Safety and Efficacy of Saracatinib In Subjects With Lymphangioleiomyomatosis

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in
tuberous sclerosis complex 1 (TSC1) or TSC2 tumor suppressor genes. TSC is characterized by
tumors in a wide range of tissues, seizures, mental retardation, autism, and organ failure.
Lymphangioleiomyomatosis (LAM), the major pulmonary manifestation in women with TSC, is a
progressive lung disease characterized by infiltration of atypical smooth muscle like cells
(TSC-/- LAM cells) and formation of parenchymal cysts. Sporadic LAM can develop in women who
do not meet the criteria for the diagnosis of TSC, owing to somatic mutations in the TSC2
gene.

The long term goal of this research is to devise novel therapeutic strategies for patients
with LAM. The observed behavior of LAM cells with respect to their infiltrative growth
pattern, metastatic potential, and altered cell differentiation is reminiscent of cells
undergoing epithelial-mesenchymal transition (EMT). Src kinases are key regulators of
cellular proliferation, motility, invasiveness and EMT. Recent results have shown that
autophagy promotes degradation of active Src. Thereby, decreased autophagy due to mTOR
activation known to occur in LAM cells, may play a significant role in accumulation of active
Src in these cells. Src suppresses transcription of E-cadherin by upregulating its
transcriptional repressors. The preliminary data reveal an increase in active Src in lung
tissues of patients with LAM as well as in cultured TSC2-/- cells. Further, in TSC2-/- cells,
E-cadherin is considerably reduced and does not localize to the plasma membrane, as it does
in wild-type cells.

The focus of this study is to examine if Src inhibition represents a potential therapeutic
strategy in LAM. It is proposed that Src activation in TSC2-/- cells results in the reduction
of E-cadherin, loss of cell-cell adhesion and elevation of oncogenic and metastatic potential
of these cells. The increased Src activity in TSC2-/- cells is likely caused by inhibition of
autophagy associated with hyper-activation of mTOR. Therefore, the use of Src inhibitors may
lead to a reduction in tumor growth and prevent dissemination of TSC2-/- cells. In this
study, the investigators will evaluate the safety and efficacy of Src inhibition in subjects
with LAM.

A number of inhibitors of Src are now in clinical trials in patients with a range of
different tumors. Dasatinib, an oral adenosine triphosphate (ATP)-competitive Src inhibitor,
is now approved for clinical use in patients with chronic myeloid leukemia or acute
lymphoblastic leukemia. However, dasatinib has wider 'off target' inhibitory activity than
saracatinib including potent activity against Abl, ephrin receptor kinases, platelet-derived
growth factor receptor and c-KIT (type of receptor tyrosine kinase and a type of tumor
marker. Also called CD117 and stem cell factor receptor.) In contrast, saracatinib has a
>10-fold preference for Src over Abl kinases and has very little activity against other
tyrosine and serine/threonine kinases. Saracatinib has been already characterized in multiple
clinical trials in terms of safety and pharmacokinetics.

The investigators have conducted a Phase1b study to test the safety of various doses of
Saracatinib in LAM subjects. The purpose of the Phase1b trial was to determine the optimal
dose in terms of safety and tolerability in LAM population. Three escalating doses of
saracatinib; 50, 125 and 175 mg were studied. Saracatinib was given orally once a day.
Overall, subjects tolerated Saracatinib well. The investigators chose the dose of 125 mg to
conduct further testing of both safety and efficacy in this Phase 2a trial.

Inclusion Criteria:

- Female patients. It should be noted that LAM occurs almost exclusively in women.

- 18 to 65 years of age.

- All patients must have a diagnosis of LAM as defined by compatible cystic changes on
chest computed tomography (CT) and one of the following:

- Open lung, transbronchial or thoracic needle biopsy consistent with LAM

- Open or needle abdominal biopsy findings consistent with LAM

- Clinical findings of tuberous scleroma complex (TSC), renal angiomyolipoma, cystic
abdominal lymphangiomas, or history of chylous effusion in the chest or abdomen

- Serum vascular endothelial growth factor D (VEGF-D) > 800 pg/ml

- Subjects must have had a recent reduction in forced expiratory volume at 1-second
(FEV1) of > 50ml/year, as shown by at least two pulmonary function testing (PFT)
measured at least 6 months apart in the last 24 months prior to enrolling study.

Exclusion Criteria:

- Current infection.

- Major surgery within the past 2 months

- Advanced hematologic, renal, hepatic, non-LAM lung disease or metabolic diseases; or
BMI of >35

- The use of another investigational drug within 30 days

- The use of mTOR (mammalian target of rapamycin) inhibitors within 30 days

- Previous lung transplantation.

- Inability to attend scheduled clinic visits

- Inability to give informed consent

- Inability to perform pulmonary function testing

- History of malignancy in the past two years, other than squamous or basal cell skin
cancer or status post successful excision or treatment.

- Nursing mothers

- Current or planned pregnancy.

- Not using adequate contraception (in woman of childbearing potential).

- Significant clinical change in health in the past 30 days