A Phase II Study of the Levonorgestrel Intrauterine Device (Mirena) to Treat Complex Atypical Hyperplasia and Grade 1 Endometrioid Endometrial Carcinoma
Phase: PHASE2
Conditions: Atypical Endometrial Hyperplasia, Stage I Uterine Corpus Cancer AJCC v7, Stage IA Uterine Corpus Cancer AJCC v7, Stage IB Uterine Corpus Cancer AJCC v7, Stage II Uterine Corpus Cancer AJCC v7
Sponsor: M.D. Anderson Cancer Center

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Protocol Page
A Phase II Study of the Levonorgestrel Intrauterine Device (Mirena) to Treat 
Complex Atypical Hyperplasia and Grade 1 Endometrioid Endometrial Carcinoma
2008-0094
Core Protocol Information
Short Title 
Levonorgestrel IUD to Treat CAH and G1EEC
Study Chair: 
Shannon Westin
Additional Contact:
Jeffry J. Cutrera
Jessica G. Granda
Robert Oum
Department:
Gynecologic Oncology
Phone:
713-745-3358
Unit:
1362
Study Manager:
Misty L. Woodall
Full Title: 
A Phase II Study of the Levonorgestrel Intrauterine Device (Mirena) to Treat Complex Atypical 
Hyperplasia and Grade 1 Endometrioid Endometrial Carcinoma
Public Description:
  
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 08/16/2019
Version:
17
Submitted by:
Robert Oum--8/12/2019 12:34:43 PM
OPR Action:
Accepted by:  Rosheta McCray -- 8/14/2019 9:25:16 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

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Protocol Body
1.0 Objectives
1.1 Primary Objective
1.1.1 To determine the efficacy of the Levonorgestrel Intrauterine Device (IUD) to treat complex 
atypical hyperplasia (CAH) and grade 1 endometrioid endometrial carcinoma (G1 EEC).
1.1.2 To determine if response to therapy can be predicted based on the
molecular profile of the tumor or by change in gene expression after therapy.
1.2 Secondary Objectives
1.2.1 To assess quality of life outcomes in patients treated with Levonorgestrel IUD.
1.2.2 To document the toxicity profile of the Levonorgestrel IUD in the treatment of complex 
atypical hyperplasia and grade 1 endometrioid endometrial cancer.
1.2.3 To evaluate the molecular profile of the hysterectomy specimen of patients treated with 
the Levonorgestrel IUD.  Compare molecular profile in pretreatment tissue to 
hysterectomy tissue between responders and non-responders to Levonorgestrel IUD 
therapy.  
1.2.4 To evaluate long-term survival, disease status, and fertility outcomes in patients with 
Levonorgestrel IUD.
2.0 Background
2.1 Endometrial Carcinoma and Complex Atypical Hyperplasia
Endometrial cancer is the most common gynecologic cancer in the United States. The American 
Cancer Society estimates that in 2007 there will be 39,080 new cases and 7,400 deaths from this 
disease[1]. The standard of care for early grade disease is complete surgical resection[2]. 
However, this may not be the preferred option in young women who have not completed 
childbearing. Furthermore, women with endometrial carcinoma may be suboptimal surgical 
candidates secondary to the presence of morbid obesity and multiple co-morbid conditions. This 
stems from the fact that these health conditions and endometrial cancer share many risk 
factors[3]. 
Complex atypical hyperplasia (CAH) is a precursor lesion to the most common histology of 
endometrial carcinoma, endometrioid type. In fact, in a study of 170 women with untreated 
endometrial hyperplasia, 29% of CAH progressed to endometrial carcinoma[4]. Trimble et al 
demonstrated that 42% of women with CAH on endometrial biopsy had a concurrent diagnosis of 
endometrial carcinoma on their subsequent hysterectomy specimen[5]. These data indicate that 
the two conditions are closely related, and often may be present together. 
Furthermore, the initial diagnosis of CAH versus grade 1 endometrioid endometrial carcinoma 
(G1EEC) can be difficult to make. In the Trimble study, three gynecologic pathologists were 
unable to reach a consensus diagnosis in 16 of 289 endometrial biopsy specimens. Of those 
patients, 10 had carcinoma on their hysterectomy specimen[5]. An assessment of the 
reproducibility of CAH diagnosis in the setting of a Gynecologic Oncology Group trial revealed 
only 38% agreement with the initial diagnosis of CAH by a consensus panel. 30% of the biopsies 
with incorrect diagnoses were noted to be adenocarcinoma[6]. Given their close association and 
the difficulties in distinguishing between the two diagnoses, the inclusion of both entities in a 
treatment trial is reasonable.
2.2 Rationale
One of the most well-established risk factors for the development of CAH and endometrial 

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carcinoma is exposure to unopposed estrogen. In fact, a majority of the key conditions 
associated with endometrial cancer are directly or indirectly related to estrogen. Progesterone is 
known to counteract the effects of estrogen in the
endometrium, thus, it has been used as a primary therapy for CAH and as an alternative primary 
therapy or adjuvant therapy for endometrial cancer[2].
Progesterone has been demonstrated to be an acceptable and efficacious option for treatment of 
complex atypical hyperplasia and grade 1 endometrioid endometrial carcinoma[3,7]. Despite the 
success of progesterone treatment, many women do not tolerate the side effects of systemic 
progesterone or are unable to maintain compliance with this therapy[8]. Montz et al evaluated the 
use of a progesterone releasing intrauterine device (Progestesert) to treat stage 1a, grade 1 
endometrioid endometrial carcinoma. They demonstrated complete regression of G1EEC in 7 of 
11 patients at 6 months and in 6 of 8 patients at 12 months[9]. Unfortunately, this therapy is no 
longer available for therapeutic use. The Levonorgestrel Intrauterine Device (LIUD) has been 
demonstrated to provide a consistent dose of progesterone to the uterine cavity with minimal 
systemic effects[10]. The toxicity of this treatment is low, with the most common complications 
consisting of irregular bleeding, expulsion, or uterine perforation during placement[11].
The studies of the LIUD for complex atypical endometrial hyperplasia are promising, but have 
been limited by low numbers. In a study of endometrial hyperplasia, there was regression of 
disease in 100% patients (n=26) treated with the LIUD compared to only 55% of patients treated 
with oral progesterone. It is important to note that only two of the patients in this study had 
CAH[12]. Wildemeersch et al noted 100% regression after Mirena placement in the eight patients 
with complex atypical hyperplasia in their study[13].
The use of the Mirena for the treatment of grade 1 endometrioid endometrial carcinoma has been 
less well studied, with only a few cases documented in the literature. Giannopoulos et al reported 
complete regression of a well-differentiated endometrial carcinoma after treatment with the 
LIUD[14]. Other case series, however, have had lower rates of success. Bahamontes et al 
treated two women with morbid obesity and G1EEC with the Mirena while awaiting gastroplasty 
for weight reduction. Both women had residual G1EEC in their hysterectomy specimens after 6 
and 7 months, respectively[15,16]. In a case series of four women with G1EEC treated with LIUD, 
only one woman had complete regression at 6 months[16]. A larger study is necessary to clarify if 
the LIUD is effective in the treatment of grade 1 endometrioid endometrial carcinoma.
Given the success of oral progesterone for the treatment of both conditions, the LIUD is a rational 
option for patients with CAH and grade 1 endometrioid endometrial carcinoma. However, the 
existing literature is conflicting regarding the success of this treatment. Therefore, we propose a 
phase II trial to assess the efficacy of the LIUD for treatment of complex atypical hyperplasia or 
Grade 1 endometrioid carcinoma. Patients will receive this treatment for one year, as the median 
time to complete regression of G1 EEC during oral progesterone therapy is generally 12 weeks, 
with a range of 4 – 60 weeks[3].
2.3 Correlative Studies
In an earlier study, we discovered a cadre of genes which were highly induced in the 
endometrium of postmenopausal women after 3 months of treatment with estrogen therapy. 
These included PR, EIG121, IGF-I, RALDH2, sFRP1, and sFRP4[17]. Given that estrogen 
excess is a key factor in the development of hyperplasia and endometrioid
type endometrial carcinoma, we subsequently studied the expression of these genes in a cohort 
of endometrial carcinoma patients. We found that G1EEC demonstrates high expression of these 
estrogen-induced genes[17]. Given the antagonistic effect of progesterone, these genes should 
be down-regulated after progesterone treatment. 
Additionally, McCampbell et al demonstrated a step-wise increase in IGF-IR expression along the 
continuum from normal endometrium to G1EEC[18]. Our data confirmed that IGF-IR was highly 

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expressed in G1EEC, but had decreasing expression with increasing grade[17]. As this protein is 
known to be involved in an estrogen-regulated endometrial proliferation pathway, it is a rational 
target to include in our mRNA analysis. We plan to perform quantitative real time reverse 
transcriptase polymerase chain reaction for the aforementioned genes in the pre-treatment D&C 
specimen and 3-month post-treatment biopsy. These studies will provide pharmacodynamic 
evidence that the LIUD is having an effect on the endometrium. This time frame is based on 
results from our NCI-funded study of chemoprevention in patients with Lynch Syndrome without 
endometrial disease, which demonstrated a change in biomarker expression after three months 
treatment with progesterone-based therapy[19]. 
In 2007, we found that loss of PTEN and activation of mTOR were associated with poor response 
to progesterone in a murine hyperplasia model[20]. Given the need for markers which predict 
response to therapy in these patients, we will perform immunohistochemistry for PTEN and 
phosphorylated mTOR on paraffin-embedded tumor specimens. 
3.0 Background Drug Information
Levonorgestrel Intrauterine Device (Mirena)
3.1 Description[11]
The Mirena releases a consistent dose of progesterone to the uterine cavity for five years. Its 
primary indication is contraception. 
3.2 Mechanism of Action[11]
The Mirena releases 20ìg of levonorgestrel into the uterine cavity daily for five 
years. 
Levonorgestrel is bound primary in the serum to proteins and is metabolized into a large number 
of inactive metabolites. Metabolic clearance rates may differ among individuals by several–fold. 
The elimination half-life of the oral form is approximately 17 hours. Both levonorgestrel and its 
primary metabolites are excreted primarily in the urine. It causes local progestogenic effects in 
the uterine cavity. Morphological changes of the endometrium are observed, including stromal 
pseudodecidualization, glandular atrophy, leukocytic infiltration and a decrease in glandular and 
stromal mitosis. Mirena provides effective contraception in 99.3% of women over a five-year 
span. 
3.3 Drug Supply[11]
Mirena is commercially available. There will be no charge to the patient or their insurance 
company for the Mirena IUD. It will be provided free of charge as part of the study.
3.4 Storage[11]
Mirena can be stored at 25°C, but can tolerate temperatures between 15° – 30°C for short time 
periods. It should remain in its sterile package until use.
3.5 Preparation and Administration[11]
The Mirena consists of a T-shaped polyethylene frame with a steroid reservoir around the vertical 
stem. The reservoir consists of a cylinder, made of a mixture of levonorgestrel and silicone and is 
covered by a silicone membrane. It contains a total of 52 mg of levonorgestrel. A monofilament 
brown polyethylene removal thread is attached to a loop at the end of the vertical stem of the 
body. 
3.6 Toxicity Data[11]
The most serious adverse events are ectopic pregnancy (1/1000), sepsis (4 cases of Group A 
Streptococcus in 1999), and pelvic inflammatory disease. Other complications reported include 
irregular bleeding, embedment in the uterus, perforation of the uterus and ovarian cysts. Minor 
adverse reactions seen in more than 5% of subjects include abdominal pain, leukorrhea, 
headache, vaginitis, back pain, breast pain, acne, depression, hypertension, upper respiratory 

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infection, nausea, nervousness, dysmenorrhea, weight increase, skin disorder, decreased libido, 
abnormal pap smear and sinusitis.
4.0 Patient Eligibility
4.1 Inclusion Criteria
4.1.1 All patients with a diagnosis of complex atypical hyperplasia or endometrial biopsy within 
three months of study enrollment OR patients with a diagnosis of grade 1 endometrioid 
endometrial carcinoma on endometrial biopsy within three months of study enrollment in 
the presence of one or more of the following:
- desire for future fertility
- morbid obesity (body mass index > 40)
- multiple co-morbidities (ASA Class 3 or 4)
4.1.2 No prior treatment for diagnoses 4.1.1
4.1.3 Women of any racial or ethnic group.
4.1.4 Ability to comply with endometrial biopsies every 3 months
4.1.5 Willing and able to sign informed consent.
4.1.6 Age greater than 18 years.
4.2 Exclusion Criteria
4.2.1 Diagnosis of grade 1 endometrioid endometrial carcinoma without the presence of one of 
the 3 criteria mentioned in 4.1.1.
4.2.2 Diagnosis of grade 2 endometrioid endometrial carcinoma or higher on endometrial 
biopsy or on dilation and curettage specimen.
4.2.3 Evidence of extrauterine spread of disease on imaging or during surgical evaluation. 
4.2.4 Congenital or acquired uterine anomaly which distorts the uterine cavity.
4.2.5 Acute pelvic inflammatory disease.
4.2.6 Acute liver disease or previously diagnosed liver tumor (benign or malignant).
4.2.7 Conditions associated with increased susceptibility to infections with microorganisms. 
Such conditions include, but are not limited to, AIDS, leukemia and IV drug abuse.
4.2.8 Genital actinomycosis.
4.2.9 Current carcinoma of the breast.
4.2.10 Current pregnancy.
4.2.11 Breastfeeding mothers.
5.0 Treatment Plan
5.1 Study Design
This study will be a Bayesian phase II, single arm clinical trial. The study will enroll up to 50 
evaluable patients. All women with the diagnosis of CAH on endometrial biopsy will be eligible. 
Women with G1 EEC on endometrial biopsy will be eligible if they desire fertility sparing options, 
are morbidly obese (BMI >40), or have co-morbid conditions which preclude a major surgical 
procedure (ASA Class 3 or 4).
5.2 Patient Accrual
All eligible patients being seen at The University of Texas M. D. Anderson Cancer Center 
Department of Gynecologic Oncology will be identified from a list generated by the clinic. Their 
primary physician will be contacted and asked permission to contact the patient for discussion of 
the trial. All Gynecologic Oncology physicians, registered nurses, advanced practice nurses and 
clinical fellows will be made aware of the trial through presentations, meetings, and fliers in the 
clinic. Benign gynecologists within the department will also be made aware of the trial through the 
same mechanisms.
In addition, the trial will be opened at the MD Anderson Cancer Center Regional Care Centers 
and the Harris Health System (Lyndon B. Johnson General Hospital).  Finally, local Houston 

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benign gynecologists will be informed of the trial through presentations and fliers, and will be 
asked to refer patients they feel are eligible for participation.
5.3 Pretreatment Evaluation
After signing the informed consent, the patients will follow one of two treatment plans depending 
on their initial biopsy diagnosis. All patients will undergo a urine pregnancy test (women of child 
bearing potential) and cervical cultures in clinic to rule out pregnancy and active cervical 
infection. Patients with G1 EEC will undergo clinical staging procedures including chest 
radiography and MRI of the abdomen and pelvis. This will be a routine MRI of the abdomen and 
pelvis with standard pulse sequences including dynamic gadolinium enhanced imaging of the 
uterus. 
Women who are unable to undergo MRI due to morbid obesity or other contraindication will have 
a CT scan of the abdomen and pelvis and transvaginal ultrasound. For those patients who are 
unable to undergo CT due to morbid obesity, transvaginal ultrasound will be performed. Scans 
will be reviewed by the diagnostic radiology collaborator on the study. Women will be excluded if 
there is evidence of extrauterine spread of disease. 
Both cohorts of patients (CAH and G1 EEC) will then undergo an exam under anesthesia (EUA) 
and a dilation and curettage (D&C) in the operating room to sample the entire endometrium. This 
specimen will be read by a certified gynecologic pathologist at our institution and report dictated 
in the electronic medical record. At the time of D&C, the LIUD will be placed. Women who have 
previously undergone D&C for this diagnosis will not be required to undergo a second D&C. The 
pathology specimen will be obtained for review and confirmation of diagnosis and for the 
correlative studies to be performed. The LIUD will then be placed in the clinic setting. 
If patients with an initial diagnosis of CAH are upgraded to G1 EEC, they will be assessed for 
eligibility through inclusion criteria 1. If the patient does not meet inclusion criteria, they will be 
removed from the study. Otherwise, they will undergo chest radiography, and MRI of the 
abdomen and pelvis and/or CT of the abdomen and pelvis and/or transvaginal ultrasound as 
detailed aove in the post-operative period. Women will remain on study if they have confirmed 
CAH and/or G1 EEC on the D&C specimen and have no evidence of extrauterine spread of 
disease. If a woman is excluded from the trial after LIUD is placed, the LIUD will be subsequently 
removed. Removal of the LIUD can be performed in the operating room if the patient proceeds 
with surgical treatment or in the clinic.
5.4 Evaluation During Study
All subjects will be evaluated at one month (+/- 1 week) after LIUD placement to confirm the 
placement of the LIUD. This visit may be performed at MD Anderson or at the subject's local 
physician office, based on patient preference. Placement will be confirmed by speculum exam and, if 
necessary, using pelvic ultrasound.
Endometrial biopsy may be performed while the LIUD is left in situ. The endometrial biopsy will 
be performed with the Pipelle endometrial suction instrument (Cooper Surgical, Trumbull, CT). 
Each patient will have a follow-up endometrial biopsy every three months for one year (+/- 2 
weeks). Endometrial evaluation every three months is the standard of care for patients with CAH 
or G1EEC undergoing conservative therapy. The pathology of the endometrial biopsies will be 
read by a certified gynecologic oncologist and report dictated in the electronic medical record.
The molecular profile of the endometrial lesion in the pre-treatment D&C specimen and 3-month 
post treatment biopsy will be determined. Using formalin-fixed, paraffin-embedded tissue, the 
mRNA expression profile will be determined by real time reverse transcriptase polymerase chain 
reaction for a panel of genes including PR, EIG121, IGF-I, IGF-IR, RALDH2, sFRP1, and sFRP4. 
The level of mRNA expression will be normalized by comparison to the expression of â-actin and 
18S, two cellular housekeeping genes. See Appendix D for RT-PCR protocol. Protein expression 

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of PTEN and phosphorylated mTOR will be determined through the performance of 
immunohistochemistry on the formalin-fixed, paraffin-embedded endometrial biopsy specimens. 
See Appendix E for the immunohistochemistry protocol.
An evaluation of any complications related to the LIUD will be completed at each follow-up visit 
by study personnel. This assessment can be found in Appendix F. It includes concerns which are 
specific to the LIUD as well as typical side effects of systemic progesterone therapy. In addition, 
the patient will be given a diary to fill out at home during the first 3 months after LIUD placement. 
This diary is provided by Bayer and monitors vaginal bleeding after LIUD placement. See 
Appendix I for this diary.
Finally, quality of life assessment will be performed at baseline and at each 3 month follow-up 
visit using the SF-36 instrument (Appendix G). This 36-question validated instrument is a generic 
measure which incorporates an 8-scale profile of functional health and well-being scores as well 
as psychometrically-based physical and mental health summary measures and a 
preference-based health utility index. These results will be compared to available standardized 
results from this instrument. This is intended to provide pilot data for future trials including the 
LIUD.
5.5 Criterion for Response
Response is defined as follows:   
Complete response is defined as no endometrial abnormality or the presence of endometrial 
hyperplasia without cytologic atypia at the one year time point.
Partial response is defined as the presence of complex endometrial hyperplasia with cytologic 
atypia in patients with an initial diagnosis of grade1 endometrial cancer, at the one year time 
point.
Stable disease is defined as no change in diagnosis at the one year time point.
Progressive disease is the presence of grade 2 cancer or above in patients with an initial 
diagnosis of grade 1 cancer OR presence of grade 1 cancer or above in patients with an initial 
diagnosis of complex atypical hyperplasia at any time point.
Patients with stable disease or progressive disease will be categorized as non-responders for the 
purposes of molecular analysis.
5.6 Criteria for Removal From Study
At the one year time point the patient will complete the study.  If progression of disease is noted 
at any time, the patient will be taken off study and at the physician’s discretion, the LIUD may be 
removed and the patient will be treated with either definitive surgical therapy or an alternative 
progesterone agent.  In the case of G1 EEC, progression will be defined as the presence of 
grade 2 endometrioid cancer or worse on the endometrial biopsy. In the case of CAH, 
progression will be defined as G1 EEC or worse on the endometrial biopsy. The patient will also 
be removed from the study and offered alternative therapies if unacceptable toxicity or 
complications occur due to the LIUD.
5.7 Study Completion
The patients that complete of one year of therapy will be offered continuation of the LIUD, 
hysterectomy, or alternative progesterone therapy. If they choose to continue LIUD treatment, 
they will be referred to their primary gynecologic oncologist for continued management and 
follow-up. The LIUD may remain in situ for five years. If they choose to have the LIUD removed 
they will be referred back to their primary gynecologic oncologist to discuss further options and 
management.
A molecular profile will be performed on the uterine specimen of any protocol patients that 

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undergo hysterectomy for progressive disease or at the completion of therapy.  This profile is 
including, but not limited to, determination of expression of estrogen-induced genes and 
expression of PTEN and phosphorylated S6 protein by IHC.  Current and future patients from MD 
Anderson Cancer Center and Harris Health System (Lyndon B. Johnson General Hospital) will be 
consented for this optional tissue collection.  For MD Anderson patients who are no longer on 
study, we will ask for a waiver of consent to collect retrospective tissue  as it may be difficult to 
locate these patients or they may be deceased and this tissue collection will pose minimal risk to 
the patients. We will use previously signed consent from the IRB approved Gyn Onc Tumor Bank 
protocol (LAB02-188) or the MD Anderson front door consent protocol (Lab03-0320)
5.8 Long-term Follow-up
All patients will be followed for 5 years from their last study-specific intervention, unless consent 
is withdrawn or the patient is lost to follow-up. No clinic visits or other patient contact is required 
for follow-up. Patient survival, disease status, and fertility outcomes will be followed annually 
through review of their medical record.
5.9 Patient Flow Diagram
Please see Appendix H for Patient Flow Diagram.
6.0 Correlative Studies
6.1 Gene Expression
6.1.1 Collection of Sample
6.1.1.1 Dilation and Curettage
This sample will be collected in the operating room. Upon collection, the specimen will be 
formalin-fixed and taken to the laboratory at room temperature. 
6.1.1.2 Three-Month Endometrial Biopsy
This sample will be collected in the clinic room using the Pipelle collection device. Adequate 
tissue amount will be determined by the clinician and research coordinator collecting the 
specimen. Upon collection, the specimen will be formalin-fixed and taken to the laboratory at 
room temperature.
6.1.2 Handling of Sample
6.1.2.1 Dilation and Curettage and Three-Month Endometrial Biopsy
A hematoxylin and eosin slide will be prepared for the gynecologic pathologist to read and obtain 
diagnosis. The remainder of the tissue will be divided for PCR and IHC. RNA extraction will be 
performed on the tissue and the resultant RNA will be stored in the -80°C refrigerator until 
analysis.
6.2 Immunohistochemistry
6.2.1 Collection of the Sample
6.2.1.1 Dilation and Curettage
This sample will be collected in the operating room. Upon collection, the specimen will be 
formalin-fixed, processed by the pathologist, and taken to the laboratory at room temperature. 
6.2.1.2 Three-Month Endometrial Biopsy
These samples will be collected in the clinic room. Adequate tissue amount will be determined by 
the clinician and research coordinator collecting the specimen. Upon collection, the specimen will 
be formalin-fixed, processed by the pathologist, and taken to the laboratory at room temperature. 

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6.2.2 Handling of Sample
6.1.2.1 Dilation and Curettage and Three-Month Endometrial Biopsy
A hematoxylin and eosin slide will be prepared for the gynecologic pathologist to read and obtain 
diagnosis. The remainder of the tissue will be divided for PCR and IHC. Four slides will be cut 
from the formalin-fixed, paraffin-embedded tissue for performance of immunohistochemistry.
6.2.3 Scoring of IHC Results
6.2.3.1 PTEN
Loss of PTEN expression will be defined as no staining in greater than 10% of the endometrial 
glands in the specimen[20].
6.2.3.2 Phosphorylated mTOR
Positive expression of phosphorylated mTOR will be defined as moderate (2+) to strong (3+) 
staining in greater than 20% of the endometrial glands in the specimen[20].
7.0 Statistical Considerations
7.1
Sample Size Calculation
A Bayesian Phase II design was employed for sample size calculation. We will enroll and 
evaluate a minimum of 20 evaluable (those who complete 12 months of therapy) patients and a 
maximum of 50 evaluable patients in this study. 
7.2 Early Stopping for Futility
We will stop the trial early if Pr (success rate < 65% | data) < 0.05.
This means that, given the outcomes of patients who have already completed the trial, if we 
determine that there is less than a 5% chance that the success rate of LIUD is at least 65%, we 
will stop the trial. We assume that the prior distribution for the success rate is Beta (1.3, 0.7), 
which has a mean of 65% and a standard deviation of 27.5%.
Therefore, we will stop the trial if:
[# of patients with complete remission / # of patients evaluated] 
9/20, 10/22, 11/24, 12/25, 13/27, 14/29, 15/31, 16/32, 17/34, 18/36,19/38, 20/39, 21/41, 22/43, 
23/44, 24/46, 25/48, 26/49.
For example, if only 9 patients had complete remission by the time 20 patients completed the 
study, we will terminate the study due to futility, as there is very little evidence (< 5% chance) that 
the success rate is at least 65% if 9 or fewer of 20 patients had a complete remission. 
The operating characteristics of this monitoring rule are shown in Table 1.
Table 1. Operating Characteristics of the Futility Monitoring Rule
True Treatment
  Probability of
Sample Size
     Success
Stopping Early
P25
P50
P75
0.50
0.793
 20
 25
 44
0.55
0.568
 22
 43
 50
0.60
0.317
 38
 50
 50

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0.65
0.133
 50
 50
 50
0.70
0.037 
   0
 50
 50
0.75
0.007
 50
 50
 50
0.80
0.001
 50
 50
 50
If the true treatment success rate is really 65% we have a 13.3% chance of stopping the trial 
early due to futility. If the true treatment success rate is really 50% we have a 79.3% chance of 
stopping the trial early due to futility. In this case 25% of the time we would have treated 20 
patients or fewer at the time of stopping the trial, 50% of the time we would have treated 25 
patients or fewer at the time of stopping the trial, and 75% of the time we would have treated 44 
patients or fewer at the time of stopping the trial.
7.3 Endpoints
The primary outcome will be response to therapy, which is defined as complete response or 
partial response (detailed in section 5.5), assessed at the one year endometrial biopsy. 
Secondary outcomes will include toxicity and complication information. The molecular profile will 
be utilized to determine if response to therapy can be predicted. Additionally, toxicity assessment 
and quality of life assessment with the SF-36 survey will be performed at baseline and at each 
3-month follow up visit as described in Section 5.4.
7.4 Analysis of primary outcome
Once we have completed the study, we will estimate the treatment success rate with a 90% 
credible interval. For example, if 27 of 50 patients (54%) have complete remission, the 90% 
credible interval for the treatment success rate will be 43.1% to 65.6%. If 35 of 50 patients (70%) 
have complete remission, the 90% credible interval for the treatment success rate will be 59.0% 
to 79.7%. 
If the upper bound of the 90% credible interval is less than our goal of 65% success rate, we will 
not pursue further study of this intervention. 
7.5 Analysis of secondary outcomes
A secondary aim of this study is to determine whether treatment success is related to a patient’s 
genetic profile. To this end, we will measure PR, EIG121, IGF-I, RALDH2, sFRP1, sFRP4, and 
IGF-IR at baseline and again at the 3-month biopsy. Change from baseline (ä) for each 
biomarker will be calculated and the hypothesis that 
H0: ä = 0 vs. H1: ä · 0
will be tested with a paired t-test. Because genetic profile information is highly skewed, natural 
log transformations will be made to the data prior to calculating change from baseline and 
completing the t-test. Previous data indicate that the standard deviation of the log-transformed 
data will be approximately 1. Table 2 shows the power of our test when we use a statistical 
significance level of 5%, both when the standard deviation is 1 and again if the standard deviation 
should be 1.25, slightly larger than we estimated. Power was assessed at sample sizes n = 20, 
25, 30, 35, 40, 45 and 50 because our actual sample size might range anywhere between 20 and 
50 patients. 
Table 2. Power to Determine Changes in Genetic 
Profile (á = 5%, two-sided test, hypothesized 
difference of 0.5)
Sample Size
Power
When SD = 1
When SD = 1.25
20
56.45%
39.70%
25
66.97%
48.40%

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30
75.40%
56.28%
35
81.95%
63.28%
40
86.94%
69.40%
45
90.66%
74.68%
50
93.39%
79.18%
Although we might stop the trial early, our median sample size is most likely 50, and therefore we 
should have at least 79% power to detect a difference of 0.5 in our genetic profile data. 
Change in immunohistochemical expression will be analyzed for association with response using 
a chi-square analysis.
Summary statistics will be calculated for quality of life scores, both at baseline and every three 
months afterwards until the patient completes the study. This analysis will be descriptive. 
Summary statistics will also be completed on LIUD toxicity. The LIUD toxicity profile is known to 
be low, and it tends to be well-tolerated, therefore we do not anticipate a need to stop the trial 
early due to toxicities. However, incidence of toxicities will be calculated.
We will calculate period prevalence and incidence of recurrence along with 95% confidence 
intervals.  Period prevalence is calculated as the number of patients who recur divided by number 
of patients at risk for recurrence.  Incidence is calculated as the number of patients who recur 
divided by person-time follow-up.  Recurrence is defined as return to original disease state or 
worse after being disease-free. Finally, the proportion of patients who return to a worsening 
disease state after an initial response will be calculated.  Specifically, it will calculate the 
proportion of patients who have progressive disease if their best response was stable disease, 
partial response, or complete response.
Summary statistics will be calculated for disease status and fertility outcomes. This analysis will 
be descriptive.
We will calculate period prevalence and incidence of recurrence along with 95% confidence 
intervals.  Period prevalence is calculated as the number of patients who recur divided by number 
of patients at risk for recurrence.  Incidence is calculated as the number of patients who recur 
divided by person-time follow-up.  Recurrence is defined as return to original disease state or 
worse after being disease-free. Finally, the proportion of patients who return to a worsening 
disease state after an initial response will be calculated.  Specifically, it will calculate the 
proportion of patients who have progressive disease if their best response was stable disease, 
partial response, or complete response.
Summary statistics will be calculated for disease status and fertility outcomes. This analysis will 
be descriptive.
8.0 Data and Protocol Management
This study is planned as a multi-site study. All patients will be centrally registered into the Clinical 
Oncology Research System (CORe) at M. D. Anderson Cancer Center. Information will include a 
completed eligibility check list, patient name, date of birth, consent date, and race. Once accrual is 
complete, study data will be combined for analysis.
Protocol Compliance: The study research nurse will be present at each visit to ensure compliance 
with protocol guidelines. Decisions for removal from study based on response will be made by the 
Study Chairman and the Study Pathologist (RRB).

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Data Entry: Data must be entered into the Gyn Oncology Departmental database for this protocol.
Accuracy of Data Collection: The Study Chairman will be the final arbiter of response or toxicity 
should a difference of opinion exist.
9.0 Adverse Event Reporting
9.1 Reporting Adverse Events
All Internal and External AEs that include all of the following will be promptly reported to IRB via 
the Office of Protocol Research (OPR): 
·
Serious 
·
Unexpected
·
Related (definitely, probably, or possibly related) to participation in the research.
Timeline for prompt reporting of Internal AEs:
1. Within 1 working day (24 hours) from the time the research team becomes aware of 
the event = All deaths that occur during treatment and within 30 days after completion of 
treatment. 
2. Within 5 working days from the time the research team becomes aware of the event = 
All serious, unexpected and related AEs other than those deaths described above in number 
1. 
Internal SAEs will be reported from the time protocol specific consent is signed, and screening or 
treatment has begun, during the course of treatment and within 30 days after the last day of 
active treatment. 
Beyond 30 days of treatment, completion of only those SAEs that, in the judgment of the 
investigator, are related to research will be reported.
Reporting Timeline for prompt reporting of External AEs:
1. Within 5 working days from the time the research team becomes aware of the event = 
All related deaths that occur during treatment and within 30 days after completion of 
treatment.
2. Within 5 working days from the time the research team becomes aware of the event = 
All serious, unexpected and related AEs other than those deaths described above in number 
1. 
External SAEs will be reported to the IRB beginning on the date of the UTMDACC IRB approval 
letter of the associated protocol.
SAEs Requiring Documentation on AE Log:
All SAEs that do not fall under the prompt reporting requirements will be reported during 
continuing review using the Internal or External SAE Log or database printout.
Note: If a trend or recurring adverse events are seen, the PI will report these events using the 
Internal or External SAE report Form for prompt reporting. 
These reporting guidelines do not affect the reporting requirements to the FDA, the 
sponsor or monitoring agency.

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Reporting for trials involving minimal risk
For protocols designated as minimal risk, AEs considered serious, unexpected and definitely, 
probably or possibly related to the study will be reported promptly as described above. [AEs 
considered to be unrelated to the study and non-serious AEs will be reported during continuing 
review (annual report)].
Reporting of SAEs for Terminated Protocols
Only those serious AEs that were unexpected and may impact the health, welfare or safety of 
subjects will be reported. For example, reports of secondary malignancies or problems with 
implanted devices.
DEFINITIONS 
Adverse Event (AE) – Any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research.
For minimal risk studies such as behavioral science, laboratory, and epidemiologic protocols, as 
well as chart reviews, reasonable judgment must be used to determine what constitutes an AE.
Expected AE - Any AE with specificity or severity that is consistent with the current Investigator 
Brochure (IB) or consistent with the risk information described in the Informed Consent Document 
(ICD) or general investigational plan. All clinical protocols should include a list of the expected 
and anticipated events or hospitalizations relating to the study treatment.
Unexpected (Unanticipated) AE - Any AE, with specificity or severity that is not consistent with 
the current IB or not consistent with the risk information described in the ICD or general 
investigational plan.
Serious Adverse Event (SAE) – Any AE associated with the subject’s participation in research 
that: 
·
results in death; 
·
is life-threatening, (places the subject at immediate risk of death from the event as it 
occurred);
·
results in inpatient hospitalization or prolongation of existing hospitalization;
·
results in persistent or significant disability/incapacity; 
·
results in a congenital anomaly/birth defect; or
·
based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition.
Internal AE - An AE occurring in a subject who is enrolled in a protocol or study that is under the 
oversight of a UTMDACC IRB. 
External AE – An AE occurring in a subject who is not enrolled in a UTMDACC protocol or is on 
a protocol at a site that is under the oversight of another IRB. Generally, the PI has received 
notification of this AE from the protocol sponsor. Example: Medwatch report, CIOMS report, 
Safety reports.
Related:
Events directly or indirectly attributed to study drug, device or procedures and/or study 
participation. Events occurring with sufficient frequency to suggest that they are not random.
Unrelated:
Events that would occur regardless of study participation, including events that are clearly 
random occurrences. If the frequency of the event suggests a possible connection to the study 

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intervention, then it should be considered related.
AE Attribution - The determination of whether an AE is related to the research (medical 
treatment or intervention): 
Definite – It is clearly related 
Probable - It is likely related 
Possible - It may be related 
Unlikely - It is doubtfully related 
Unrelated - It is clearly NOT related 
AE Severity - Refers to the intensity (grading) of a specific AE. All clinical trials conducted at 
UTMDACC must use the “CTCAE v3.0 grading scale” for AE documentation and reporting 
(Publish date June 10, 2003). For the purpose of this policy, toxicity is synonymous with AE.
Minimal Risk - Minimal risk means that the probability and magnitude of harm or discomfort 
anticipated in the research are not greater than those ordinarily encountered in daily life or during 
the performance of a routine physical examination, physiological examination or laboratory 
testing. 
Designation of minimal risk will be determined by the IRB at the time of initial approval and 
reviewed at least annually during continuing review. 
Multicenter Studies
Since UTMDACC PIs participating in multicenter trials are unable to prepare a meaningful 
summary of SAEs, at the time of continuing review they should submit the current report from the 
monitoring entity (e.g. research sponsor, coordinating statistical centre, or DSMB/DMC). The 
report should include the following: 
·
a statement as to what information was reviewed by the monitoring entity (e.g. study-wide 
AEs, interim findings, recent literature relevant to the research); 
·
date of the review;
·
monitoring entity’s assessment of the information. Information that is considered inadequate 
by the PI should be returned to the monitoring agency/sponsor for completion
9.2 Eliciting Adverse Event Information
Adverse events will be elicited at each clinic visit during participation in the study. Patients will be 
given a worksheet to record the occurrence of adverse events throughout the study. All adverse 
events which are directly observed and all adverse events which are spontaneously reported by 
the patient are to be documented by the investigator.
9.3 Grading/Rating Scale
All adverse events reported during the study will be evaluated and graded on a scale of 1-4. 
Grade
Rating
Description
1
Mild
Adverse event is transient and easily tolerated by the 
patient; asymptomatic
2
Moderate
Adverse event causes the patient discomfort and interrupts 
the patient’s usual activities; symptomatic but does not 
interfere with function
3
Severe
Adverse event causes considerable interference with the 
patient’s usual activities
4
Life-Threatening
Adverse event is incapacitating or life-threatening

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10.0 Data Confidentiality Plan
On enrollment, patients will be assigned a study number. All study documents will be de-identified of 
any patient information such as name, social security number, date of birth, or medical record 
number. Data collection files will be stored in a locked file cabinet. The document which links the 
identifiable patient information to a study number will be stored in a password-protected computer file. 
Once the data have been analyzed, all identifiers will be destroyed.
11.0 References
1.
Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57:43-66, 2007
2.
Amant F, Moerman P, Neven P, et al: Endometrial cancer. Lancet 366:491-505, 2005
3.
Ramirez PT, Frumovitz M, Bodurka DC, et al: Hormonal therapy for the management of grade 1 
endometrial adenocarcinoma: a literature review. Gynecol Oncol 95:133-8, 2004
4.
Kurman RJ, Kaminski PF, Norris HJ: The behavior of endometrial hyperplasia. A long-term study 
of "untreated" hyperplasia in 170 patients. Cancer 56:403-12, 1985
5.
Trimble CL, Kauderer J, Zaino R, et al: Concurrent endometrial carcinoma in women with a 
biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. 
Cancer 106:812-9, 2006
6.
Zaino RJ, Kauderer J, Trimble CL, et al: Reproducibility of the diagnosis of atypical endometrial 
hyperplasia: a Gynecologic Oncology Group study. Cancer 106:804-11, 2006
7.
Randall TC, Kurman RJ: Progestin treatment of atypical hyperplasia and well-differentiated 
carcinoma of the endometrium in women under age 40. Obstet Gynecol 90:434-40, 1997
8.
Thigpen JT, Brady MF, Alvarez RD, et al: Oral medroxyprogesterone acetate in the treatment of 
advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic 
Oncology Group. J Clin Oncol 17:1736-44, 1999
9.
Montz FJ, Bristow RE, Bovicelli A, et al: Intrauterine progesterone treatment of early endometrial 
cancer. Am J Obstet Gynecol 186:651-7, 2002
10. Hubacher D, Grimes DA: Noncontraceptive health benefits of intrauterine devices: a systematic 
review. Obstet Gynecol Surv 57:120-8, 2002
11. Mirena Prescribing Information. 
12. Vereide AB, Arnes M, Straume B, et al: Nuclear morphometric changes and therapy monitoring in 
patients with endometrial hyperplasia: a study comparing effects of intrauterine levonorgestrel 
and systemic medroxyprogesterone. Gynecol Oncol 91:526-33, 2003
13. Wildemeersch D, Janssens D, Pylyser K, et al: Management of patients with non-atypical and 
atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term 
follow-up. Maturitas 57:210-3, 2007
14. Giannopoulos T, Butler-Manuel S, Tailor A: Levonorgestrel-releasing intrauterine system 
(LNG-IUS) as a therapy for endometrial carcinoma. Gynecol Oncol 95:762-4, 2004
15. Bahamondes L, Ribeiro-Huguet P, de Andrade KC, et al: Levonorgestrel-releasing intrauterine 
system (Mirena) as a therapy for endometrial hyperplasia and carcinoma. Acta Obstet Gynecol 
Scand 82:580-2, 2003
16. Dhar KK, NeedhiRajan T, Koslowski M, et al: Is levonorgestrel intrauterine system effective for 
treatment of early endometrial cancer? Report of four cases and review of the literature. Gynecol 
Oncol 97:924-7, 2005
17. Westin SN, Broaddus RR, Lu KH, et al: Quantitative Analysis of Estrogen Regulated Transcripts 
to Sub-Classify Endometrial Carcinomas. Unpublished Data, 2008
18. McCampbell AS, Broaddus RR, Loose DS, et al: Overexpression of the insulin-like growth factor I 
receptor and activation of the AKT pathway in hyperplastic endometrium. Clin Cancer Res 
12:6373-8, 2006
19. Lu KH, Broaddus RR, Sun CC: Modulation of surrogate endpoint biomarkers in endometrial 
biopsies from women with HNPCC. Unpublished Data, 2008
20. Milam MR, Soliman PT, Chung LH, et al: Loss of phosphatase and tensin homologue deleted on 
chromosome 10 and phosphorylation of mammalian target of rapamycin are associated with 
progesterone refractory endometrial hyperplasia. Int J Gynecol Cancer, 2007

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