Safety and Efficacy of Saracatinib In Subjects With Lymphangioleiomyomatosis (SLAM-2)
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|ClinicalTrials.gov Identifier: NCT02737202|
Recruitment Status : Recruiting
First Posted : April 13, 2016
Last Update Posted : January 26, 2018
|Condition or disease||Intervention/treatment||Phase|
|Pulmonary Lymphangioleiomyomatosis||Drug: saracatinib||Phase 2|
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 (Clinical Trial)|
|Estimated Enrollment :||28 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Safety and Efficacy of Saracatinib In Subjects With Lymphangioleiomyomatosis|
|Actual Study Start Date :||April 2016|
|Estimated Primary Completion Date :||July 30, 2019|
|Estimated Study Completion Date :||July 30, 2020|
Saracatinib will be given orally at a dose of 125 milligrams once daily for 9 months. Saracatinib is provided as a pink tablet.
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 Name: AZD0530
- FEV1 [ Time Frame: 9 months ]
- Angiomyolipoma measured volumetrically on MRI [ Time Frame: 12 months ]
- Lung Cyst size measured on chest CT [ Time Frame: 9 months ]
- VEGF-D serum levels [ Time Frame: 12 months ]
- Pulmonary Function Testing [ Time Frame: 12 months ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02737202
|Contact: Melissa A Brockfirstname.lastname@example.org|
|Contact: Caryn o Popeemail@example.com|
|United States, California|
|Stanford, California, United States, 94305|
|Contact: Susan Jacobs, RN MS 650-725-8083 firstname.lastname@example.org|
|Principal Investigator: Stephen Ruoss, MD|
|United States, Illinois|
|Loyola Medical Center||Recruiting|
|Chicago, Illinois, United States, 90153|
|Contact: Elizabeth Kirwan, RN 708-216-2057 email@example.com|
|Principal Investigator: Daniel Dilling, MD|
|United States, Maryland|
|Laboratory of Translational Research NHLBI||Recruiting|
|Bethesda, Maryland, United States, 20814|
|Contact: Mary Haughey, RN 301-496-3632 firstname.lastname@example.org|
|Principal Investigator: Joel Moss, MD|
|United States, Ohio|
|University of Cincinnati||Recruiting|
|Cincinnati, Ohio, United States, 45267|
|Contact: Tammy Roads 513-558-2148 email@example.com|
|Principal Investigator: Frank X McCormack, MD|
|United States, Texas|
|Baylor College of Medicine - Ben Taub General Hospital||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Caryn O Pope 713-873-2471 firstname.lastname@example.org|
|Principal Investigator: Nicola A Hanania, MD|
|Study Chair:||Tony Eissa, MD||Baylor College of Medicine|
|Principal Investigator:||Nicola A Hanania, MD||Ben Taub Hospital|
|Principal Investigator:||Francis X McCormack, MD||University of Cincinnati|
|Principal Investigator:||Daniel Dilling, MD||Loyola University|
|Principal Investigator:||Stephen Ruoss, MD||Stanford University|
|Principal Investigator:||Joel Moss, MD||Laboratory of Translational Research - NHLBI|