression.  
• 
Inflammatory response to 4-OHT therapy will be evaluated by measuring COX2 and p16 proteins, 
and recruitment of CD68 monocytes by immunohistochemistry. 
 
8.3.6 
To examine whether any reductions in mammographic density seen after 1 year of 4-OHT vs. 
placebo gel application persist at 24 months (or longer under the COVID-19 Contingency Plan), one year 
after gel application has stopped. 
 
 
8.4 
Off-Agent Criteria  
 
Participants may stop applying the study gel for the following reasons: completed the protocol-prescribed 
intervention, adverse event or serious adverse event, inadequate agent supply, noncompliance, concomitant 
medications, medical contraindication, or pregnancy. Participants will continue to be followed, if possible, 
for safety reasons and in order to collect endpoint data according to the schedule of events. We plan to 
accrue 7 more participants per arm to account for women who are not evaluable because they discontinued 
participation prior to meeting criteria for contributing evaluable results. Women who discontinue the agent 
for any reason should continue on study if possible to allow for collection of their routine mammograms. 
8.5 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-
required follow-up period is completed, adverse event/serious adverse event, lost to follow-up, non-
compliance, concomitant medication, medical contraindication, withdraw consent, or death.  Participants 
found to be ineligible during the screening phase and after signing the Informed Consent document and 
assigning the PID number, will be considered “screen failures”.  Such participants will be taken off study 
and the appropriate end of study CRFs will be completed for these participants. 
8.6 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the study at any time.  
 
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Rationale for Methodology Selection 
 
Section 8 outlines our primary and secondary endpoint biomarkers. The primary endpoint measurement 
will be done by assessing MD using standard clinical methods. For secondary endpoints, again, we choose 
methods that have been previously published, either by our group or other investigators, that are widely 
available, practical, and financially preferable.  
 
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9.2 
Comparable Methods 
 
The methodologies described above are those previously used (see details above), and the resulting data 
will be able to be compared to existing data. 
 
 
10. 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
 
10.1.1 4-OHT metabolite analysis will be performed at the IIT Research Institute, Chicago, IL in plasma 
and in tissue. 
 
10.1.2 F VIII, vWB factor, SHBG, lipid profile, CRP, and estradiol will be performed at UT MD Anderson 
Outpatient Laboratory. 
 
10.1.3 Plasma IGF pathway biomarkers will be performed in Dr. Arun’s research laboratory. 
 
10.1.4 Exploratory tissue biomarkers (TDLU involution; collagen structural changes; SETER/PR index: 
estrogen related transcription; Ki-67, COX-2, p16, and CD68) will be performed by our pathology 
collaborator, Dr. Fraser Symmans in the Departments of Pathology and Translational Molecular Pathology 
at UT MD Anderson Cancer Center.  
 
10.2 
Collection and Handling Procedures 
 
Note: data from Month 13-18 visit instead of Month 12 visit will be used if participants were seen under 
the COVID-19 Contingency Plan. If data were not collected at Month 6 under the COVID-19, such 
participants will have missing data. 
 
Submission of mammographic data Using TRIAD  
TRIAD is the American College of Radiology’s (ACR) image exchange application. TRIAD provides 
sites participating in clinical trials a secure method to transmit DICOM RT and other objects. TRIAD 
anonymizes and validates the images as they are transferred.  
 
TRIAD Access Requirements  
Site staff who will submit images through TRIAD will be provided necessary log in information.  
To submit images, the site staff must be on the delegation of task log and be assigned the 'TRIAD 
site user' role.  
 
TRIAD Installations  
The TRIAD site user will need to have the TRIAD application installed on his/her workstation to 
be able to submit images. 
TRIAD installation documentation can be found by following this link 
https://triadinstall.acr.org/triadclient/  
If you have any questions regarding this information, please send an e-mail to the TRIAD 
Support mailbox at TRIAD-Support@acr.org.  
 
Procedures for Data Submission via TRIAD  
Mammograms with their corresponding Diagnostic Imaging Report should be submitted for each 
participant in this study at the following time points:  
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1. The original mammogram taken at most 3 months prior to registration.  
2. The mammogram taken as near as possible to one year after registration;  
3. The mammogram taken as near as possible to two years after registration.  
 
Submission of mammographic data  
Digital mammography systems produce images in two forms, commonly referred to as the ‘raw’ 
image and the ‘processed’ images. For analysis of mammographic density raw images will be 
required, both raw images and ‘processed’ images will be collected.  
All centers involved perform Digital Breast Tomography.  As the current standard for 3D digital 
breast tomography is to include 3D images and either a conventional dose 2D mammogram or a 
synthesized 2D image, both the 3D and 2D images should be submitted. Only the 3D images will 
be analyzed, but 2D images will also be collected to create a data resource for future studies.  
Digital files must be in DICOM format. Ensure that software used to de-identify images does not 
remove the date of the scan and specifics of the physics/image acquisition such as breast 
thickness and compression.  
These files may be submitted electronically preferably with TRIAD. Alternatively, the images and 
reports may be submitted via secure portal to UT MD Anderson. 
 
Research Blood collection:  
Peripheral blood will be obtained by venipuncture at baseline, at 6 and at 12 months.  
 
For the purpose of tracking samples: a pre-printed label will be attached to identify all sample vials. 
 
Approx. 25 mL of blood will be collected and processed as per the Laboratory Manual. Refer to the 
Laboratory Manual for storage instructions. 
 
Breast Core Biopsy (see also section 7.6):  
The breast core biopsy (image guided) is optional. A 14-gauge needle will be used. Every effort will be 
made to collect 4 cores of tissue, with the minimum of 2 cores per participant at each time point.  
 
Tissue will be considered adequate for research assays if the H&E stained slide from the block demonstrates 
at least one TDLU in every tissue core. One H&E slide will be prepared for adequacy and histological 
assessment. Usually each TDLU contains 200 to 2500 cells. If no TDLUs are seen, deeper sections will be 
obtained. Subsequent slides will be used for biomarker analysis.    
 
• Samples should be collected and processed in the order below: 
Breast Biopsy Sample Priority: 
Sample 1 
FF 
Sample 2-3 
PE 
Sample 4 
RNALater® 
 
• Flash Frozen (FF) sample: Biopsy sample (#1) should be placed directly into pre-labeled cryovial 
and snap frozen on isopentane, or liquid nitrogen, and then temporary storage on dry ice for 
transport to freezer at  -80°C for storage.  
• If the institution does not have access to isopentane, liquid nitrogen may be used.  
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• Snap freeze your samples in liquid nitrogen and put them in a cool rack on dry ice for 
transport to freezer. 
 
• Paraffin Embedded (PE) samples: Two core specimens (#2 and #3) will be placed in a pre-
labeled container of 10% formalin for a maximum of 24-72 hours prior to embedding and processed 
using standard institutional procedures.  
• The minimum number of biopsies required is 2.   
• If this is the case, Sample 1 will be flash frozen and Sample 2 will be paraffin 
embedded. 
 
• RNALater® sample: Biopsy sample (#4) should be placed directly into a pre-labeled cryovial 
containing 5-10 volumes of RNAlater® (we pre-aliquoted at 1.25ml per tube), tube with sample 
should be placed at 4⁰C for at least 24 to 72hrs, then transfer to -80°C for long term storage before 
it’s shipped to MD Anderson on dry ice.  
 
 
10.3 
Shipping Instructions 
 
All samples will be shipped in compliance with the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 
 
All research specimens will be shipped to the laboratory of the Principal Investigator, Banu Arun, M.D. 
The laboratory is equipped with  -80 degree freezers which serve as repositories for research samples.  Ship 
all specimens to the address below: 
 
Angelica Gutierrez Barrera  
6565 MD Anderson Blvd 
Z12.4032 
Houston, TX 77030 
Direct phone: 713-792-1986  
Email: angutier@mdanderson.org 
 
Use Appendix I: Specimen Inventory Form when shipping specimens.  Fill Out One Form Per Patient, 
Per Time-Point. 
 
Do not ship on Thursday, Friday or the day prior to a public holiday. 
 
 
10.4 
Tissue Banking 
 
Biologic specimens collected during the conduct of this clinical trial that are not used during the course of 
the study will be considered deliverables under the contract and thus the property of the NCI. At study 
completion, NCI reserves the option to either retain or relinquish ownership of the unused biologic 
specimens. If NCI retains ownership of specimens, the Contractor shall collect, verify and transfer the 
requested biologic specimens from the site to a NCI-specified repository or laboratory at NCI’s expense.  
 
 
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11. 
REPORTING ADVERSE EVENTS  
 
DEFINITION: AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign), 
symptom, or disease temporally associated with participation in a study, whether or not related to that 
participation. This includes all deaths that occur while a participant is on a study. 
 
Please note that all abnormal clinical laboratory values that are determined to be of clinical significance 
based on a physician’s assessment are to be reported as AEs. Those labs determined to be of no clinical 
significance or of unknown clinical significance (per the physician’s assessment) should not be reported as 
AEs. Any lab value of unknown clinical significance should continue to be investigated/followed-up further 
for a final determination, if possible. 
 
A list of AEs that have occurred or might occur  can be found in §6.2 Reported Adverse Events and Potential 
Risks, as well as the Investigator Brochure or package insert.  
 
 
11.1 
Adverse Events 
 
11.1.1 Reportable AEs 
 
All AEs that occur after the informed consent is signed and baseline assessments are completed (including 
run-in) must be recorded on the AE CRF (paper and/or electronic) whether or not related to study agent. 
 
11.1.2 AE Data Elements: 
 
The following data elements are required for AE reporting. 
• 
AE verbatim term 
• 
NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) AE term 
(MedDRA lowest level term) 
• 
CTCAE (MedDRA) System Organ Class (SOC) 
• 
Event onset date and event ended date 
• 
Treatment assignment code (TAC) at time of AE onset 
• 
Severity grade 
• 
Attribution to study agent (relatedness) 
• 
Whether or not the event was reported as a SAE 
• 
Whether or not the participant dropped out due to the event 
• 
Outcome of the event 
 
11.1.3  Severity of AEs 
 
 
 
11.1.3.1 
Identify the AE using the CTCAE version 4.0. The CTCAE provides descriptive 
terminology (MedDRA lowest level term) and a grading scale for each AE listed. A copy of the CTCAE 
can be found at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
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AEs will be assessed according to the grade associated with the CTCAE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used in the 
CTCAE v4.0. as stated below.  
 
CTCAE v4.0 general severity guidelines:  
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
 
 
ADL 
 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
11.1.4 Assessment of relationship of AE to treatment 
 
 
The possibility that the AE is related to study agent will be classified as one of the following: not related, 
unlikely, possible, probable, definite. 
  
11.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will be 
followed according to good medical practices and documented as such.  
 
 
11.2 
Serious Adverse Events  
 
11.2.1 DEFINITION: Regulations at 21 CFR §312.32 (revised April 1, 2014) defines an SAE as any 
untoward medical occurrence that at any dose has one or more of the following outcomes: 
 
• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to perform normal life 
functions 
• 
A congenital anomaly or birth defect 
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• 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization should also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require intervention to 
prevent one of the other outcomes. 
 
11.2.2 Reporting SAEs  
The organization that experiences the serious adverse event (SAE) should report the SAE to the following 
four (4) entities: 1) NCI DCP; 2) DCP’s regulatory contractor CCSA; 3) MDACC, the CLO; and 4) BHR 
Pharma, LLC.  Detailed reporting instructions are provided below.  In addition, all participating 
organizations will follow Central IRB (CIRB) and their local IRB requirements for SAE reporting.   
 
11.2.2.1 
The Lead Organization and all Participating Organizations will report SAEs on the DCP SAE 
Report Form found at https://prevention.cancer.gov/clinical-trials/clinical-trials-management/protocol-
information-office/pio-instructions-and-tools/2012-consortia. 
 
11.2.2.2 
Contact the DCP Medical Monitor by phone within 24 hours of knowledge of the event.  
 
Marjorie Perloff, MD 
Division of Cancer Prevention 
National Cancer Institute 
9609 Medical, Rm 5E544 
Rockville, MD 200850 
Office Tel (240)276-7097 
Cell (240)731-1772 
FAX (240)276-7847 
Email: perloffm@mail.nih.gov 
 
 
Include the following information when calling the Medical Monitor: 
• 
Date and time of the SAE 
• 
Date and time of the SAE report 
• 
Name of reporter 
• 
Call back phone number 
• 
Affiliation/Institution conducting the study 
• 
DCP protocol number 
• 
Title of protocol 
• 
Description of the SAE, including attribution to drug 
 
11.2.2.3 
Contact the Consortium Lead Organization (CLO) PI, Dr. Powel Brown, or designee by 
phone, fax or email listed on the protocol face page within 24 hours of knowledge of the event.  The same 
information reported to the DCP Medical Monitor should be provided to the CLO PI or designee via email, 
phone or fax within 24 hours of knowledge of the event. 
 
11.2.2.4 
The Lead Organization and all Participating Organizations will email written SAE reports 
to DCP’s Regulatory Contractor CCS Associates, Inc. (CCSA; phone: 650-691-4400) at 
safety@ccsainc.com within 48 hours of learning of the event using the fillable SAE Report Form.    
 
11.2.2.5 
The CLO PI, Dr. Brown, or designee must be copied on the email sent to DCP’s Regulatory 
Contractor CCS Associates, Inc. 
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11.2.2.6 
BHR Pharma, LLC and Besins Pharmacovigilance (pharmacovigilance@besins-
healthcare.com) must be copied on the email sent to DCP’s Regulatory Contractor CCS Associates, Inc. 
 
11.2.2.7 
The DCP Medical Monitor and CCSA regulatory and safety staff will make an initial 
assessment of the SAE and communicate with BHR Pharma, LLC who will determine which SAEs require 
FDA submission as IND safety reports.  
 
11.2.2.8 
BHR Pharma, LLC will provide a standard report for the Lead Organization and all 
Participating Organizations to comply with applicable regulatory requirements related to reporting SAEs 
to the CIRB/IRB/IEC.  
 
11.2.3 Follow-up of SAE 
Site staff should send follow-up reports as requested when additional information is available. Additional 
information should be entered on the DCP SAE Report Form in the appropriate format. Follow-up 
information should be sent to DCP as soon as available, with a copy to BHR Pharma, LLC and Besins 
Pharmacovigilance (pharmacovigilance@besins-healthcare.com). SAEs related to the study agent will be 
followed until resolved.  
 
 
12. 
STUDY MONITORING 
 
12.1 
Data Management 
 
This study will report clinical data using the Data Management Initiative (DMI) web-based application 
managed by the Consortium Biostatistics and Data Management Core.  Data Management Initiative (DMI) 
infrastructure has been developed in the Division of Quantitative Sciences (DQS), MD Anderson Cancer 
Center.  This infrastructure supplies integrated database and software services for web-based data 
collection, randomized treatment assignment, reporting, query, data download, and data quality 
management.  The DMI will be the database of record for the protocol and subject to NCI and FDA audit.  
All DMI users will be trained to use the DMI system and will comply with the instructions in the protocol-
specific “DMI User Manual” as well as applicable regulatory requirements such as 21 CFR; Part 11.  Data 
management procedures for this protocol will adhere to the Data Management Plan (DMP) on file at the 
DCP for contract HHSN261201200034I.  
 
12.2 
Case Report Forms 
 
Participant data will be collected using protocol-specific CRF developed from the standard set of DCP 
Chemoprevention CRF Templates and utilizing NCI-approved Common Data Elements (CDEs). The 
approved CRFs will be used to create the electronic CRF (e-CRF) screens in the DMI application. Site staff 
will enter data into the e-CRFs in DMI. CRF amendments, if needed, will be submitted to the DCP Protocol 
Information Office for review and approval prior to deployment in DMI.  Approved changes will be 
programmed into the DMI database by the Consortium Biostatistics and Data Management Core. 
 
 
12.3 
Source Documents 
 
Source documentation will include only those documents containing original forms of data, including clinic 
charts, shadow files, hospital charts, and physician notes.  Data recorded directly on the CRFs designated 
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as source documents (i.e., no prior written or electronic record of data) will be considered source data.  All 
other data recorded on the CRFs will not be considered source documentation. 
 
 
12.4 
Data and Safety Monitoring Plan 
 
The Data and Safety Monitoring Plan for the MD Anderson Consortium is on file at the DCP.  This study 
will be monitored yearly by the MDACC Data and Safety Monitoring Board (DSMB), the data and safety 
monitoring board of record for this study.   The DSMB reports to the President, or his designee, as the on-
campus representative of The University of Texas Board of Regents. It oversees the data and patient safety 
issues for randomized clinical trials that originate at MD Anderson; that are coordinated or analyzed by 
MD Anderson and are not being monitored by any other DSMB; or have been designated as requiring 
DSMB monitoring at the request of the IRB, the CRC, or institution. The primary objectives of the DSMB 
are to ensure that patients' rights pertaining to participation in a research study are protected, and that 
patients' interests are prioritized over the interests of the scientific investigation. Responsibilities include: 
(a) Review interim analyses of outcome data (prepared by the study statistician or other responsible 
person at the time points defined in the study) approved by the IRB and additional time points 
as determined by the DSMB, and to recommend, if necessary, whether the study needs to be 
changed or terminated based on these analyses; 
(b) Determine whether, and to whom, outcome results should be released prior to the reporting of 
study results; 
(c) Review interim toxicity data and efficacy of treatment; 
(d) Review major research modifications proposed by the investigator or appropriate study 
committee prior to implementation (e.g., termination, dropping an arm based on toxicity results 
from the study or results of other studies, increasing target sample size). 
 
Refer to the Data and Safety Monitoring Plan for the MD Anderson Consortium on file at the DCP for 
further details. 
 
 
12.5 
Sponsor or FDA Monitoring 
 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may 
monitor/audit various aspects of the study. These monitors will be given access to facilities, databases, 
supplies and records to review and verify data pertinent to the study.  
 
 
12.6 
Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to study 
eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as IRB 
records and other regulatory documentation will be retained by the Investigator in a secure storage facility 
in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of Human 
Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidances, and 
NCI/DCP requirements, unless the standard at the site is more stringent. The records for all studies 
performed under an IND will be maintained, at a minimum, for two years after the approval of a New Drug 
Application (NDA). For NCI/DCP, records will be retained for at least three years after the completion of 
the research. NCI will be notified prior to the planned destruction of any materials. The records should be 
accessible for inspection and copying by authorized persons of the Food and Drug Administration. If the 
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study is done outside of the United States, applicable regulatory requirements for the specific country 
participating in the study also apply. 
 
 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) 
 
The agent(s) supplied by DCP, NCI, used in this protocol, is/are provided to the NCI under a Collaborative 
Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) (hereinafter referred to as 
Collaborator(s)) 
and 
the 
NCI 
Division 
of 
Cancer 
Prevention. 
Therefore, 
the 
following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to Collaborator” 
contained within the terms of award, apply to the use of Agent(s) in this study: 
 
12.7.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) 
are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The 
protocol documents for studies utilizing investigational agents contain confidential information and should 
not be shared or distributed without the permission of the NCI. If a participant taking part in the study or 
participant’s family member requests a copy of this protocol, the individual should sign a confidentiality 
agreement. A suitable model agreement can be downloaded from the DCP website. 
 
12.7.2 For a clinical protocol where there is an Investigational Agent used in combination with (an) other 
investigational Agent(s), each the subject of different collaborative agreements, the access to and use of 
data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be 
referred to as "Multi-party Data”). 
 
12.7.3 NCI must provide all Collaborators with prior written notice regarding the existence and nature of 
any agreements governing their collaboration with NIH, the design of the proposed combination protocol, 
and the existence of any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
12.7.4 Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any 
other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain 
regulatory approval, or commercialize its own investigational agent. 
 
12.7.5 Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing 
prior to the commencement of the trials that it will use the Multi-Party Data solely for development, 
regulatory approval, and commercialization of its own investigational agent. 
 
12.7.6 Clinical Trial Data and Results and Raw Data developed under a collaborative agreement will be 
made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate. All data made 
available will comply with HIPAA regulations. 
 
12.7.7 When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators of Collaborator's wish to contact them. 
 
12.7.8 Any manuscripts reporting the results of this clinical trial must be provided to DCP for immediate 
delivery to Collaborator(s) for advisory review and comment prior to submission for publication. 
Collaborator(s) will have 30 days (or as specified in the CTA) from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in 
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order to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to DCP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to DCP prior to release. Copies of any 
manuscript, abstract, and/or press release/ media presentation should be sent to the Protocol Information 
Office at NCI_DCP_PIO@mail.nih.gov.  
 
 
 
 
The Protocol Information Office will forward manuscripts to the DCP Project Officer for distribution to the 
Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/proprietary information. 
 
 
13. 
STATISTICAL CONSIDERATIONS 
 
Note: Mammogram, blood, and tissue samples for participants seen under COVID-19 contingency plan 
will have a range of Month 13-18.  Laboratory tests and research bloods not collected at Month 6 under the 
COVID-19 contingency plan, will result in missing data. 
 
13.1 
Study Design/Description 
 
A total of 198 potentially eligible participants will be consented and screened for eligibility and, with a 
conservative estimate, 158 (80%) participants are expected to be eligible.  These 158 women will be 
randomized 1:1 into one of two groups: placebo or 4-OHT gel 2 mg per breast. Treatment will last for 52 
weeks.  Considering an attrition rate of approximately 19%, we expect to have 128 evaluable women who 
will have both baseline and 52-week measurements of percent MD of the breast, 64 women in each group.   
 
With 64 women in each group, we will have an 80% power to detect a decrease of percent MD of 6% in 
treatment group against 2% in placebo group, with a common standard deviation of 8%, using a two-sided 
t-test with a significance level of 0.05. The proposed difference between the active treatment and placebo 
groups and the standard deviation are based on conservative estimates from the published work by Cuzick 
et al 8. The sample size calculation is performed using nQuery + nTerim 3.0. 
 
 
13.2 
Randomization/Stratification  
 
Participants will be assigned a randomization number once the following has been accomplished: eligibility 
has been verified at the site level, eligibility has been confirmed by the site PI, and eligibility CRF has been 
entered into the DMI web application.  The randomization number will be generated by the database and 
assigned to the participant. 
 
A total of 158 women will be enrolled and randomized 1:1 into one of two groups. Treatment will last for 
52 weeks.  Considering an attrition rate of approximately 19%, we expect to have 128 evaluable women 
who will have both baseline and 52-week measurements of percent MD of the breast, 64 women in each 
group.   
 
We will stratify the randomization by study site (UT MD Anderson Cancer Center, Dana Farber Cancer 
Institute, Northwestern University, Moffitt Cancer Center, University of Arizona Cancer Center, University 
of Minnesota, and University of Wisconsin) and baseline breast density category (heterogeneously dense 
(C), extremely dense (D)) using random permutated block design with the block size of 4.  
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13.3 
Accrual and Feasibility 
 
We plan to consent and screen 198 potential participants over 25 to 30 months at seven clinical centers.  
Our goal is to randomize 158 eligible participants.    The randomized participants will receive the 
intervention for 52 weeks.  They will be followed closely to monitor the toxicity and drug compliance. 
 
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
The primary objective of this study is to evaluate the change in percent MD (using Cumulus software) from 
baseline to the week 52 in women applying 4 mg OHT gel versus placebo based on the intent-to-treat 
principle. The intent-to-treat population is defined as all participants who are randomized and have MD 
measurements from both baseline and 52 weeks.  The primary analysis will be performed comparing the 
active group versus placebo group per randomization, regardless of the compliance of each participant.  
 
The percent MD is the MD (percent dense area) that is visually estimated using both the mediolateral 
oblique (MLO) view and the craniocaudal (CC) view as the proportion of the total breast area that was 
composed of dense tissue (to the nearest 5%). For the study purpose, the densest breast will be the target 
lesion for the primary endpoint. Breast biopsy for secondary and exploratory endpoints will be performed 
in the opposite (non-target) breast. 
 
At the end of the study, all participants who have MD measurements from both baseline and 52 weeks, 
regardless of the compliance, will be included in the primary analysis.  Change in percent MD of the breast 
from baseline to 52 weeks will be summarized using descriptive statistics, such as mean, standard deviation, 
median and range for each arm.  With visual assessments of MD from both the MLO and CC views for 
evaluating the primary endpoint, Hotelling’s T2 test will be used to conduct multivariate hypothesis testing 
which includes both views.  Hotelling’s T2 test represents the multivariate generalization to the independent 
two-sample t-test in the univariate setting. The correlation and variance-covariance matrix will be assessed 
to estimate the level of dependency between the MLO and the CC views.  The mean change in percent MD 
at 52 weeks incorporating both the MLO and CC views will be compared between the two groups utilizing 
Hotelling’s T2 test. Q-Q plots, used to visually assess the assumption of normality, will be constructed for the 
marginal distributions associated with observations emanating from both the MLO and the CC view.  Assuming the 
mean difference in density between the observations between the 4-OHT and the placebo groups is 
approximately normally distributed, then the primary analysis will be conducted as previously described.   
Additionally, a 95% confidence ellipse (simultaneous confidence intervals) for the mean vector containing 
information from both views will be provided.  If the change in density is not normally distributed, then we 
will try to rescale to achieve approximate normality by using the Box-Cox transformation. In our prior 
experience evaluating change in density in response to oral tamoxifen,12 change in density was scaled and 
raised to the 1.75th power to approximate normality. We will have to determine what power to use in the 
Box-Cox transformation based on the data that we have on hand.   Transformations may be performed when 
necessary to make the measure of MD close to normal distribution before evaluating the change of MD 
over time between two groups.  If the Hotelling’s T2 test is significant, we will further examine whether the 
significant difference between the 4-OHT gel group and the placebo group is in the MLO view or the CC 
view or both.  Note that the sample size calculation is based on the two-sample t-test. It provides a 
conservative estimate of the statistical power because the Hotelling’s T2 test is more efficient than the two-
sample t-test.  
 
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We will evaluate if the change of breast density is different in patients with heterogeneously dense (C) vs 
extremely dense (D) breast at baseline, by incorporating this covariate and its interaction with treatment 
over time in the repeated measures analysis.   
 
Due to the COVID-19 closures of clinical research activities, a small number of participants (less than 20) 
will have their month 12 visits by telephone.  These participants will continue the randomized treatments 
and have mammograms in the month 13-18 visits.  The measurements of breast density from the month 13-
18 (instead of month 12) visits will be used as the primary endpoint. We will first provide summary statistics 
for the breast density from the month 13-18 visits, from the month 12 visit, and then graphically explore 
any impact of potentially longer exposures of the treatment on the primary endpoint of mammographic 
breast density. If appropriate, we will incorporate the timing of the measurement as a covariate in the 
analysis to estimate the effect of prolonged exposure of the treatment on mammographic breast density.  
We will also perform a sensitivity analysis by including month 13-18 measures as primary endpoint, and 
by excluding month 13-18 measures to evaluate the impact of the different timing of measurements on the 
primary endpoint analysis.  For the sample size calculation, we have factored in a 19% inevaluable rate.  
Based on the current estimate, even including the follow-up delayed caused by COVID-19, the inevaluable 
rate is still within 19%.  Note that patients who were randomized but never started treatments will be 
replaced if the inevaluable rate is above 19%. 
 
 
13.5 
Secondary and Exploratory Objectives, Endpoints, Analysis Plans 
 
Note: data from Month 13-18 visit instead of Month 12 will be used if participants were seen under the 
COVID-19 Contingency Plan. 
 
The secondary objectives are:  
 
1. To estimate and compare the percent change in mammographic breast density (using Volpara) 
from Baseline to Month 12 in women applying 2mg 4-OHT gel per breast versus placebo.  
2. To estimate and compare the percent change in mammographic breast density (using LIBRA) 
from Baseline to Month 12 in women applying 2mg 4-OHT gel per breast versus placebo.  
3. To compare the percentage of women who underwent a change in BIRADS category, 
comparing pre-and post- treatment measurements, for recipients of active agent versus placebo.  
4. To conduct subgroup analyses including BIRAD category, menopausal status, cup size, and 
total breast volume. 
5. To estimate percentage of women with ≥ 10% absolute decrease in quantitative mammographic 
density percentage between baseline and 12 months, comparing between treated group 2mg 
per breast 4-OHT gel to placebo based on Cumulus method.  
6. To describe symptoms assessed by BCPT Eight Symptom Scale (BESS) questionnaire and 
laboratory toxicity assessment (Factor VIII (F VIII), Von Willebrand (vWB) factor, Sex 
Hormone-Binding Globulin (SHBG), lipid profile). 
7. To evaluate plasma measurements of 4-OHT and related metabolite levels and factors related 
to tamoxifen exposure. 
8. To evaluate tissue measurements of 4-OHT and related metabolite levels and factors related to 
tamoxifen exposure. 
 
 
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The exploratory objectives are: 
 
1. To compare the Cumulus vs. Volpara vs. LIBRA breast density measurement methods to 
estimate percent change in mammographic breast density from baseline to Month 12 in women 
applying 2mg of 4-OHT gel per breast vs. placebo. 
2. To perform correlation of drug concentrations in the plasma and the tissue. 
3. To evaluate plasma measurements of Insulin-like growth factor (IGF) pathway members, C-
reactive protein (CRP), and estradiol. 
4. To compare the 2D natural vs. 2D synthetic breast density measurement using the Cumulus 
method to estimate percent change in mammographic breast density from baseline to Month 
12 in women applying 2mg of 4-OHT gel per breast vs. placebo. 
5. To evaluate tissue biomarkers (among women undergoing optional pre- and post-treatment 
biopsies): 
Terminal duct lobular unit (TDLU) Involution  
Collagen structural changes  
SETER/PR index: estrogen related transcription 
Ki-67, COX-2, p16, CD68.  
6. To examine whether any reductions in mammographic density seen after 1 year of 4-OHT vs. 
placebo gel application persist at 24 months (or longer under the COVID-19 Contingency 
Plan), one year after gel application has stopped. 
 
 
All available data will be summarized and analyzed for the secondary analysis.  At the end of the study, 
participant demographic characteristics; the following measurements at baseline and 52 weeks:  1) MD of 
the breast, 2) tissue biomarkers (among women undergoing optional pre- and post-treatment biopsies: 
TDLU Involution, Collagen structural changes, SET index, Ki-67, COX-2, p16, CD68, etc.), 3) plasma 
measurements of parent drug and related metabolite levels and factors related to 4-OHT exposures, such as 
IGF pathway members, CRP, estradiol, bisphenol and 4-OHT; and the percentage of women with ≥ 10% 
absolute decrease in percent MD between baseline and 52 weeks will be summarized using descriptive 
statistics, such as mean, standard deviation, median and range for continuous variables and 
frequency/percentage for discrete variables.  The difference of continuous variables between baseline and 
52 weeks may be compared between two groups using t-test or Wilcoxon rank sum test, whichever is 
appropriate.  Multivariate analogues to the before mentioned univariate tests, such as Hotelling’s T2 test 
and multivariate multiple regression will be employed when appropriate.  Transformation may be 
performed when necessary to make continuous variables close to normal distribution before evaluating the 
change of these continuous variables over time between two groups using repeated measures analysis where 
the intra-participant correlation is taken into consideration, adjusting for other important covariates. In 
addition, longitudinal data analysis such as the linear mixed effect model will be applied to evaluate the 
mammogram density change over time. The treatment effect will be evaluated adjusting for other important 
covariates. The effect of compliance will be evaluated in the per protocol analysis. 
 
The percentage of women with at least 10% decrease in percent change of MD will be estimated and 
compared between two groups using chi-squared or Fisher’s exact test whichever appropriate.  We will also 
explore the correlation between percent change in MD and other markers using Spearman correlation at 
baseline or by employing repeated measures analysis when both baseline and 52-week data are included 
and intra-participant correlation is accounted for.  We will also monitor and summarize any adverse events 
observed in women on this study. 
 
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The change in percent MD of the breast from the end of the treatment at 1 year to 1 year after the treatment 
ends will also be summarized using descriptive statistics, such as mean, standard deviation, median and 
range for each arm.  The difference of this change in percent MD will be compared between two treatment 
groups using t-test or Wilcoxon rank sum test, when appropriate.  Multivariate methods such as 
simultaneous 95% confidence intervals will be used for estimation purposes when appropriate.   
 
We will define three groups of participants by the menopausal status change during the study, pre-
menopausal/pre-menopausal, pre-menopausal/post-menopausal and post-menopausal/post-menopausal, 
and compare the change of MD and other secondary endpoints among these three groups of participants 
by Kruskal-Wallis test. We may incorporate this grouping covariate in the repeated measures analysis to 
evaluate any differential effect of menopausal status change on the change of endpoints by treatment over 
time.  Sensitivity analysis on the treatment effect with and without including women who undergo 
menopausal transition will be performed. Sensitivity analysis on the treatment effect with and without 
including women on hormone replacement therapy will be performed. The treatment effect will be 
analyzed by incorporating the longitudinally measured compliance data as a covariate.     
 
If prior imaging is available (mammogram or other modalities), the data will be collected and summarized. 
Other statistical methods, such as the MANOVA and multivariate multiple regression, may be used when 
appropriate. 
 
 
13.6 
Reporting and Exclusions 
 
Every reasonable attempt will be made to recover any missing data.  If any data for the primary efficacy 
measure remains missing, then the change of the primary endpoint will not be calculated, and the participant 
will not be evaluable for the primary endpoint.  We will also consider multiple imputations using predictive 
values based on regression models under the assumption of missing at random to supplement the primary 
analysis.  In addition, any available data will be included in the repeated measure analysis for both primary 
and secondary endpoints, which allows for all participants with complete or partial data.   
 
 
13.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of 4-OHT gel 4 mg or placebo.  
The grade, attribution, onset and resolve date of all toxicities will be recorded and summarized for each 
arm and reported to the DCP monthly and to the DSMB annually as well as at the end of the study.  
 
 
13.8 
Evaluation of Response 
 
All participants included in the study must be assessed for response to intervention, even if there are major 
protocol deviations or if they are ineligible.  
 
All of the participants who met the eligibility criteria (with the possible exception of those who did not 
receive study agent) will be included in the main analysis. All conclusions regarding efficacy will be based 
on all eligible participants. 
 
Subanalyses may be performed on the subsets of participants, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation of intervention, 
major protocol violations, etc.). However, subanalyses may not serve as the basis for drawing conclusions 
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concerning efficacy, and the reasons for excluding participants from the analysis should be clearly reported. 
For all measurements of response, the 95% confidence intervals should also be provided. 
 
 
13.9 
Interim Analysis 
 
There is no interim analysis planned. 
 
 
13.10 Ancillary Studies  
 
No ancillary studies are planned. 
 
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1 
Form FDA 1572 
 
Prior to initiating this study, the Protocol Lead Investigator at the Lead or Participating Organization(s) will 
provide a signed Form FDA 1572 stating that the study will be conducted in compliance with regulations 
for clinical investigations and listing the investigators, at each site that will participate in the protocol. All 
personnel directly involved in the performance of procedures required by the protocol and the collection of 
data should be listed on Form FDA 1572. 
 
 
14.2 
Other Required Documents 
 
14.2.1 Current (within two years) CV or biosketch for all study personnel listed on the Form FDA 1572 
and Delegation of Tasks form for the Lead Organization and all Participating Organizations.  
 
14.2.2 Current medical licenses (where applicable) for all study personnel listed on Form FDA 1572 and 
Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.3 Lab certification (e.g., CLIA, CAP) and lab normal ranges for all labs listed on Form FDA 1572 
for the Lead Organization and all Participating Organizations. 
 
14.2.4 Documentation of training in “Protection of Human Research Subjects” for all study personnel 
listed on the FDA Form 1572 and Delegation of Tasks form for the Lead Organization and all Participating 
Organizations. 
 
14.2.5 Documentation of training in “Good Clinical Practice” for all study personnel listed on the FDA 
Form 1572 and Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.6 Documentation of Federalwide Assurance (FWA) number for the Lead Organization and all 
Participating Organizations. 
 
14.2.7 Signed Investigator’s Brochure/Package Insert acknowledgement form. 
 
14.2.8 Delegation of Tasks form for the Lead Organization and all Participating Organizations signed by 
the Principal Investigator and all study personnel listed on the form for each site. 
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14.2.9 Signed and dated NCI, DCP Financial Disclosure Form for all study personnel listed on Form FDA 
1572 for the Lead Organization and all Participating Organizations. 
 
 
14.3 
Institutional Review Board Approval 
 
Prior to initiating the study and receiving agent, the Investigators at the Lead Organization and the 
Participating Organization(s) must obtain written approval to conduct the study from the CIRB. Should 
changes to the study become necessary, protocol amendments will be submitted to the DCP PIO according 
to DCP Amendment Guidelines. The DCP-approved amended protocol must be approved by the CIRB 
prior to implementation 
 
 
14.4 
Informed Consent 
 
All potential study participants will be given a copy of the CIRB and IRB-approved Informed Consent to 
review. The investigator will explain all aspects of the study in lay language and answer all questions 
regarding the study. If the participant decides to participate in the study, she will be asked to sign and date 
the Informed Consent document. The study agent(s) will not be released to a participant who has not signed 
the Informed Consent document. Individuals who refuse to participate or who withdraw from the study will 
be treated without prejudice. 
 
Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues 
obtained during testing, operative procedures, or other standard medical practices for further research 
purposes. If applicable, statement of this option may be included within the informed consent document or 
may be provided as an addendum to the consent. A Model Consent Form for Use of Tissue for Research is 
available through a link in the DCP website. 
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, the 
Consortium Lead Organization, and the IRB at each Organization at which the protocol will be 
implemented. Any subsequent changes to the informed consent must be approved by NCI, DCP, the 
Consortium Lead Organization’s IRB, and then submitted to each organization’s IRB for approval prior to 
initiation. 
 
 
14.5 
Submission of Regulatory Documents 
 
All regulatory documents are collected by the Consortia Lead Organization and reviewed for completeness 
and accuracy. Once the Consortia Lead Organization has received complete and accurate documents from 
a participating organization, the Consortium Lead Organization will forward the regulatory documents to 
DCP’s Regulatory Contractor: 
 
 
Paper Document/CD-ROM Submissions: 
 
Regulatory Affairs Department 
 
CCS Associates, Inc. 
2001 Gateway Place, Suite 350 West 
San Jose, CA 95110 
 
Phone: 650-691-4400 
 
Fax: 650-691-4410 
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E-mail Submissions: 
 
regulatory@ccsainc.com 
 
Regulatory documents that do not require an original signature may be sent electronically to the Consortium 
Lead Organization for review, which will then be electronically forwarded to DCP’s Regulatory Contractor. 
 
14.6 
Other 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
Participants will not be responsible for non-standard of care costs of this study. Study agent will be provided 
at no cost to the participant. There will be compensation for additional expenses associated with study visits, 
such as additional travel expenses, time missed from work or other expenses.   The amount of compensation 
will be $100 associated with the Baseline study visit, Month 6 and Month 12, and $150 at the time of each 
biopsy for those who agree to the procedure. Under the COVID-19 Contingency Plan, the amount of 
compensation will be $100 associated with the Baseline study visit, Month 6 telephone call and Month 13-
18 visit, and $150 at the time of each biopsy for those who agree to the procedure.   If, as a result of 
participation in this study, an individual experiences injury from known or unknown risks of the research 
procedures as described in the informed consent, immediate medical care and treatment, including 
hospitalization, if necessary, will be available.  No monetary compensation is available for the costs of 
medical treatment for an injury, thus, the participant will be responsible for the costs of such medical 
treatment, either directly or through their medical insurance and/or other forms of medical coverage.   
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REFERENCES 
 
 
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Huo Z, Giger ML, Olopade OI, et al: Computerized Analysis of Digitized Mammograms 
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Boyd NF, Martin LJ, Yaffe MJ, et al: Mammographic density and breast cancer risk: 
current understanding and future prospects. Breast Cancer Res 13:223, 2011 
 
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age: implications for breast cancer screening. AJR Am J Roentgenol 198:W292-5, 2012 
 
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Cuzick J, Warwick J, Pinney E, et al: Tamoxifen-induced reduction in mammographic 
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Nyante SJ, Sherman ME, Pfeiffer RM, et al: Prognostic significance of mammographic 
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Ko KL, Shin IS, You JY, et al: Adjuvant tamoxifen-induced mammographic breast density 
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Breast Cancer Res Treat 142:559-67, 2013 
 
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Lienart V, Carly B, Kang X, et al: Effect of preventive hormonal therapy on breast density: 
a systematic qualitative review. ScientificWorldJournal 2014:942386, 2014 
 
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Russo J, Hu Y-F, Yang X, et al: Chapter 1: Developmental, Cellular, and Molecular Basis 
of Human Breast Cancer. JNCI Monographs 2000:17-37, 2000 
 
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Milanese TR, Hartmann LC, Sellers TA, et al: Age-Related Lobular Involution and Risk 
of Breast Cancer. Journal of the National Cancer Institute 98:1600-1607, 2006 
 
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Baer HJ, Collins LC, Connolly JL, et al: Lobule type and subsequent breast cancer risk: 
results from the Nurses' Health Studies. Cancer 115:1404-11, 2009 
 
18. 
Ghosh K, Vachon CM, Pankratz VS, et al: Independent association of lobular involution 
and mammographic breast density with breast cancer risk. J Natl Cancer Inst 102:1716-23, 2010 
 
19. 
Boyd NF: Tamoxifen, mammographic density, and breast cancer prevention. J Natl Cancer 
Inst 103:704-5, 2011 
 
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Boyd NF, Martin LJ, Bronskill M, et al: Breast tissue composition and susceptibility to 
breast cancer. J Natl Cancer Inst 102:1224-37, 2010 
 
21. 
Provenzano PP, Eliceiri KW, Campbell JM, et al: Collagen reorganization at the tumor-
stromal interface facilitates local invasion. BMC Med 4:38, 2006 
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22. 
Provenzano PP, Eliceiri KW, Yan L, et al: Nonlinear optical imaging of cellular processes 
in breast cancer. Microsc Microanal 14:532-48, 2008 
 
23. 
Provenzano PP, Inman DR, Eliceiri KW, et al: Collagen density promotes mammary tumor 
initiation and progression. BMC Med 6:11, 2008 
 
24. 
Provenzano PP, Inman DR, Eliceiri KW, et al: Contact guidance mediated three-
dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys J 
95:5374-84, 2008 
 
25. 
Conklin MW, Eickhoff JC, Riching KM, et al: Aligned collagen is a prognostic signature 
for survival in human breast carcinoma. Am J Pathol 178:1221-32, 2011 
 
26. 
Symmans WF, Hatzis C, Sotiriou C, et al: A genomic index of sensitivity to endocrine 
therapy of breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 28:4111-9, 2010 
 
27. 
Harper-Wynne C, Ross G, Sacks N, et al: Effects of the Aromatase Inhibitor Letrozole on 
Normal Breast Epithelial Cell Proliferation and Metabolic Indices in Postmenopausal Women: A Pilot 
Study for Breast Cancer Prevention. Cancer Epidemiol Biomarkers Prev 11:614-621, 2002 
 
28. 
Fabian CJ, Kimler BF, Zalles CM, et al: Reduction in proliferation with six months of 
letrozole in women on hormone replacement therapy. Breast Cancer Res Treat, 2007 
 
29. 
Fabian C, Kimler B, Donnelly J, et al: Favorable modulation of benign breast tissue and 
serum risk biomarkers is associated with >10 % weight loss in postmenopausal women. Breast Cancer 
Research and Treatment 142:119-132, 2013 
 
30. 
Fabian CJ, Kimler BF, Zalles CM, et al: Reduction in Ki-67 in Benign Breast Tissue of 
High-Risk Women with the Lignan Secoisolariciresinol Diglycoside. Cancer Prevention Research 3:1342-
1350, 2010 
 
31. 
Fabian CJ, Kimler BF, Anderson J, et al: Breast Cancer Chemoprevention Phase I 
Evaluation of Biomarker Modulation by Arzoxifene, a Third Generation Selective Estrogen Receptor 
Modulator 
10.1158/1078-0432.CCR-04-0171. Clin Cancer Res 10:5403-5417, 2004 
 
32. 
Herschman HR: Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. 
Cancer Metastasis Rev 13:241-56, 1994 
 
33. 
Harris RE: Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. Subcell 
Biochem 42:93-126, 2007 
 
34. 
Harris RE: Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the 
colon, breast, prostate, and lung. Inflammopharmacology 17:55-67, 2009 
 
35. 
Kamb A, Gruis NA, Weaver-Feldhaus J, et al: A cell cycle regulator potentially involved 
in genesis of many tumor types. Science 264:436-40, 1994 
 
36. 
Shin E, Jung WH, Koo JS: Expression of p16 and pRB in invasive breast cancer. Int J Clin 
Exp Pathol 8:8209-17, 2015 
 
37. 
Mantovani A, Marchesi F, Porta C, et al: Inflammation and cancer: breast cancer as a 
prototype. Breast 16 Suppl 2:S27-33, 2007 
 
38. 
Rinaldi S, Peeters PHM, Berrino F, et al: IGF-I, IGFBP-3 and breast cancer risk in women: 
The European Prospective Investigation into Cancer and Nutrition (EPIC). Endocrine-Related Cancer 
13:593-605, 2006 
 
39. 
Bonanni B, Johansson H, Gandini S, et al: Effect of low dose tamoxifen on the insulin-like 
growth factor system in healthy women. Breast Cancer Res Treat 69:21-7, 2001 
 
40. 
Torrisi R, Baglietto L, Johansson H, et al: Effect of raloxifene on IGF-I and IGFBP-3 in 
postmenopausal women with breast cancer. Br J Cancer 85:1838-41., 2001 
 
41. 
Arun B, Valero V, Liu D, et al: Short-term biomarker modulation prevention study of 
anastrozole in women at increased risk for second primary breast cancer. Cancer Prev Res (Phila) 5:276-
82, 2012 
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Appendix A 
 
 
APPENDIX A 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
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Appendix B 
 
Appendix B 
 
GEL APPLICATION INSTRUCTIONS 
 
1. Flammable: do not apply near fire, flame or heat, or while smoking.  
 
2. If you had a biopsy, start applying the gel at least 24 hours after the biopsy.  
 
3. Apply the gel to your own breasts after bathing, preferably in the morning and at approximately the same 
time each day.  Night-time application is acceptable, but caution should be taken to limit transfer to other 
individuals. 
 
4. To apply, remove the cap from the bottle. When you use a bottle for the first time, you must prime it by 
pressing the pump fully several times until gel is dispensed (point the spout toward a sink or wastebasket 
and do not use the first dose, which may be incorrect).  
 
5. Once the bottle is primed, hold it in one hand and place the palm of your other hand under the pump to 
catch the gel. Be sure to press down completely on the pump and release it completely to dispense one dose 
of gel.  
 
6. Apply one pump worth of gel to each breast at one time.  Do not apply more or less than this amount 
to each breast. Be sure to release the pump completely between actuations.  
 
7. If you accidentally pump more than is needed for one breast, please discard this dose and try again to get 
the correct dose. If you do discard pumped doses, please record this on your study diary.  
 
8. Start around the nipple.  Spread outwards until you reach edge of breast bone, below collar bone 
(clavicle), to the fold under the breast, and to the outer edge of the breast (see picture below). 
 
9. Do not apply to the nipple. Starting at the areola spread the gel evenly over the entire surface of your 
breast (see green area in the picture below). Do not rub the gel into the skin. 
 
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10. The gel should not be applied to any other part of the body. 
 
11. Wash your hands with soap and water immediately after applying the gel.  
 
12. Allow the gel on your breasts to air dry for 2 minutes and then immediately cover with clothing (the gel 
is colorless and will not stain your clothing). Once dry, the gel is no longer flammable. Do not expose your 
bare breasts to sunlight at any time.  
 
13. Do not apply any other cream, lotion or moisturizer to your breasts for at least 4 hours following 
application of the study gel.  If cream, lotion, or moisturizer is used between applications, wash the breast 
skin before applying the next dose. 
 
14. Do not wash your breasts or immerse in water (bath, swim) for at least 4 hours following application of 
the gel. If this is not possible, delay application of the gel that day until after immersion, and be sure to 
follow all the above instructions. If you regularly swim in the morning, it is better to apply the gel 
afterwards, after your shower.  
 
15. After use, replace the cap on the bottle.  
 
16. Avoid exposure of the treated breast skin to natural or artificial sunlight. This includes sunbathing or 
the use of tanning beds with the breasts exposed. Also, if you have dermatologic conditions causing the 
breakdown of skin in the area of gel application, you should not use 4-OHT gel. 
 
 
RECOMMENDATIONS:  
 
1. If you forget to apply a dose, do not double the dose to “catch up”. If your next dose is scheduled within 
the next 12 hours, it is best just to wait; if it is more than 12 hours until your next dose, apply the dose you 
missed and resume your normal dosing after that.  
 
2. For the duration of the study, avoid contact between the application area and the skin of other individuals 
(i.e. your child, your sexual partner, or other persons). If necessary, skin contact is allowable after the 
breasts have been washed. As noted above, you must wait at least 4 hours following application before 
washing the application area, otherwise, delay application until after washing and contact.  
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Appendix B 
 
 
3. Do not ingest or swallow the gel. For external use only.  
 
4. Please record your use of 4-OHT in your 4-OHT diary.  
 
5. If the pump doesn’t come back up correctly or if there’s no gel delivered when you press down on the 
pump, do not use this bottle and notify your doctor immediately.  
 
6. After the end of study treatment, be sure to take back to your doctor all the gel bottles you have been 
given (even if empty or not used). This is very important for the success of the study.  
 
 
 
STORAGE INSTRUCTIONS:  
 
1. Keep your gel bottles in a cool room temperature, between 59°F and 77°F.  
 
2. Avoid extreme heat or cold during transportation from the clinic to home, and when traveling. 
 
3. Keep the gel bottles out of the reach of children.  
 
 
TRAVEL:  
 
Your gel is a prescription medication.  You may bring the gel in your carry-on bag. Please refer to the 
Transportation Security Administration web site for further details: https://www.tsa.gov/travel/special-
procedures 
 
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Appendix C 
 
APPENDIX C 
 
COMPLIANCE DRUG LABELS 
 
(Use this Form at Randomization and Month 6) 
 
INSTITUTION CODE 
 
__________________________ 
PARTICIPANT ID 
 
________________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY)  
___ ___ / ___ ___ / ___ ___ ___ ___ 
 
Affix Labels Here: 
 
Were Labels Affixed?   
 
 Yes  
 
 No  
 
 
 
 
 
Investigator’s Signature: ____________________      Date of Investigator’s Signature: _ _ / _ _ / _ _ _ _  
                                                                                                                                                        (MM/DD/YYYY) 
 
Investigator’s Name (Please Print): ________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix D 
 
 
APPENDIX D 
 
4-OHT Diary 
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–1– 
 
4-OHT Diary [IRB #:                     ] 
 
 
PID: __ __ __ __ __ __ __ __ __ __     Site: __ __ __ __ __ 
Amount of Agent Provided: _______ canisters 
Canister ___of   5 
Total Daily Dose: 1 pump actuation to each breast once a day [4 mg total (2 mg per 
breast)] 
Number of Canisters Returned: ________ 
Weight of Canisters Returned: ________(grams) 
Agent Returned:  □ Yes □ No 
Visit#: ______ 
 
INSTRUCTIONS: 
1. Please complete daily.  You should apply 1 pump actuation to each breast once a day. 
2. If you forget to apply a dose, do not double the dose to “catch up”. If your next dose is 
scheduled within the next 12 hours, it is best just to wait; if it is more than 12 hours until 
your next dose, apply the dose you missed and resume your normal dosing after that. 
3. Each canister provides 40 days of gel application for both breasts.  After 40 days of gel 
application, switch to a new canister and calendar.  Do not discard any canisters.  Bring all 
used and unused canisters and calendars to your next appointment. 
4. Store the study gel at home at room temperature and avoid extreme heat or cold during 
transportation from the clinic to home. 
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–2– 
4-OHT Diary Continued 
Please Bring this Sheet to Your Next Visit 
Day 
Date 
Initials 
# of pump actuations to 
right breast 
# of pump actuations to 
left breast 
Did you experience 
any symptoms, if 
“Yes” list below 
1 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
2 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
3 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
4 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
5 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
6 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
7 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
8 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
9 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
10 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
11 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
12 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
13 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
14 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
15 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
16 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
17 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
18 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
19 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
20 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
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Participant Signature:       __________________________________________ 
Date: ___________________ 
 
Reviewer’s Signature: _____________________________________________  
Date: ___________________ 
21 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
22 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
23 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
24 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
25 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
26 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
27 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
28 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
29 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
30 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
31 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
32 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
33 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
34 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
35 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
36 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
37 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
38 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
39 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
40 
 
 
_____     or   □Missed 
Dose 
_____     or   □Missed 
Dose 
 
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Comments: 
__________________________________________________________________________________________
__________________________________________________________________________________________ 
__________________________________________________________________________________________ 
 
 
Proprietary of MD Anderson Cancer Center 


MDA2016-07-02 
Protocol Version 20, Dated 02/07/2022 
Appendix E 
 
APPENDIX E 
 
BESS QUESTIONNAIRE 
 
*The completed form is to be used as source  
 
Proprietary of MD Anderson Cancer Center 


MDA2016-07-02 
Protocol Version 20, Dated 02/07/2022 
1 
 
 
BESS QUESTIONNAIRE 
 
We are interested in knowing whether you have had any of the following problems during the PAST TWO 
WEEKS. Please mark the number which best describes how much each problem bothered you. 
 
 PROBLEM 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
 
Extremely 
 
C1 
Difficulty concentrating 
0 
1 
2 
3 
4 
C2 
Easily distracted 
0 
1 
2 
3 
4 
C3 
Forgetfulness 
0 
1 
2 
3 
4 
M1 
Joint pain 
0 
1 
2 
3 
4 
M2 
Muscle stiffness 
0 
1 
2 
3 
4 
M3 
General aches and pains 
0 
1 
2 
3 
4 
V1 
Night sweats 
0 
1 
2 
3 
4 
V2 
Hot flashes 
0 
1 
2 
3 
4 
V3 
Cold sweats 
0 
1 
2 
3 
4 
Ga1 
Vomiting 
0 
1 
2 
3 
4 
Ga2 
Nausea 
0 
1 
2 
3 
4 
Ga3 
Diarrhea 
0 
1 
2 
3 
4 
D1 
Vaginal dryness 
0 
1 
2 
3 
4 
D2 
Pain with intercourse 
0 
1 
2 
3 
4 
W1 
Weight gain 
0 
1 
2 
3 
4 
W2 
Unhappy with the 
appearance of my body 
0 
1 
2 
3 
4 
Gy1 
Vaginal discharge 
0 
1 
2 
3 
4 
Gy2 
Genital itching/irritation 
0 
1 
2 
3 
4 
Gy3 
Vaginal bleeding or spotting 
0 
1 
2 
3 
4 
B1 
Difficulty with bladder 
control (when laughing or 
crying) 
0 
1 
2 
3 
4 
 
 
 
INSTITUTION CODE 
 
__________________________ 
PARTICIPANT ID 
 
________________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY)  
___ ___ / ___ ___ / ___ ___ ___ ___ 
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BESS QUESTIONNAIRE (cont’d) 
 
 
        PROBLEM 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
 
Extremely 
 
B2 
Difficulty with bladder control  
(at other times) 
0 
1 
2 
3 
4 
P1 
Headaches 
0 
1 
2 
3 
4 
P2 
Blind spots, fuzzy vision 
0 
1 
2 
3 
4 
P3 
Constipation 
0 
1 
2 
3 
4 
P4 
Cramps 
0 
1 
2 
3 
4 
P5 
Breast sensitivity/tenderness 
0 
1 
2 
3 
4 
P6 
Ringing in ears 
0 
1 
2 
3 
4 
P7 
Chest pains 
0 
1 
2 
3 
4 
P8 
Swelling of hands or feet 
0 
1 
2 
3 
4 
P9 
Difficulty breathing 
0 
1 
2 
3 
4 
P10 
Dry mouth 
0 
1 
2 
3 
4 
P11 
Weight loss 
0 
1 
2 
3 
4 
P12 
Decreased appetite 
0 
1 
2 
3 
4 
P13 
Feeling of suffocation 
0 
1 
2 
3 
4 
P14 
Excitability 
0 
1 
2 
3 
4 
P15 
Short temper 
0 
1 
2 
3 
4 
P16 
Tendency to take naps; stay in 
bed 
0 
1 
2 
3 
4 
P17 
Tendency toward accidents 
0 
1 
2 
3 
4 
P18 
Avoidance of social affairs 
0 
1 
2 
3 
4 
P19 
Dizziness, faintness 
0 
1 
2 
3 
4 
P20 
Numbness, tingling 
0 
1 
2 
3 
4 
 
 
 
INSTITUTION CODE 
 
__________________________ 
PARTICIPANT ID 
 
________________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY)  
___ ___ / ___ ___ / ___ ___ ___ ___ 
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Protocol Version 20, Dated 02/07/2022 
3 
 
 
BESS QUESTIONNAIRE (cont’d) 
 
 
P21 
Early awakening 
0 
1 
2 
3 
4 
P22 
Abdominal pain 
0 
1 
2 
3 
4 
P23 
Pain or cramps in the legs or 
feet 
0 
1 
2 
3 
4 
P24 
Back pain or problems 
0 
1 
2 
3 
4 
P25 
Low energy 
0 
1 
2 
3 
4 
P26 
Blurred vision 
0 
1 
2 
3 
4 
P27 
Any other problems? 
Please Specify:_________________________________ 
_____________________________________________ 
_____________________________________________ 
 
 
 
 
___________________________ 
Participant Name 
 
 
__________________________ 
Participant Signature 
 
 
__________________________ 
Date 
 
 
 
INSTITUTION CODE 
 
__________________________ 
PARTICIPANT ID 
 
________________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY)  
___ ___ / ___ ___ / ___ ___ ___ ___ 
Proprietary of MD Anderson Cancer Center 


MDA2016-07-02 
Protocol Version 20, Dated 02/07/2022 
Appendix F 
 
 
APPENDIX F 
 
Alcohol and Tobacco Use Assessment Questionnaires – Baseline 
Proprietary of MD Anderson Cancer Center 


MDA2016-07-02 
Protocol Version 20, Dated 02/07/2022 
1 
 
ALCOHOL ASSESSMENT – BASELINE 
 
Instructions: 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. beer, a 5 oz. 
glass of wine, or one and a half ounces of liquor. 
 
1. In your entire life, have you had at least 12 drinks of any kind of alcoholic beverage?  
 
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. In the past 12 months, on average, how often did you drink any type of alcoholic beverage?  
 
________ (Enter the number of days you drank based on the timeframe checked below.  Enter 0 if 
you never drank and skip to Question 6.)  
 Week  
 Month 
 Year 
 Refused 
 Don’t know/Not sure 
 
3. In the past 12 months, on those days that you drank alcoholic beverages, on average, how many drinks   
did you have per day?  
 
________ (Enter the average number of drinks per day) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 12 months, on how many days did you have 5 or more drinks of any alcoholic beverage?  
 
_________ (Enter the number of days you had 5 or more drinks, or enter 0 if none.) 
 
 Refused 
 Don’t know/Not sure 
 
5. Was there ever a time or times in your life when you drank 5 or more drinks of any kind of alcoholic 
beverage almost every day?  
 
 Yes 
 No  
 Refused 
INSTITUTION CODE 
 
________________ 
PARTICIPANT ID 
 
______________ 
VISIT TYPE 
 
________________ 
VISIT DATE 
(MM/DD/YYYY)  
___ ___ / ___ ___ / ___ ___ ___ ___ 
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MDA2016-07-02 
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2 
 
 Don’t know/Not sure 
 
6. If you do not currently drink alcoholic beverages, but did in the past, how long has it been since 
you last drank regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago  
 Don’t know/Not sure 
 Never drank regularly 
 
7. At the heaviest point, either now or in the past, on the days when you drank, about how many drinks 
did you drink a day on the average?  
 
__________ (Enter the number of drinks a day) 
 Refused 
 Don’t know/Not sure 
 
8. How many years have you been drinking (or did drink) regularly?  
 
______ years 
 Refused 
 Don’t know/Not sure  
 
9. At what age did you begin drinking regularly?  
 
______ years of age 
 Refused 
 Don’t know/Not sure  
 
10. What type(s) of alcohol do you drink? (Mark ALL that apply) 
 
 Wine 
 Liquor 
 Beer 
 Wine cooler 
 
 
Signature of Individual Completing This Form___________________   Date  __ __ / __ __ / __ __ __ __ 
(MM/DD/YYYY) 
Name of Individual Completing This Form (please print) ______________________________________ 
 
 
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MDA2016-07-02 
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TOBACCO ASSESSMENT – BASELINE 
 
 
Section A. Basic Cigarette Use Information 
 
1. Have you smoked at least 100 cigarettes (5 packs = 100 cigarettes) in your entire life? 
 
Yes  
 
 No → Skip to Section B 
 Don’t know/Not sure → Skip to Section B 
 
2. How old were you when you first smoked a cigarette (even one or two puffs)? 
 
_______ Years old  
 
3. How old were you when you first began smoking cigarettes regularly?   
 
_______ Years old  
  Check here if you have never smoked cigarettes regularly. 
 
4. How many total years have you smoked (or did you smoke) cigarettes? Do not count any time you may 
have stayed off cigarettes. 
 
______ Years (If you smoked less than one year, write “1.”)  
 
5. On average when you have smoked, about how many cigarettes do you (or did you) smoke a day? (A 
pack usually has 20 cigarettes in it).  
 
_____ Number of cigarettes per day 
 
6. Do you NOW smoke cigarettes?  
 
 Everyday 
 Some days 
 Not at all → Skip to question 8 
 
7.  How soon after you wake up do you smoke your first cigarette?  
 
  Within 30 minutes 
  After 30 minutes 
 
 
INSTITUTION CODE 
 
________________ 
PARTICIPANT ID 
 
______________ 
VISIT TYPE 
 
________________ 
VISIT DATE 
(MM/DD/YYYY)  
___ ___ / ___ ___ / ___ ___ ___ ___ 
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4 
 
 
8. How long has it been since you last smoked a cigarette (even one or two puffs)? 
 
First check which one of the following choices applies to you. Then, if applicable, write a number on 
the line 
for how many days, weeks, months, or years it has been since your last cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette  ________ 
 Less than 1 month → Number of weeks since last cigarette  _________ 
 Less than 1 year → Number of months since last cigarette  __________ 
 More than 1 year → Number of years since last cigarette  ___________ 
 Don’t know/Don’t remember 
 
Section B. Use of Other Forms of Tobacco 
 
9.  Have you ever used other forms of tobacco, not including cigarettes? 
  
 Yes  
 No → Skip to Section C 
 
10. How often do you/did you use other forms of tobacco?  
 
 Every day → Number of times per day  ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
Year 
 
11. Which of the following products have you ever used regularly? 
 Check all that apply  
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Please specify:___________________________ 
 
 
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12. If you do not currently use other forms of tobacco, but did in the past, how long has it been since you 
last used other forms of tobacco regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
Section C. Second-Hand Smoke Exposure 
 
13. Are you currently living with a smoker?   
 
Yes 
 
 No  
 
14. In the past 30 days, have you lived in a place where other people smoked cigarettes indoors?  
 
Yes 
 
 No  
 
15. In the past 30 days, have you worked in a place where other people smoked cigarettes indoors? 
 
Yes 
 
 No  
 
16. Thinking of all your childhood and adult years, have you ever lived in a place where other people 
smoked cigarettes indoors? 
 
 Yes 
In total, for about how many years?_______ If less than 1, write “1.”   
 No  
 
17. Thinking of all the years you have worked, have you ever worked in a place where other people 
smoked cigarettes indoors?    
 
Yes 
→ In total, for about how many years?_______ If less than 1, write “1.”    
 No 
 
 
Signature of Individual Completing This Form___________________   Date  __ __ / __ __ / __ __ __ __ 
(MM/DD/YYYY) 
Name of Individual Completing This Form (please print) ______________________________________
Proprietary of MD Anderson Cancer Center 


MDA2016-07-02 
Protocol Version 20, Dated 02/07/2022 
Appendix G 
 
APPENDIX G 
 
Alcohol and Tobacco Use Assessment Questionnaires – Month 12 
 
 
Proprietary of MD Anderson Cancer Center 


MDA2016-07-02 
Protocol Version 20, Dated 02/07/2022 
1 
 
ALCOHOL ASSESSMENT – MONTH 12 
 
Instructions: 
 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. beer, a 5 oz. 
glass of wine, or one and a half ounces of liquor. 
 
1. During the past 30 days, did you drink any alcoholic beverages?  
 
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. During the past 30 days, how many days per week or per month did you drink any alcoholic beverages, 
on the average?  
 
________ (Enter number of days you drank based on the timeframe checked below.  Enter 0 if you 
did not drink.)  
 
 Week  
 Month 
 Refused 
 Don’t know/Not sure 
 
3. On the days when you drank, on average, about how many drinks did you have?  
 
________ (Enter the average number of drinks you had per day.) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 30 days, on how many days did you have 5 or more drinks per day?  
 
_____________Number of times 
 
 None  
 Do not know/Not sure 
 
 
Signature of Individual Completing This Form___________________   Date  __ __ / __ __ / __ __ __ __ 
(MM/DD/YYYY) 
Name of Individual Completing This Form (please print) ______________________________________ 
 
 
INSTITUTION CODE 
 
________________ 
PARTICIPANT ID 
 
______________ 
VISIT TYPE 
 
________________ 
VISIT DATE 
(MM/DD/YYYY)  
___ ___ / ___ ___ / ___ ___ ___ ___ 
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MDA2016-07-02 
Protocol Version 20, Dated 02/07/2022 
2 
 
TOBACCO ASSESSMENT – MONTH 12 
 
 
 
1. Do you NOW smoke cigarettes?  
 
 Everyday 
 Some days 
 Not at all → Skip to Question 3 
 Never Smoked → Skip to Question 4. 
 
 
2. On average, when you smoked, about how many cigarettes do you (or did you) smoke a day? (A pack 
usually has 20 cigarettes in it).    
 
_____ Number of cigarettes per day 
 
3. How long has it been since you last smoked a cigarette (even one or two puffs)?    
 
First check which one of the following choices applies to you. Then, if applicable, write a number on 
the line  
for how many days, weeks, months, or years it has been since your last cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette ________ 
 Less than 1 month → Number of weeks since last cigarette _________ 
 Less than 1 year → Number of months since last cigarette __________ 
 More than 1 year → Number of years since last cigarette ___________ 
 Don’t know/Don’t remember 
 
4. Since your last visit, have you used other forms of tobacco, not including cigarettes?  
 
 Yes 
  No (End) 
 
5. How often do you/did you use other forms of tobacco?  
 
 Every day → Number of times per day ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
Year 
 
 
 
 
INSTITUTION CODE 
 
________________ 
PARTICIPANT ID 
 
______________ 
VISIT TYPE 
 
________________ 
VISIT DATE 
(MM/DD/YYYY)  
___ ___ / ___ ___ / ___ ___ ___ ___ 
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3 
 
 
 
 
 
 
6. Since your last visit, which of the following products have you used?  Check all that apply 
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Specify____________________________________________________________________ 
 
7. If you do not currently use other forms of tobacco, but did in the past, how long has it been since you 
last used other forms of tobacco regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
The following instructions pertain to questions 8 - 10.  During each of the following time frames, please 
indicate whether you smoked cigarettes every day, some days, or not at all. 
 
8.  During study treatment 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable  
 
9.  After the end of study treatment 
 
 
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MDA2016-07-02 
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4 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable (I have not completed the study treatment) 
 
 
 
 
10.  Since your last visit to this clinic 
 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 
 
 
Signature of Individual Completing This Form___________________   Date  __ __ / __ __ / __ __ __ __ 
 
(MM/DD/YYYY) 
Name of Individual Completing This Form (please print) ______________________________________ 
 
 
 
 
Proprietary of MD Anderson Cancer Center 


MDA2016-07-02 
Protocol Version 20, Dated 02/07/2022 
Appendix H 
 
 
APPENDIX H 
 
Resources for tobacco and alcohol quitting 
 
Proprietary of MD Anderson Cancer Center 


MDA2016-07-02 
Protocol Version 20, Dated 02/07/2022 
1 
 
National and local resources to help with alcohol abuse and 
alcoholism 
NIAAA’s online guide Treatment for Alcohol Problems: Finding and Getting Help is written 
for individuals, and their family and friends, who are looking for options to address alcohol 
problems. It is intended as a resource to understand what treatment choices are available and 
what to consider when selecting among them. 
https://pubs.niaaa.nih.gov/publications/treatment/treatment.htm 
Other resources: 
National Institute on Alcohol Abuse and Alcoholism www.niaaa.nih.gov  
301–443–3860  
National Institute on Drug Abuse www.nida.nih.gov  
301–443–1124  
National Clearinghouse for Alcohol and Drug Information www.samhsa.gov  
1–800–729–6686  
Substance Abuse Treatment Facility Locator www.findtreatment.samhsa.gov  
1–800–662–HELP  
Alcoholics Anonymous (AA) www.aa.org  
212–870–3400 or check your local phone directory under “Alcoholism”  
Moderation Management www.moderation.org 
212–871–0974  
Secular Organizations for Sobriety www.sossobriety.org  
323–666–4295  
SMART Recovery www.smartrecovery.org  
440–951–5357  
Women for Sobriety www.womenforsobriety.org  
215–536–8026  
Al-Anon Family Groups www.al-anon.alateen.org  
1–888–425–2666 for meetings  
Adult Children of Alcoholics  www.adultchildren.org 
310–534–1815  
 
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National and local resources to help with quitting smoking 
NCI’s Smokefree.gov offers science-driven tools, information, and support that has helped 
smokers quit. You will find state and national resources, free materials, and quitting advice from 
NCI. 
Smokefree.gov was established by the Tobacco Control Research Branch of NCI, a component 
of the National Institutes of Health, in collaboration with the Centers for Disease Control and 
Prevention and other organizations. 
Publications available from the Smokefree.gov Web site include the following: 
• 
Clearing the Air: Quit Smoking Today for smokers interested in quitting. 
• 
Clear Horizons for smokers over age 50. 
• 
Forever Free™  for smokers who have recently quit. 
• 
Forever Free for Baby and Me™, in English and Spanish, for pregnant smokers who have 
recently quit. 
• 
Pathways to Freedom: Winning the Fight Against Tobacco for African American 
smokers. 
NCI’s Smoking Quitline at 1–877–44U–QUIT (1–877–448–7848) offers a wide range of 
services, including individualized counseling, printed information, referrals to other resources, 
and recorded messages. Smoking cessation counselors are available to answer smoking-related 
questions in English or Spanish, Monday through Friday, 8:00 a.m. to 8:00 p.m., Eastern time. 
Smoking cessation counselors are also available through LiveHelp, an online instant messaging 
service. LiveHelp is available Monday through Friday, 8:00 a.m. to 11:00 p.m., Eastern time. 
Your state has a toll-free telephone quitline. Call 1–800–QUIT–NOW (1–800–784–8669) to get 
one-on-one help with quitting, support and coping strategies, and referrals to resources and local 
cessation programs. The toll-free number routes callers to state-run quitlines, which provide free 
cessation assistance and resource information to all tobacco users in the United States. This 
initiative was created by the Department of Health and Human Services. For more information 
about quitlines, speak to an expert on the Smokefree.gov Web site. 
 
Proprietary of MD Anderson Cancer Center 


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Appendix I 
 
Appendix I.  
 
Specimen Inventory Form.  
Proprietary of MD Anderson Cancer Center 


Dr. Banu Arun’s Laboratory 
 
        
 
 
      6565 MD Anderson Blvd., Z12.3032 
ATTN:  Angelica Gutierrez Barrera 
 
 
 
 
 
        Houston, TX 77030 
     Direct phone: 713-792-1986 
          Email: angutier@mdanderson.org 
 
MDA2016-07-02 Protocol Version 20, Dated 10/20/2022 
 
 
MDA2016-07-02: Specimen Inventory Form  
(Fill Out One Form Per Patient, Per Time-Point) 
 
Collection Institution:  
 
 
 
 
 
 
 
 
 
 
Unique Specimen ID:  
 
Study Staff Name:  
 
Date Shipped:  
 
Specimen Collected: 
Indicate the quantity of each sample collected: 
 NaCit/Blue Top Plasma ______ (1 mL aliquots)   
/ 
 (Other aliquots/volume) 
 EDTA/Purple Top Plasma ______ (1 mL aliquots)  
/ 
 (Other aliquots/volume) 
 Fresh Frozen Biopsy Tissue ______ (# of cryovials) 
 RNALater:  ______ (# of cryovials) Room Temp Time: 
 
: 
 ( am / pm ) 
Refrigeration Time (4°C or on ice):   
: 
 ( am / pm ) 
Date/Time frozen (-80°C):  
   /   
 / 
   
  
: 
 ( am / pm ) 
 Paraffin embedded Biopsy Blocks:    ______ (# of blocks)  
Date/Time Embedded:  
/ 
/ 
   
  
: 
 ( am / pm ) 
 Formalin Fixed for paraffin embedding: ______ (# of specimens)–MDA only 
Date/Time in Formalin:  
/ 
/ 
  
  
: 
 ( am / pm ) 
 
Notes/Comments:  
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For the Receipt at the Lab: 
STATE OF BLOOD SAMPLES/TISSUE:  □ good condition    □ poor condition, specify:    
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DATE RECEIVED: __________ ___________  RECEIVED BY: ___ 
     ____ _________________  
[Return a copy of this form to the Sender] 
Proprietary of MD Anderson Cancer Center