Safety and Efficacy of Saracatinib In Subjects With Lymphangioleiomyomatosis (SLAM-2)

July 28, 2020 updated by: Nicola Hanania, Baylor College of Medicine
This study is being done to determine if there is a potential benefit of saracatinib in LAM subjects. Based on the information of this trial, additional clinical development trials will be needed. The study will also test the tolerability of 125 mg of saracatinib given once daily over a 9 month period.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

28

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Stanford, California, United States, 94305
        • Stanford University
    • Illinois
      • Chicago, Illinois, United States, 90153
        • Loyola Medical Center
    • Maryland
      • Bethesda, Maryland, United States, 20814
        • Laboratory of Translational Research NHLBI
    • Ohio
      • Cincinnati, Ohio, United States, 45267
        • University of Cincinnati
    • Texas
      • Houston, Texas, United States, 77030
        • Baylor College of Medicine - Ben Taub General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Saracatinib
Saracatinib will be given orally at a dose of 125 milligrams once daily for 9 months. Saracatinib is provided as a pink tablet.
Drug: saracatinib
Subjects will receive enough tablets for 90 days +/- 14 days at each visit. Subject will have visits every 90 days for drug accountability as well as safety and efficacy testing to include pulmonary function testing, laboratory testing to include liver and kidney profile, urine pregnancy testing at each visit, vital signs, physical examination - any medically significant changes from baseline visit will be recorded, all adverse events will be monitored until resolution.
Other Names:
  • AZD0530

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
FEV1
Time Frame: 9 months
9 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Angiomyolipoma measured volumetrically on MRI
Time Frame: 12 months
12 months
Lung Cyst size measured on chest CT
Time Frame: 9 months
9 months
VEGF-D serum levels
Time Frame: 12 months
12 months

Other Outcome Measures

Outcome Measure
Time Frame
Pulmonary Function Testing
Time Frame: 12 months
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Baylor College of Medicine

Collaborators

University of South Florida
National Institutes of Health (NIH)
Brigham and Women's Hospital
Stanford University
University of Cincinnati
Loyola University

Investigators

  • Principal Investigator: Francis X McCormack, MD, University of Cincinnati
  • Study Chair: Tony Eissa, MD, Baylor College of Medicine
  • Principal Investigator: Nicola A Hanania, MD, Ben Taub Hospital
  • Principal Investigator: Daniel Dilling, MD, Loyola University
  • Principal Investigator: Stephen Ruoss, MD, Stanford University
  • Principal Investigator: Joel Moss, MD, Laboratory of Translational Research - NHLBI

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2016

Primary Completion (Actual)

July 30, 2019

Study Completion (Actual)

July 30, 2019

Study Registration Dates

First Submitted

March 31, 2016

First Submitted That Met QC Criteria

April 12, 2016

First Posted (Estimate)

April 13, 2016

Study Record Updates

Last Update Posted (Actual)

July 30, 2020

Last Update Submitted That Met QC Criteria

July 28, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SLAM 7602
  • 4UH3TR000961-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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