Safety and Efficacy of Saracatinib In Subjects With Lymphangioleiomyomatosis

NCT ID: NCT02737202

Last Updated: 2020-07-30

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-04-30
• Study Completion Date: 2019-07-30

Brief Summary

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.

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.

Conditions

Pulmonary Lymphangioleiomyomatosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Saracatinib

Saracatinib will be given orally at a dose of 125 milligrams once daily for 9 months. Saracatinib is provided as a pink tablet.

Group Type: EXPERIMENTAL

saracatinib

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

AZD0530

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

University of Cincinnati

OTHER

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: collaborator

Stanford University

OTHER

Sponsor Role: collaborator

Loyola University

OTHER

Sponsor Role: collaborator

University of South Florida

OTHER

Sponsor Role: collaborator

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Baylor College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Nicola Hanania

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tony Eissa, MD

Role: STUDY_CHAIR

Baylor College of Medicine

Nicola A Hanania, MD

Role: PRINCIPAL_INVESTIGATOR

Ben Taub Hospital

Francis X McCormack, MD

Role: PRINCIPAL_INVESTIGATOR

University of Cincinnati

Daniel Dilling, MD

Role: PRINCIPAL_INVESTIGATOR

Loyola University

Stephen Ruoss, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Joel Moss, MD

Role: PRINCIPAL_INVESTIGATOR

Laboratory of Translational Research - NHLBI

Locations

Stanford University

Stanford, California, United States

Loyola Medical Center

Chicago, Illinois, United States

Laboratory of Translational Research NHLBI

Bethesda, Maryland, United States

University of Cincinnati

Cincinnati, Ohio, United States

Baylor College of Medicine - Ben Taub General Hospital

Houston, Texas, United States

Countries

United States

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Other Identifiers

4UH3TR000961-02

Identifier Type: NIH

Identifier Source: secondary_id

View Link

SLAM 7602

Identifier Type: -

Identifier Source: org_study_id