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.