Trial of Aromatase Inhibition in Lymphangioleiomyomatosis (TRAIL)

• ClinicalTrials.gov Identifier: NCT01353209
• Recruitment Status: Completed
• First Posted: May 12, 2011
• Last Update Posted: August 26, 2015
• Sponsor: University of Cincinnati
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): Francis McCormack, University of Cincinnati

Study Description

Brief Summary:

The hypothesis in this study is that estrogen suppression by an aromatase inhibitor in postmenopausal women with Lymphangioleiomyomatosis (LAM) will prevent or delay progression of lung disease and result in a decrease in the rate of decline in FEV1

Condition or disease	Intervention/treatment	Phase
Lymphangioleiomyomatosis	Drug: Letrozole; Drug: Placebo	Phase 2

Detailed Description:

Lymphangioleiomyomatosis, or LAM, is an uncommon, progressive, cystic lung disease that predominantly affects young women. Pulmonary parenchymal changes consistent with LAM are found in about one third of women with tuberous sclerosis complex (TSC), an autosomal dominant tumor suppressor syndrome. LAM also occurs in a sporadic form that is not associated with germ line mutations in TSC genes. Recent evidence that recurrent LAM after lung transplantation results from seeding of the graft from a remote source and suggests a metastatic mechanism for the disease.

Since LAM occurs almost exclusively in women, and exposure to estrogen either exogenously or during pregnancy can exacerbate LAM, estrogen suppression might be expected to prevent or delay progression of disease. In preclinical studies, estrogen induces the growth of TSC2-deficient cells and tumor cells derived from LAM patients. In a xenograft model of lymphangioleiomyomatosis presented by Dr. Yu at the 2008 LAM Research Meeting, estrogen promoted the pulmonary metastases of tuberin-deficient ELT3 cells (TSC2-deficient rat uterine leiomyoma cells) in female ovariectomized CB-17-scid mice, while the estrogen inhibitor fulvestrant completely blocked estrogen-promoted pulmonary metastases. This work was recently published.

Letrozole is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis)(14). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)diben-zonitrile.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A TRIAL OF LETROZOLE IN PULMONARY LYMPHANGIOLEIOMYOMATOSIS
• Study Start Date: May 2011
• Actual Primary Completion Date: September 2014
• Actual Study Completion Date: September 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Letrozole	Drug: Letrozole; 2.5 mg daily for twelve months; Other Name: Femara
Placebo Comparator: Placebo	Drug: Placebo; sugar pill given daily for twelve months

Outcome Measures

Primary Outcome Measures :

1. The effect on Forced Expiratory Volume in one second [ Time Frame: twelve months ]

Secondary Outcome Measures :

1. Other measures of pulmonary function [ Time Frame: twelve months ]
   FVC, DLCO, TLC,RV, FRC, 6MWT
2. Quality of life measures [ Time Frame: twelve months ]
   Quality of Life, dyspnea and fatigue, functional performance
3. Serum VEGF-D [ Time Frame: twelve months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• All patients at least must have a diagnosis of pulmonary lymphangioleiomyomatosis as defined by one of the following:

  • CT chest compatible with LAM and a biopsy or cytology consistent withLAM.
  • CT chest consistent with LAM in the setting of tuberous sclerosis, renal angiomyolipomata, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen , or serum VEGF-D > 800 pg/uL.
• All patients must have a post bronchodilator FEV1 ≤80% predicted or DLCO ≤70% predicted or RV≥120% predicted

• All patients must be postmenopausal females as defined by one of the following:

  • Prior bilateral oophorectomy or bilateral ovarian irradiation.
  • If age greater than 55 years, no menstrual period for 12 months or longer.
  • If age 55 years or younger, must have an estradiol level in the postmenopausal range in the absence of current use of progestational agents.
  • If still premenopausal, may enter if rendered medically postmenopausal on clinical grounds with the use of gonadotropin releasing hormone (e.g. leuprolide), as long as serum estradiol, FSH, and LH are in the postmenopausal range
• Patients with osteopenia or osteoporosis must be receiving appropriate treatment for their osteoporosis or osteopenia at entry into this study.

• Patients must have adequate hematologic and hepatic function as defined by the following at the time of randomization.:

  • Neutrophils > 1500/mm3 and platelets > 100,000/mm3
  • Bilirubin < 1.25 X upper limit of normal
  • SGPT (ALT) and SGOT (AST) < 2.5 X upper limit of normal

Exclusion Criteria:

• Known allergy to letrozole
• Inability to comply with pulmonary function tests or follow up visits.
• Treatment with investigational agents within 30 days
• Hormonal therapy (e.g. estrogen, progestin, LHRH agonists or antagonists, estrogen receptor blockers, estrogen receptor down regulators, aromatase inhibitors) within 30 days month of registration
• Medical or psychiatric conditions that would interfere with the ability to provide informed consent.

Contacts and Locations

Locations

United States, California

Stanford University Medical Center

Stanford, California, United States, 94305

United States, Florida

Mayo Clinic

Jacksonville, Florida, United States, 32224

University of Miami

Miami, Florida, United States, 33136

United States, Georgia

Emory University School of Medicine

Atlanta, Georgia, United States, 30322

United States, Illinois

Loyola University Medical Center

Maywood, Illinois, United States, 60153

United States, Missouri

Washington University School of Medicine

St. Louis, Missouri, United States, 63110

United States, Ohio

University of Cincinnati

Cincinnati, Ohio, United States, 45267

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Washington

Minor and James

Seattle, Washington, United States, 98122

Sponsors and Collaborators

University of Cincinnati

United States Department of Defense

Investigators

• Principal Investigator: Francis X McCormack, MD; University of Cincinnati

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lu C, Lee HS, Pappas GP, Dilling DF, Burger CD, Shifren A, Veeraraghavan S, Chapman JT, Parambil J, Ruoss SJ, Young LR, Hammes SR, Kopras EJ, Roads T, Krischer JP, McCormack FX; Trial of an Aromatase Inhibitor in Lymphangioleiomyomatosis Group. A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with Lymphangioleiomyomatosis. Ann Am Thorac Soc. 2017 Jun;14(6):919-928. doi: 10.1513/AnnalsATS.201610-824OC.

• Responsible Party: Francis McCormack, Pulmonary Director, University of Cincinnati
• ClinicalTrials.gov Identifier: NCT01353209
• Other Study ID Numbers: 5708
• First Posted: May 12, 2011
• Last Update Posted: August 26, 2015
• Last Verified: August 2015

Additional relevant MeSH terms:

Lymphangioleiomyomatosis; Lymphangiomyoma; Lymphatic Vessel Tumors; Neoplasms by Histologic Type; Neoplasms; Perivascular Epithelioid Cell Neoplasms; Neoplasms, Connective and Soft Tissue; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Letrozole; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs