Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis (SAIL)

• ClinicalTrials.gov Identifier: NCT01687179
• Recruitment Status: Completed
• First Posted: September 18, 2012
• Results First Posted: October 11, 2018
• Last Update Posted: October 11, 2018
• Sponsor: Brigham and Women's Hospital
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Elizabeth Henske, Brigham and Women's Hospital

Study Description

Brief Summary:

Specific Aim 1: To investigate whether, in Lymphangioleiomyomatosis (LAM) patients, the combination of sirolimus and hydroxychloroquine is safe and well tolerated

Specific Aim 2: To investigate whether, in LAM patients, 6 months of combination therapy with sirolimus and hydroxychloroquine results in improvement of indicators of disease, and whether the gains are sustained after stopping therapy.

Specific Aim 3: To investigate the potential role of a LAM-specific peripheral blood signature to predict rates of disease progression and determine responsiveness to combination therapy.

This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken orally daily. Up to 18 adult women with LAM will be enrolled.

Condition or disease	Intervention/treatment	Phase
Lymphangioleiomyomatosis	Drug: "Sirolimus" and "Hydroxychloroquine" 200 mg; Drug: "Sirolimus" and "Hydroxychloroquine" 400 mg	Phase 1

Detailed Description:

This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken orally daily for 6 months. The study is to be conducted at 2 sites. Up to 18 adult women with LAM will be enrolled, and each recruiting site will recruit between 8-12 subjects. The protocol will use the following eligibility criteria.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus
• Study Start Date: September 2012
• Actual Primary Completion Date: August 2015
• Actual Study Completion Date: August 2015

Arms and Interventions

Arm

Intervention/treatment

Experimental: "Sirolimus" and "Hydroxychloroquine"; Subjects will take Sirolimus at an initial dose of 2mg followed by dose adjustment to keep Sirolimus trough levels between 5-15ng/ml consistent with the effective dose in the MILES trial. In addition to Sirolimus subjects will receive Hydroxychloroquine at 200 mg daily for 6 months. Once safety is established at the lower dose ("Sirolimus" and "Hydroxychloroquine" 200 mg), subjects enrolled henceforth will receive Sirolimus and Hydroxychloroquine 400 mg (200 mg twice a day) for 6 months.

Drug: "Sirolimus" and "Hydroxychloroquine" 200 mg; This will be a phase I dose escalation study of the combination of "Sirolimus" (2 mg adjusted to keep trough levels between 5-15 ng/ml) and "Hydroxychloroquine" 200 mg taken orally daily.; Other Name: sirolimus(rapamune), hydroxychloroquine (plaquenil); Drug: "Sirolimus" and "Hydroxychloroquine" 400 mg; Once safety is established with the lower dose, (Sirolimus and Hydroxychloroquine 200 mg), subjects will receive Sirolimus 2 mg (adjusted to keep trough levels between 5 to 15 ng/ml) and hydroxychloroquine 200 mg twice a day.; Other Name: Sirolimus (Rapamune), Hydroxychloroquine (plaquenil)

Outcome Measures

Primary Outcome Measures :

1. Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients [ Time Frame: 48 weeks ]
   The Primary endpoint of this study was safety. Safety was assessed based on the adverse events and serious adverse events that occurred in these patients when they were on this combination therapy. Percentage of adverse events in each system at a dose was calculated from the total adverse events at that dose. Subjects were closely monitored and adverse events were classified and graded according to the "Common Terminology Criteria for Adverse Events, (CTCAE) Version 4.0".

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Female age 18 or older
• Ability to give informed consent

• Diagnosis of LAM as defined as typical cystic change on CT plus:

  • biopsy or cytology of any tissue demonstrating LAM
  • angiomyolipoma, chylothorax, lymphangioleiomyoma, or tuberous sclerosis
  • serum VEGFD greater or equal to 800pg/ml
• Post-bronchodilator FEV1 equal or less than 80% of predicted or DLCO equal equal or less than 70% of predicted, or RV > 120% of predicted at baseline
• Women of childbearing potential must agree to use 2 forms of barrier contraception during and for 8 weeks after the last dose of medication.

Exclusion Criteria:

• History of intolerance of mTOR inhibitors
• History of intolerance to hydroxychloroquine
• History of severe psoriasis
• History of porphyria cutanea tarda
• Uncontrolled intercurrent illness
• Pregnant, breast feeding, or plan to become pregnant in the next year
• Inadequate contraception
• Significant hematological or hepatic abnormalities
• Use of an investigational drug within 30 days of study start
• Inability to attend scheduled clinic visits
• Inability to perform PFTs
• Creatinine > 2.5mg/dL
• Recent pneumothorax within 8 weeks of screening
• History of malignancy in the last 2 years other than basal cell skin cancer
• Use of estrogen containing medication within 30 days of screening
• Abnormal G6PD levels at baseline
• Preexisting maculopathy or retinopathy
• Preexisting myopathy
• Currently taking doxycycline, metformin, lupron, simvastatin
• Unable to undergo CT or MRI
• History of seizure within last year
• Hepatitis B, C, HIV positive serology
• Use of alternative medical therapies for LAM for at least 6 weeks prior to study participation
• History of myocardial infarct, angina, or stroke related to atherosclerosis
• History of cardiomyopathy
• Previous lung transplant
• Surgery (involving entry into a body cavity or requiring 3 or more stitches) within 2 months of initiation of study drug
• Uncontrolled cholesterol > 350mg/dL, triglycerides > 400mg/dL

Contacts and Locations

Locations

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02120

Sponsors and Collaborators

Brigham and Women's Hospital

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Elizabeth P Henske, MD; Brigham and Women's Hospital
• Principal Investigator: Joel Moss, MD, PhD; National Heart, Lung, and Blood Institute (NHLBI)

More Information

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

Tang Y, El-Chemaly S, Taveira-Dasilva A, Goldberg HJ, Bagwe S, Rosas IO, Moss J, Priolo C, Henske EP. Alterations in Polyamine Metabolism in Patients With Lymphangioleiomyomatosis and Tuberous Sclerosis Complex 2-Deficient Cells. Chest. 2019 Dec;156(6):1137-1148. doi: 10.1016/j.chest.2019.05.038. Epub 2019 Jul 9.

Lamattina AM, Taveira-Dasilva A, Goldberg HJ, Bagwe S, Cui Y, Rosas IO, Moss J, Henske EP, El-Chemaly S. Circulating Biomarkers From the Phase 1 Trial of Sirolimus and Autophagy Inhibition for Patients With Lymphangioleiomyomatosis. Chest. 2018 Nov;154(5):1070-1082. doi: 10.1016/j.chest.2018.08.1029. Epub 2018 Aug 23.

El-Chemaly S, Taveira-Dasilva A, Goldberg HJ, Peters E, Haughey M, Bienfang D, Jones AM, Julien-Williams P, Cui Y, Villalba JA, Bagwe S, Maurer R, Rosas IO, Moss J, Henske EP. Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis: Results of a Phase I Clinical Trial. Chest. 2017 Jun;151(6):1302-1310. doi: 10.1016/j.chest.2017.01.033. Epub 2017 Feb 10.

• Responsible Party: Elizabeth Henske, Overall Principal Investigator, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01687179
• Other Study ID Numbers: SAIL-1100; 1ZIAHL002541-21 ( U.S. NIH Grant/Contract )
• First Posted: September 18, 2012
• Results First Posted: October 11, 2018
• Last Update Posted: October 11, 2018
• Last Verified: September 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Elizabeth Henske, Brigham and Women's Hospital:

LAM; TSC; lymphangioleiomyomatosis

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; Sirolimus; Hydroxychloroquine; Temsirolimus; MTOR Inhibitors; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Antirheumatic Agents