Trial of Aromatase Inhibition in Lymphangioleiomyomatosis

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.

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.