The Tolerability of Saracatinib in Subjects With Lymphangioleiomyomatosis (LAM) (SLAM-1)
The Tolerability of Saracatinib in Subjects With Lymphangioleiomyomatosis (LAM) (SLAM-1)
Lymphangioleiomyomatosis (LAM) is a rare lung disease that mostly affects women of childbearing age. In LAM, abnormal, muscle-like cells begin to grow out of control in the lungs. As a result, air can't move freely in and out of the lungs. In some cases, this means the lungs can't supply the body's other organs with enough oxygen.
This study is being conducted to find out what dose of a drug called saracatinib is best tolerated by people with LAM. This drug has been tested in patients with certain types of cancer but is not currently approved by the United States Food and Drug Administration (FDA). Saracatinib may work in cancer by preventing the growth, movement and invasiveness of cancer cells. The use of saracatinib to treat LAM is considered experimental. Preliminary testing already completed suggests that the study drug, saracatinib, may suppress certain substances in the lungs of patients with LAM thus may be effective in slowing down the disease process
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.
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.
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:
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: