The Tolerability of Saracatinib in Subjects With Lymphangioleiomyomatosis (LAM) (SLAM-1)

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in
tuberous sclerosis complex 1 (TSC1) or tuberous sclerosis complex 2 (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 and formation of cysts.

The long term goal of this research is to devise novel therapeutic strategies for patients
with LAM. Our preliminary data reveal an increase in active Src in lung tissues of patients
with LAM as well as in laboratory cultured cells.

The focus of this study is to examine if Src inhibition represents a potential therapeutic
strategy in LAM. In this study, we will evaluate the safety, tolerability of Src inhibition
in subjects with LAM.

The Quality Assurance (QA) plan is put forth in the Manual of Operations for this study.
This study is utilizing the services of the Data Coordinating Center (DCC) at the University
of Southern Florida. The data collected and entered in the electronic clinical research form
(CRF) at each site will be reviewed by the site clinical research associate and the DCC data
manager. Data check will be made throughout the study for all 3 sites and for all patients
enrolled. Data checks to compare data entered into the registry against predefined rules for
range or consistency with other data fields in the registry.

Source data verification will be done to assess the accuracy, completeness, or
representativeness of registry data. This will be done by a DCC Clinical Research Associate
(CRA).

Each site has received a copy of the general Manual of Operations, the Pharmacy Manual of
Operations and the Laboratory Manual of Operations. Standard Operating Procedures to address
registry operations and analysis activities, such as patient recruitment, data collection,
data management, data analysis, reporting for adverse events, and change management.

We will apply the standards set forth in the National Cancer Institute (NCI), Common
Terminology Criteria for Adverse Events (CTCAE)version V 4.0.

Adverse events related to study medication will be tabulated by body system and by severity
using the NCI CTCAE v4.0. A dose-limiting toxicity (DLT) is defined as any CTCAE grade ≥3
toxicity despite adequate treatment and considered by the investigator to be possibly
related to saracatinib treatment. A grade 3 adverse event is defined as severe or medically
significant but not immediately life-threatening; hospitalization or prolongation of
hospitalization indicated; disabling; limiting self-care.

Adverse events related to study medication will be tabulated by body system and by severity
using the NCI CTCAE v4.0. A dose-limiting toxicity (DLT) is defined as any CTCAE grade ≥3
toxicity despite adequate treatment and considered by the investigator to be possibly
related to saracatinib treatment. A grade 3 adverse event is defined as severe or medically
significant but not immediately life-threatening; hospitalization or prolongation of
hospitalization indicated; disabling; limiting self-care. Below are some examples of what
would be considered DLT. Other grade 3 events will be evaluated by investigator on a
case-by-case basis to determine if they are drug related.

1. Allergic reaction: Prolonged (e.g., not rapidly responsive to symptomatic medication;
recurrence of symptoms following initial improvement; hospitalization indicated for
clinical sequelae (e.g., renal impairment, pulmonary infiltrates)

2. Anaphylaxis: Symptomatic bronchospasm, with or without urticaria; parenteral
intervention indicated; allergy-related edema/angioedema; hypotension

3. Anemia: Hgb <8.0 g/dL and transfusion is indicated.

4. Neutrophil count decrease: <1000 - 500/mm3

5. Lymphocyte count: severe decrease (<500 - 200/mm3) or increase (>20,000/mm3) in blood
lymphocytes.

6. Platelet count decrease: <50,000 - 25,000/mm3

7. Nausea: Inadequate oral caloric or fluid intake; tube feeding, total parenteral
nutrition (TPN), or hospitalization indicated.

8. Vomiting: ≥ 6 episodes (separated by 5 minutes) in 24 hrs; tube feeding, TPN or
hospitalization indicated

9. Diarrhea: Increase of ≥ 7 stools per day over baseline; incontinence; hospitalization
indicated; severe increase in ostomy output compared to baseline; limiting self care
activities of daily life.

10. Pneumonitis: Sudden worsening of shortness of breath, reduction in pulmonary function
tests, new interstitial infiltrates on chest X-ray and fever.

As much as possible data quality is assessed at the data entry point using intelligent
on-line data entry via visual basic designed screen forms. Data element constraints, whether
independent range and/or format limitations or 'relative' referential integrity limitations,
can be enforced by all methods employed for data input. QA reports assess data quality
post-data entry. As we note, data quality begins with the design of the data collection
forms and procedures and incorporates reasonable checks to minimize transcription and
omission errors. Of the more important quality assurance measures are the internal validity
checks for reasonableness and consistency.

- Data Monitoring: The DCC identifies missing or unclear data and generates a data query
to the consortium administrator contact.

- Data Delinquency Tracking: The Data Coordinating Center will monitor data delinquency
on an ongoing basis.

Phase 1b study will require 9 to 15 evaluable subjects. Assuming a 20% drop out rate and 20%
screen failure, the target enrollment will be 9-21 subjects. As the primary analysis, the
safety data generated from this study will be analyzed to generate an optimum range of dose
to be utilized in Phase 2a study. The secondary endpoints will be summarized to help more
detailed evaluation in Phase 2a study.

Deviations from the protocol are not allowed. It is the responsibility of each study site to
use continuous vigilance to identify and report any protocol deviations. Upon determination
that a protocol deviation has occurred, the study staff will a) notify the Principal
Investigator, b) notify Project Manager and c) complete the Protocol Deviation form. The
Principal Investigator will complete and sign the Protocol Deviation form and submit it to
the site Institutional Review Board (IRB), per IRB regulations. Major protocol deviations
will be reported to the Data and Safety Monitoring Board. The Investigation New Drug (IND)
sponsor will also be informed and will be responsible for notifying the FDA.

Inclusion Criteria:

- Male or female patients. It should be noted, however, that LAM occurs predominantly
in women.

- 18 to 65 years of age.

- All patients must have a diagnosis of LAM as defined by one of the following:

Open lung, transbronchial or thoracic needle biopsy consistent with LAM Open or needle
abdominal biopsy findings consistent with LAM Computed tomography (CT) of chest or abdomen
consistent with LAM in the setting of TSC, renal angiomyolipoma (AML), cystic abdominal
lymphangiomas, or history of chylous effusion in the chest or abdomen CT of chest
consistent with LAM plus serum vascular endothelial growth factor (VEGF-D) > 800 pg/ml In
cases where the diagnosis of LAM is based on biopsy, review of the pathology specimens by
pathologists who are experienced with LAM, such as those at the NIH or the Mayo Clinic,
will be obtained (if not done so previously).

Exclusion Criteria:

- Current infection.

- Major surgery within the past 2 months

- Advanced hematologic, renal, hepatic, or metabolic diseases

- The use of another investigational drug within 30 days

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

- Previous lung transplantation or active on transplant list.

- 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 mild cervical cancer.

- 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