Conditions: Leiomyosarcoma Uterine Neoplasm
Keywords: Uterine Leiomyosarcoma Uterine Neoplasm Uterine Sarcomas Uterine Cancer Uterus LMS ER Positivity Femara Letrozole
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is learn if taking Femara (letrozole) after a hysterectomy (surgical removal of the uterus) for uterine leiomyosarcoma will delay or prevent the cancer from coming back.

Detailed description:
Letrozole is an aromatase inhibitor. Aromatase is the enzyme that produces estrogen in post-menopausal women. By interfering with the production of estrogen triggered by aromatase, letrozole reduces the total amount of estrogen in the body. As a result, less estrogen can reach cancer cells, thus preventing their growth.

Before you can start treatment on this study, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. These exams, tests, or procedures are part of regular cancer care and may be done even if you do not join the study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.

Your complete medical history will be recorded, and you will have a physical exam (including a pelvic exam). Your vital signs and blood pressure will be measured. Blood (about 2-3 teaspoons) will be drawn for routine tests. You will also have a blood test (1 teaspoon) to check your cholesterol. You will have an electrocardiogram (ECG -- a test that measures the electrical activity of the heart). You will also have a chest x-ray, and either a computed tomography (CT) scan or a magnetic resonance imaging (MRI) to check the status of the disease. Your doctors will test previously collected tumor tissue to learn if the estrogen receptor is positive or negative.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to 1 of 2 groups. Group 1 will receive letrozole by mouth once a day. Group 2 will receive no treatment. Both groups will be followed closely every 3 months. You will have an equal chance of being placed in either group.

If you are in Group 1, you will take letrozole by mouth every day for 12 weeks. Every 12 weeks is considered a study "cycle." You will only be given the amount of drug needed for 1 cycle of therapy at a time. You will keep a diary during the study that will list when and how much drug you took. This diary will be reviewed after each cycle of therapy by the research nurse or doctor and filed in your chart.

Every 12 weeks, all participants will have blood (about 3-4 teaspoons) drawn for routine tests. CT scan of the chest, abdomen (stomach area), and pelvis will be done every 24 weeks. In addition, all participants will have a physical exam (including a pelvic exam), and your vital signs and blood pressure will be measured.

You may remain on study for as long as you are benefitting. You will be taken off study if intolerable side effects occur.

Once you are off study, blood (about 2-3 teaspoons) will be drawn for routine tests and to measure your cholesterol level. You will have a physical exam (including a pelvic exam), and an MRI or CT scan.

This is an investigational study. Letrozole is approved by the FDA for treatment of some breast cancer patients after surgery. Its use in patients with leiomyosarcoma is experimental. Up to 80 patients will take part in this study. All will be enrolled at M. D. Anderson.

Arms:
arm 1: Letrozole 2.5 mg Tablet By Mouth Daily for 12 Weeks. arm 2: Patients receive no treatment. Follow up every 3 months.

Interventions: intervention 1: Letrozole
Intervention descriptions: intervention 1: 2.5 mg Tablet By Mouth Daily for 12 Weeks.

Protocol document:
Prot_SAP_000.pdf: 
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Protocol Page
A Randomized Phase II Study of Letrozole Versus Observation in Patients with 
Newly Diagnosed Uterine Leiomyosarcoma
2006-0453
Core Protocol Information
Short Title 
Letrozole versus observation in patients with newly diagnosed uterine leiomyosarcoma
Study Chair: 
Robert Coleman
Additional Contact:
Aileen Maloney
Jacalyn B. Gano
PDOL OPR DMC Addl Cont
Department:
Gynecologic Oncology
Phone:
713-794-1422
Unit:
1352
Full Title: 
A Randomized Phase II Study of Letrozole Versus Observation in Patients with Newly 
Diagnosed Uterine Leiomyosarcoma
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 07/24/2017
Version:
08
Submitted by:
Aileen Maloney--6/8/2009 10:18:41 AM
OPR Action:
Accepted by:  Leola M. Jones -- 6/16/2009 1:06:28 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


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Protocol Body
1.0 Objectives
To prolong the time to recurrence for patients with clinical stage I and II uterine LMS assigned 
to letrozole therapy.  The primary endpoint of this study will be a prolongation of time to disease 
recurrence. 
2.0 Background
Letrozole (4,4'-(1H-1,2,4-Triazol-1-ylmethylene)bis-benzonitrile) is a synthetic achiral 
benzydryltriazole derivative. It is an orally active highly selective non-steroidal competitive 
inhibitor of the aromatase enzyme system [1,2]. Aromatase inhibitors block the aromatase 
enzyme, consequently lowering estrogen levels and thereby deprive the tumor of its growth 
stimulus. Letrozole effectively inhibits the conversion of androgens to estrogens in both in vitro 
and in vivo [1]. This property makes it in particular suitable for postmenopausal women whose 
main source of estrogen is via peripheral aromatization of androgen precursors.
Letrozole is up to 150-250 times more potent than the first generation aromatase inhibitor 
Aminoglutethimide (AG), in vitro and more than 10,000 times as potent as AG in inhibiting 
aromatase in vivo [3].  The high potency of letrozole is not accompanied by any significant 
effect on adrenal steroidogenesis in vitro or in vivo over its maximally effective dose range [1,4].  
Inhibition of adrenal steroidogenesis resulting in adrenal hypertrophy does occur with 
therapeutic doses of AG. The high potency and selectivity of letrozole explains its 
pharmacological profile and high therapeutic index. In postmenopausal patients with advanced 
breast cancer, daily doses of 0.1 to 5 mg letrozole suppressed plasma levels of estradiol, estrone 
and estrone sulfate to 75-95% from baseline [1,5]. A Phase III global, multicenter, randomized 
clinical trial evaluated Letrozole (2.5 mg/day) as a first line hormonal therapy as compared to the 
present standard of treatment, tamoxifen (20 mg once daily) [6]. This trial accrued 907 
postmenopausal women with ER and/or PR positive or unknown receptor breast cancer and 
locally advanced disease, metastatic disease, or loco-regional recurrence not amenable to 
treatment by surgery or radiotherapy.  Patients received treatment until disease progression or 
discontinuation for any other reason.
The primary endpoint was time to progression. letrozole was superior to tamoxifen in TTP, 
reducing the risk of progression by 28% (hazard ratio 0.72, p < .0001).  The median TTP was 
prolonged by 57%, from 6.0 months for tamoxifen to 9.4 months for letrozole The secondary 
endpoints included overall tumor response rate, clinical benefit, and time to treatment failure. 
Overall tumor response rate (complete and partial response) was significantly higher with 
letrozole (32 % vs 21%, p= .0002, irrespective of dominant site of disease. Clinical benefit (CR, 
PR or stabilization of disease lasting at least 24 weeks was 50% for letrozole vs 38% tamoxifen, 
p=. 0004. Time to treatment failure was significantly better for letrozole 9.0 months vs 5.7 
months for tamoxifen, p =. 0001.
The median overall survival was slightly prolonged for letrozole 34 versus 30 months for 
tamoxifen. This difference is not significant. However, the study design included a crossover to 
the other treatment arm at the discretion of the investigator. An analysis was done in the patients 


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who did not crossover, which demonstrated a 15-month survival advantage in the letrozole 
treatment group [7].  The data cutoff for this analysis was September 2001, when median 
follow-up was 32 months, with a maximum observation period of 57 months [6].
Tolerability was similar in both arms of the trial, with 2% of patients on letrozole and 3% of 
patients on tamoxifen discontinuing core therapy due to adverse events. In conclusion, letrozole 
has a highly favorable toxicity profile and is superior in TTP and CR compared to tamoxifen in 
patients with locally advanced and metastatic breast cancer. Based on this study and other 
supportive data, FDA approved letrozole for first-line hormonal therapy in locally advanced or 
metastatic breast cancer in January 2001.
A recently completed randomized, double-blind, multicenter study compared the efficacy of 4 
months of therapy with letrozole 2.5 mg daily and tamoxifen 20 mg daily as primary treatment in 
the neoadjuvant  setting [8]. The response rate, assessed by clinical palpation (primary endpoint), 
was 55% for letrozole compared to 36% for tamoxifen (p<0.001). Response rates were similarly 
significant in favor of letrozole when assessed by ultrasound or mammography.
A double-blind crossover study was conducted in 12 estrogen receptor-postive postmenopausal 
metastatic breast cancer patients to compare the effects of letrozole and anastrozole on 
total-body aromatization and plasma estrogen levels. Each regimen was administered for 6 
weeks. The data revealed that letrozole suppresses plasma estrogen levels more completely than 
anastrozole [9]. Letrozole was statistically superior to anastrozole in reducing plasma levels of 
both estrone sulfate (p=0.019) and estrone (p=0.0037). Patients switching from 6 weeks of 
anastrozole to 6 weeks of letrozole consistently achieved further estrogen suppression. 
Conversely, patients switching from 6 weeks of letrozole to 6 weeks of anastrozole experienced 
an increase in estrogen plasma levels.
A multicenter, double-blind study randomized over 8,000 postmenopausal women with
resected, receptor-positive early breast cancer to one of the following arms:
        A. Tamoxifen for 5 years
        B. Femara for 5 years
        C. Tamoxifen for 2 years followed by Femara for 3 years
        D. Femara for 2 years followed by Tamoxifen for 3 years
Of 8,010 women with evaluable data, 4,003 were in the letrozole group and 4,007 in the 
tamoxifen group. After a median follow-up of 25.8 months, there were 351 events of recurrence, 
locally or at distant sites, in the letrozole group, and 428 events in the tamoxifen group. 
Five-year disease-free survival estimates were 84.0% and 81.4%, respectively. [25]
Compared with tamoxifen, letrozole reduced the risk for an event ending a period of disease-free 
survival (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70 - 0.93; P = .003). This 
reduction especially applied to the risk for distant recurrence (HR, 0.73; 95% CI, 0.60 - 0.88; P = 
.001).
Adverse events have been analyzed irrespective of whether a symptom was present or


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absent at baseline. Most adverse events reported (82%) were Grade 1 and Grade 2 applying
the Common Toxicity Criteria Version 2.0.
When considering all grades, a higher incidence of events were seen for Femara regarding
fractures (5.7% vs 4%), myocardial infarctions (0.6% vs 0.4%), and arthralgia (21.2% vs
13.5%) (Femara vs tamoxifen respectively). A higher incidence was seen for tamoxifen
regarding thromboembolic events (1.2% vs 2.8%), endometrial cancer (0.2% vs 0.4%),
endometrial proliferative disorders (0.3% vs 1.8%) Femara vs tamoxifen respectively.
In the adjuvant setting, an increase in total cholesterol (generally non-fasting) in
patients who had baseline values of total serum cholesterol within normal range, and then
subsequently had an increase in total serum cholesterol of 1.5 ULN was 173/3203 (5.4%) on
letrozole vs 40/3224 (1.2%) on tamoxifen. Lipid lowering drugs were used by 18% of patients
on letrozole and 12% on tamoxifen.
Uterine leiomyosarcomas (LMS) are rare, accounting for less than five percent of all malignant 
uterine neoplasms. Approximately 85% of women present with clinical stage I or II disease (i.e., 
disease limited to disease that is limited to the uterus and cervix).  Lymph node metastasis is not 
common for patients with LMS, therefore, clinical staging is adequate and surgical 
re-exploration is not necessary for patients who are not initially staged [10].  Despite the low 
incidence of high stage disease, approximately 50% of patients will recur within two years 
[10-12].  Most of these patients recur outside of the pelvis.  The Gynecologic Oncology Group 
evaluated the role of adjuvant radiation therapy in patients (n=48) with clinical stage I and II 
disease [11].  There was no difference in the progression-free interval, absolute two-year 
survival rate, or site of first recurrence between patients who received pelvic radiation (n= 11) 
and those that did not (n=37).  This is not surprising since most recurrences were outside of the 
pelvis (83%).  48% of the patients recurred and most of these patients recurred within 17 months 
of diagnosis. Adjuvant chemotherapy was also evaluated for patients with this disease [12].  In 
patients treated with adjuvant adriamycin, 44% recurred versus 61% in patients who did not 
receive chemotherapy.  This difference was not statistically significant.
Several studies have evaluated the rate of hormone receptor expression in patients with LMS of 
the uterus [13-21].  40-87% of leiomyosarcomas express the estrogen receptor (ER) and 38-80% 
express the progesterone receptor (PR).  Because of this high expression, estrogen may act as a 
growth factor that stimulates cell proliferation and tumor growth. 
Hormonal manipulation is commonly used to control the growth of benign leiomyomas.  Given 
the relatively high rate of hormone receptor positivity for LMS, we hypothesize that by 
decreasing systemic estrogen using an aromatase inhibitor, we may be able to prolong the time to 
recurrence for patients with this disease. [26-28]
3.0 Treatment Plan
3.1.
Overall study design
This is a randomized phase II study of  Femara (letrozole) administered orally on a daily basis to 
patients with newly diagnosed clinical stage I and II LMS.  Using an adaptive randomization, 


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patients will be assigned to either the treatment arm (letrozole group) or observation.  The 
primary outcome for this trial is the time to progression or death.
3.3.
Study population
3.3.1. Patient population
Patient enrollment will be open to any individual with clinical stage I and II 
uterine LMS seen in the Gynecologic Oncology Center at M. D. Anderson Cancer 
Center. Hormone receptor positivity is an eligibility requirement.
3.3.2. Inclusion and exclusion criteria
Inclusion criteria
To be eligible for the study, patients must fulfill all of the following criteria:
Patients must have signed an approved informed consent.
1.
Histologically confirmed uterine leiomyosarcoma with disease limited to the 
2.
uterus (determined by surgical staging or radiologic imaging).
Tumors must express ER positivity by immunohistochemistry (ER expression 
3.
>10% by immunohistochemistry).
Patients must have a hysterectomy and bilateral oophorectomy prior to 
4.
initiation of therapy.
All patients must have no measurable disease. Measurable disease is defined 
5.
as lesions that can be measured by physical examination or by means of 
imaging techniques. Imaging must be done within 6 weeks of study entry.
Patients must have a Zubrod performance status of 0, 1, or 2.
6.
Patients must have a pretreatment granulocyte count (i.e., segmented 
7.
neutrophils + bands) of >1,000/Fl, a hemoglobin level of >9.0 gm/dL and a 
platelet count of >75,000/dL.
Patients must have an adequate renal function as documented by serum 
8.
creatinine <2.0 mg/dL.
Patients must have adequate hepatic function as documented by a serum 
9.
bilirubin <2.5 mg/dL. 
Aspartate transaminase (SGOT) must be <3x institutional upper limit of 
10.
normal.
Patients must have recovered from the effects of prior surgery.
11.
No more than 12 weeks must have elapsed from hysterectomy.
12.
Patients must be 18 years of age or older.
13.
Exclusion criteria
Patients meeting any of the following criteria are ineligible to participate in this study:
Patients who do not have pure uterine sarcomas (i.e., no mixed malignant 
1.
mullerian tumors).
Patients with any other severe concurrent disease, which would make the 
2.
patient inappropriate for entry into this study, including significant hepatic, 
renal, or gastrointestinal diseases.
Patients with a history of prior malignancy except for adequately treated basal 
3.
cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for 


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which the patient has been disease-free for at least five years.
Patients who were taking or have a history of taking letrozole or any other 
4.
aromatase inhibitor.
Patients with active or uncontrolled systemic infection. 
5.
Patients with history of uncontrolled cardiac disease; i.e., uncontrolled 
6.
hypertension, unstable angina, recent myocardial infarction (within prior 6 
months), uncontrolled congestive heart failure, and cardiomyopathy with an 
ejection fraction under 40%.
Patients who are pregnant or breast-feeding.
7.
Presence of clinically apparent untreated central nervous system metastases
8.
Presence of carcinomatous meningitis.
9.
Patients currently receiving chemotherapy or radiation therapy.
10.
MDACC will not exclude any potential subject from participating in this or any 
study solely on the basis of ethnic origin or socioeconomic status. Every attempt 
will be made to enter all eligible patients into this protocol and therefore address 
the study objectives in a patient population representative of the MDACC cancer 
population.
3.3.3. Interruption or discontinuation of treatment
A genuine effort must be made to determine the reason(s) why a patient 
fails to return for the necessary visits or is discontinued from the trial. 
Information regarding the reason for not completing the trial will be 
recorded in the patient's medical record.
Reasons that a patient may discontinue participation in this clinical study 
include:
adverse event(s)
1.
abnormal laboratory value(s)
2.
abnormal test procedure result(s)
3.
unsatisfactory therapeutic effect
4.
subject's condition no longer requires study drug
5.
protocol violation
6.
subject withdrew consent
7.
lost to follow-up
8.
death.
9.
Any patient who receives at least one dose of trial medication will be 
included in the safety analysis.
3.4.
Drug Information
Description:
Letrozole is used to treat certain types of breast cancer in women.  Female hormones that 
occur naturally in the body can increase the growth of some cancers.  Letrozole works by 
decreasing the amounts of these hormones in the body.  The medicine is meant to be used 


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only by women who have already stopped menstruation.
 The most commonly used brand name is Femara.  The chemical name is 
4,4'-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile.
Drug Supply: Letrozole will be supplied by Norvartis Pharmaceuticals.
Availability and storage:  Available as 2.5 mg tablet or oral administration.  Should be 
stored at room temperature.
Dosage: 2.5mg tablet PO daily
Pharmacokinetics: Letrozole is rapidly and completely absorbed from the gastrointestinal 
tract.  The terminal elimination half-life is about two days.  Daily doses of 0.1mg to 5 mg 
Letrozole suppresses plasma concentrations of estrone, and estrone sulfate by 75% to 
95% from baseline with maximal suppression achieved within two to three days.
Toxicity: Letrozole is well tolerated by most patients.  The common adverse effects 
reported with daily administration of letrozole include headache, mild nausea, hot 
flashes, diarrhea, fluid retention and muscle cramps. Other side affects include burning, 
dryness or itching of the vagina.  It may cause vaginal bleeding or discharge.
Letrozole may cause breast pain, chills, fever, flu-like symptoms and mental depression.  
It may also cause bone pain, joint or muscle pain.  It may cause anxiety, confusion, 
increased thirst and urination, loss of appetite or weight loss.  It has also been associated 
with skin rash, or itching, sleepiness, trouble sleeping, unusual tiredness and weakness.  
Letrozole sometimes causes a loss of hair. Letrozole may increased risk for blood clots, 
which could lead to a heart attack or a stroke.  
Adverse Effects are usually mild to moderate and rarely necessitate discontinuation of 
treatment
Treatment compliance
Patients will remain on study until disease progression. For the purposes of this trial the 
final data collection point is at the time of disease progression. For those patients 
assigned to the treatment group, records of study medication used and dosages 
administered will be kept during the study.  Drug accountability will be noted during 
follow-up visits and at the completion of the trial.  Patients will be asked to return all 
unused medication.
3.5.
Visit schedule and assessments
3.5.1. Visit schedule
Examination
Screening
Pre-
treatment
Q 12
Weeks
Q 24
Weeks
Q 12
months
End of 
study


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Informed consent
X
Medical history
X
X
X
X
Concurrent medications
X
X
X
X
X
Inclusion/exclusion criteria
X
Zubrod performance status
X
X
X
X
X
Vital signs/weight
X
X
X
X
X
Physical examination
X
X
b
X
X
X
Pelvic exam
X
X
b
X
X
X
ECG
X
CBC/DIFF/PLT 
X
b
X
X
X
Magnesium, SGOT, total bilirubin, 
BUN, serum creatinine, electrolytes
X
b
X
X
X
Serum cholesterol
X
X
X
X
Toxicity assessment
X
X
c
X
c
X
c
CXR
X
X
X
CT scan of chest, abdomen/pelvis
a
 
 
          X
 
 
a. within 6 weeks of study entry
b. within 14 days of study entry
c. treatment-related toxicities  (study drug arm)
3.5.2. Screening/Baseline
To be completed within 6 weeks of study entry
CT scan of the chest, abdomen/pelvis
1.
To be completed within four weeks prior to initiation of therapy 
Medical history including list of current medications and dosing schedules, 
1.
history of previous therapies for current disease; and any residual toxicity 
from prior therapies should be recorded by using the grading schema in NCI 
Common Terminology Criteria for Adverse Events, Version 3.0. 
Chest x-ray
2.
ECG 
3.
To be completed within 14 days of initiation of therapy:
Weight
1.
Complete blood count with leukocyte differential and platelet count, serum 
2.
chemistries (magnesium, SGOT, total bilirubin, BUN, serum creatinine), and 
electrolytes. 
Serum cholesterol
3.
Vital Signs (blood pressure, pulse, respiratory rate, temperature)
4.
Physical exam including pelvic exam
5.
Zubrod performance status
6.
To be obtained every 12 weeks (+/- 7 days):
Weight
1.
Complete blood count with leukocyte differential and platelet count, serum 
2.


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chemistries (magnesium, SGOT, total bilirubin, BUN, serum creatinine), 
electrolytes
Serum cholesterol
3.
Vital Signs (blood pressure, pulse, respiratory rate, temperature)
4.
Physical exam (including pelvic exam) 
5.
Zubrod performance status 
6.
Assessment of treatment-related toxicities (study drug arm) using the grading 
7.
schema in NCI Common Terminology Criteria for Adverse Events, Version 
3.0. 
To be obtained every 24 weeks (+/- 7 days):
Chest Xray
1.
CT scan of the chest, abdomen and pelvis
2.
To be obtained every 12 months (+/-7 days):
Weight
1.
Complete blood count with leukocyte differential and platelet count, serum 
2.
chemistries (magnesium, SGOT, total bilirubin, BUN, serum creatinine), 
electrolytes
Serum cholesterol
3.
Vital Signs (blood pressure, pulse, respiratory rate, temperature)
4.
Physical exam (including pelvic exam) 
5.
Zubrod performance status 
6.
Assessment of treatment-related toxicities (study drug arm) using the grading 
7.
schema in NCI Common Terminology Criteria for Adverse Events, Version 
3.0. 
To be obtained at the end of treatment:
Weight
1.
Complete blood count with leukocyte differential and platelet count, serum 
2.
chemistries (magnesium, SGOT, total bilirubin, BUN, serum creatinine), and 
electrolytes.
Serum cholesterol 
3.
Vital signs (blood pressure, pulse, respiratory rate, temperature)
4.
Physical exam (including pelvic exam)
5.
Zubrod performance status
6.
Assessment of treatment-related toxicities (study drug arm) using the grading 
7.
schema in NCI Common Terminology Criteria for Adverse Events, Version 
3.0. 
Follow-up and further imaging:
Follow-up will be at the discretion of the patient’s primary physician and based 
on physical findings.


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3.5.3. Safety assessments
Safety assessments will consist of monitoring and recording all adverse events 
and serious adverse events, the regular monitoring of hematology, blood 
chemistry and urine values, regular measurement of vital signs and the 
performance of physical examinations.
Adverse events
Information about all adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical examination, 
laboratory test or other means, will be collected and recorded. An adverse event is 
any undesirable sign, symptom or medical condition occurring after starting study 
drug (or therapy) even if the event is not considered to be related to study drug (or 
therapy). Study drug (or therapy) includes the drug (or therapy) under evaluation, 
and any reference or placebo drug (or therapy) given during any phase of the trial.
Medical conditions/diseases present before starting study treatment are only 
considered adverse events if they worsen after starting study treatment (any 
procedures specified in the protocol). Adverse events occurring before starting 
study treatment but after signing the informed consent form will also be recorded. 
This study will utilize the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 for adverse event reporting. A copy of the CTCAE version 
3.0 can be downloaded from the CTEP home page (http:/www.ctep.info.nih.gov/) 
and is appended to this protocol. Life-threatening toxicities should be reported 
immediately to the Study Chairman, who in turn must notify the IRB. Reporting 
of adverse reactions is in addition to and does not supplant the reporting of 
toxicities as part of the results of the clinical trial. 
This protocol will follow the Guidelines for Adverse Event Reporting appended 
to this protocol. In addition, the reporting requirements for Novartis are defined 
below.
Protocol Safety Requirements for Novartis
The principal investigator has the obligation to report all serious adverse events to 
the FDA, IRB, and Novartis Pharmaceuticals Clinical Safety and Epidemiology 
Department (CS&E).
Any Serious Adverse event occurring in a patient after providing informed 
consent, while receiving study drug, and until four weeks after stopping study 
drug must be reported by FAX 
) to Novartis Pharmaceuticals 
CS&E Department within 24 hours of learning of it's occurrence, even if it is not 
felt to be drug related.  It is requested that SAEs are reported to Novartis using the 
Norvartis SAE form (Appendix E)


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Serious adverse events
A serious adverse event is an undesirable sign, symptom or medical condition 
which:
is fatal or life-threatening
1.
required or prolonged hospitalization
2.
results in persistent or significant disability/incapacity 
3.
constitutes a congenital anomaly or a birth defect
4.
are medically significant, may jeopardize the subject and may require medical 
5.
or surgical intervention to prevent one of the outcomes listed above.
Any serious adverse event occurring after the patient has provided informed 
consent and until 4 weeks after the patient has stopped study participation must be 
reported. 
Grading/Rating Scale
All adverse events reported during the study will be evaluated and graded on a 
1.
scale of 1-5. The NCI Common Terminology Criteria for Adverse Events, 
v3.0 (CTCAE) will be used to determine the grade for all toxicities.
For any adverse events, which are not listed in the CTCAE the following 
2.
rating system, will be used:
Grade 
Description
   0 
No AE or within normal limits
   1 
Mild AE (minor; no specific medical intervention; asymptomatic 
laboratory findings only, radiographic findings only; marginal clinical 
relevance)
   2 
Moderate AE (minimal intervention; local intervention; noninvasive 
intervention [packing, cautery])
   3 
Severe and undesirable AE (significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective 
interventional radiological procedure; therapeutic endoscopy or 
operation)
   4 
Life-threatening or disabling AE (complicated by acute, 
life-threatening metabolic or cardiovascular complications such as 
circulatory failure, hemorrhage, sepsis. Life-threatening physiologic 
consequences; need for intensive care or emergent invasive procedure; 
emergent interventional radiological procedure, therapeutic endoscopy 
or operation)
   5 
Fatal AE
Attribution is the determination of whether an AE is related to medical treatment 
or procedure. CTCAE does not define an AE as necessarily ‘caused by a 
therapeutic intervention.’ The clinical investigator must assign attribution for an 
adverse event after naming and grading of the event.


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Attribution 
Description
Unrelated 
The AE is clearly NOT related to the intervention
Unlikely 
The AE is doubtfully related to the intervention
Possible 
The AE may be related to the intervention
Probable 
The AE is likely related to the intervention
Definite 
The AE is clearly related to the intervention
3.5.4. Drug levels and pharmacokinetic assessments
Drug levels/pharmacokinetic assessments will not be performed
3.6
Efficacy Assessment
Patients receiving letrozole will continue until progression or drug related toxicity.  
Those assigned to the observation group will be followed until disease progression.  
Progression will be defined as appearance of one or more new lesions on clinical exam or 
on radiologic imaging. At the physician’s discretion, clinical findings can warrant further 
radiologic imaging. If the imaging reveals a new lesion, recurrent disease should be 
biopsy proven.
4.0 Protocol amendments
Any changes to the protocol will be made in the form of an amendment and will be approved by 
Novartis and the MD Anderson Cancer Center Institutional Review Board. Changes in study 
conduct are not permitted. Any unforeseen changes in study conduct will be recorded  per 
institutional policy.
5.0 Data management
Registration: 
This is a randomized, phase II trial of letrozole verses observation for patients with newly 
diagnosed, stage I and II, uterine leiomyosarcoma. All patients who meet eligibility criteria and 
are enrolled in this trial will be registered in Clinical Oncology Research Database (CORe) at the 
University of Texas MD. Anderson Cancer Center. The date in the current informed consent 
document is displayed to ensure only the most current IRB approved version is used.  Consent 
date, registration date, off study date, and evaluability data are required for all registrants.
Data Collection: 
Data will be collected and stored in the MD Anderson Protocol Data Management System 
(PDMS). Reporting to the sponsor, if applicable, will follow the contract agreement.
6.0 Statistical Design
We will accrue a minimum of 10 patients and a maximum of 80 patients at a rate of 2 patients 
per month.  The primary outcome for this trial is the time to progression or death.  Patients 
treated with standard of care (observation) have median progression-free survival (PFS) of 24 
months [10].  We will follow all patients for at least 24 months following treatment.


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Patients will be randomized between observation and letrozole using a Bayesian adaptive 
algorithm [22]. Details of this methodology are given in the “Technical Details” section below.  
The first 10 patients will be randomized fairly between the 2 treatment arms. After 10 patients 
are enrolled there will be 5 patients on each treatment arm.  As the trial progresses and data 
accrue the randomization will become unbalanced in favor of the treatment that, on average, has 
better results in terms of PFS, so that each successive patient is more likely to receive the 
treatment showing better results.
The trial will be stopped early and a treatment selected as being “better” if the probability is 0.90 
or more that one treatment’s PFS is longer than the other treatment’s PFS.  However, if all 80 
patients are enrolled, then a treatment will be selected as being “better” if the probability is 0.80 
or more that one treatment’s PFS is longer than the other treatment’s PFS.
The operating characteristics of this study design are summarized in Table 1.  These operating 
characteristics are based on 1000 simulations of the study design for 6 possible scenarios.
6.1
Outcomes
6.1.1 Primary Outcome
We will report the posterior probability that the letrozole arm has longer PFS than the 
observation arm.  We will also provide a 95% posterior credible interval for the 
probability that the letrozole arm has longer PFS than the observation arm.
We will estimate the PFS with the Kaplan-Meier 23 product-limit estimator for each arm, 
and we will compare the PFS between the 2 arms with the log-rank test.  We will model 
PFS with the Cox [24] proportional hazards regression model to estimate the hazard ratio 
for treatment (letrozole : observation), and we will construct the 95% confidence interval 
for this hazard ratio.
6.1.2  Secondary Outcome
We will estimate the overall survival (OS) with the Kaplan-Meier product-limit estimator 
for each arm, and we will compare the OS between the 2 arms with the log-rank test.  We 
will model OS with the Cox proportional hazards regression model to estimate the hazard 
ratio for treatment (letrozole : observation), and we will construct a 95% confidence 
interval for this hazard ratio.
6.2
Technical Details
Let MO and ML be the median PFS for treatments “observation” (O) and “letrozole” (L), 
respectively.  We assume that MO and ML each have an inverse gamma prior 
distribution with mean 24 months and variance 57.6 months.  The middle 95% of this 
prior distribution is between 13.4 and 42.6 months.
For each patient, the randomization probability for treatment O will be the posterior 
probability that it has the longer PFS, that is pO(data) = Pr(MO > ML| data) and the 
randomization probability for treatment L is pL(data) = 1- pO(data).  If at any point 
during the trial pL(data) > 0.90 (< 0.10) the trial will be terminated and treatment L will 


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be selected as superior (inferior).  If the maximum number of patients is enrolled in the 
trial and pL(data) > 0.80 (< 0.20) treatment L will be selected as superior (inferior).  If at 
any time during the trial we find that Pr(MO > 24 | data) < 0.05 or Pr(ML > 24 | data) < 
0.05 we will suspend accrual to arm O or L, respectively, until this probability is 0.05 or 
greater.
7.1
Administrative procedures
7.1.1. Changes to the protocol
Any change or addition to this protocol requires a written protocol amendment that 
must be approved by the principle investigator, Novartis and the IRB before 
implementation.  Examples of amendments requiring such approval are:
an increase in drug dosage or duration of exposure of subjects
1.
a significant change in the study design (e.g. addition or deletion of a control 
2.
group)
an increase in the number of invasive procedures to which subjects are exposed
3.
addition or deletion of a test procedure for safety monitoring.
4.
These requirements for approval should in no way prevent any immediate action 
from being taken by the investigator in the interests of preserving the safety of all 
subjects included in the trial. If an immediate change to the protocol is felt to be 
necessary by the investigator and is implemented by him/her for safety reasons, the 
IRB/IEC/REB at the center should be informed within 10 working days.
7.2
Recording of data and retention of documents
An Investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the 
investigation on each individual treated with the investigational product or entered as 
a control in the investigation.
The Investigator must retain investigational product disposition records and source 
documents for the maximum period required by applicable regulations and 
guidelines, or Institution procedures.
If the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed upon designee (e.g., another Investigator, 
IRB). Notice of such transfer will be given in writing to Novartis.
7.2.3 Handling of study medication
It is the responsibility of the Investigator to ensure that a current record of 
study drug disposition is maintained at each study site where the study drug is 
inventoried and disposed. Records or logs must comply with applicable 
regulations and guidelines.


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7.2.4. Publication of results
Any formal presentation or publication of data from this trial may be 
considered as a joint publication by the Principle Investigator and appropriate 
Novartis personnel. Authorship will be determined by mutual agreement. For 
multicenter studies, it is mandatory that the first publication is based on data 
from all centers, analyzed as stipulated in the protocol, and not by the 
investigators. Investigators participating in multicenter studies agree not to 
present data gathered from one center or a small group of centers before the 
full publication, unless formally agreed to by the Principle Investigator and 
Novartis.
Novartis must receive copies of any intended communication in advance of 
publication (at least 15 working days for an abstract or oral presentation and 
45 working days for a journal submission). Novartis will review the 
communications for accuracy (thus avoiding potential discrepancies with 
submissions to health authorities), verify that confidential information is not 
being inadvertently divulged and provide any relevant supplementary 
information. 
7.2.5. Disclosure and confidentiality
By signing the protocol, the investigator agrees to keep all information 
provided by Novartis in strict confidence and to request similar 
confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (protocols, investigators' brochures,  and other material) 
will be stored appropriately to ensure their confidentiality. The information 
provided by Novartis to the investigator may not be disclosed to others 
without direct written authorization from Novartis, except to the extent 
necessary to obtain informed consent from patients who wish to participate in 
the trial. 
7.2.6. Discontinuation of study
Novartis reserves the right to discontinue any study under the conditions 
specified in the clinical trial agreement.
7.3.
Ethics and Good Clinical Practice
This study must be carried out in compliance with the protocol and in accordance 
with Good Clinical Practice, as described in: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.
1.
Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
2.
Community.
US 21 Code of Federal Regulations dealing with clinical studies (including parts 
3.
50 and 56 concerning informed consent and IRB regulations).
Declaration of Helsinki, concerning medical research in humans 
4.
(Recommendations Guiding Physicians in Biomedical Research Involving 
Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 


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1989, Somerset West 1996).
7.3.1.
Institutional Review Board/Independent Ethics Committee
Before implementing this study, the protocol, the proposed informed consent form 
and other information to subjects, must be reviewed by a properly constituted 
Institutional Review Board/Independent Ethics Committee (IRB/IEC/REB). A signed 
and dated statement that the protocol and informed consent have been approved by 
the IRB/IEC/REB must be given to Novartis before study initiation. Any 
amendments to the protocol, other than administrative ones, must be approved by this 
committee.
7.3.2.
Informed consent
The investigator must explain to each subject (or legally authorized representative) 
the nature of the study, its purpose, the procedures involved, the expected duration, 
the potential risks and benefits involved and any discomfort it may entail. Each 
subject must be informed that participation in the study is voluntary and that she may 
withdraw from the study at any time and that withdrawal of consent will not affect 
her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, 
written in nontechnical language. The subject should read and consider the statement 
before signing and dating it, and should be given a copy of the signed document. No 
patient can enter the study before his/her informed consent has been obtained.
The informed consent form is considered to be part of the protocol, and must be 
submitted by the investigator for IRB/IEC/REB approval. Novartis supplies a 
proposed informed consent form, which complies to regulatory requirements and is 
considered appropriate for the study. Any changes to the proposed consent form 
suggested by the Investigator must be agreed to by Novartis before submission to the 
IRB/IEC/REB, and a copy of the approved version must be provided to Novartis after 
IRB/IEC/REB approval.
7.3.3.
Declaration of Helsinki
The investigator must conduct the trial in accordance with the Declaration of 
Helsinki.
8.0 References
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Bhatnagar, A. S., Batzl, C., Hausler, A. & Nogues, V. The role of estrogen in the feedback 
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Hornback, N. B., Omura, G. & Major, F. J. Observations on the use of adjuvant radiation 
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Berry, D. A. & Eick, S. G. Adaptive assignment versus balanced randomization in clinical 
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