Letrozole for Lymphangioleiomyomatosis

Phase 2

Completed

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 germline 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 is exacerbated by pregnancy, menses and hormonal therapies suggest that estrogen suppression might be expected to prevent or delay progression of disease.

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 can therefore be achieved by specifically inhibiting the aromatase enzyme. Letrozole is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis) that has been shown to be effective in other neoplasms that affect women, such as breast cancer.

Recruitment & Eligibility

Inclusion Criteria

Definite diagnosis of based on compatible chest CT and at least one of the following:
1. biopsy or cytology consistent with LAM, or
2. tuberous sclerosis, renal angiomyolipoma, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen, or
3. serum VEGF-D ≥ 800 pg/uL.
post bronchodilator FEV1 ≤80% predicted or DLCO ≤70% predicted or RV≥120% predicted
female and postmenopausal status as defined by one of the following:
1. prior bilateral oophorectomy or bilateral ovarian irradiation, or
2. age greater than 55 years, and no menstrual period for 12 months or longer.
3. age 18-55 years and 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.

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.
abnormal 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) or SGOT (AST) >2.5 X upper limit of normal

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Patients are placed on placebo, 1 tablet daily for one year
Letrozole	Letrozole	Patients are placed on letrozole, 1 tablet (2.5 mg) daily for one year

Primary Outcome Measures

Name	Time	Method
Rate of Change in Forced Expiratory Volume in 1 Second in ml/Month	12 months	FEV1 values reported are in liters or milliliters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. Higher FEV1 scores indicate better lung function.

Secondary Outcome Measures

Name	Time	Method
Post-bronchodilator FVC	twelve months	Post-bronchodilator FVC in milliliters
St George Respiratory Questionnaire	twelve months	Quality of Life scale for respiratory symptoms. This is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating worse quality of life.
Serum VEGF-D	twelve months	VEGF-D values represent serum VEGF-D levels in pg/ml. Higher levels of VEGF-D are associated with Lymphangioleiomyomatosis. A serum VEGF-D greater than 400 pg/ml is a diagnostic biomarker for LAM.

Locations (9): Loyola University Medical Center
🇺🇸
Maywood, Illinois, United States
Emory University School of Medicine
🇺🇸
Atlanta, Georgia, United States
Stanford University Medical Center
🇺🇸
Stanford, California, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
Minor and James
🇺🇸
Seattle, Washington, United States
Mayo Clinic
🇺🇸
Jacksonville, Florida, United States
University of Miami
🇺🇸
Miami, Florida, United States
University of Cincinnati
🇺🇸
Cincinnati, Ohio, United States