Trial of Aromatase Inhibition in Lymphangioleiomyomatosis

Study Overview
=================
Brief Summary
-----------------
The hypothesis in this study is that estrogen suppression by an aromatase inhibitor in postmenopausal women with Lymphangioleiomyomatosis (LAM) will prevent or delay progression of lung disease and result in a decrease in the rate of decline in FEV1

Detailed Description
-----------------
Lymphangioleiomyomatosis, or LAM, is an uncommon, progressive, cystic lung disease that predominantly affects young women. Pulmonary parenchymal changes consistent with LAM are found in about one third of women with tuberous sclerosis complex (TSC), an autosomal dominant tumor suppressor syndrome. LAM also occurs in a sporadic form that is not associated with germ line mutations in TSC genes. Recent evidence that recurrent LAM after lung transplantation results from seeding of the graft from a remote source and suggests a metastatic mechanism for the disease. Since LAM occurs almost exclusively in women, and exposure to estrogen either exogenously or during pregnancy can exacerbate LAM, estrogen suppression might be expected to prevent or delay progression of disease. In preclinical studies, estrogen induces the growth of TSC2-deficient cells and tumor cells derived from LAM patients. In a xenograft model of lymphangioleiomyomatosis presented by Dr. Yu at the 2008 LAM Research Meeting, estrogen promoted the pulmonary metastases of tuberin-deficient ELT3 cells (TSC2-deficient rat uterine leiomyoma cells) in female ovariectomized CB-17-scid mice, while the estrogen inhibitor fulvestrant completely blocked estrogen-promoted pulmonary metastases. This work was recently published. Letrozole is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis)(14). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)diben-zonitrile. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Official Title
-----------------
A TRIAL OF LETROZOLE IN PULMONARY LYMPHANGIOLEIOMYOMATOSIS

Conditions
-----------------
Lymphangioleiomyomatosis

Intervention / Treatment
-----------------
* Drug: Letrozole
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All patients at least must have a diagnosis of pulmonary lymphangioleiomyomatosis as defined by one of the following: CT chest compatible with LAM and a biopsy or cytology consistent withLAM. CT chest consistent with LAM in the setting of tuberous sclerosis, renal angiomyolipomata, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen , or serum VEGF-D > 800 pg/uL. All patients must have a post bronchodilator FEV1 ≤80% predicted or DLCO ≤70% predicted or RV≥120% predicted All patients must be postmenopausal females as defined by one of the following: Prior bilateral oophorectomy or bilateral ovarian irradiation. If age greater than 55 years, no menstrual period for 12 months or longer. If age 55 years or younger, must have an estradiol level in the postmenopausal range in the absence of current use of progestational agents. If still premenopausal, may enter if rendered medically postmenopausal on clinical grounds with the use of gonadotropin releasing hormone (e.g. leuprolide), as long as serum estradiol, FSH, and LH are in the postmenopausal range Patients with osteopenia or osteoporosis must be receiving appropriate treatment for their osteoporosis or osteopenia at entry into this study. Patients must have adequate hematologic and hepatic function as defined by the following at the time of randomization.: Neutrophils > 1500/mm3 and platelets > 100,000/mm3 Bilirubin < 1.25 X upper limit of normal SGPT (ALT) and SGOT (AST) < 2.5 X upper limit of normal Exclusion Criteria: Known allergy to letrozole Inability to comply with pulmonary function tests or follow up visits. Treatment with investigational agents within 30 days Hormonal therapy (e.g. estrogen, progestin, LHRH agonists or antagonists, estrogen receptor blockers, estrogen receptor down regulators, aromatase inhibitors) within 30 days month of registration Medical or psychiatric conditions that would interfere with the ability to provide informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letrozole<br> | Drug: Letrozole<br>* 2.5 mg daily for twelve months<br>* Other names: Femara;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* sugar pill given daily for twelve months<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect on Forced Expiratory Volume in one second |  | twelve months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Other measures of pulmonary function | FVC, DLCO, TLC,RV, FRC, 6MWT | twelve months | 
| Quality of life measures | Quality of Life, dyspnea and fatigue, functional performance | twelve months | 
| Serum VEGF-D |  | twelve months |