Mirena® IUD's Effect on Fallopian Tube Fimbriae and Ovarian Cortical Inclusion Cyst Cell Proliferation
Phase: NA
Conditions: Epithelial Ovarian Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB #: 15-105 A(4) 
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Mirena® IUD's Effect on Fallopian Tube Fimbriae and Ovarian Cortical Inclusion Cyst Cell 
Proliferation 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: 
Dennis Chi, MD 
Surgery 
Co-Principal 
Investigator(s)/Department: 
Malcolm Pike, PhD 
Epidemiology-Biostatistics 
Investigator(s)/Department: 
Nadeem Abu-Rustum, MD 
Richard Barakat, MD 
Vance Broach, MD 
Carol Brown, MD 
Ginger Gardner, MD 
Elizabeth Jewell, MD 
Mario Leitao, MD 
Kara Long Roche, MD 
Jennifer Mueller, MD 
Yukio Sonoda, MDOliver 
Zivanovic, MD 
Renee Cowan, MD 
Joao Casanova Goncalves, 
MDMaria Schiavone, MD 
Alessia Aloisi, MD Brooke 
Schlappe, MD 
Jill Tseng, MD 
Paulina Cybulska, MD 
Katherine LaVigne, MD 
Emeline Aviki 
Marina Stasenko 
Irene Orlow, PhD 
Kay Park, MD 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Epidemiology-Biostatistics 
Pathology 
Consenting Professional(s)/Department: 
Nadeem Abu-Rustum, MD 
Surgery 
Richard Barakat, MD 
Surgery 
Carol Brown, MD 
Surgery 
Dennis Chi, MD 
Surgery 
Ginger Gardner, MD 
Surgery 
Elizabeth Jewell, MD 
Surgery 
Mario Leitao, MD 
Surgery 
Kara Long Roche, MD 
Surgery 
Jennifer Mueller, MD 
Surgery 
Yukio Sonoda, MD 
Surgery 
Oliver Zivanovic, MD 
Surgery 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 

Memorial Sloan Kettering Cancer Center 
IRB #: 15-105 A(4) 
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OneMSK Sites 
Manhattan 
Westchester 
Basking Ridge 
Commack 
Monmouth 
Rockville Center 
 
 
Participating Institutions – If multicenter 
study coordinated by MSK: 
PI's Name 
Site's Role 
University of Southern California 
Frank Stanczyk, MD 
Specimen Analysis 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEM A ........................................................................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 4 
3.0 
BACKGROUND AND RATIONALE ............................................................................................ 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................ 6 
4.1 
Design ....................................................................................................................... 6 
4.2 
Intervention ................................................................................................................ 7 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ....................................................................................... 8 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................ 8 
6.1 
Subject Inclusion Criteria ................................................................................................ 8 
6.2 
Subject Exclusion Criteria ........................................................................................... 8 
7.0 
RECRUITMENT PLAN ........................................................................................................ 9 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 10 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 10 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................... 11 
11.0 TOXICITIES/SIDE EFFECTS ................................................................................................ 13 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....................... 13 
13.0 CRITERIA FOR REM OVAL FROM STUDY ............................................................................. 13 
14.0 BIOSTATISTICS ........................................................................................................................ 14 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 15 
15.1Research Participant Registration .......................................................................................... 15 
15.2 Randomization ................................................................................................................... 15 
16.0 DATA MANAGEMENT ISSUES ............................................................................................... 15 
16.1 Quality Assurance ........................................................................................................ 15 
16.2 Data and Safety Monitoring .......................................................................................... 16 
17.0 PROTECTION OF HUMAN SUBJECTS ........................................................................... 17 
17.1 Privacy ..................................................................................................................... 18 
17.2 Serious Adverse Event (SAE) Reporting ...................................................................... 18 
18.0 INFORMED CONSENT PROCEDURES ............................................................................... 19 
19.0 REFERENCES ...................................................................................................................... 20 
20.0 APPENDICES ............................................................................................................................. 21 

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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Combination-type oral contraceptives (COCs) have been shown to significantly reduce the 
risk of invasive epithelial ovarian cancer (IEOC); this protective effect may be achieved to a 
large extent through COCs ability to reduce cell proliferation in the fallopian tube fimbriae 
(FTF). The progestin-releasing Mirena® intra-uterine device (IUD) is an increasingly popular 
method of contraception, but it is not known if its use will reduce a woman‟s risk of IEOC. 
Mirena® use does not block ovulation in most women, but it may release sufficient progestin 
to also reduce cell proliferation in the FTF. This study aims to evaluate the effects of the 
Mirena® IUD on cell proliferation in the FTF as a possible biomarker of protection against 
IEOC. 
 
In this study, a Mirena® IUD will be inserted into volunteers scheduled for a risk-reducing 
salpingo-oophorectomy (RRSO) or risk-reducing salpingectomy (RRS) at Memorial Sloan 
Kettering Cancer Center (MSK). Alternatively, women with a Mirena® IUD already in place 
and who will be scheduled for an RRSO or RRS at MSK can also participate. We are seeking 
14 evaluable participants. FTF tissue (and ovarian inclusion cyst tissue, when available) 
collected at the time of risk-reducing surgery will be tested by immunochemistry staining for 
Ki67 (a protein that is significantly increased when cells are preparing for division). The goal 
of this testing is to determine whether the cell proliferation in the FTF is reduced in these 
women compared to such proliferation during the normal cycle (data obtained under MSK  
IRB Protocol #14-165). 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• 
Primary Objective: To determine in women undergoing an RRSO or RRS at MSK 
whether cell proliferation in the FTF is reduced in those using a progestin-releasing 
Mirena® IUD compared to such proliferation during the normal menstrual cycle. 
• 
Secondary Objective: To determine in women undergoing an RRSO at MSK 
whether cell proliferation in ovarian cortical inclusion cysts (CICs) is reduced in those 
using a progestin-releasing Mirena® IUD compared to such proliferation during the 
normal menstrual cycle. 
3.0 
BACKGROUND AND RATIONALE 
 
Approximately 21,000 new diagnoses and 14,000 deaths occur each year as a result of 
invasive epithelial ovarian cancer (IEOC; also referred to as ovarian carcinoma or ovarian 
cancer) in the US.1 Five-year survival is less than 50%, and there is currently no effective 
screening approach.2   Preventive strategies are of paramount importance. 
 
There are 5 main subtypes of ovarian cancer: high-grade serous, low-grade serous, 
endometrioid, clear cell, and mucinous. All subtypes demonstrate a Mullerian-tissue 
phenotype except for mucinous tumors, which sometimes demonstrate a gastrointestinal 
phenotype.3 High-grade serous ovarian cancer (HGSC) accounts for approximately 70% of 
ovarian cancer cases.4 Until recently the favored proposed cell of origin of HGSC was the 
mesothelial ovarian surface epithelium (OSE).5 The mechanism was entrapment of the OSE 
into OSE-CICs within the ovary with subsequent metaplastic transformation into Mullerian- 
type epithelium (Mullerian-CICs), which most commonly has the appearance of fallopian tube 

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epithelium. More recently, the Mullerian FTF has been proposed as the direct cell of origin of 
a high proportion of HGSCs;6-12 this was based on the finding that the most common site of 
occult „ovarian cancer‟ lesions in BRCA1/2 mutation (BRCA1/2mut) carriers undergoing an 
RRSO was the FTF. There is good evidence that many non-BRCA-associated HGSCs also 
develop in the FTF.10 There is also good evidence that some ovarian cancers arise in 
Mullerian-CICs.5,12,13 
 
COCs, with an estrogen and a progestin in each active pill, provide substantial protection 
against ovarian carcinoma.14 The protective effect extends to all histological subtypes of 
ovarian cancer and lasts for more than 30 years after COC use is stopped.14 The protective 
effect has also been found in BRCA1/2mut carriers.15-19 “Incessant ovulation” was long 
considered to be the driving force in ovarian cancer etiology,20 and it was generally believed 
that the protective effect of COCs arose from their action of blocking ovulation. 
However, it 
is now clear that postmenopausal estrogen therapy (ET) significantly increases the risk of 
ovarian cancer and this effect is much reduced by the addition of a progestin.21 Since 
postmenopausal ET use is not associated with any increase in ovula tion, this suggests that 
endogenous and exogenous estrogen and progestin levels influence ovarian cancer risk 
directly. 
 
Cell proliferation in the FTF over the menstrual cycle has been reported to closely follow cell 
proliferation in the endometrium.22 23 There is proliferation throughout the follicular phase of 
the cycle, and little or no proliferation from a few days after ovulation with the rise in 
progesterone until the end of the cycle; our preliminary data confirm this (MSK IRB Protocol 
#14-165; PI K. Park, MD). To our knowledge, there are no data on cell proliferation in FTF or 
CICs from women using COCs or a Mirena® IUD. Furthermore, there is no literature on cell 
proliferation in CICs relative to the phase of the menstrual cycle. 
 
We propose that the protection against HGSC from COC use is due in large part to the 
action of the progestin component of COCs as this component significantly reduces cell 
proliferation in the FTF and in CICs.  A central role for proliferation in the etiology of many 
cancers was emphasized in two papers published in 1990,24,25 and the supportive 
epidemiological evidence was presented by Preston-Martin and colleagues.26   The recent 
paper by Tomasetti and Vogelstein27 presented new evidence of the important association 
between proliferation and cancer rates.  The clearest evidence of the importance in the 
etiology of a cancer site is the association between menopausal estrogen replacement 
therapy and endometrial cancer.28-30   This association also provides the explanation of the 
strong association between obesity and endometrial cancer including its importance in 
premenopausal women through increasing the frequency of anovulation. 31,32   The 
effectiveness of an analysis based on cell proliferation to quantitatively explain the age 
incidence and many risk factors for the major female cancers can be found in references 33 
and 34. A reduction in cell proliferation would be protective, as proliferating cell populations 
are more susceptible to carcinogenic effects due to increased chances of mutation and 
progression. (Note: the progestin component of COCs blocks cell proliferation in the 
endometrium and this is generally accepted as the mechanism of COC protection against 
endometrial cancer.) 

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We hypothesize that when a Mirena® IUD is used, despite its associated very low serum 
level of progestin (see below), cell proliferation in the FTF will be very low (comparable to the 
proliferation in the luteal phase of the menstrual cycle). We further hypothesize that the same 
may be true of cell proliferation within CICs. The results from this study will provide crucial 
information regarding the possible protection against IEOC from use of the Mirena® IUD. 
 
FTF tissue from premenopausal women undergoing an RRSO or RRS and ovarian tissue 
from premenopausal women undergoing an RRSO will allow us to study the mechanism of 
protection against HGSC from COC use as well as the possible protection from use of the 
Mirena®. BRCA1/2mut carriers are at high risk of ovarian cancer. They often choose to 
undergo RRSO surgery at a premenopausal age as this surgery is proven to dramatically 
decrease their ovarian cancer risk as well as their risk of breast cancer.35 Tissue from these 
women is most appropriate for study as the protective effect of COCs against ovar ian 
cancers is also seen in BRCA1/2mut  carriers.15-19 Many other women with a strong family 
history of ovarian/breast cancer also choose to undergo an RRSO or RRS, and study of their 
FTF and their ovarian tissue, when available, is also appropriate. 
 
We currently have an NCI-funded grant (1R21 CA181923-01A1; MSK IRB Protocol #14-165) 
to do a comprehensive study of proliferation in the FTF and CICs over the menstrual cycle 
and in the postmenopausal period using archived specimens from RRSOs conducted at  
MSK. Also, the University of Southern California and the British Columbia Cancer Agency 
(associated with the University of British Columbia), with which Dr. Pike is associated, also 
have an NCI-funded grant to study the effect of a COC on such proliferation. In this latter 
study, a COC is administered for 7-14 days before the RRSO procedure. Such short duration 
treatment should be sufficient to observe the effects on the FTF, as cellular proliferation in  
the FTF appears to be exquisitely sensitive to changes in the hormonal milieu. 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a non-randomized study of the effect of Mirena® IUD use of at least 10 days before 
an RRSO or RRS on cell proliferation within the FTF and, when available, within ovarian 
CICs in women aged 35 through 50. The study will compare the results from 14 women 
using Mirena® with the results from 28 normally cycling women identified under MSK IRB 
Protocol #14-165 described above; all patients will be aged 35-50 years, and will have 
undergone the RRSO at MSK. To date, we have identified approximately 100 suitable 
controls and are continuing to identify further suitable controls among women who have 
recently undergone RRSOs at MSK. The balancing/matching factors will be BRCA status 
(BRCA1/BRCA2/BRCA-ve), age (35-39/40-44/45-50), parity (nulliparous/parous), and BMI 
(<30/30+ kg/m2). As each Mirena® patient completes the study and is deemed evaluable, 
she will be matched on each of these factors with 2 controls. If only one exact match is 
available, then her second control will be chosen according to the balancing scheme of 
Pocock and Simon,36 with choice between controls with equal (low) imbalance being made 
with preference for balancing in the following order: BRCA, age, parity, and BMI. If no exact 
match is available, the same scheme will be used to choose the 2 controls. This approach 

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will ensure that at the completion of the study with 14 Mirena® patients and 28 controls, the 
matching criteria will be closely balanced between the 2 groups. If at any stage of the choice 
of controls, more than one equally good control is identified, the one with the most recent 
RRSO will be chosen. 
 
We expect to enroll women during months 3-30 of the study. Immunohistochemical analysis 
of the tissue will be done throughout and completed in months 31-33. Data analysis and a 
manuscript describing the results will be completed in months 34-36. 
 
4.2 
Intervention 
 
This current proposal is intended to study the effect of use of the increasingly popular 
progestin-containing (levonorgestrel, or LNG) Mirena® IUD on FTF and CIC proliferation. 
The Mirena® IUD releases 20 mcg of LNG per day and is associated with a very low serum 
concentration of LNG, no more than 10% of the average LNG concentration with a standard 
LNG-containing COC.37-419   We propose that the Mirena® IUD be in use for >10 days before 
the RRSO or RRS. 
 
Use of an earlier version of a Mirena®-type IUD releasing 30 mcg/day of LNG was found in a 
single study to be associated with a concentration of LNG in the fallopian tube equal to that 
seen in women using a standard 250 mcg LNG COC;42 the dose of LNG in the most 
commonly used current COC is 150 mcg. Significant improvement of symptoms of 
endometriosis are commonly seen with treatment with a Mirena® IUD.43   These results 
suggest that the daily dose of progestin released by the IUD may be sufficient to affect the 
fallopian tube. 
 
FTF cell proliferation is observed within a few days of the start of the follicular phase of the 
menstrual cycle (estrogen exposure with very low progesterone), with little or no proliferation 
from a few days after ovulation until the end of the cycle. We estimate that cell proliferation 
will be maximal from early on after the start of menses, and certainly by day 5 until around 
day 15 of the cycle. This study is to determine whether FTF cell proliferation during this 
period is significantly reduced if the woman is using a Mirena® IUD. We have therefore 
chosen the follicular phase (approximately between 5 and 15 days after the start of the cycle 
and to be determined by blood sample on the day of surgery) as the appropriate period in 
which to compare cell proliferation between the Mirena® group and the retrospective control 
group. For the Mirena® group, it is essential that the participant has very low serum 
progesterone (P4) at the time of sampling; if her P4 is high at the time of sampling, it will not 
be possible to determine whether or not any observed low proliferation rate is due to the 
endogenous P4 level. We will measure estradiol (E2) and P4 from a blood sample taken on 
the day of surgery. A P4 value >1 ng/ml will be considered unsatisfactorily high; if such a 
value is found, the sample FTF and CIC cell proliferation values will be ignored and the 
patient will not be counted towards the 14 Mirena®-treated patients planned for the study. 
The E2 measurement will be performed to confirm that there is follicular phase estradiol 
production: if E2 is <30 pg/ml, the samples will be ignored and the patient will not be counted 
towards the planned 14 evaluable subjects. This E2 restriction is necessary as Mirena® use 
is generally associated with regular premenopausal estrogen levels. 

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If the hypothesized effects are seen, Mirena® use may be an attractive contraceptive option 
for BRCA1/2mut carriers and other women at high risk of IEOC. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
This study is investigating the effects of the Mirena® IUD. This is an FDA approved 
intrauterine contraceptive that is indicated for use up to 5 years. It is also indicated for the 
treatment of heavy menstrual bleeding in women who choose to use intrauterine 
contraception as their method of contraception. Mirena® contains 52 mg of levonorgestrel 
(LNG), which is released at a rate of approximately 20 mcg/day. 
 
Mirena® will be supplied for this study at no cost by its manufacturer, Bayer HealthCare 
Pharmaceuticals. 
 
Mirena® is available in a carton of one sterile unit (NDC# 50419-423-01). Mirena® is 
supplied sterile. Mirena® is sterilized with ethylene oxide and should not be resterilized. It is 
for single use only. It should not be used if the inner package is damaged or open. It should 
be inserted before the end of the month shown on the label. It should be stored at 25°C 
(77°F), with excursions permitted between 15–30°C (59–86°F). 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
We will recruit women seeking an RRSO or RRS at MSK, including BRCA1/2mut  carriers and 
women with a strong family history of breast and/or ovarian cancer. 
 
Approximately 130 women undergo an RRSO or RRS per year at MSK, of whom ~30% meet 
our eligibility criteria. Enrollment will be carried out over 30 months. We expect there will be 
~97 eligible women receiving an RRSO or RRS during this recruitment period. 
 
6.1 
Subject Inclusion Criteria 
• 
Women between 35 and 50 years of age (inclusive) 
• 
Women who will be scheduled to undergo an RRSO or RRS 
• 
Women who will have at least one fallopian tube removed for risk-reducing reasons 
(with or without removal of ovar(ies)) 
• 
Women who are willing to have a Mirena® IUD inserted at least 10 days prior to risk- 
reducing surgery or who already have the Mirena® in place 
• 
Women using non-hormonal forms of contraception 
(Note: If a copper IUD is being used, the IUD must be removed prior to or at time of 
Mirena insertion.) 
6.2 
Subject Exclusion Criteria 
 
• 
Any medical contraindication to use of a Mirena® IUD, including: 
o Pregnancy (a pregnancy test is required prior to study entry) 
o Known uterine anomaly that distorts the shape of the uterine cavity 
o Acute pelvic inflammatory disease 
o Postpartum endometritis or endometrial infection 
o Known or suspected uterine or cervical neoplasia 
o Known history or suspected breast cancer or other progestin-sensitive cancer 

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o Uterine bleeding of unknown etiology. 
o Untreated acute cervicitis, vaginitis, or other lower genital tract infections 
o Acute liver disease or liver tumor (benign or malignant) 
• 
Use of tamoxifen, raloxifene, or chemotherapy within the previous 6 months 
• 
Positive pregnancy test 
• 
Breastfeeding 
• 
Use of a copper IUD if the patient is not willing to have it removed prior to surgery and 
replaced with a Mirena® IUD 
 
 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient‟s treatment team, the 
protocol investigator, or research team at Memorial Sloan Kettering Cancer Center (MSK). If 
the investigator is a member of the treatment team, s/he will screen their patient‟s medical 
records for suitable research study participants and discuss the study and their potential for 
enrolling in the research study. Potential subjects contacted by their treating physician will be 
referred to the investigator/research staff of the study. 
 
The principal investigator may also screen the medical records of patients with whom they do 
not have a treatment relationship for the limited purpose of identifying patients who would be 
eligible to enroll in the study and to record appropriate contact information in order to 
approach these patients regarding the possibility of enrolling in the study. Patients identified 
in this manner would subsequently be approached for study enrollment after consultation  
with their treating physician. 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary for the 
recruitment and enrollment process. The investigator/research staff may also review portions 
of their medical records at MSK in order to further assess eligibility. They will use the 
information provided by the patient and/or medical record to confirm that the patient is  
eligible and to contact the patient regarding study enrollment. If the patient turns out to be 
ineligible for the research study, the research staff will destroy all information collected on the 
patient during the initial conversation and medical records review, except for any information 
that must be maintained for screening log purposes. 
 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator, or the research staff working in consultation with the treatment 
team. The recruitment process outlined presents no more than minimal risk to the privacy of 
the patients who are screened and minimal PHI will be maintained as part of a screening log. 
For these reasons, we seek a (partial) limited waiver of authorization for the purposes of (1) 
reviewing medical records to identify potential research subjects and obtain information 
relevant to the enrollment process; (2) conversing with patients regarding possible 
enrollment; (3) handling of PHI contained within those records and provided by the potential 
subjects; and (4) maintaining information in a screening log of patients approached (if 
applicable). 

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Potential study participants who meet our basic inclusion/exclusion criteria will be  
approached by their physician to volunteer for this study. If the patient indicates a willingness 
to participate, an investigator will explain the study in detail. Women who volunteer and sign 
an informed consent will have a Mirena® IUD inserted by a trained physician if they do not 
already have the Mirena® IUD in place. Our goal is to obtain 14 evaluable patients. We 
anticipate needing to consent 28 women in order to obtain the 14 evaluable patients because 
some patients may not be in the follicular phase at the time of their RRSO/RRS, which is 
necessary for appropriate evaluation of cell proliferation. 
 
 
8.0 
PRETREATMENT EVALUATION 
 
Women who consent to the study will have up to two in-person study visits prior to 
RRSO/RRS (see below) occuring in conjunction with their regular care visits. 
 
Patients determined likely to be eligible will be approached about the study at their first 
regular care visit with their surgeon if possible. Any patient without a Mirena® already in 
place and interested in participating should be scheduled to have the Mirena® placed on 
study at a regular care visit at least 10 days prior to surgery. 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Following informed consent to the study and at any time prior to surgery, all patients will 
complete a short questionnaire. This is a simple structured form based on forms in use in 
epidemiological studies at MSK. It will be used to request a brief reproductive history and to 
capture inclusion and exclusion criteria information. 
 
All patients will have a serum pregnancy test at the time of a clinical blood draw or a urine 
pregnancy test. For patients planning to have a Mirena® placed on study, this test must be 
done prior to Mirena® placement. If this test is positive, the patient is ineligible for the study 
and the Mirena® will not be placed. 
 
Patients who will have a Mirena® placed on study will undergo chlamydia and gonorrhea 
testing at the time of Mirena® placement. If patients are positive for chlamydia or gonorrhea, 
they will be treated. The Mirena® will be inserted according to the technique described in the 
prescribing information. 
 
Patients can have the Mirena® placed at a regional site by an investigator, provided that 
Investigational Drug Services and the regional pharmacy are given at least 3 business days‟ 
notice. 
 
Day of Surgery: On the day of surgery, we will collect a blood sample in a 10mL red top tube 
with no additives for measurement of E2, P4, and LNG. All patients who had the Mirena® 
placed on study will have it removed at the time of RRSO/RRS. FTF processing and, if 
applicable, CIC processing will occur as described below. 

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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Ovarian tissue (if removed) and fallopian tube(s) will be submitted in toto as per standard 
MSK clinical protocol for RRSO/RRS specimens. According to this protocol, the fimbriated 
end of the fallopian tube is amputated and serially sectioned along its length, and submitted 
in toto. This maximizes the amount of fallopian tube epithelium available for histological 
examination. This is part of normal clinical care and is not affected by this study. 
 
Blood will be collected in 10mL red top tubes according to standard procedures and 
processed by Dr. Irene Orlow‟s Molecular Epidemiology Laboratory at Memorial Sloan 
Kettering Cancer Center. This laboratory is located on the 7th floor of the Schwartz building, 
and the research blood tube will be delivered in accordance with instructions on the 
requisition uploaded to Study Related Documents (specifically to Other Specimen Related 
Documents) in the Protocol Information Management System (PIMS). 
 
Serum will be sent to the University of Southern California Reproductive Endocrine Research 
Laboratory at the address below, and E2, P4, and LNG will be assayed under the direction of 
Dr. Frank Stanczyk (fstanczyk@att.net) for comparability to the assays being conducted in 
the COC study: 
 
USC Reproductive Endocrine Research Laboratory 
1321 North Mission Road 
Livingston Research Building, Room 207 
Los Angeles, CA 90033 
Attn: Stan Patel 
Phone: 323-224-5590 (office) 
310-462-1259 (cell) 
sherfaraz.patel@med.usc.edu (email) 
 
Specimens to be shipped for testing at the USC Reproductive Endocrine Research 
Laboratory will be labeled with their sample IDs. A shipping manifest will accompany the 
shipment and will provide the following information: Processing and shipping lab at MSKCC, 
list of sample IDs, date of collection, type of specimen, and sample volume. No other 
participant identifiers will be sent to USC, within the shipment or via email. Specimens will be 
shipped overnight on dry ice. Shipments will be agreed on in advance and in general will 
occur on Monday, Tuesday, or Wednesday, avoiding vespers of holidays and weekends. 
 
Cell Proliferation Measurements 
 
We will only use specimens of FTF and ovaries after standard pathology review has 
determined that there is no evidence of malignancy or a premalignant lesion in the 
specimens. 
 
10.1 
FTF Cell Proliferation 
 
Fixation and tissue processing will be conducted according to standard MSK Pathology 
Department procedures. To assess proliferation in the FTF epithelium, a „random‟ block 
containing fimbriae will be obtained for each patient and adjacent 1 m sections cut, 

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deparaffinized, and hydrated. FTF cells are extremely tightly packed and 1 m sections have 
been found necessary for successful automated counting of individual cells. All slides will be 
subject to antigen retrieval for IHC analysis. The slides will be stained for Ki67(MIB-1; cell 
proliferation), PAX-8 (secretory cells),44-45 and estrogen receptor α (ERα), and progesterone 
receptor A/B (PR) using MSK standard methods with MIB-1 (Dako Cytomation, Carpenteria, 
CA, USA), PAX-8 (AC1438A, Biocare, Concord, CA), ERα (Clone SP1, Ventana Medical 
systems, Hoffmann-La Roche, Nutley, NJ) and PR (Clone 1E2, Ventana Medical systems, 
Hoffmann-La Roche, Nutley, NJ). The slides will then be scanned using the Aperio® slide 
scanning system and quantitative analysis of the labeling (% positive cells) will be done with  
a systematic „blind‟ choice of regions of interest (ROIs) using an overlaying grid covering the 
whole slide until at least 1,000 FTF epithelial cells have been counted. The count of total 
cells and positive cells is done by a validated automated system. We will use manual 
mapping of the adjacent PAX-8 stained slides to estimate the proportion of FTF cells that are 
ciliated for each ROI and thereby estimate the proliferation index for secretory and ciliated 
cells separately. The proportion of FTF cells that are secretory in the follicular phase of the 
cycle is estimated to be ~45%.23,45   Additional slides from other random blocks will be 
obtained if the slide does not contain sufficient FTF epithelial cells. This will be carried out 
under the supervision of the MSK study pathologist, Dr. Kay Park. 
 
The main focus of analysis will be all FTF epithelial cells. Separate analyses of secretory and 
ciliated cells will be performed in order to gain potentially useful information. The main 
analysis will be conducted with staining for Ki67; the other stains may be of help in 
understanding the Ki67 results. 
 
10.2 
Cell Proliferation in the CICs 
 
Fixation and tissue processing will again be done according to standard MSK Pathology 
Department procedures. To assess proliferation in the CIC epithelium, all hematoxylin and 
eosin (H&E) stained slides will be inspected to find the block with the largest number of CICs. 
This block will have adjacent 3 m sections cut, deparaffinized, and hydrated (3 m sections 
are the thinnest sections that can be successfully cut from an ovary). All slides will be subject 
to antigen retrieval for IHC analysis. The slides will be stained for Ki67, PAX-8, ERα, and PR 
using methods as described above. The slides will also be stained for calretinin to detect  
OSE cells (5A5, NCL-L-Calretinin, Leica Microsystems, Buffalo Grove, IL). The slides will  
then be scanned using the Aperio® slide scanning system and quantitative analysis of the 
labeling (% positive cells) will be done for all CICs. The count of total cells and positive cells  
is done by a validated automated system. We will use manual mapping of the adjacent PAX- 
8 stained slides to estimate the proportion of FTF-type cells that are secretory for each 
Mullerian CIC, and thereby estimate the proliferation index for secretory cells separately. 
Additional slides from other blocks will be obtained if the slide does not contain sufficient 
FTF-like epithelial cells. Previous studies suggest that ~60% of the slides will contain no 
CICs, and the average number of CICs on slides with ≥1 CIC will be ~10 44,46. A detailed 
study by Li et al.37 found that 66% of CICs are PAX-8 positive (FTF secretory-like), 12% are 
tubulin positive (FTF ciliated-like), and 22% are calretinin positive (OSE-like), and that the 
average number of cells per CIC was 146 (no breakdown by type of CIC was given). We 
therefore estimate that the number of PAX-8 or tubulin positive cells per CIC-containing slide 
will be ~1,135 (~960 and ~175 for PAX-8 positive and tubulin positive, respectively), while 

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the number of calretinin positive cells will be ~320. We plan on analyzing multiple slides, 
sufficiently separated from each other to avoid overlap of cells, until we have 1,000 PAX-8 
positive cells in total; this will give us in total ~2,115 PAX-8 positive cells, ~385 tubulin 
positive cells, and ~705 calretinin positive cells. This will be carried out under the supervision 
of the MSK study pathologist, Dr. Kay Park. 
 
The main focus of analysis will be the FTF-like cells combined (in agreement with the 
analysis of FTF cell proliferation in the FTF described above) and of calretinin positive cells. 
Separate analysis of PAX-8 positive cells will be conducted to gain potentially useful 
information. 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Insertion of the Mirena® IUD is an office procedure. A speculum examination is performed, 
and the cervix is grasped with a tenaculum. The Mirena® IUD system is advanced into the 
uterine cavity, where the Mirena® is deployed. During insertion of the Mirena® IUD, reported 
side effects include pain, uterine cramping, dizziness, and lightheadedness. Uncommonly, 
bleeding occurs at the tenaculum site and requires use of hemostatic measures. There is a 
remote chance of uterine perforation during placement of the Mirena® (approximately 
1/1000); this can cause injury to surrounding organs or tissues as well as extra-uterine 
placement of the IUD. Expulsion of the IUD occurs less than 5% of the time. Other 
uncommon side effects that have been reported with Mirena® IUD use include amenorrhea, 
dysmenorrhea, benign ovarian cysts with associated complications, headache, acne, 
depression, vaginal discharge, nausea, back pain, unusual hair growth or alopecia, 
vulvovaginitis, breast tenderness/ pain, and pelvic inflammatory disease or endometritis. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The primary outcome is the extent of proliferation in the FTF in women on the Mirena® IUD 
compared to FTF proliferation during the normal follicular phase. Women will be deemed 
evaluable for this primary outcome if they successfully underwent placement of the Mirena® 
IUD, received a RRSO/RRS as planned, and had a P4 value ≤1 ng/ml. 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient is found to be ineligible for the protocol as designated in the section 
on Criteria for Patient/Subject Eligibility (e.g., a change in diagnosis), the patient will be 
removed from the study. 
 
Mirena® insertion on study will be immediately stopped at any time the subject requests, and 
she will be removed from the study. Similarly, if at any time after the insertion on study but 
before the RRSO/RRS, the subject requests that the Mirena® be removed, the Mirena® will 
be removed and the subject will be taken off the study. Additionally, should expulsion of the 
Mirena® occur prior to surgery or should it be discovered that the Mirena® was placed in an 
extra-uterine location, the patient will be removed from the study. 

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14.0 
BIOSTATISTICS 
 
Our study is powered based on obtaining evaluable data from 14 women. 
 
Our primary endpoint is the difference in cell proliferation in the FTF epithelium (FTFE) of 
women on a Mirena® and control women during the follicular phase of their menstrual cycle 
(14 women in the Mirena® group vs 28 women in the control group). Experience in analyzing 
data on cell proliferation in the FTFE of different women shows that cell proliferation results 
should be logarithmically  transformed to achieve a more normal distribution of values. We 
will use analysis of variance for this analysis. All analyses will be done using Stata 12 (Stata 
Corporation, College Station, TX, USA). 
 
In their study of proliferation in normal premenopausal women in the follicular phase of the 
menstrual cycle, Donnez et al.22 found a standard deviation on a logarithmic scale of 1.17. 
This is very similar to the results from our pilot study where we analyzed proliferation in the 
FTFE of 5 such premenopausal RRSO patients in the follicular phase and found a standard 
deviation of 1.21. (This standard deviation is greatly in excess of the standard deviation 
predicted by assuming that all women have the same true proliferation rate and shows that 
our analysis of a total 2,500 cells per woman is more than sufficient to ensure that this 
number has only a minor effect on the between women standard deviation.) The difference in 
cell proliferation observed by Donnez et al.22 between the follicular phase and the luteal  
phase of the cycle was ~88% (a 75% reduction in the „early secretory‟ phase and a 100% 
reduction in the „late secretory‟ phase). These results were confirmed in our pilot study, in 
which we analyzed specimens from 5 women in the follicular phase and 5 women in the  
luteal phase of the cycle at their RRSO. 
 
Using the slightly larger value of 1.21 as an estimated standard deviation between different 
women, our sample size of 14 Mirena® women vs 28 control women affords us 90% power 
to detect a 72% decrease, and an 80% power to detect a 67% decrease, in FTFE 
proliferation with a two-sided alpha level of 5%. This shows that we have adequate power to 
detect a difference between the Mirena® group and the control group if the Mirena® affects 
the FTFE to the same extent as is achieved in the luteal phase of the cycle. 
 
We have no preliminary data on cell proliferation in CICs in premenopausal women, and  
there are no data in the literature as far as we have been able to discern.. There are certainly 
no data on cell proliferation in CICs by phase of the menstrual cycle. This aspect of the 
proposal must therefore be considered exploratory. In the study by Li et al.,45 where no  
results are given by menopausal status, cell proliferation in PAX-8 positive CICs was  
reported as 1.1%, some 10 times higher than in calretinin positive cells. This suggests that  
we may have sufficient power to investigate FTF-like cells in CICs, but not sufficient power to 
investigate calretinin positive cells. 

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15.0 
RESEARCH PARTICIPANT REGISTRATION/ RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
 
Eligibility will be confirmed for all patients as defined in the section entitled “Criteria for 
Patient/Subject Eligibility”. The screening eligibility checklist will be completed at time of 
consent to the study. Informed consent will be obtained following the procedures outlined in 
the section entitled “Informed Consent Procedures”. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist, and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.2 
Randomization 
 
This is not a randomized study and no randomization of treatment will occur. Comparison to 
non-study participants will be on a 2:1 matched basis as outlined in the Study Design 
Section. 
 
16.0 
DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the protocol study team. 
 
The data collected for this study will be entered into a secure database. Source 
documentation will be available to support the computerized patient record. 
 
All efforts will be made to ensure maintenance of patient confidentiality and HIPAA 
compliance. All data will be maintained on the MSK Clinical Research Database and the 
Protocol Management System. All data collected will be stored on a secure server at MSK 
and access will be password protected. This will only be accessible by trained study 
investigators. 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team at a minimum of two times per year and more frequently if indicated. 

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Research Staff will verify eligibility, informed consent, and accuracy of the demographic data 
collected for all patients whenever a patient is enrolled onto the study. This will ensure the 
quality of the data collected and verify the presence of all pertinent study data and 
documents. 
16.2 
Data and Safety Monitoring 
 
The study investigators will be responsible for ensuring the safety of the study participants. 
The investigators will stress the importance of reporting adverse events to the participants 
and the investigators will assess for adverse events at each instance of contact with the 
participants. Should adverse events occur, the study investigators will document these 
appropriately in the medical record and report these events to the IRB. CTCAE Version 4.0 
will be used to assess adverse events. 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials,” which can be found at:  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSK were 
established and are monitored by the Office of Clinical Research. The MSK Data and Safety 
Monitoring Plans can be found on the MSK Intranet at:  
http://mskweb5.MSK.org/intranet/_assets/_tables/content/359709/DSMPlans07.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff  
education on clinical research QA) and departmental procedures for quality control . In 
addition, there are two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs: the Data and Safety Monitoring Committee (DSMC) 
for Phase I and Phase II clinical trials, and the Data and Safety Monitoring Board (DSMB) for 
Phase III clinical trials. These committees report to the Center‟s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
16.3 
Regulatory Documentation 
 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol 
document and each participating site will utilize that document. 
 
Participating sites that are conducting specimen analysis should submit this protocol to their 
IRB according to local guidelines. Copies of any site IRB correspondence should be 
forwarded to MSK. 

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17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Every effort will be made to ensure the safety of our patients and the confidentiality of their 
medical information. During the enrollment and consent process, all risks, benefits, side 
effects, and alternatives will be discussed. Also, it will be stressed that this is a voluntary 
study and that the patient can withdraw without prejudice at any time. 
 
Benefits and Risks: The potential benefit of this study is to understand the way in which 
progestin, as delivered by a Mirena® IUD, affects tubal cell proliferation. As tubal proliferation 
appears to be related to the genesis of epithelial ovarian cancer, the provision of this 
information could have impact on the use of Mirena® IUD as a preventative measure for 
ovarian carcinoma. While this information could have a potentially vast benefit to society, 
there will be no direct benefit to the patients in the study as they will all be undergoing 
RRSO/RRS a priori. 
 
The risks of participation include the risks associated with Mirena® IUD insertion and use, as 
outlined in the Toxicities and Side Effects Section (11.0). Given the rarity of those side  
effects and the very short use of the Mirena® IUD in these patients, it is unlikely that 
participants will incur injury as a result of participation. 
 
Alternatives: The current standard treatment option for patients eligible for this study would 
be surgery without the insertion of the Mirena® IUD. A patient‟s decision on whether or not to 
participate in this study will not affect the availability of standard, supportive, or other 
investigational treatment at MSK. 
 
Costs: There will be no additional cost incurred by the patients who participate in the study. 
The Mirena® IUD systems will be provided at no charge by the manufacturing company, 
Bayer. Patients will not be charged for IUD insertion or removal, nor will they be charged for 
chlamydia or gonorrhea testing or associated tests. 
 
Voluntary Nature of the Study: Participation in this study is entirely voluntary. 
 
Inclusion of Children in Research: This protocol/project does not include children because 
the number of children undergoing RRSO/RRS is limited. This statement is based on 
exclusion 4b of the NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects. 
 
Patients will be informed of the extent of the risks, benefits, toxicities/side effects, 
alternatives/options for treatment, financial costs/burdens, and the voluntary nature of the 
study. The responsible investigator will ensure that this stu dy is conducted in agreement with 
the Declaration of Helsinki (Tokyo, Venice, Hong Kong, Somerset West , and Edinburgh 
amendments). The study will seek in every way to protect the rights of human subjects. No 
patient will be required to participate in the study, and participation or lack of participation will 
not affect the patient‟s subsequent care or treatment. 
 
The patient will not incur any financial cost as a result of participation in the study. 
Participation will be entirely voluntary and subjects will not be reimbursed for participation in 
the study. Throughout the study, patient confidentiality will be maintained. No results of the 
study will be presented or discussed in a fashion that will allow identification of a particular 

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patient in the study. All adverse events will be fully disclosed to the IRB in a timely fashion as 
required. 
 
17.1 
Privacy 
 
MSKCC‟s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
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 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30 days after the participant‟s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of Serious 
Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows. 
 
Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org.  All other 
reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‟s initials 
• 
Medical record number 

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• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI‟s signature and the date it was signed are required on the completed report. 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain   
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study . 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. T he participant must 
receive a copy of the signed informed consent form. 

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20.1 
APPENDICES 
 
A. Mirena® Prescribing Information