The Tolerability of Saracatinib in Subjects With Lymphangioleiomyomatosis (LAM) (SLAM-1)
Condition: Pulmonary Lymphangioleiomyomatosis
MeSH terms: Lymphangioleiomyomatosis
Study type: Interventional
Phase: Phase 1

Summary: 
      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
    

Detailed description: 
      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.
    

Intervention name(s): Saracatinib
Intervention type(s): Drug
Intervention description(s): Saracatinib is escalated as follows: Three dose levels will be administered for 1 month each: 50 mg, 125 mg and 175 mg. Three subjects will be treated at the lowest daily dose of 50 mg. If no subject experiences DLT (dose limiting toxicity), the dose level is escalated to 125 mg/day for the next cohort of 3 different subjects and so on to next dose.
Other intervention name(s): AZD0530
Intervention MeSH terms: Saracatinib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: LAM; saracatinib; Lymphangioleiomyomatosis