Phase IIB Randomized Trial of Oral Tamoxifen vs. Topical 4-hydroxytamoxifen Gel vs. Control in Women With Atypical Hyperplasia, Lobular Carcinoma in Situ, or Increased Breast Cancer Risk
Phase: PHASE2
Conditions: Breast Atypical Hyperplasia, Breast Lobular Carcinoma in Situ, Breast Atypical Lobular Hyperplasia, Breast Carcinoma
Sponsor: Mayo Clinic

 
 
 
 
 
CA237607 / 19-011444 
 
 
Phase IIB Randomized Trial of Oral Tamoxifen vs. Topical 4-
hydroxytamoxifen gel vs. Control in Women with Atypical 
Hyperplasia, Lobular Carcinoma in Situ, or Increased Breast 
Cancer Risk 
 
 
NCT04570956 
 
 
Document Date: 07/29/2024 

 
1 
 
DCP Protocol #: CA237607 
 
Local Protocol # ID: 19-011444 
 
Phase IIB Randomized Trial of Oral Tamoxifen vs. Topical 4-hydroxytamoxifen gel vs. Control in 
Women with Atypical Hyperplasia, Lobular Carcinoma in Situ, or Increased Breast Cancer Risk 
 
 
 
 
Principal Investigator:  
Amy C. Degnim, M.D. 
 
 
 
 
Professor, Department of Surgery 
 
Mayo Clinic 
 
200 First Street SW 
 
Rochester, MN 55905 
 
507-284-6357 
 
 
 
 
IND Sponsor:  
Amy C. Degnim, M.D. 
 
Professor, Department of Surgery 
 
Mayo Clinic 
 
200 First Street SW 
 
Rochester, MN 55905 
 
507-284-6357 
 
 
 
Northwestern University Site PI 
 
Seema A. Khan, MD 
 
 
 
MD Anderson Cancer Center at Cooper Site PI 
 
Catherine E. Loveland-Jones, MD, MS, FACS 
 
 
 
 
Trial Supported by: National Cancer Institute 
 
 

 
2 
 
Drug Availability: 
 
4hydroxytamoxifen gel and placebo available via drug company (BHIR) 
Contact: 
BESINS HEALTHCARE IRELAND Ltd. (BHIR) 
16 Pembroke Street Upper 
D02 HE63 
Dublin 2, Ireland 
Oral tamoxifen and placebo available via MRI Global. Contact: 
Jonathan White, Ph.D. 
MRI Global 
Telephone: 816-326-5294 
E-mail: jwhite@mriglobal.org 
 
Site Investigators & Participating Sites: 
 
Amy Degnim, MD 
 
 
 
Seema A. Khan, MD 
Mayo Clinic 
 
 
 
Northwestern University 
2200 First Street SW 
 
 
 
250 E. Superior 
Rochester, MN 55905 
 
 
 
Chicago, Ill 60611 
507/284-6357 
 
 
 
312/503-4236 
 
 
Catherine E. Loveland-Jones, MD, MS, FACS 
MD Anderson Cancer Center at Cooper 
Two Cooper Plaza 
Camden, NJ 08103 
855.632.2667 
 
IND Sponsor: 
Amy C. Degnim, MD 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
507/284-6357 
IND #:  153332 
 
Agent(s)/Supplier: 
4OHT gel and placebo - BHIR Pharma, LLC 
Tamoxifen oral pill and placebo –MRI Global 
 
NCI Contract #: CA237607 
 
Protocol Version Date: V9 July 29, 2024 
 
      NCI-2022-02973 
 
 
 

 
3 
 
Table of Contents 
Cover Page 
 
1 
Resources 
 
2 
Schema 
 
4 
Definitions 
 
5 
Background 
 
5 
Goals 
 
9 
Patient Eligibility 
 
9 
Test Schedule 
 
11 
On-Study Procedures (Stratification, Randomization) 
13 
Treatment and Post-Treatment Samples 
16 
Study Conduct 
 
19 
Protocol Treatment Table 
 
20 
Data Safety Monitoring 
 
21 
Breaking Codes 
 
23 
Ancillary Treatment/Supportive Care 
24 
Adverse Events Monitoring and Reporting 
25 
Unanticipated Problems 
 
27 
Treatment Evaluation/Measurement Effect 
30 
Treatment/Follow-up Decisions at Evaluation of Patient 
33 
Blood and Body Specimens  
34 
Remuneration 
 
36 
References 
 
37 
Appendices 
 
40 
 
 

 
4 
 
1.0  Schema 
Recruit 104 Women with Atypical Hyperplasia (ADH, ALH), LCIS or Increased Breast Cancer Risk 
Targeted Accrual: 42 at Mayo Clinic Rochester, 42 at Northwestern University,  
and 20 at MD Anderson Cancer Center at Cooper  
 
 
Baseline Evaluation 
Detailed History & Physical Exam, Symptom/Safety assessment 
Breast Cancer Prevention Trial (BCPT) Symptom Survey 
Breast Tissue Biopsy: Evaluated for Ki67 (primary endpoint) and Other 
Biomarkers (secondary); OPTIONAL in select pts with adequate 
diagnostic bx for tissue endpoints 
Baseline CBC, Liver Function, creatinine, and coagulation tests.  
Pregnancy Test and FSH will be done if needed 
Blood: Sample of 20 ml Obtained and Banked for Future Use 
Digital Mammogram: Mammographic Density 
MBI: Mayo patients only 
 
 
 
Randomize 2:2:1 
 
 
Oral Tamoxifen 10 mg/day 
+ Gel Placebo 
 
Topical 4-OHT gel 4 mg/Each 
Breast/Day + Oral Placebo 
 
Control 
Oral and Gel Placebo 
 
 
 
4 Weeks of Treatment 
 
 
 
 
 
 
 
 
Post-Treatment Evaluation 
- 
Physical Exam and Evaluation of Side Effects 
- 
Breast Cancer Prevention Trial (BCPT) Symptom Survey 
- 
Breast Tissue Biopsy or Tissue Collected at the Time of Surgery: Ki67, 
Other Biomarkers, Tamoxifen/4-OHT Bioavailability 
- 
Blood: Sample of 20 ml Obtained and Banked for Future Use, plus 4 ml to 
Assess Tamoxifen/4-OHT Bioavailability 
- 
Post Treatment CBC, Liver Function Labs, and coagulation tests. Digital 
Mammogram: Mammographic Density  
- 
MBI: Mayo patients only 
 
 
 
 
 
 
 
Endpoints (All Evaluating Change from Baseline to After Treatment 
Primary: Ki67 
Secondary: 
- 
Novel genes identified by previous NanoString assays and RNA 
sequencing will be evaluated using NanoString 
- 
Mammogram volumetric % density and dense volume 
- 
MBI background parenchymal uptake 
- 
Tamoxifen/4-OHT bioavailability in blood and tissue 
- 
BCPT symptoms 
 
 
 

 
5 
 
Definitions 
Generic name: Tamoxifen 
Brand name(s): Nolvadex, Soltamox 
Availability: MRI Global 
Generic name: Topical 4-OHT 
Brand name(s): NA 
Availability: BHIR Pharma, LLC 
 
2.0 Background 
We plan to prospectively study breast tissue changes after a short course of Tamoxifen (Tam). 
Women with atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) are at increased risk of 
breast cancer (BC) (~1-2 % per year). Over two decades ago, placebo-controlled randomized trials 
established that oral tamoxifen (20 mg/day) reduces breast cancer risk by 50% in generally defined 
high risk women, with ~70% reduction in women at high risk specifically due to atypical 
hyperplasia.[1] Years later, the side effects and toxicity of oral tamoxifen at 20 mg/day remain a 
significant barrier to its uptake and long-term compliance.[2, 3] To address the issue of toxicity, two 
main strategies have been pursued: 1) using a lower dose of oral tamoxifen, and 2) using a topical 
formulation of tamoxifen to avoid systemic side effects. Here we will perform a prospective study of 
women with AH, LCIS, or increased risk of BC based on risk model calculations concordant with 
current consensus guidelines (described in detail below) who will take a short course of prevention 
therapy; breast tissue samples will be evaluated pre- and post-therapy to identify and evaluate 
very early biomarkers of response. The overall goal of the study is to evaluate short- term changes 
in background breast tissue induced by either low-dose oral tamoxifen or topical 4-OHT gel in 
women with AH, LCIS, or increased risk of BC based on risk model calculations. 
 
4hydroxytamoxifen (4-OHT) gel is a novel formulation of tamoxifen with local tissue 
absorption and less toxicity. 
Recent experience with 4-hydroxytamoxifen gel (4-OHT) gel shows promise for improved local 
breast tissue absorption and efficacy, with low systemic toxicity. 4-OHT is an active tamoxifen 
metabolite. 4-OHT and another tamoxifen metabolite, endoxifen, are known to account for the anti-
cancer activity of tamoxifen.[4] 4-OHT has greater affinity for the ERα receptor and better 
suppression of normal and BC cell growth in vitro than tamoxifen. [5-8] Transdermal 4-OHT is 
locally absorbed at effective doses. Human and animal studies show that transdermal delivery of 
4-OHT via gel applied to the breast skin results in local absorption and concentration in breast 
tissue. [9-12] Compared to oral tamoxifen (20 mg dose), transdermal 4-OHT delivery achieves 
equivalent tissue doses with a simultaneous 80% reduction in plasma levels. [9, 13] In clinical 
trials, 4-OHT gel results in Ki67 reduction with less toxicity. In neoadjuvant window trials in DCIS 
and invasive BC, women treated with two to ten weeks of 4-OHT gel (2 mg/breast/day) versus oral 
tamoxifen (20 mg/day) show similar decreases in cellular proliferation (50-60%) assessed by 
Ki67.[9, 13] The elevation of serum coagulation proteins seen in patients taking oral tamoxifen 
does not occur in patients treated for the same time period with 4-OHT gel,[9] and patients report 
fewer vasomotor symptoms with 4-OHT.[14] 
 
Low-dose (5 mg/day) oral tamoxifen shows similar efficacy to standard historical dose (20 
mg/day) for breast cancer prevention, with few side effects. 
Reducing the dose of oral tamoxifen is another alternate strategy to address toxicity and poor 
compliance with standard oral tamoxifen (20 mg/day), with a recently published trial by deCensi et 
al showing similar reductions in breast cancer risk with an approximate 5 mg/day dose (actually 
taken as 10 mg every other day or a split pill every day).[15] Minimum effective dose biomarker 
studies showed that 5 mg/day was not inferior to 20 mg/day in inhibiting breast cancer proliferation 
[16] and a prospective cohort study showed that 10 mg every other day reduced DCIS recurrence 
by 50%.[17] Based on these findings, a Phase III placebo-controlled randomized trial was 
undertaken to evaluate the efficacy of low-dose tamoxifen (~5 mg/day) for breast cancer 
prevention in women with breast intraepithelial neoplasia (AH, LCIS, or DCIS).[15] It is important to 
note that tamoxifen is not commercially available as a 5 mg pill, but rather only as a 20 mg or a 10  

 
6 
 
mg pill. Therefore, the women enrolled in this published study of low-dose tamoxifen vs placebo had 
the option to either take an entire pill every other day, or they could split their pills and take roughly a 
half of a pill every day. 
 
Among the 500 enrolled women with median follow-up of 5.1 years, breast cancer events in either 
breast were reduced by approximately half (hazard ratio 0.48, p=0.02), with a 75% reduction of 
breast cancer events in the contralateral breast (i.e., “true” prevention; hazard ratio 0.25, p= 0.02). 
Patient reported toxicity for low-dose tamoxifen was similar to placebo in all symptom categories 
except for daily hot flashes, which were more slightly common in the tamoxifen group (2 per day) 
compared to the placebo group (1.5 per day). Thus, this trial of low- dose (~5 mg/day) oral 
tamoxifen showed a similar degree of breast cancer risk reduction, with lower toxicity, than seen in 
prior Phase III trials using the 20 mg/day dose of oral tamoxifen.[1] Based on the results of this 
recently published randomized trial of deCensi et al, low-dose tamoxifen is now recognized by 
ASCO as a valid alternate option for breast cancer risk reduction in women with atypical 
hyperplasia or LCIS.[18] 
 
In this proposed trial we plan to utilize a reduced dose of tamoxifen (10 mg/day) as the comparator 
to the topical 4OHT gel intervention.  There are several reasons for this approach. In the deCensi 
study, the ~5 mg/day oral tamoxifen resulted in breast cancer risk reduction similar to that seen in 
prior trials of 20 mg/day. Therefore, we expect that 10 mg/day oral tamoxifen would be at least as 
effective as the ~5 mg/day dose in terms of risk reduction, while likely also reducing side effects 
compared to the 20 mg/day dose. Given the very short (4 weeks) intervention timeframe, our 
primary goal is to evaluate biomarker changes. Additionally, other published studies have shown 
similar reductions in breast tissue proliferation markers whether the daily oral tamoxifen doses is 5 
mg, 10 mg, or 20 mg, [19-21] including the biomarker Ki67 which is the primary endpoint of our 
proposed study.  Based on the other studies described above, transdermal 4-OHT delivery should 
be able to achieve tissue concentrations at least equivalent to those resulting from 10 mg/day oral 
tamoxifen. Lastly, the study proposed here has a much shorter intervention (4 weeks), and thus 
compliance with dosing may have a greater effect on the planned primary endpoint (reduction in 
Ki67). Pill splitting would result in imprecise daily dosing and taking 10 mg every other day would 
increase the risk of missed doses due to a non-daily schedule. We have explored the cost of 
custom formulation of oral 5 mg pills and matching placebos but the cost is prohibitive ($250,000). 
Therefore, we plan for oral tamoxifen 10 mg/day as the active oral drug and dosage in the 
comparator arm versus the 4OHT gel. We anticipate that using a 10 mg/day dose of tamoxifen in 
the current clinical trial will also enhance patient accrual due to expected lower side effects 
compared to 20 mg/day. This approach has been discussed extensively with the supporting grant 
program officer at NCI (Dr. Brandy Heckman-Stoddard) and the investigational agent sponsor 
(Besins Healthcare), and this is judged to be the best approach, considering the many factors 
impacting this decision, including scientific justification, patient acceptance, feasibility, and cost. 
 
The proliferation marker Ki67 is a promising biomarker of short-term response to 
tamoxifen. 
There is a strong rationale and existing data to support Ki67 as a biomarker in BC prevention 
studies. In women with AH, Ki67 in the atypia lesion is a time-dependent marker of long-term BC 
risk, with higher 10-year BC risk in women with Ki67≥2%.[22] We have also reported that Ki67 in 
background normal lobules in SA is associated with long-term BC risk,[23] similar to recent 
findings reported in the Nurses Health Study in BBD tissues.[24] Furthermore, Ki67 is also reduced 
after short courses of tamoxifen. In several prospective window-of-opportunity trials of Tam 
(ranging from 3-8 weeks of treatment), Ki67 levels in background normal breast lobules show 
relative reductions of ~50% with oral tamoxifen doses of 5, 10, or 20 mg per day.[19-21] Recently, 
we have developed a method to quantitate Ki67 (as % cells positive) in benign breast tissues using 
digital image assessment with Aperio algorithms. Within 40 samples, the digital image measure of 
Ki67 % cells positive in background normal lobules correlated very strongly with a manual 
pathologist score (r = 0.95). 

 
7 
 
 
 
Reduction in mammographic density after tamoxifen use is associated with decreased BC 
risk. 
Tam has consistently been shown to reduce mammographic density.[25-28] Our group recently 
demonstrated reductions in volumetric density in breast cancer patients after one year of treatment 
with Tam or aromatase inhibitors.[29] Importantly, these reductions in mammographic density after 
prevention therapy have been shown to be associated with decreased risk of later breast cancer in 
high risk women taking Tam for prevention,[30] as well as reduced recurrence and mortality in 
breast cancer patients taking Tam as adjuvant therapy.[25-28] Thus, in the planned study we will 
assess change in area and volumetric density measures from mammograms to determine if 
changes are detectable after only one month of treatment. Early imaging changes are a feasible 
potential endpoint, since short-term Tam use can induce detectable breast changes with sound 
speed ultrasound tomography after 1-3 months,[31] on MRI within 90 days,[32] and on molecular 
breast imaging (MBI) at 4 weeks (Fig 1). 
 
Background Parenchymal Uptake (BPU) on MBI is a promising noninvasive imaging 
biomarker of response. 
Molecular breast imaging (MBI) is a low- 
radiation dose nuclear medicine test that uses 
a high-resolution, semiconductor- based 
gamma camera to image the uptake of Tc-
99m sestamibi in the breast.[33] As MBI is a 
functional imaging technique that relies on 
differences in preferential uptake of Tc- 99m 
sestamibi in metabolically-active cells, it is 
able to reveal cancers hidden among dense 
fibroglandular tissue on a mammogram 
(published incremental cancer detection of 
7.5-16.5 per1000 women screened.[34, 35] In 
addition to detecting BC, MBI also depicts the  
level of Tc-99m sestamibi uptake in  non- 
cancerous background fibroglandular tissue,  
termed background parenchymal uptake (BPU). BPU is subjectively assessed according to a 
validated lexicon as one of four categories (photopenic, minimal to mild, moderate, and marked), 
with high reader agreement (inter-reader κ=0.84, intra-reader κ=0.87) that describe the relative 
intensity of uptake in fibroglandular tissue.[36, 37] Importantly, BPU was recently shown to be 
associated with BC risk; women with moderate or marked BPU have 3.4 to 4.8-fold increased risk 
compared to women with photopenic or minimal-mild BPU, even when adjusted for percent 
mammographic density and hormonal influences. The exact mechanism of uptake of Tc-99m 
sestamibi in breast tissue is not entirely understood, but has been correlated with blood flow, 
mitochondrial activity, and mitotic activity in BCs.[38, 39] In a recent study led by Dr. 
Hruska, women with high BPU on screening MBI underwent 4 weeks of low-dose (5 mg or 10 mg) 
oral tamoxifen, with early decreases in BPU (Fig 1).[40] Therefore BPU is promising as a non-
invasive measure of proliferative activity in the breast tissue. 
 
Breast Cancer Prevention Trial (BCPT) Symptom Checklist 
The BCPT Symptom Checklist was developed to assess side effects of medical interventions to 
prevent and treat breast cancer. Items were adapted from several existing questionnaires. The scale 
was then validated on women diagnosed with breast cancer receiving cancer treatment, women at 
risk for breast cancer receiving chemoprevention, menopausal women, and women undergoing 
normal aging. Factor analysis associations confirmed eight factors including hot flashes, nausea, 
bladder control, vaginal problems, musculoskeletal pain, cognitive problems, weight problems and 
arm problems and included 18 questions. [41, 42] Additional questions (N=7) have been added to 
Figure 1. Images from a patient with mammographically 
dense breasts undergoing supplemental screening with MBI 
(A,B) and MBI again after 4 weeks low-dose (5 mg) oral 
tamoxifen (C). 
A 
B 
Mammogram 
MBI-pre-Tam 
Dense breast 
Marked BPU 
C 
MBI-post-Tam 
Minimal PBU 

 
8 
 
measure fatigue and sexual interest (Stanton, 2016 personal communications). 
 
We plan to increase the dose of the investigational agent, 4hydroxytamoxifen (4OHT) gel, from the 
original dose of 4 mg/day (2 mg/breast/day) to 8 mg/day (4 mg/breast/day), for all remaining 
subjects accrued to the trial who are randomized to the 4OHT gel arm.  Since the design is double-
blinded, all participants who are not assigned to the 4OHT gel arm (i.e. the placebo and oral 
Tamoxifen arms) will also need to double the amount of placebo gel applied so that all participants 
are applying two pumps of gel per breast every day while on study intervention. 
 
This modification is motivated by recent unpublished clinical trial findings showing lower than 
expected tissue concentrations with the 4 mg/day gel dose and lack of anticipated antiproliferative 
effect as measured by Ki67 in a study of women with DCIS.  This recent multicenter presurgical 
phase 2 window trial was led by Dr. Seema Khan at Northwestern University, with 107 women 
accrued with ER+ DCIS who were randomized to oral tamoxifen “TAM” (20 mg/day + placebo gel) or 
4OHT gel “4OHT” (2 mg/breast daily + oral placebo), for 4-10 weeks prior to surgery.  72 of 87 
compliant women (39 oral tamoxifen and 33 4OHT gel) were evaluable for the primary endpoint, i.e. 
reduction in DCIS Ki67 labeling index.  
 
Mean treatment duration was 47 days for TAM and 44 days for 4OHT gel (p=0.2). The median 
absolute decline in Ki67 (post-treatment compared to pre-treatment) was significant in the TAM (-
3.7%, p<0.001) but not in 4OHT gel arm (-1.3%, p=0.2); between-arm p=0.002.  Ki67 results 
following menopausal stratification also favored the TAM arm, especially in postmenopausal women: 
between-arm p=0.06 in 37 premenopausal women and p=0.02 in 35 postmenopausal women. 
Breast tissue 4OHT concentrations were lower (although not significantly) in the 4OHT arm in both 
superficial and deep tissue samples compared to the TAM arm (mean superficial tissue 
concentrations were 6.1 and 4.2 ng/g for TAM and 4OHT gel, respectively, p= 0.55; and in deep 
tissues were 5.7 and 3.8 ng/g, respectively, p= 0.06).  Endoxifen (another active metabolite of 
tamoxifen) was abundant in plasma (11 ng/mL) and deep tissue (13 ng/g) of TAM arm, but present 
in only trace amounts in the 4OHT gel arm (undetectable in plasma and 0.31 ng/g in tissue), 
between-arm p <0.0001.  Circulating TAM responsive markers (insulin like growth factor 1, sex 
hormone binding globulin, von Willebrand factor, and protein S total) and vasomotor symptoms were 
significantly and unfavorably modulated by TAM, but not by 4-OHT gel therapy.  
 
In summary, these trial results showed that the anti-proliferative effect of 4 mg/day transdermal 
4OHT gel was inferior to 20 mg oral TAM in DCIS. Tissue 4OHT concentration in gel treated 
subjects was lower, especially in deep tissues, although this did not quite reach significance 
(p=0.06).  Endoxifen exposure was markedly higher with oral TAM therapy and is a likely 
explanation for the inferiority of 4-OHT gel. The study authors recommended that in future studies, 
use of higher 4OHT gel doses may overcome this difference. 
 
Safety Data on 4OHT gel dose 8 mg/day.  Safety data is available for the 8 mg/day dose from a 
BHR Pharma sponsored study of 4OHT gel for reduction in breast density (BHR-700-301, see 
attached Investigator’s Brochure February 10, 2022, pages 59-60).  In this trial 149 subjects with 
dense breasts (BI-RADS C/D) received 8 mg/day 4OHT gel and 73 subjects received placebo for up 
to 52 weeks.  
 
Adverse Events for 8 mg/day dose.  The 149 subjects in the 4OHT gel group experienced a total of 
358 AEs, and the 73 subjects in the placebo group experienced a total of 178 AEs. Overall, the 
incidence of AEs and treatment-related AEs was similar in both treatment groups. With regards to 
the non-serious AEs reported during the clinical trial, approximately 70% of the AEs that occurred in 
subjects receiving 4OHT gel and 74% of those in subjects receiving placebo were deemed unrelated 
to study treatment. Only 5% of AEs reported by the 4OHT gel group and 2.8% of AEs in the placebo 
group were thought to be ‘probably related’ to study treatment. A summary of AEs by Medical 

 
9 
 
Dictionary for Regulatory Activities (MedDRA) body system is presented on pages 59-60 in the 
Investigators Brochure (updated February 10, 2022). 
 
Serious Adverse Events with 8 mg/day dose. Five subjects, all of whom were treated with BHR-700 
4-OHT gel, experienced 1 SAE each: invasive ductal breast carcinoma (N = 2), intraductal 
proliferative breast lesion (N = 1), endometrial adenocarcinoma (N = 1), and pulmonary embolism (N 
= 1). None of the SAEs had a fatal outcome. Of the 5 reported SAEs, 3 were deemed possibly 
related to study treatment (invasive ductal breast carcinoma, endometrial adenocarcinoma, and 
pulmonary embolism). However, they could not be determined as related as there were other factors 
that could also have been possible causes of these events. Concerning the reported SAEs, 5 
reported SAEs for 222 subjects over the reporting period of the trial is extremely low and shows the 
safety and tolerability of 4OHT gel. Complete details on safety data are reported in the Investigators 
Brochure (updated February 10, 2022). 
 
Planned implementation of increased 4OHT gel dose into ongoing clinical trial  
As of 10/12/2022, 12 patients have already accrued to the trial and have been randomized to 
placebo, oral TAM, and 4OHT gel arms of the study.  10 have completed intervention and trial-
related research studies, with 2 who have started and will complete the planned ongoing 
interventions.  A temporary hold was placed on new enrollment on 10/12/22 so that all future patients 
enrolled may be treated with the higher 8 mg/day dose of 4OHT if randomized to that treatment arm.  
 
Expansion of Eligibility Criteria April 2023 
In order to expand the pool of eligible patients for the trial we will include patients without atypical 
hyperplasia or LCIS but who are at increased risk for breast cancer based on risk model 
calculations that are concordant with current consensus guidelines. For women at increased risk 
based on Gail / Breast Cancer Risk Assessment Tool 5-year risk 3%, or International Breast 
Intervention Study 10-year risk 5%, breast cancer prevention therapy is RECOMMENDED 
(Visvanathan Journal of Clinical Oncology 2019;37(33):3152-65, NCCN Guidelines v1.2023), and 
therefore these women are appropriate for inclusion in this trial of short-term oral versus 4OHT 
topical tamoxifen. In addition, we will also allow short periods of prior use of risk-reducing 
medications with corresponding periods without use prior to study participation (see Exclusion 
criteria). 
 
Database 
The study coordinators and stats team will use RAVE Medidata database for data entry. This 
secured database will only be accessed by study members. Each patient will be assigned a 
research ID for entry of data into this database. The research ID/participant name match will be 
kept in a secured file at each institution. Only the investigator, statisticians and study coordinators 
at the respective sites will have access to this file. 
 
3.0 Goals 
 
3.1 
Primary Aim.  Change in Ki67 from pre-treatment to post-treatment 
 
3.2 
Secondary Aims. Changes from pre-treatment to post-treatment in: 
• 
Mammographic volumetric % density 
• 
Mammographic dense volume 
• 
Breast Cancer Prevention Trial Symptom Survey 
• 
Molecular Breast Imaging background parenchymal uptake 
• 
Changes in novel tissue biomarkers from our previous work; will be assessed with 
NanoString and immunohistochemistry 
• 
4-OHT and metabolite levels in blood and tissue 
• 
Coagulation parameters 
 
4.0 Patient Eligibility 
 
4.1 
Screening Inclusion Criteria 

 
10 
 
 
 
4.1.1 
Willing to return to enrolling institution for follow-up. 
 
 
4.1.2 
Willing to complete required testing. 
 
 
4.1.3 
Ability to complete questionnaire. 
 
 
4.1.4 
Female (sex that was assigned at birth). 
 
 
4.1.5 
Age ≥ 18 years. 
 
 
4.1.6 
Ipsilateral intact breast with histology confirmation of atypical ductal or lobular 
hyperplasia, or LCIS, within the last 5 years, whether surgically excised or not; 
OR neither AH nor LCIS but increased breast cancer risk defined as either: 
 
 
 
a) Gail model (Breast Cancer Risk Assessment Tool) 5 year breast cancer risk 
of ≥3%, or 
 
 
 
b) International Breast Intervention Study model 10 year breast cancer risk of 
≥5%. 
 
 
4.1.7 
ECOG performance status ≤1 (Karnofsky ≥70%; see Appendix A). 
 
 
4.1.8 
The effects of topical 4-OHT gel on the developing human fetus at the 
recommended therapeutic dose are unknown. However, oral tamoxifen is 
Pregnancy Category D—positive evidence of human fetal risk. For this reason, 
and because triphenylethylene antiestrogens, including tamoxifen, are known 
to be teratogenic, women of childbearing potential and their male partners 
must agree to use at least one effective form of birth control (abstinence is not 
an allowed method) prior to study entry and for the duration of study 
participation, and for 2 months following the last dose of study medications 
(participant can resume oral birth control pills for effective birth control 
measures after post-treatment biopsy is done). Effective birth control methods 
during treatment are copper and Mirena IUD [intrauterine device], 
diaphragm/cervical cap/shield, spermicide, contraceptive sponge, condoms. 
Women of childbearing potential must have a negative pregnancy test within 
five days before starting study medications. Tubal Ligation is also an 
acceptable form of birth control.  Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she should inform her 
study physician immediately. 
 
 
4.1.9 
Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e., 
tanning beds) for the duration of the study. 
 
 
4.1.10 Participants must have acceptable organ and marrow function as judged by 
treating physician’s evaluation of baseline laboratory data. 
 
 
4.2 
Screening Exclusion Criteria 
 
 
4.2.1 
Clinically suspicious mass/lesions. 
 
 
4.2.2 
Breast cancer in the past 5 years. 
 
 
4.2.3 
Patients with any history of venous thromboembolic disease, regardless of 
timeframe (history of varicose veins and superficial phlebitis is allowed). 
 
 
4.2.4 
Current pregnancy or lactation. 
 
 
4.2.5 
History of other prior breast cancer-specific therapy within the previous 2 years 
(chemotherapy, anti-HER2 agents, endocrine agents, everolimus, CDK4-6 
inhibitors). 
 
 
4.2.6 
Cytotoxic chemotherapy for any indication in last 2 years. 
 
 
4.2.7 
Prior use of SERMS or Als including tamoxifen, raloxifene, anastrozole, 
letrozole, or exemestane for prevention or therapy within the past 5 years. 
UNLESS 
 
 
 
a) Use was less than 6 months duration in the past 5 years and not used in the 
1 year prior to enrollment, OR 
 
 
 
b) Use was no greater than 2 months duration in the past 1 year and not used 
in the 6 months prior to enrollment. 
 
 
 
4.2.8 
Exogenous sex steroid, including oral contraceptive pill use within 1 month 

 
11 
 
prior to Pretreatment breast biopsy (). Use of vaginally administered estrogens 
and hormone coated IUD such as Mirena is permitted  
 
 
4.2.9 
History of any prior ipsilateral breast radiotherapy. Previous unilateral radiation 
of the contralateral side is allowed. 
 
 
4.2.10 Skin lesions on the breast that disrupt the stratum corneum (e.g., eczema, 
ulceration). 
 
 
4.2.11 History of endometrial neoplasia. 
 
 
4.2.12 Current smoker. Cessation for at least 6 weeks. 
 
 
4.2.13 Current users of potent inhibitors of tamoxifen metabolism. The potent 
inhibitors of tamoxifen metabolism are: bupropion, cinacalcet, fluoxetine, 
paroxetine, quinidine. 
 
 
4.2.14 Participants may not be receiving any other investigational agents within 90 
days of enrollment or during this study. 
 
 
4.2.15 History of allergic reactions to tamoxifen. 
 
 
4.2.16 Uncontrolled intercurrent illness that in the judgement of the treating physician 
would make them unsuitable for study participation. 
 
 
4.2.17 Current use of anticoagulation medications. 
 
 
4.2.18 Patients who are breastfeeding. 
 
 
4.2.19 Participant will be excluded with any one or more of the following results within 
30 days of randomization: 
- 
Hemoglobin < 10 g/dL 
- 
Leukocytes < 3,000/microliter 
- 
Platelets < 100,000/microliter 
- 
Total bilirubin > 1.5 x institutional upper limit of normal (ULN) 
- 
AST (SGOT) > 1.5 x ULN 
- 
ALT (SGPT) > 1.5 x ULN 
- 
Alkaline phosphatase, S > 1.5 x ULN 
- 
Albumin, S >1.5 x ULN 
- 
Protein, total, S >1.5 x ULN 
- 
Creatinine > 1.5 x ULN 
- 
Antithrombin III <80% of normal 
- 
Fibrinogen >1000 mg/dL 
 
 
4.2.20 Patients who are taking any medications, herbal products, or OTC products 
that are moderate or strong CYP2D6 inhibitors or CYP3A inducers.  Patients 
should also refrain from starting any drug or product with these properties 
during the study. This is to avoid any potential interactions with tamoxifen or 4-
OHT. (Please see Appendix G.) 
4.2.21 Clinically significant arrhythmia requiring ongoing medication for control / 
treatment, especially those with high risk of QT prolonging effects (Appendix 
H). 
 
 
 
 
4.3 
Enrollment – Inclusion Criteria 
 
 
4.3.1 
Negative pregnancy (serum or urine) test if of childbearing potential and/or 
FSH to verify menopausal status. 
 
 
4.4 
Enrollment – Exclusion Criteria 
 
 
4.4.1 
Identification of a clinically suspicious mass on examination 
 
 
4.5 
Identification of Potential Participants 
 
 
Study coordinators will identify potential patients by reviewing breast clinic and breast 
surgeons’ patient schedules for women diagnosed with ALH, ADH, LCIS or increased 
breast cancer risk as calculated by the breast clinic or other medical provider . Their 

 
12 
 
return appointment(s) schedule(s) will be reviewed for possible patient contact times. 
Patient charts will be reviewed to identify if they meet inclusion and exclusion criteria. 
 
 
4.6 
Patient Consent 
 
The patients who meet study eligibility will be approached by the study coordinator prior 
to, during or after their clinical appointment to discuss the purpose of the study and what 
involvement in the study would entail. The consent form will be reviewed. If the patient 
agrees to be part of the study, they will be asked to sign the consent. A copy of the 
signed consent will be provided to the patient.  
 
 
5.0 Test Schedule 
 
 
Test & Procedures 
Baseline 
End of Treatment 
(at the end of 4 
weeks of 
treatment)12 
Pregnancy Test (serum or urine) 
X1,2 
 
Follicle stimulating hormone (FSH) 
X2,3 
 
Baseline labs [CBC and Liver Function 
testing (ALP, ALT, AST, ALB, TP, BILI), 
creatinine coagulation labs (fibrinogen, 
Antithrombin 3)] 
X2 
X2 
Physical Examination 
X2,4 
X2 
Two 10 ml amounts of blood (will be 
stored for future research)5 
X2 
X2 
Blood Draw (4-OHT bioavailability)6 
 
X2 
Research Biopsy of Breast Tissue 
- 
same quadrant as diagnostic 
biopsy7 [Ki67, NanoString, 4-OHT 
bioavailability (post-treatment 
only);] 
Pretreatment diagnostic biopsy is 
OPTIONAL if meets 
requirements8  
 
X2,8 
X2,9 
Digital Screening Mammogram 
X2,10 
X2,10 
MBI (Mayo Clinic site only) 
X2,11 
X2 
BCPT Symptom Survey 
X2 
X2 
Symptom /safety/AE assessment  
X2 
X2 
1. For women of childbearing potential only. 
2. Research Funded (Note: clinical surgical consult will not be research funded.) 
3. For women with unknown menopausal status 
4. Physical exam could be done within 3 months before treatment starts. 

 
13 
 
5. Blood for storage two 10 ml blood draws using purple top EDTA tubes – protect from 
light exposure (i.e., wrap in tin foil, use light sensitive brown bags). First EDTA tube-
Aliquot (1) 4000uL blood pour for DNA extraction. Refrigerate, Centrifuge at lab 
standards. Process for three 1 ml aliquots of plasma into 3 cryovials 1 ml plasma each 
and 1ml WBC.  Light Sensitive. Store in -80 freezer. Second EDTA vial is stored as 
whole blood. 
6. Blood for 4-OHT bioavailability. 4 ml. green top heparin tube. Process for plasma. 
Protect from light exposure as light sensitive (i.e., wrap in tin foil, use light sensitive 
brown bags). Store in -80 freezer. 
7. Baseline Pretreatment research tissue core biopsy information is located in Appendix 
F. 
8. Pretreatment (baseline OPTIONAL) research tissue.  This is optional if the subject has 
a pretreatment diagnostic breast biopsy that is 1) within 6 months of enrollment, 2) no 
exogenous sex steroids other than vaginal estrogen or hormone coated IUD within 
one month prior to the diagnostic biopsy, 3) has at least 4 normal TDLUs by 
pathologist review, and 4) if the FFPE tissue from the diagnostic biopsy will be 
available to the research study for primary (Ki67) and secondary tissue endpoints 
(RNA extraction).  If Pretreatment research biopsy is performed, tissue will be 
collected by doing vacuum assist core biopsy, using a 9-11G needle. At Mayo Clinic, 
snap frozen tissues will be stored in BAP, and batch shipped to Dr. Radisky’s lab in 
Jacksonville, FL; formalin fixed cores will be delivered to the Clinical Histology lab to 
create a single FFPE block if possible and a single H&E stain for each block. The H&E 
stained slide(s) will be delivered by the study coordinator to the breast pathologist, Dr. 
Solanki, or her designee, for core biopsy read within 21 days of biopsy. After the 
breast pathologist’s review is complete, the FFPE blocks and H&E will be stored and 
batch shipped to Dr. Radisky’s lab in Jacksonville, FL for Ki67 IHC, slide scanning at 
40X, and Aperio quantitation. At Northwestern University and MD Anderson Cancer 
Center at Cooper, snap frozen cores will be stored at -80, and shipped to Dr. Radisky 
lab in Jacksonville; formalin fixed cores will be put up as a single FFPE block if 
possible (see details section 6.8.3). (Note, there will not be 4OHT testing on 
pretreatment breast tissue samples.) 
9. The post-treatment research breast tissue sample is MANDATORY and can be 
obtained by either needle core approach (if no surgical excision is done for clinical 
care) or can be obtained by the surgical team intraoperatively after excision of the 
lesion and negative margins are obtained diagnostically. If core biopsy approach is 
used for the post-treatment sample, follow guidelines in #8 above. If surgical excisional 
biopsy is performed for clinical care, the post-treatment samples will be obtained by 
the surgical team. Two 1 cm2 pieces of tissue will be excised by the surgeon after 
negative margins have been obtained diagnostically. One of these two pieces of tissue 
should be cut in half and placed into two separate sterile tubes for snap freezing-- one 
piece will go for 4-OHT to Dr. Reid’s lab, and one for RNA extraction to Dr. Radisky’s 
lab. The other 1 cm2 piece of tissue will be put in formalin and processed in the Clinical 
Histology Lab for a single FFPE block and one single H&E stain. The H&E stain will be 
delivered by the study coordinator to the breast pathologist, Dr. Solanki, or her 
designee, for core biopsy read within 21 days of biopsy. After the breast pathologist’s 
review is complete, the FFPE blocks and H&E will be stored and batch shipped to Dr. 
Radisky’s lab in Jacksonville, FL for Ki67 IHC, slide scanning at 40X, and Aperio 

 
14 
 
quantitation.  
10. Bilateral CC view (FFDM), 1 CC view of each breast.  
11. MBI to be obtained at baseline. This will not be required if a current MBI was done 
within one month of starting treatment. 
Tests to be scheduled as described above, with the last dose of study drug within 2    
days (preferably within 24 hours) prior to the post-treatment biopsy and blood draw. 
All other tests (mammogram, MBI) should be scheduled PRIOR to the post-
treatment breast biopsy, but no more than 3 days prior.   
Participants will receive a total of $350.00 to $500.00 for completing the study. This 
will be paid as $350 upon completion of study intervention and post treatment tests 
and biopsy, with an additional $150 for subjects who undergo the pretreatment 
research biopsy (given at completion of pretreatment research biopsy).  All 
participants will also receive a small gift of appreciation.   
 
6.0 Stratification Factors 
• 
Study site 
• 
Diagnosis (ADH vs ALH/LCIS vs increased risk without AH or LCIS) 
• 
Menopausal status (pre- vs. postmenopausal) 
For the purposes of this trial, post-menopausal is defined as: 
- 
A history of at least 12 months without spontaneous menstrual bleeding, or 
- 
A prior documented hysterectomy and bilateral salpingo-oophorectomy, or 
- 
A prior hysterectomy without oophorectomy or in whom the status of the ovaries 
is unknown, with a documented FSH level > or equal to 40, demonstrating 
confirmatory elevation in the postmenopausal range. 
 
 
6.1 
Randomization Procedures 
 
 
6.1.1 
After the patient has completed the informed consent process, confirmed 
eligibility and the values of the stratification factors are recorded in Medidata 
RAVE, the patient will be assigned a research ID, and will be randomly 
assigned to one of the treatment groups. 
Randomization will be performed using dynamic allocation, implemented 
within the Medidata RAVE system. The Medidata RAVE system will randomize 
the patient after the study coordinators have recorded the stratification factors 
as part of the blinded data input. Pharmacy will be notified of the 
randomization via email to a pharmacy email account prompting the 
pharmacist to log in and view the unblinded treatment assignment.  
Randomization groups: 
 
•  Tamoxifen tablet, placebo gel 
•  4-OHT gel, placebo tablet 
•  Control (placebo tablet, placebo gel) 
 
 
6.2 
Verification of Materials 
- 
Prior to randomization, verify the following: 
- 
IRB approval at the registering institution 
- 
Patient eligibility 
- 
Existence of a signed consent form 
 
 
6.3 
Document of IRB Approval 
 
This must be on file before registering any patients. 

 
15 
 
 
 
6.4 
Correlative Research 
 
 
6.4.1 
Mandatory 
A mandatory correlative research component is part of his study; the patient 
will be automatically registered onto this component. 
 
 
6.5 
Banking 
 
 
At the time of informed consent, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research of atypical hyperplasia or breast cancer at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
 
6.6 
Treatment on Protocol 
 
 
Treatment on this protocol must commence at Mayo Clinic Rochester Northwestern 
University, or MD Anderson Cancer Center at Cooper under the supervision of Dr. 
Amy Degnim, Dr. Seema Khan, or Dr. Catherine Loveland-Jones respectively. 
 
 
6.7 
Treatment Start 
After study randomization and all baseline evaluations are obtained, patients will begin 
treatment.  Treatment must start within three months of baseline physical exam and 
labs, with Mammogram, MBI, and research core biopsy (if applicable) performed no 
longer than 7 days prior to starting treatment. 
  
 
These studies should be coordinated with the date they can return for follow-up testing 
(or date of surgical excision if applicable). 
 
 
6.8 
Pretreatment 
 
 
Pretreatment tests/procedures (see Section 5.0) must be completed within the 
guidelines specified on the test schedule. 
 
 
6.8.1 
Baseline Symptoms 
 
 
In the medical records, verified by participant and/or identified on physical 
examination will be recorded. 
 
 
6.8.2 
Pretreatment Blood Samples 
 
 
 
•   Two 10 ml purple top EDTA vials of blood will be obtained at baseline.  
These will be used for banking purposes. These tubes should be protected 
from light exposure (i.e., wrap in tine foil, use light sensitive brown bags). At 
Mayo, these tubes will be delivered to the BAP lab. Northwestern and MD 
Anderson Cancer Center at Cooper will process the blood and store in -80 
freezer and send in batches to Mayo Rochester. 
 
 
 
•   Specimen labels will be preprinted and should be used for the pretreatment 
blood and tissue specimens. Collection/companion form will be completed 
at time of collection and specimen information will be entered into RAVE 
database. 
 
 
 
 
6.8.3 
Pretreatment Tissue Samples 
Pretreatment Research Biopsies 
See Appendix F for details on breast tissue research biopsy. 
 

 
16 
 
The pretreatment cores will be divided as follows: 
For 9-11 G vacuum assist biopsy cores, 4-6 cores will be collected: 
   -  Two of the largest cores will be distributed between 2 separate tubes 
and snap frozen (1 core per tube). 
   
 
All remaining cores will be placed in formalin.  
 
 
 
 
  
At Mayo Clinic, the snap frozen cores will be stored in BAP, and batch 
shipped to Dr. Radisky’s lab in Jacksonville, FL; all remaining cores will be 
placed in formalin, delivered to the Clinical Histology lab to create a single 
FFPE block if possible, and a single H&E stain per block. The H&E stained 
slide(s) will be delivered by the study coordinator to breast pathologist, Dr. 
Solanki, or her designee, for core biopsy read within 21 days of biopsy. If 
DCIS or invasive cancer is identified by the breast pathologist during the 
clinical read of the research biopsy H&E, then this information will be relayed 
to the assigned clinical care provider (surgeon if upcoming surgery or Breast 
Clinic physician if no surgery is planned). 
After the breast pathologist’s read is complete, the FFPE blocks and H&E 
will be stored by the study team and batch shipped to Dr. Radisky’s lab in 
Jacksonville, FL for Ki67 IHC, slide scanning at 40X, and Aperio 
quantitation. 
If research breast biopsy is not performed, then 6 unstained 5 micron and 3 
unstained 10 micron FFPE sections from the pretreatment diagnostic breast 
biopsy will be stored by the study team and batch shipped to Dr. Radisky’s 
lab in Jacksonville, FL for Ki67 IHC, slide scanning at 40X, and Aperio 
quantitation.  
 
 
At Northwestern University and MD Anderson Cancer Center at Cooper, the 
snap frozen cores will be stored at -80, and the remaining cores will be put 
up as an FFPE block (remaining cores in one block if possible) with a single 
H&E stain per block, to be reviewed by the designated study pathologist at 
Northwestern University and MD Anderson Cancer Center at Cooper for 
core biopsy read within 21 days of biopsy. If DCIS or invasive cancer is 
identified by the breast pathologist during the clinical read of the research 
biopsy H&E, then this information will be relayed to the site PI, Dr. Khan, or 
Dr. Catherine Loveland-Jones respectively.  All frozen samples and tissue 
blocks will be shipped to Dr. Radisky’s lab in Jacksonville.   
 
If pretreatment research breast biopsy is not performed, then 6 unstained 5 
micron and 3 unstained 10 micron FFPE sections from the pretreatment 
diagnostic breast biopsy will be stored by the study team and batch shipped 
to Dr. Radisky’s lab in Jacksonville, FL for Ki67 IHC, slide scanning at 40X, 
and Aperio quantitation.  

 
17 
 
 
 
Batch shipments will occur after every 5 patients via shipping kit provided by 
Mayo Clinic Rochester BAP with ambient shipping supplies for the FFPE 
blocks, and frozen shipping supplies for the frozen cores and unstained 
slides. 
 
• 
Specimen labels will be preprinted and should be used for the 
pretreatment blood and tissue specimens. Collection/companion 
form will be completed at time of collection and specimen information 
will be entered into RAVE database. 
 
Specimens should be shipped to the following addresses: 
 
Post-treatment blood and tissue for tamoxifen/4-OHT levels 
Mayo Clinic-BAP LAB 
150 Third Street SW 
Stabile SL-16 
Rochester, MN 55905 
507-284-5777 
 
Frozen tissue for RNA extraction (pre- and post-treatment) 
and FFPE blocks/slides (pre- and post-treatment) 
 
Derek Radisky Laboratory 
Attn: Lab Personnel 
Mayo Clinic Jacksonville 
4500 San Pablo Road 
Griffin Building 3_331 
Jacksonville, FL 32224 
904-625-2844  
 
Blood specimens for banking (pre- and post-treatment) 
Mayo Clinic-BAP LAB 
150 Third Street SW 
Stabile SL-16 
Rochester, MN 55905 
507-284-5777 
 
 
 
 
6.8.4 
Digital Mammogram 
Digital mammogram will be obtained AT BASELINE TO INCLUDE Bilateral 
craniocaudal (CC) view (full field digital mammogram=FFDM), i.e., 1 CC view 
of each breast.  
Northwestern University and MD Anderson Cancer Center at Cooper will scrub 
patient identifiers from mammograms (retaining date of mammogram, laterality 
markers, study ID, and image acquisition parameters) and transfer them using 
a research code on a second digital file to the study team. 
 
 
 
6.8.5 
Patient Questionnaire Booklets 
 
 
 
The Breast Cancer Prevention Trial (BCPT) Symptom Checklist will be 
administered to patients.  This data will be entered into the study database 
(RAVE). Permission to use the BCPT was provided by Annette L. Stanton, 
PhD, Professor Departments of Psychology and Psychiatry and Biobehavioral 

 
18 
 
Sciences, UCLA (see Appendix B). 
 
7.0 Treatment 
 
7. 1 
Study Drug 
The research team will perform a placebo-controlled randomized study of four weeks 
(± 3 days) of oral tamoxifen vs. 4-OHT gel vs. Placebo (see schema). Oral and gel 
placebos will be used to create a double-blind study. Tablets will be in an opaque 
gelatin capsule. Tamoxifen will be mixed with microcrystalline cellulose powder. 
Placebo will be only microcrystalline cellulose powder in an identical opaque gelatin 
capsule. 
 
Transdermal 4-OHT/placebo gel will come in a 1 mL canister pump and a protective 
cap. The pouch in the canister will contain 88 g of gel. A single pump contains 1 mL 
of gel at a 4-OHT concentration of 2 mg/mL.  The canister will be labeled as “4- 
Hydroxytamoxifen 2 mg/mL or Placebo gel” and “Caution: New Drug-Limited by 
Federal law (US) to investigational use only”. Directions for gel application will also 
be included on the label. Patients will also be provided with more detailed directions, 
to apply 2 doses/pumps of gel to each breast every day (See Appendix D). BHIR 
Pharma will provide identically packaged 4-OHT gel and placebo gel that will be 
shipped to MRI Global. 
 
MRI Global will provide oral tamoxifen (10 mg) and matching placebo. They will ship 
the oral and topical medications and matching placebos to the research pharmacist 
at each site, who will formulate kits for patient use. Each kit will include 2 canisters of 
4- OHT/placebo gel and one bottle of tamoxifen/placebo capsules. Each kit will be 
labelled with kit number, protocol number and contents and storage temperature and 
the notice and “Caution: New Drug-Limited by Federal law (US) to investigational use 
only”.  
 
MRI Global will perform dissolution, disintegration, and stability testing on the 
tamoxifen tablets and disintegration testing on the placebo. Additionally, weights are 
checked during manufacturing. Stability testing will be done on an annual basis. 
 
Tamoxifen and placebo capsules will be packaged in bottles of 31 capsules. The 
bottle will have a label printed as “tamoxifen citrate 10 mg or placebo” with treatment 
kit number, protocol number, expiration date and directions to take one tablet daily. 
Additional details on a product insert will be provided (See Appendix C). 
 
Pharmacy will remove the portion of the label indicating placebo or active drug when 
dispensing a kit. The pharmacy will remove the un-blinding label from the study drug 
container (and retain within the pharmacy), then attach the patient-specific research 
pharmacy label to each drug container. This label provides all relevant details 
including patient name, clinic number, IRB number, provider name, directions for 
use, name of drug, and quantity. 
 
Patients will be asked to bring their kit back on their return visit. Any remaining pills will 
be counted, and gel dispensers will be weighed by research pharmacy. Along with the 
kit, a calendar will be provided where they mark each day the pill and gel were used, 
and any wasted pumps (see Appendix E). Non-compliance with study treatment will be 
considered for patients who have less than 80% compliance with daily drug use or have 
missed more than 3 doses in the final 14 days. All study persons will be evaluated for 
toxicities. Deviation(s) from the prescribed dosage regimen will be recorded and 
reported to the IRB at continuing review.   

 
19 
 
 
 
 
7.2 
Participant Contact 
 
 
Participants will be contacted 1 week (+/- 2 days) after study drug initiation. A phone 
call, portal message, or email at Week 1 will be to assess compliance, toxicity, and 
changes in medication and to address any questions by the participant. 
 
 
7.3 
Post-Treatment Biopsy 
 
 
7.3.1 
Core Biopsy 
See Appendix F for details on post treatment core biopsy. 
At Mayo Clinic, the two snap frozen cores will be delivered to BAP by the 
study coordinators. After accessioning, Dr. Joel Reid’s lab will be paged to 
pick up and store tissue for tamoxifen/4-OHT levels; and the other snap 
frozen core will be stored and sent to Dr. Radisky’s lab for RNA extraction; 
the remaining two cores will be put in formalin for a single FFPE block if 
possible. Dr. Reid’s lab will additionally need to know the date and time of 
the last dose of tamoxifen/placebo and 4-OHT/placebo. 
 
At Northwestern University and MD Anderson Cancer Center at Cooper, two 
of the largest cores will be distributed between 2 separate tubes and snap 
frozen (1 core per tube), one tube is designated for Dr. Reid’s lab and the 
other is designated for Dr. Radisky’s lab. These will be stored at -80 and will 
then be batch shipped to Mayo Clinic Rochester BAP and Dr. Radisky’s 
laboratories respectively. The remaining cores will be put up as a single 
FFPE block (if possible) and shipped to Dr. Radisky’s lab also in batches. 
 
 
 
7.3.2 
Surgical Biopsy 
If the patient will undergo excisional biopsy, the post-treatment tissue 
samples can be taken at the time of surgery. Two 1 cm2 pieces of tissue will 
be needed. One of these will be put in formalin for a single FFPE block; the 
other tissue piece should be cut in half and placed into two separate sterile 
tubes for snap freezing. 
One of these two cut pieces will be snap frozen and designated for Dr. 
Joel Reid’s lab for tissue tamoxifen/4-OHT levels), and the other will be 
snap frozen and designated for Dr. Radisky’s lab for RNA extraction.  
 
 
 
 
7.3.3 
Specimen Handling 
Preprinted labels will be provided and should be used for the post-treatment 
tissue specimens. 
Collection/companion form will be completed at time of collection and 
specimen information will be entered into RAVE database.  
 
Directions for Mayo Clinic: Collect tissue specimens. The snap frozen cores 
will be stored in BAP, and batch shipped to Dr. Radisky’s lab in 
Jacksonville, FL; the remaining cores will be placed in formalin, delivered to 
the Clinical Histology lab to create a single FFPE block if possible and a 
single H&E stain per block. The H&E stain will be delivered by the study 
coordinator to breast pathologist, Dr. Solanki, or her designee, for core 
biopsy read within 21 days of biopsy. The FFPE blocks and H & E will be 
stored and batch shipped to Dr. Radisky’s lab in Jacksonville, FL for Ki67 
IHC, slide scanning at 40X, and Aperio quantitation after the breast 
pathologist’s read is complete. 

 
20 
 
Northwestern University and MD Anderson Cancer Center at Cooper will 
snap freeze two of the largest cores, which will be distributed between 2 
separate tubes and snap frozen (1 core per tube). and store in -80 freezer. 
One frozen core (or piece of tissue) will be designated for Mayo Clinic 
Rochester BAP and one for Dr. Radisky’s lab. Northwestern University 
and MD Anderson Cancer Center at Cooper will process the remaining 
core samples for formalin (remaining cores or a single surgical tissue 
piece in a single FFPE block if possible) with research H&E stain cut for 
each block, to be reviewed by designated pathologist within 21 days of 
biopsy. Frozen samples and blocks will be shipped in batches to Dr. 
Radisky’s lab. 
 
Shipping Directions for Northwestern University and MD Anderson Cancer 
Center at Cooper: Specimens for Dr. Radisky’s laboratory will be batch 
shipped to Jacksonville. Remaining specimens should be batch shipped to 
Mayo Clinic Rochester BAP (4OHT blood and frozen tissue),  
 
Send an email to RSTBBD@mayo.edu prior to all tissue shipments and 
obtain confirmation that the receiving party is available to receive the 
shipment. 
 
Use same shipping addresses as per section 6.8.3. 
 
 
7.4 
Post-Treatment Blood Samples 
Post-treatment, two purple top 10 ml EDTA vials of blood will be obtained within 2 
days of completing the study intervention. These will be used for banking purposes. 
At Mayo these tubes will be delivered to the BAP lab. Northwestern University and 
MD Anderson Cancer Center at Cooper will process the blood and store in -80 freezer 
and send in batches to Mayo Clinic Rochester BAP. 
 
In addition, one 4 ml green top heparin tube will be used for tamoxifen/4-OHT and 
metabolite levels. The tube will need to be processed for plasma and stored in -80 
freezer. Instructions at Mayo Clinic site will be to deliver to BAP, after accessioning 
and processing, Dr. Joel Reid’s lab will be contacted to pick up and store for 
tamoxifen/4-OHT levels. Northwestern University and MD Anderson Cancer Center 
at Cooper will batch ship these specimens. The labels should include the patient 
research identifier, IRB # 19- 011444, the date the specimen was collected. 
Collection/companion form will be completed at time of collection and will additionally 
include the date and time the patient took their last dose of tamoxifen/4-OHT.  
Preprinted labels will be provided and should be used for post-treatment blood 
samples for banking. Collection/companion form will be completed at time of 
collection and specimen information will be entered into RAVE database. 
 
 
8.0 Study Conduct 
Mayo Clinic IRB approval of the protocol and any amendments will be required prior to 
implementation. Subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol. Master files of essential 
clinical documents will be maintained for the duration of the study. 
During the patient’s clinical visit to discuss findings of AH, LCIS, or increased breast 
cancer risk, the patient’s physician will introduce the study to the patient. If the patient 

 
21 
 
agrees to participate in the study, a study coordinator will answer any additional study 
questions and start the informed consent process.  The study coordinator will also 
provide, as indicated, appointments for a pregnancy test and FSH levels, baseline labs 
along with all other pre-treatment tests and procedures. The patient will be given a study 
kit by the RN study coordinator with directions for taking the pills and applying the gel. 
The study coordinator will also schedule a return visit appointment, in which the patient 
will complete the BCPT symptom questionnaire, along with post-treatment blood tests, 
study mammogram, breast biopsy (core or excisional), and study MBI (only at Mayo 
clinic) at the completion of treatment. Post-study breast biopsy and blood draw must be 
scheduled between days 25-31 of drug treatment with the last dose of study drug within 2 
days (preferably within 24 hours) prior to the post-treatment biopsy and blood draw.  
 
Other post-treatment tests will be scheduled PRIOR to the breast biopsy but not more than 
3 days prior to the post-treatment breast biopsy. The RN coordinator will instruct patient that 
they need to avoid pregnancy during this treatment and 2 months after treatment and 
instruct: The effects of topical 4-OHT gel on the developing human fetus at the 
recommended therapeutic dose are unknown. However, oral tamoxifen is Pregnancy 
Category D—Positive evidence of human fetal risk. For this reason, and because 
triphenylethylene antiestrogens, including tamoxifen, are known to be teratogenic, women 
of childbearing potential and their male partners must agree to use at least one effective 
form of birth control (abstinence is not an allowed method) prior to study entry and for the 
duration of study participation, and for two months following the last dose of study 
medications (participant can resume oral birth control pills for effective birth control 
measures after post-treatment biopsy is done). Effective birth control methods are copper 
and Mirena IUD (intrauterine device), diaphragm/cervical cap/shield, spermicide, 
contraceptive sponge, condoms; these may be used during and after treatment. Oral 
contraceptives may only be used after the 4-week treatment is complete, and the post-
treatment biopsy is obtained. Women of childbearing potential must have a negative 
pregnancy test (either serum or urine pregnancy test) within five days before starting study 
medications. Tubal Ligation is also an acceptable form of birth control.  Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she should 
inform her study physician immediately. 
 
If DCIS or invasive cancer is identified by the breast pathologist during the clinical read of 
the research biopsy H&E, then this information will be relayed to the assigned clinical care 
provider (surgeon if upcoming surgery or Breast Clinic physician if no surgery is planned). 
 
9.0  Protocol Treatment Table 
 
Arm 
Agent 
Dose Level 
Route 
Day 
Treatment 

 
22 
 
 
 
 
 
 
 
I 
 
 
 
 
 
 
Oral Tamoxifen and 
placebo gel 
 
 
 
10 mg oral 
tamoxifen; 
No active 
ingredient in gel 
 
 
 
 
 
 
Oral and 
Topical 
 
 
 
 
One daily 
dose orally 
and two 
topical 
doses to 
each breast 
 
Pill - Tamoxifen or placebo. 
Take one tablet daily. 
 
Gel – 4-OHT or placebo. 
Apply two pumps to each 
breast, one pump at a time. 
Spread 1 pump of gel 
across entire breast. After 
1st pump has dried apply 
2nd pump. Caution: New 
Drug- Limited by Federal 
law (US) to investigational 
use. 
 
 
 
 
 
 
2 
 
 
 
 
 
Placebo tamoxifen 
and 4-OHT gel 
 
 
 
 
No active oral 
ingredient; 
2 ml of gel with 
4OHT 
concentration of 2 
mg/ml to each 
breast (total 4 mg 
per breast; 8 mg 
total for both 
breasts) 
 
 
 
 
 
Oral and 
Topical 
 
 
 
One daily 
dose orally 
and two 
topical 
doses to 
each breast 
 
Pill - Tamoxifen or placebo. 
Take one tablet daily. 
 
Gel – 4-OHT or placebo. 
Apply two pumps of gel 
to each breast, one 
pump at a time. Spread 
1 pump of gel across 
entire breast. After 1st 
pump has dried apply 2nd 
pump. Caution: New 
Drug- Limited by Federal 
law (US) to 
investigational use. 
 
 
 
 
3 
 
 
 
 
Placebo 
tamoxifen/placebo gel 
 
 
 
 
No active 
ingredients orally 
nor in gel 
 
 
 
 
Oral and 
Topical 
 
One daily 
dose orally 
and two 
topical 
doses to 
each breast 
Pill - Placebo. Take one 
tablet daily. 
 
Gel –placebo. Apply two 
pumps of gel to each 
breast, one pump at a time. 
Spread 1 pump of gel 
across entire breast. After 
1st pump has dried apply 
2nd pump. Caution: New 
Drug- Limited by Federal 
law (US) to investigational 
use. 
 
 
 
9.1 
Self-Administration Statement 
 
 
Patients can be instructed in administration techniques, given written directions (see 
Appendix C and Appendix D), and granted treatment independence with coordinator 
approval. Patients will be instructed to apply gel and take their tablet about the same 
time every day. The gel should be applied after both breasts are washed, either by a 
shower or bath using a washcloth. Mornings are preferable time to use gel to minimize 
transferring to anyone while sleeping. Care needs to be taken to avoid flames or 
smoking while applying the gel due to alcohol content while in gel form. Once dry, this 
is no longer a problem. The treated breasts should be covered at all times to decrease 
the possible transfer to others and to protect from light. No washing or immersion of 
the area for a minimum of 4 hours after application. 
 
 
9.2 
Return to Consenting Institution 

 
23 
 
 
 
For this protocol, the patient must return to the consenting institution for evaluation at 
the end of treatment. 
 
 
9.3 
Data and Safety Monitoring Board (DSMB) 
The Mayo Clinic Department of Surgery (DOS) Data and Safety Monitoring Board 
(DSMB) exists as a component of the Division of Surgery Research. The DOS DSMB 
is structured to serve clinical intervention trials. The function of a DSMB is to review 
data and endpoints on a timeline set forth by the Data Safety Monitoring Plan (DSMP) 
in the IRB approved protocol. The DSMB will evaluate Serious Adverse Events as 
reported.  These events will also be reported to the IRN and NCI DCP. Membership of 
the DSMB includes the physician chair, physician representatives, a biostatistician, 
and an allied health program manager. The DSMB conducts an initial review of the 
protocol, informed consent, and the Data Safety Monitoring Plan (DSMP) prior to 
enrollment of subjects to determine the study’s risks and benefits and safety of 
research subjects, suggest improving the study design, identify what data will be 
required for review and identify early stopping rules. The DOS DSMB meets quarterly 
reviewing each study at least bi-annually. Special meetings of the DSMB may be 
convened more often, as necessary, to address urgent concerns regarding patient 
safety and data integrity. Studies identified by the IRB for more intensive monitoring 
may be reviewed on a quarterly, rather than semiannual basis. Special sessions of the 
DSMB may be held to address protocol specific issues, as necessary if the events of 
that protocol require review prior to the next scheduled DSMB meeting. Such meetings 
may occur through an electronic format. 
 
Evaluation of the study to help facilitate ongoing study management and compliance 
with applicable regulations, laws, and mandates will be conducted by the Mayo Clinic 
Office of Research Regulatory Support (ORRS) at the Mayo Clinic site and a to be 
named Mayo employee, will monitor Northwestern University and MD Anderson 
Cancer Center at Cooper. The study monitor will review processes after the first five 
subjects are entered into the database to ascertain all processes have been followed. 
After determining that the process is being followed, the monitor will assess at least 
annually. 
 
 
 
9.3.1 
Subject Safety 
Study eligibility is confirmed by study coordinators. Breast Clinic physicians 
and Breast Surgeons will receive information when this study is activated 
through presentations by the study PI. The study coordinator will review 
medical records of patient with a diagnosis of ADH, ALH, LCIS, and/or 
increased breast cancer risk to confirm that they meet eligibility criteria. The 
patient’s physician will be notified by the study coordinator of the intent to 
approach the patient for inclusion in this study. 
 
There are no safety tests/questionnaires. 
 
The patients will be informed that they are to contact the study coordinator if 
they encounter any problems with their treatment. The study coordinators will 
update the BBD study team of any anticipated adverse event  at team 
meetings every other week (Dr. Khan’s and Dr. Catherine Loveland-Jones’ 
group will send an e-mail to the coordinator team at RSTBBD@mayo.edu 
who will bring this to the regular meeting and get back to Dr. Khan’s or Dr. 
Catherine Loveland-Jones’ team that the side effect was reviewed). If a 
serious adverse effect occurs, the study coordinator will contact the PI (Drs. 

 
24 
 
Degnim, Khan or Catherine Loveland-Jones), or her designee when PI is 
away from the clinical setting (Dr. Tina Hieken, Dr. Karthik Ghosh, Dr. 
Christine Klassen). Serious Adverse Events and contact processes are 
covered under 10.2. 
 
 
 
9.3.2 
Data Integrity 
Data regarding study start and consent will be kept in PTRAX at Mayo. 
Northwestern University and MD Anderson Cancer Center at Cooper will 
follow their institution’s tracking system. The following data will be recorded 
in the study database (RAVE) by the study coordinators: 
•  Study sample attainment dates 
•  Drug start and stop dates 
•  Deviation(s) from the prescribed dosage 
regimen will be recorded. 
• Missed drug dates or deviations for the prescribed dosage regimen reported 
by the patient will be reviewed with participant and documented in the study 
database. Participant diaries will be retained in the subject folder as source 
documents.   
• Attribution to the study agent 
• Adverse effects assessed according to CTAE terminology, along with 
start and stop dates; CTAE severity score (AEs without a CTCAE term 
will be graded according to general severity guidelines) 
• SAEs, date and level, whether codes were broken to identify agent  
• BCPT symptom survey results 
 
9.3.3 
Product Accountability 
• 
The research pharmacy will store the drug kits in their area at each 
institution. 
• 
When a patient has agreed to participate in the study, they will be 
randomized per the RAVE Medidata database.  Once randomized, the 
research pharmacy will be notified of randomization results and will 
prepare kit for dispensing when the order and communication form is 
received from the study coordinators. The pharmacist will then dispense 
the kit to the study coordinator, who will deliver it to the patient, and 
provide instructions to the patient. 
• 
The research pharmacy will be accountable for the drug kits. 
 
 
 
9.3.4 
Study Documentation 
 
 
 
Study coordinators will maintain subject files. They are responsible for keeping 
these files up to date. 
 
 
 
9.3.5 
Study Coordinator 
The BBD group works as a team and has study coordinators available to 
support the study. Funding for this study coordinator support is provided by 
the parent R01 grant funding the study. Team meetings will be held every 
other week. We will have monthly communications with Dr. Khan at 
Northwestern University and Dr. Catherine Loveland-Jones at MD 
Anderson Cancer Center at Cooper.  A SAE will stimulate an immediate 
meeting with Dr. Degnim and the DSMB. 
 
 
9.4 
Breaking Codes in Double-Blinded Studies 
A) 
Situations requiring codes to be broken: There are three distinct 
situations in which it is appropriate to break the codes for individual patients 

 
25 
 
enrolled in double-blind trials: 
(1) In the event of an emergency or a serious adverse event for an individual 
patient. 
(2) In the event that it would be helpful for the future clinical  care of an 
individual patient after she/he has completed participation in the trial. 
(3) When it is necessary to know the specific treatment assignment of each 
patient in the trial in order to manage them all appropriately after they 
have completed participation in the trial. 
 
Study participants will receive study medications, blinded, from the investigational 
pharmacy.  The blind will be maintained through the effort of the research pharmacist 
and the pharmacy.  
 
In the event of an emergency or a serious adverse event, the PI (or their designee) will 
be notified to assess the medical necessity of unblinding. Emergency unblinding should 
only occur in medical events where not knowing the treatment assignment will affect 
ongoing treatment or significantly compromise the clinical management of the patient.   
 
Unblinding due to a Serious and Unexpected Adverse Event will happen only with 
permission of Dr. Amy Degnim, or designated site PI in the event of emergency if Dr. 
Degnim cannot be reached.   
 
Breaking the blind for serious and unexpected adverse events could occur when: 
1. The blind should be broken for serious and unexpected adverse events that would 
meet the criteria for reporting as single occurrences or one or more occurrences. The 
blind would need to be broken to determine if there is a reasonable possibility that the 
drug caused the adverse event.  
2. If the blind is broken and the subject was receiving placebo, the event should not be 
reported in an IND safety report because there is not a reasonable possibility that the 
study drug caused the adverse event.  
3. If the blind is broken and the subject was receiving drug treatment, the suspected 
adverse reaction must be reported in an IND safety report. (Note: the case must meet 
the definitions of suspected adverse reaction, serious, and unexpected.)  
 
If unblinding is necessary and after PI approval, the Mayo Clinic team designee will 
contact the site-specific pharmacy or statistical team / data manager to break the code 
while protecting the PI from the unblinded information, unless unblinding the PI is 
deemed necessary for either patient management or required event reporting. The 
reason and date of unblinding should be documented in Medidata RAVE by the 
statistical team / data manager.   
 
Contact information for Dr. Degnim:  
507-284-4499 (Medical Administrative Assistant) 
For after hours or emergency notification, Dr. Degnim can be reached at: 
Phone #  507-250-4149 or 
Pager # 507-284-6357 
 
Mayo Clinic Research Pharmacy:   
Phone Number:  507-538-0008  
Email:  MCPHARMACYORSS@mayo.edu 
 
Northwestern University Pharmacy:  

 
26 
 
Phone:  312-926-0747 
Email:  NMInvestigationalDrugService@nm.org 
MD Anderson Cancer Center at Cooper Pharmacy:  
Phone Number: 856-735-6231 
Email:  Pharmacy-MDA-IDS@CooperHealth.edu 
If, in the judgment of the attending physician, it would be helpful for the future clinical 
care of the individual patient, the code may be broken if requested by the patient, 
and after the patient has discontinued any duration of the study drug interventions, 
and no sooner than one month AFTER discontinuation of the study drug 
interventions while protecting the PI from the unblinded information. That is, after the 
patient has been fully evaluated and all evaluation information has been recorded by 
the attending physician and the patient (if appropriate), the patient’s clinical care 
team (but not the study PI) may request tinformation on which study therapy the 
patient was receiving and share this information with the patient. Information on the 
assigned treatment arm may be obtained per preferred institutional process, either 
via the Research Pharmacy or via a designated study team member other than the 
PI (Mayo Clinic). 
 
 
9.5 
Ancillary Treatment/Supportive Care 
 
 
The duration of the intervention is short; thus, short-term toxicity is expected to be 
limited to only temporary vasomotor symptoms. 
 
 
9.6 
Dose Discontinuation Criteria 
 
 
Any subject with an adverse event Grade 3 or higher (unless judged to be definitely 
unrelated to study agents) will be discontinued from both oral and topical 
interventions. These subjects may choose either to proceed with post-intervention 
blood and tissue samples, to continue participation with only clinical and symptom 
survey follow-up, or to withdraw from all further participation in the study. 
 
 
9.7 
Full Supportive Care 
 
 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. 
 
 
9.8 
Definitions 
Protocol Deviations 
Noncompliance with the research protocol that does not increase risk or decrease 
benefit and/or affect the integrity of the data 
 
Protocol Violation 
Noncompliance with the IRB-approved protocol without prior sponsor and IRB approval. 
Violations generally increase risk or decrease benefit, affect the subject's rights, safety, 
or wellbeing, or impact the integrity of the data 
 
Noncompliance 
Defined as a failure to follow the regulations, applicable law, institutional policy, and 
deliberations of the IRB 
 
Adverse Event 
Any unfavorable symptom, sign, or disease (including an abnormal laboratory 

 
27 
 
finding) temporally associated with the use of a medical treatment or 
procedure, whether or not considered drug related.   
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event. 
 
Expedited Reporting 
Expedited Reporting Requirements for IND/IDE Agents 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited 
reporting, but that for a specific protocol are being reported via expedited means in 
order to facilitate the review of safety data (may be requested by the FDA or the 
sponsor).  
 
 
9.9 
Adverse Event Characteristics 
Adverse events will be collected starting at the On Study visit and ending 30 days 
after the post-treatment biopsy is completed.  Each participant will be asked about 
AEs at every study visit and participant contact.  AEs will be documented and 
logged in the RAVE Database. 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for AE reporting. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site:  https://prevention.cancer.gov/clinical-
trials/clinical-trials-management/cp-ctnet-instructions-forms   
 
a. Identify the grade and severity of the event using the CTCAE version 5.0. 
b. Determine whether the event is expected or unexpected (see Section 6.11). 
c. Determine if the adverse event is related to the study intervention (agent, 
treatment, or procedure). 
d. Determine whether the event must be reported as an expedited report. If 
yes, determine the timeframe/mechanism (see Section 10.3) 
e. Determine if other reporting is required (see Section 10.0-10.2) 
f. 
Note: All AEs reported via expedited mechanisms must also be reported 
via the routine data reporting mechanisms defined by the protocol. 
Note: A severe AE is NOT the same as a serious AE, which is defined in 
Section 10.2 
 
 
9.10 Expected vs. Unexpected Events 
Expected events - are those described within the Section 9.10 of the protocol, 
the study specific consent form, package insert (if applicable), and/or the 
investigator brochure, (if an investigator brochure is not required, otherwise 
described in the general investigational plan). 
 
Unexpected adverse events or suspected adverse reactions are those not listed in 
Section 10.2 of the protocol, the study specific consent form, package insert (if 
applicable), or in the investigator brochure (or are not listed at the specificity or 
severity that has been observed); if an investigator brochure is not required or 

 
28 
 
available, is not consistent with the risk information described in the general 
investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have 
not been observed with the drug under investigation. 
 
An investigational agent/intervention might exacerbate the expected AEs associated with 
a commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with 
a higher degree of severity or specificity, expedited reporting is required. 
 
9.11 
Attribution to Agent(s) or Procedure 
 
 
When assessing whether an adverse event (AE) is related to a medical agent(s) 
medical or procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure.  
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
 
CTCAE1 
System Organ Class 
(SOC) 
 
Adverse event/ 
Symptoms 
CTCAE Grade at which the event 
will not be reported in an 
expedited manner2 
Vascular Disorders 
Hot flashes 
<Grade 3 
 
Musculoskeletal and 
Connective Tissue 
Disorders 
Generalized muscle 
weakness 
 
<Grade 3 
Gastrointestinal 
Disorders 
Nausea 
<Grade 3 
Nervous System 
Disorders 
Paresthesia 
<Grade 3 
1 Report any CTCAEs on https://prevention.cancer.gov/clinical-trials/clinical-trials-management/cp-
ctnet-instructions-forms  Additional instructions: The research coordinator will work with Site PI and 
complete IRB reporting to determine if FDA submission is needed. 
 
Grades from aforementioned CTCAE site: 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this general guideline: 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated.  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*.  
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 
 
2These exceptions only apply if the adverse event does not result in hospitalization. If the adverse event 
results in hospitalization, then the standard expedited adverse events reporting requirements must be 
followed. 

 
29 
 
 
10.0 Other Required Reporting 
 
 
10.1 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
 
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general include any incident, experience, or outcome that meets all of the following 
criteria: 
 
10.1.1 Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
 
10.1.2 Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
 
10.1.3 Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
 
 
10.2 Serious Adverse Event (SAE) Monitoring and Reporting 
The site principal investigator is responsible for reporting any/all serious adverse 
events to the sponsor as described within the protocol, regardless of attribution to 
study agent or treatment procedure. 
 
The site principal investigator is responsible for notifying FDA, Mayo Clinic 
Department of Surgery Data Safety Monitoring Board, and all participating 
investigators in a written safety report of any of the following: 
 
• 
Any suspected adverse reaction that is both serious and unexpected. 
 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not 
conducted by the sponsor Amy Degnim, M.D., that suggest a significant risk in 
humans exposed to the drug. 
 
• 
Any clinically important increase in the rate of a serious suspected adverse 
reaction over the rate stated in the protocol. 
 
• 
Grade 4 AEs regardless of attribution to the study treatment or procedure. 
 
• 
Grade 5 AEs (Deaths) 
 
• 
Any death within 30 days of the patient’s last study treatment or procedure 
regardless of attribution to the study treatment or procedure. 
 
• 
Any death more than 30 days after the patient’s last study treatment or procedure 
that is felt to be at least possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution assigned. 

31 
 
 
 
 
SAE Reporting Summary 
 
 
WHO 
SAE 
 
WHAT FORM 
WHERE TO SEND 
 
All sites 
Pregnancy 
Reporting 
 
https://prevention.cancer.
gov/clinical-trials/clinical-
trials-management/cp-
ctnet-instructions-forms   
RSTBBD@mayo.edu 
 
 
 
 
 
 
MedWatch 3500A: 
http://www.fda.gov/downloads/AboutFDA/Reports 
ManualsForms/Forms/UCM048334.pdf 
The Mayo Clinic 
Office of Research 
and Regulatory 
Support will assist 
Mayo Clinic 
Rochester in filing 
the MedWatch 
3500A form to the 
FDA.   Please refer 
to section 10.3 for 
reporting timelines. 
Mayo Clinic 
Rochester will report 
the SAE to the 
following: 
DCP Regulatory 
Contractor, CCS 
Associates: 
safety@ccsainc.com 
 
 
 
All sites 
FDA 
Repo
rting 
MedWatch 3500A: 
http://www.fda.gov/downloads/AboutFDA/Reports 
ManualsForms/Forms/UCM048334.pdf 
 
 
RSTBBD@mayo.edu 
All sites 
SAEs 
Mayo Clinic Department of Surgery Data and 
Safety Monitoring Board (DSMB) 
 
Mayo Clinic 
Rochester will 
contact DSMB within 
24 hours of 
notification of SAE  
 
 

 
31 
 
 
 
 
 
 
 
 
 
 
Mayo Clinic Rochester study team will contact the Mayo Clinic Department of Surgery (DOS) 
Data and Safety Monitoring Board (DSMB) within 24 hours of notification of SAE.   The team 
will also report as indicated in section 10.2 SAE Reporting Summary. 
Report the following SAE information when contacting the Mayo Clinic Department of Surgery 
(DOS) Data and Safety Monitoring Board (DSMB): 
• 
Date and time of the SAE 
• 
Date and time of the SAE report 
• 
SAE description and attribution to drug 
• 
Reporter name, email, and telephone number 
• 
Affiliation/Institution where SAE occurred 
• 
DCP and IRB protocol number 
• 
Title of protocol 
 
 
10.2.1 An initial assessment of the SAE will be made by the DSMB. The study team 
will submit to the Institutional Review Board who will determine which SAEs 
require FDA submission as IND safety reports as noted in section 10.2. 
 
 
10.2.2 Follow-up of SAE 
 
Mayo Clinic, Northwestern University and MD Anderson Cancer Center at 
Cooper will send requested follow-up reports to DCP as soon as possible. 
This information should be entered on the DCP SAE Report Form. 
 
 
BHIR Besins Pharmacovigilance will not have any monitoring or reporting 
requirements.  Besins will receive reports at the time of the annual 
Continuing Review. 
  
10.3 
Expedited Reporting Requirements for IND Agents 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for 

 
32 
 
Adverse Events that Occur on Studies under an IND/IDE within 30 days of the 
Last Administration of the Investigational Agent/Intervention.1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
AdEERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs. 
 
10 Calendar 
Days 
 
 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs. 
 
Not required 
 
10 Calendar 
Days 
NOTE: Protocol-specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hourreport. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
 
10.4 Protocol Deviations 
 
Minor protocol deviations must be documented and reported at the time of continuing review.  
Notifying the IRB through a reportable Event submission is required if a deviation that imposes 
a suspected increase in the risk of harm to participants or adversely affects the integrity of the 
data. 
 

 
33 
 
Study staff will refer to the protocol and study specific SOPs, institutional and departmental 
policies.  All associated source documents will be collected, including all pertinent outside 
medical information, which will be reviewed and assessed by the PI or Co-investigator.  The PI 
will determine whether event meets UPIRTSO or significant new information criteria and/or 
protocol violation/deviation definition. 
 
Events will be reported per the Investigator’s direction in alignment with the institutional 
policies to: 
-Mayo IRB 
-Data Safety Monitoring Board (DSMB) 
-Food and Drug administration (FDA)-  if Mayo sponsor/investigator holds the Investigational 
New Drug (IND) or Investigational Device Exemption, (IDE) contact Office of Research 
Regulatory Support (ORRS) 
(See Section 10.0 Other Required Reporting)  
 
Event will be documented in the Deviation Log at Mayo Clinic and all associated 
documentation will be retained.  Northwestern University and MD Anderson Cancer Center at 
Cooper will follow their institutional policy for documentation.   
 
11.0 Statistical Considerations 
The primary hypothesis is that the reduction in Ki67 will not be inferior to that seen with oral 
tamoxifen. A sample size of 36 per treatment arm (36 receiving oral tamoxifen and 36 
receiving 4OHT gel, with 18 placebo controls) will provide >80% power at α=0.05 to test 
this hypothesis. Volume density and MBI will be compared across study arms from pre-to 
post-treatment. Risk predictors identified from Nanostring-based mRNA expression assay 
(conducted under IRB 75-87) and biomarkers of tamoxifen response (conducted under IRB 
15-000279) will also be tested. 
 
Randomization and intervention. To achieve the planned sample size of N=90 women, we 
will over-accrue by ~15% to allow for cancellation, ineligibility, non-evaluable samples, or 
major treatment deviations and thus plan to enroll a total of N=104 at two study sites (42 at 
Mayo-Rochester, 42 at Northwestern University, 20 at MD Anderson Cancer Center at 
Cooper). Patients will be randomized 2:2:1 to oral Tam (10 mg/day), 4-OHT gel (4 mg/each 
breast/day), or placebo controls for four weeks. Estimated numbers of randomized subjects 
to each arm will be: 42 to oral Tam, 42 to 4OHT gel, and 21 double placebo, in order to 
arrive at final sample size of 36, 36, and 18. Treatment randomization will be stratified with 
respect to menopausal status (pre- vs. postmenopausal), diagnosis (ADH vs ALH/LCIS vs 
increased BC risk based on risk model calculations), and study site. Oral and gel placebos 
will be used to create a double-blinded study. After four weeks, blood draw, physical exam, 
BCPT symptom survey, digital mammogram (and MBI in Mayo subjects) will be repeated. A 
second breast tissue sample will be obtained from the same quadrant, either as a core 
biopsy or as tissue adjacent to the surgical excision site. 
 
Feasibility. At Mayo Clinic in Rochester, MN, we see an average of 55 patients per year 
with ADH or ALH who would be eligible for this study. At Mayo Clinic, Drs. Degnim, 
Hieken, and Ghosh have successfully led accrual of over 500 women to prospective 
studies in the last six years, therefore successful accrual of women to this prospective 
study is feasible. At Northwestern University, there is a similar volume of women with 
diagnoses of ADH or ALH, and they have accrued ~400 women over five years to various 
studies requiring some form of intervention (either medication or biopsy). Accrual plan is 
for 42 subjects at Mayo Clinic, 42 at Northwestern University and 20 subjects at MD 
Anderson Cancer Center at Cooper. With an anticipated timeframe of 48 months to 
complete accrual, this averages to 1-2 patients per month per site. This study should be 
acceptable to patients as the duration of intervention is short and therefore short-term 

 
34 
 
toxicity is expected to be limited to only temporary vasomotor symptoms. 
 
Translational studies. The primary endpoint will be change in Ki67 in background normal 
breast lobules (% cells positive by Aperio quantitation). Additional endpoints will include 
changes in volumetric density (% and dense volume) measured using VolparaTM both at 
baseline and after four weeks of treatment. In addition, promising genes from discovery 
work in Aim 2 will be evaluated using NanoString. 
 
Changes in background parenchymal uptake (BPU) on MBI will also be employed as an 
exploratory endpoint. Blood samples and residual breast tissues collected pre/post Tam 
will be stored for future correlative studies. 
 
Endpoints. The primary endpoint is change in Ki67 level pre/post treatment. The primary 
analysis for the primary endpoint will include all eligible patients who began study drug 
intervention and have available tissue measures of Ki67 levels at both timepoints (pre- and 
post-treatment).  
 
A sensitivity analysis for the primary endpoint will also be performed.  This sensitivity analysis 
will include eligible patients who have available tissue measures of Ki67 levels at both 
timepoints and were compliant with study treatment.   Patients will be classified as non-
compliant with the study treatment (and thus excluded from the sensitivity analysis) using 
criteria outlined above (patients who have less than 80% compliance with daily drug use or 
have missed more than 3 doses in the final 14 days).  
 
As for the primary endpoint, primary analyses for secondary endpoints will include all eligible 
patients who began study drug and have available endpoint measurements at both timepoints; 
sensitivity analyses for each secondary endpoint will exclude non-compliant patients (as 
defined above). For analyses of adverse events, all patients whostarted the study treatment 
will be included, regardless of treatment compliance or availability of endpoint measurements 
at both timepoints.  
 
Statistical analysis. The primary hypothesis is that the reduction seen with 4-OHT gel will be 
not inferior to that seen with oral tamoxifen. We also hypothesize that oral tamoxifen and 4-
OHT gel will each be superior to placebo with respect to the percent change in Ki67 in 
background normal lobules between baseline and four weeks. Analyses will assess if 
significant changes in Ki67 are observed after four weeks of treatment by paired t- 
tests/Wilcoxon signed rank tests, stratified by treatment group. We will assess the non- 
inferiority of 4-OHT gel compared to oral tamoxifen by estimating a 95% confidence interval 
for the mean difference in percent change between the two agents after four weeks of 
treatment; if the lower limit of the confidence interval is less than the non- inferiority margin 
(described below), we will conclude that 4-OHT gel is non-inferior to oral tamoxifen. As 
exploratory analyses, we will assess pairwise differences between samples on active 
treatment (oral tamoxifen or 4-OHT gel, separately and combined) vs. placebo using two-
sample t-tests/Wilcoxon rank sum tests. Similarly, we will assess changes from baseline in 
the expression of the candidate genes identified in Aim 2 (absolute log2 fold- change>2 
and/or q-value<0.05). Volumetric density changes from baseline within treatment group will 
be assessed continuously, and evaluated using paired t-tests on the log-transformed 
density or Wilcoxon signed-rank tests; pairwise differences between treatment groups will 
be assessed with two-sample t-tests/Wilcoxon rank sum tests. BPU on MBI is measured as 
a four category ordinal scale; we will compare pre-to-post changes within group using 
Wilcoxon signed rank tests and will compare the percent of subjects decreasing BPU 
category by one or more level between groups using chi-square tests. We will assess the 
correlation between changes in volumetric density and changes in BPU, using Spearman 
correlation. Symptoms from the BCPT survey are measured on a five- level ordinal scale. 
We will compare differences in pre- to post-treatment symptom severity changes across 

 
35 
 
treatment arms using Wilcoxon rank sum tests.  
 
Sample size/power. Prior studies suggest that oral tamoxifen will lead to a 50% mean 
relative reduction in Ki67 in normal lobules at four weeks compared to baseline.[19-21, 43] 
We assume that the standard deviation for the percent change in Ki67 is 30 percentage 
points, estimated based on a plausible range from published literature.[19-21, 43]] A sample 
size of 36 per active treatment arm will provide >80% power at α=0.05 to test the 
hypothesis that 4-OHT gel is not inferior to oral tamoxifen with a non-inferiority margin of 20 
percentage points (e.g., if oral tamoxifen results in a 50% mean reduction of Ki67, 4- OHT 
gel will be considered non-inferior if we can conclude that 4-OHT gel results in a mean 
reduction of Ki67 of at least 30%). Further 18 subjects enrolled in a placebo arm will provide 
>90% power to detect a mean difference of 50% reduction for either treatment arm versus 
an assumed mean difference of 0% for placebo assuming a two-sided, two-sample t-test 
with α=0.05. Therefore n=90 subjects are required, but the study will over-accrue by 15% 
(n=104 patients) to account for cancellation, ineligibility, non-evaluable samples, or major 
treatment deviations. 
 
Updates to Sample size/power with 4OHT dose modification 10/12/22. 
We expect that the higher dose of 4OHT gel (8 mg/day) will be at least as effective as the 
original dose (4 mg/day), and therefore the primary endpoint, sample size, and power 
calculations remain the same and may even be conservative, assuming analysis including all 
subjects treated with 4OHT gel at either dose. We also plan to conduct sensitivity analyses for 
the primary endpoint excluding the 4mg/day group (this will be N=5 patients on the 4 mg/dose 
that would be excluded).  
 
To date, 12 patients have been accrued (5 oral Tam, 5 4OHT gel 4 mg/day dose, and 2 
controls). Subtracting these N=12 patients accrued from the total original planned sample size 
of N=104, there will be N=92 patients remaining to accrue who will be randomized after the 8 
mg/day 4OHT gel dose is implemented, per existing 2:2:1 schema.  
 
With anticipated sample size of 92 patients to be randomized after approval of the higher (8 
mg/day) 4OHT gel dose, we estimate final total randomized numbers will be as follows: Total 
N=104, with 41 on oral Tam, 5 at the 4 mg/day dose of 4OHT gel, 36 at the 8 mg/day dose of 
4OHT gel, and 22 dual-placebo controls.   
 
Anticipated power for the primary endpoint. 
Primary endpoint is noninferiority of Ki67 change between 4OHT gel and oral Tam arms. 
 
For a combined analysis including ALL subjects receiving 4OHT gel at EITHER dose, ie 41 
oral Tam versus 41 with 4OHT gel (5 at 4mg/day dose plus 36 at 8 mg/day dose), keeping the 
original assumption of 15% attrition results in final sample of 36 per group and power of 80%.   
 
For a subgroup analysis including ONLY the subjects receiving the higher 8 mg/day dose of 
4OHT gel, the power ranges from 76% to 82%, depending on the amount of attrition (see 
Table below).   
 
Table 1. Sample size and power considerations for primary endpoint, non-inferiority in Ki67 
change between gel and oral 
 
Sample size & 
power assuming 
15% attrition 
Sample size & 
power assuming 
10% attrition 
Sample size & 
power assuming 
5% attrition 
Sample size & 
power assuming no 
attrition 
 
 
 
 
 
Use entire 
sample, 
36 per group  
(Power: 80%) 
37 per group 
(Power 81%) 
39 per group 
(Power 83%) 
41 per group 
(Power: 85%) 

 
36 
 
including 
subjects with 
either 4 
mg/day or 8 
mg/day 4OHT 
gel 
 
Subgroup 
analysis 
including only 
those with 8 
mg/day dose 
36 oral Tam group, 
31 in 8 mg/day 
4OHT gel group 
(Power 76%) 
37 oral Tam group, 
32 in 8 mg/day 
4OHT gel group  
(Power 78%) 
39 oral Tam group, 
34 in 8 mg/day 
4OHT gel group  
(Power 80%)  
41 oral Tam group, 
36 in 8 mg/day 
4OHT gel group 
(Power 82%) 
 
 
 
12.0 Descriptive Factors 
Examination of differences between groups on BCPT will occur across study arms on the 8 
identified scales and on additional items measuring fatigue and sexual function. 
 
13.0 Treatment/Follow-up Decision at Evaluation of Patient 
 
 
 
Reason Off Treatment 
Study Complete 
Adverse Event 
Death 
Disease Progression 
Lost to Follow-up 
Non-Compliance 
Participant Withdrawal 
Participant Refused Follow-up 
Physician Decision 
Protocol Defined Follow-up Completed 
Protocol Violation 
Ineligible  
Other 
 
 
13.1 
Ineligible 
A patient is deemed ineligible if the patient did not satisfy each and every eligibility 
criteria for study entry. If the patient received treatment, the patient may continue 
treatment at the discretion of the physician as long as there are not safety concerns. 
The patient will continue in the Active Monitoring/Treatment phase of the study. 
 
 
13.2   Major Violation 
A patient is deemed a major violation, if protocol requirements regarding treatment 
are severely violated that evaluability for primary end point is questionable. If the 
patient received treatment, the patient may continue treatment at the discretion of the 
physician as long as there are not safety concerns. The patient will continue in the 
Active Monitoring/Treatment phase of the study. 
 
 
13.3 Withdrawal / Screen Failure 
A patient is deemed a withdrawal if she meets all eligibility criteria, consented to 

 
37 
 
participate, and is removed from the study or chooses not to participate for any 
reason. A patient is deemed a screen failure if she fails to meet all study inclusion / 
exclusion criteria, whether consented or not. Reasons for withdrawals and screen 
failures will be recorded in the study database.   
 
Patients who withdraw from the study will be offered follow-up for resolution of 
adverse events, and this will consist of telephone or in-person visit evaluation as 
clinically needed and agreed upon by the patient. 
 
If a patient withdraws from the study prior to initiating any of the study drug 
interventions, then she may be replaced with another patient toward the accrual 
total.  If a patient withdraws from the study AFTER initiating any of the study drug 
interventions, then she will not be replaced with another patient toward the accrual 
total. 
 
14.0 Body Fluid and Tissue Biospecimens 
 
Body fluid and tissue biospecimens will be obtained both pre- and post-treatment. 
 
Blood: 2 vials of whole blood, each 10 ml, drawn in purple top EDTA tubes (blood card 
specifies 2 - 10ml EDTA tubes). BAP will accession and label. Aliquot (1) 4000uL blood 
pour for DNA extraction. Refrigerate. Centrifuge at lab standards.  
First EDTA vial should be processed for three 1 ml aliquots of plasma into 3 cryovials 1 ml 
plasma each and 1ml WBC.  Second EDTA vial is stored as whole blood. 
Freeze products from both vials. Post-treatment only-One 4 ml. vial of whole blood, drawn 
in green top heparin tube, processed for plasma. Stored at -80 freezer. 
 
Tissue: Core biopsies or surgical tissue will be used to create two snap frozen samples and 
a single paraffin block (if applicable).  
 
For more details, please see individual sections above as follows:  
Pre-Treatment Blood Samples- section 6.8.2. 
Pre-Treatment Tissue Samples- section 6.8.3.  
Post-Treatment Biopsy- section 7.3.  
Post-Treatment Blood Samples- section 7.4 
 
 

 
38 
 
15.0 Summary Table of Research Blood and Tissue Specimens to be Collected for this 
Protocol 
 
 
 
Research 
 
Specimen 
Purpose 
 
Mandatory 
or Optional 
 
Blood or Body Fluid 
being Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
 
Pre- 
Interv
en- 
tion 
 
Post
- 
Inter
ven- 
tion 
 
 
 
 
 
 
Blood 
 
 
 
 
 
 
Banking 
 
 
 
 
 
 
Mandatory 
Whole blood - Aliquot 
(1) 4000uL 
blood pour for 
DNA extraction. 
Refrigerate. 
Centrifuge at 
lab standards. 
First EDTA 
vial should be 
processed for 
three 1 ml 
aliquots of 
plasma into 3 
cryovials 1 ml 
plasma each 
and 1ml WBC.  
Second EDTA 
vial is stored as 
whole blood 
 Freeze. Light Sensitive 
 
 
 
 
 
Purple/ 
EDTA 
 
 
 
 
 
10 mL (2 
tubes) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Blood 
 
 
 
 
4-OHT 
levels 
 
 
 
 
Mandatory 
One 4 ml green top heparin 
tube will be used for 4-OHT 
levels. This tube is to be 
wrapped in tin foil due to 
light sensitivity. 
The tube will need to be 
processed for plasma and 
stored in - 80 freezer. 
 
 
 
 
Green/ 
Heparin 
 
 
 
 
4 mL 
 
 
 
 
 
X 
Breast 
Tissue Pre 
Treatment 
from 
Diagnostic 
Clinical 
Biopsy 
 
 
 
 
 
 
 
 
 
 
 
Ki67 and 
RNA 
extraction 
 
 
 
 
 
 
 
 
 
 
 
Mandatory if 
opting out of 
PreTreatmen
t Research 
Biopsy 
 
 
 
PreTreatment- 
6 5 micron FFPE sections 
for H&E and Ki67, and to 
be determined IHC 
biomarker assays 
3  10 micron FFPE 
sections for RNA 
extraction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FFPE 
 
 
 
 
 
 
 
 
 
 
 
FFPE sections. 
See pathology 
manual for 
details of cores 
per tube, 
processing, 
and handling. 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 

 
39 
 
Breast 
Tissue 
PreTreatmen
t Research 
Biopsy 
 
 
 
 
 
 
 
 
 
 
 
banking 
 
 
 
 
 
 
 
 
 
 
 
Optional 
4 vacuum assist 
cores- either 9 or 11 G  
For  
PreTreatment-Two cores 
snap frozen for RNA; two 
cores in formalin for single 
FFPE block 
 
 
The remaining 
cores/pieces placed in 
formalin and  processed 
into 1 paraffin block if 
possible 
 
 
 
 
 
 
 
 
 
 
 
Sterile 
 
 
 
 
 
 
 
 
 
 
 
3 tubes-2 snap 
frozen, 1 in 
formalin.  See 
pathology 
manual for 
details of cores 
per tube, 
processing, 
and handling. 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breast 
Tissue 
Post 
Treat
ment 
 
 
 
 
 
 
 
 
 
 
 
banking 
 
 
 
 
 
 
 
 
 
 
 
Mandatory 
4 vacuum assist 
cores- either 9 or 11 G  
For tissue taken during 
surgery two 1 cm2 pieces. 
 
Post-Treatment- Two 
cores / tissue pieces snap 
frozen; one for 4OHT 
levels (see row below) and 
one for RNA extraction 
 
The remaining 
cores/pieces placed 
in formalin and  
processed into 1 
paraffin block if 
possible 
 
 
 
 
 
 
 
 
 
 
 
Sterile 
 
 
 
 
 
 
 
 
 
 
 
3 tubes-2 snap 
frozen, 1 in 
formalin.  See 
pathology 
manual for 
details of cores 
per tube, 
processing, 
and handling. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Research 
 
Specimen 
Purpose 
 
Mandatory 
or Optional 
 
Blood or Body Fluid 
being Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
 
Pre- 
Interv
en- 
tion 
 
Post
- 
Inter
ven- 
tion 

 
40 
 
 
 
 
Breast 
Tissue 
 
 
 
4-OHT 
levels 
 
 
 
Mandatory 
 
 
One core/piece snap 
frozen for 4-OHT levels 
 
 
 
Sterile 
 
 
 
1 tube-see 
pathology 
manual for 
details. 
 
 
 
 
X 
 
16.0 Remuneration 
Participants will receive remuneration of $350-500. This will be prorated as follows: $150 upon 
completion of the optional baseline study biopsy, and $350 upon completion of study 
intervention and post-treatment biopsy. All Participants will also receive a small gift of 
appreciation.   
 
 

 
41 
 
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44 
 
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. 

 
45 
 
Percent 
Description 
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. 
 
 
 

 
46 
 
Appendix B 
 
Breast Cancer Prevention Trial Symptom Checklist 
 
EVERYDAY PROBLEMS DURING THE PAST 4 WEEKS 
 
__________________________________________________________ 
 
We are interested in knowing how much you have been bothered by any of the following 
problems during the PAST 4 WEEKS. (Circle one number on each line. If you do not have the 
problem, circle “not at all”.) 
 
During the past 4 weeks, how much were you bothered by: 
 
 
Not at All 
Slightly Moderately 
Quite a Bit Extremely 
1. Hot flashes 
0 
1 
2 
3 
4 
2. Nausea 
0 
1 
2 
3 
4 
3. Vomiting 
0 
1 
2 
3 
4 
4. Difficulty with bladder control  
0 
1 
2 
3 
4 
when laughing or crying 
 
5. Difficulty with bladder control 
0 
1 
2 
3 
4 
at other times 
 
6. Vaginal dryness 
0 
1 
2 
3 
4 
7. Pain with intercourse 
0 
1 
2 
3 
4 
8. General aches and pains 
0 
1 
2 
3 
4 
9. Joint pains 
0 
1 
2 
3 
4 
10. Muscle stiffness 
0 
1 
2 
3 
4 
11. Weight gain 
0 
1 
2 
3 
4 
12. Unhappy with appearance  
0 
1 
2 
3 
4 
of my body 
 
13. Forgetfulness 
0 
1 
2 
3 
4 
14. Night sweats 
0 
1 
2 
3 
4 
15. Difficulty concentrating 
0 
1 
2 
3 
4 
16. Easily distracted 
0 
1 
2 
3 
4 
17. Arm swelling (lymphedema) 
0 
1 
2 
3 
4 
18. Decreased range of motion 
0 
1 
2 
3 
4  
in arm on surgery side 
 
19. Vaginal Discharge 
0 
1 
2 
3 
4 
20. Vaginal bleeding or spotting 
0 
1 
2 
3 
4 
21. Genital itching/irritation  
0 
1 
2 
3 
4 
22. Lack of energy 
0 
1 
2 
3 
4 
23. Tiredness 
0 
1 
2 
3 
4 
24. Lack of interest in sex 
0 
1 
2 
3 
4 
25. Low sexual enjoyment 
0 
1 
2 
3 
4 
 
 

 
47 
 
Appendix C 
Instructions Oral Tamoxifen 
 
1. Take your pill at the same time every day. 
2. If you miss a dose, take the dose as soon as you remember unless it is almost time for your 
next dose. If it is almost time for your next dose, wait until then and take a regular dose. 
Mark the missed dose on the calendar provided. Do not take a double dose. 
3. You can take the pill with or without food. There are no specific foods to avoid. 
4. If you start any new medication while you are on study, please call your study coordinator at 
1-877-588-9301 to let them know. She will check with the study doctor and your personal 
physician so that possible interactions are managed safely. 
5. If you develop hot flashes, some suggestions for managing them: 
• 
Dress in layers, avoid turtlenecks, wool and synthetic material. 
• 
Keep your bedroom cool. 
• 
Avoid alcohol, caffeine, hot or spicy foods. 
• 
Avoid hot tubs, hot showers and saunas. 
• 
Engage in physical activity such as walks. 
 
 

 
48 
 
Appendix D 
Instructions 4-OHT Gel Application 
 
1. The gel is flammable while in gel form: do not apply near fire, flame, heat or smoke.  Once 
dry, the gel is not flammable. 
2. Prior to applying gel, shower or wash breasts with a washcloth and dry thoroughly. 
3. Remove the cap, point the canister toward the sink or a wastebasket, prime the canister 
by pushing on the pump all the way several times until gel is dispensed. Do not use the 
first dose as it may not be a full dose. 
4. If you don’t push the pump all the way or you discard more than one dose, discard the 
pumped doses and record this in your diary. 
5. Pump one dose into the palm of your hand and make sure to release pump completely 
between doses. 
6. Spread the gel evenly across your entire breast, without rubbing. 
7. Repeat for the other breast. 
8. After the gel is dry, apply a second pump of gel to each breast. 
9. Wash your hands immediately with soap and water. 
10. Replace the cap on the canister. 
11. Allow the gel to air dry for 2 minutes and then cover immediately with clothing. The gel 
is colorless and will not stain clothing. 
12. Do not wash your breasts or immerse in water for a minimum of 4 hours after 
application. If this is not possible, delay application until after immersion, such as after 
you swim. 
13. If you miss a dose, do not double the dose. If your next dose is within 12 hours, skip it, 
note it on the provided calendar and just resume the gel at the next scheduled time. If 
your next dose is more than 12 hours later, apply the missed dose and resume your 
normal dose at the next scheduled time. 
14. Mark on each canister the date and the time of your first dose. 
15. Keep the canisters at room temperature and keep out of the reach of children. 
16. Do not expose treated area to sunlight at any time. 
17. For the duration of the study, do not apply any other cream, lotion, or moisturizer to 
your breasts at any time. 
18. Avoid contact between the application area and the skin of another person. Skin contact 
is allowable after area is washed. However, don’t wash this area for at least 4 hours 
after application. 
19. At the end of the study bring the canisters back with you to your follow-up visit with the 
study coordinator. 
 
 

 
49 
 
Appendix E 
Patient Diary 
 
Protocol Number 
Start Date:  
Stop Date:  
 
Name 
Subject ID 
Site 
 
Thank you for our participation. Please complete this diary every day by circling the correct answer and bring it with 
you for your follow-up visit. 
 
You will need to apply the gel to both breasts and take your capsule every morning. 
DAY 
MONDAY 
TUESDAY 
WEDNESDAY 
THURSDAY 
FRIDAY 
SATURDAY 
SUNDAY 
DATE 
 
 
 
 
 
 
 
Did you 
apply your 
gel? 
 
 
Wasted 
pumps/ 
discarded 
gel 
Right- 
No / yes 
Left- 
No / yes 
 
No / yes 
If yes, how 
many? 
_________ 
Right- 
No / yes 
Left- 
No / yes 
 
No / yes 
If yes, how 
many? 
_________ 
Right- 
No / yes 
Left- 
No / yes 
 
No / yes 
If yes, how 
many? 
_________ 
Right- 
No / yes 
Left- 
No / yes 
 
No / yes 
If yes, how 
many? 
_________ 
Right- 
No / yes 
Left- 
No / yes 
 
No / yes 
If yes, how 
many? 
_________ 
Right- 
No / yes 
Left- 
No / yes 
 
No / yes 
If yes, how 
many? 
_________ 
Right- 
No / yes 
Left- 
No / yes 
 
No / yes 
If yes, how 
many? 
_________ 
Did you 
take your 
capsule 
Yes 
No 
 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
How many 
hot flashes 
did you 
have in the 
past 24 
hours? 
0 
1-5 
6-10 
11-15 
0 
1-5 
6-10 
11-15 
0 
1-5 
6-10 
11-15 
0 
1-5 
6-10 
11-15 
0 
1-5 
6-10 
11-15 
0 
1-5 
6-10 
11-15 
0 
1-5 
6-10 
11-15 
Did you 
have night 
sweats in 
the past 24 
hours? 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Did you 
have any 
muscle 
weakness 
in the past 
24 hours? 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Did you 
experience 
any nausea 
in the past 
24 hours? 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Did you 
experience 
any 
numbness 
or tingling 
in your 
hands or 
feet in the 
past 24 
hours? 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
 
Last dose of Tamoxifen capsule: Date  
Time 
  
Last dose of gel application to breast: Date  
 
Time  
  

 
50 
 
Appendix F  Radiology Guide 
 
Percutaneous needle cores will be taken in radiology with imaging guidance. 
1. Baseline/pretreatment research biopsies:  
o Performed by needle core approach using a 9-11G vacuum assist needle, with 
guidance. 
o The biopsy should target a dense area of tissue; the goal is to obtain more glandular 
rather than adipose tissue. 
o For patients enrolled after biopsy of ADH/ALH/LCIS, the research biopsy should 
consistently be in the same quadrant, to the patient’s lateral and/or above the 
diagnostic biopsy site in the same breast targeting 1 cm from the previous clip (if clip 
at biopsy site).  
 
If clip is >2 cm away from the biopsy site, then the research biopsy should be 
obtained at a location estimated to be 1 cm lateral or above from the biopsy site, 
maintaining adequate distance from the clip so that it is not removed with the tissue 
sampling.  The radiologist will save detailed information on the location of biopsy. If 
the biopsy is performed using stereotactic or tomosynthesis guidance, recording the 
following two metrics is recommended: (1) compression thickness, and (2) depth of 
the biopsy target. If the biopsy is performed by ultrasound, capturing post-biopsy 
cine clips of the biopsy site using virtual convex imaging (when using a linear array 
transducer) in the transverse, longitudinal, radial, and antiradial directions is 
recommended. Document in the biopsy note the location of the research biopsy in 
relationship to the diagnostic biopsy site.  Clip placement at the site of the research 
biopsy is favored but at the discretion of the radiologist performing the research 
biopsy.  A new clip should be placed at the research biopsy site if the original 
diagnostic biopsy clip had migrated >2 cm and was not in good position.  
 
o For patients enrolled by high risk criteria (no recent biopsy of high risk lesion), the 
pretreatment research biopsy may be obtained from either breast.  The goal is to 
obtain more glandular rather than adipose tissue, so targeting a denser area of 
tissue is desired.  The research biopsy location is at the discretion of the radiology 
team at each institution. The radiologist will save detailed information on the location 
of biopsy. Clip placement at the site of the research biopsy is favored but at the 
discretion of the radiologist performing the research biopsy.  If no clip is placed and 
the research biopsy demonstrates malignant disease, then the patient should return 
as soon as possible for clip placement while the biopsy site can be discerned by 
imaging. 
 
 
For 9-11G vacuum assist cores, 4-6 cores will be collected: 
- Two of the cores will be placed in 2 separate tubes and snap frozen 
- The remaining cores will be placed in formalin 
      
 

 
51 
 
 
Study coordinators will provide collection tubes, labels, Dewar with liquid nitrogen  
 
and specimen collection/companion form prior to procedure and will pick up   
 
samples after collection is complete. 
• 
Preprinted labels will be provided and should be used for pretreatment tissue 
samples. (Provided by Study Coordinator).  
• 
Collection/companion form containing additional specimen collection details will be 
completed at time of collection  
 
 
2. Post-treatment research biopsies: 
- 
When performed by needle core approach using a 9-11G needle 
- 
The biopsy should target a dense area of tissue and should consistently be in the 
same quadrant, medial or below the diagnostic biopsy site in the same breast 
targeting 1 cm from the previous clip. Again, the goal is to obtain more glandular 
rather than adipose tissue. 
 
If clip is >2 cm away from not located the biopsy site, then the research biopsy should 
be obtained at a location estimated to be 1 cm medial or below from the biopsy site, 
maintaining adequate distance from the clip so that it is not removed with the tissue 
sampling.  The radiologist will save detailed information on the location of biopsy. If the 
biopsy is performed using stereotactic or tomosynthesis guidance, recording the 
following two metrics is recommended: (1) compression thickness, and (2) depth of the 
biopsy target. If the biopsy is performed by ultrasound, capturing post-biopsy cine clips 
of the biopsy site using virtual convex imaging (when using a linear array transducer) in 
the transverse, longitudinal, radial, and antiradial directions is 
recommended.  Document in the biopsy note the location of the research biopsy in 
relationship to the diagnostic biopsy site.  Clip placement at the site of the research 
biopsy is favored but at the discretion of the radiologist performing the research biopsy. 
A new clip should be placed at the research biopsy site if the original diagnostic biopsy 
clip had migrated >2 cm and was not in good position. 
 
o For patients enrolled by high risk criteria (no recent biopsy of high risk lesion), the 
pretreatment research biopsy may be obtained from either breast.  The goal is to 
obtain more glandular rather than adipose tissue, so targeting a denser area of 
tissue is desired.  The research biopsy location is at the discretion of the radiology 
team at each institution. The radiologist will save detailed information on the location 
of biopsy. Clip placement at the site of the research biopsy is favored but at the 
discretion of the radiologist performing the research biopsy.  If no clip is placed and 
the research biopsy demonstrates malignant disease, then the patient should return 
as soon as possible for clip placement while the biopsy site can be discerned by 
imaging. 
 
 
For 9-11G vacuum assist cores, 4-6 cores will be collected: 
- 
Two of the cores will be placed in 2 separate tubes and snap frozen 
- 
The remaining cores will be placed in formalin 

 
52 
 
 
Study coordinators will provide collection tubes, labels, Dewar with liquid nitrogen  
 
and specimen collection/companion form prior to procedure and will pick up   
 
samples after collection is complete. 
• 
Preprinted labels will be provided and should be used for post-treatment tissue 
samples. (Provided by Study Coordinator).  
• 
Collection/companion form containing additional specimen collection details will be 
completed at time of collection  
 
 
Post-treatment research breast tissue sample can be obtained by either needle core 
approach (if no surgical excision is done for clinical care) or can be obtained by the surgical 
team intraoperatively after excision of the lesion. 
 
If patient has bilateral or multi-centric atypia/LCIS, at Mayo Dr. Degnim will review and 
recommend one side for research biopsy. At Northwestern University, Dr. Seema Khan will 
review and make recommendation. At MD Anderson Cancer Center at Cooper, Dr. Catherine 
Loveland-Jones will review and make recommendations. 

 
53 
 
Appendix G  
Medications with potential interactions with tamoxifen or 4hydroxytamoxifen 
 
Inhibitors of Cytochrome P450 (CYP2D6) Enzymes 
Strong Inhibitors: 
 
 
 
Moderate Inhibitors:  
Quinidine  
 
 
 
 
Terbanafine 
Cinacalcet 
 
 
 
 
Duloxetine 
Bupropion 
 
 
 
 
Sertraline 
Fluoxetine 
Paroxetine 
 
Inducers of Cytochrome P450 (CYP3A4/5) Enzymes 
Glucocorticoids 
 
 
 
Pioglitazone   
 
Efavirenz 
 
 
 
 
Fosamprenavir 
 
 
Nevirapine 
 
 
 
 
Rifampin 
 
 
Carbamazepine  
 
 
 
Eslicarbazepine 
 
Oxcarbazepine 
 
 
 
Phenobarbital  
 
Phenytoin 
 
 
 
 
St. John’s Wort 
 
 
Modafinil 
 
 
 
 
 
Legend:  The extent of inhibition may not be well defined and/or the degree of inhibition may vary for 
the drugs listed.  Note that if a drug inhibits CYP3A4, it is expected to induce CYP3A5, although 
literature proving this for each drug is not available.  All information from Pharmacogenomic 
Associations Tables, Mayo Clinic: Mayo Medical Laboratories.  Retrieved from 
http://intranet.mayo.edu/charlie/center-individualized-medicine/files/2017/05/Pharmacogenomic-
Inhibitor-Inducer-and-Substrates-table.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
54 
 
Appendix H 
Drug-Induced Prolongation of the QT Interval  
http://online.factsandcomparisons.com/lco/action/doc/retrieve/docid/1081/5909323 
 
 
 
 
 
 
 
 
 
 

 
55 
 
 
*Drugs not available in the United States