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

Primary Purpose

Lymphangioleiomyomatosis

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
"Sirolimus" and "Hydroxychloroquine" 200 mg
"Sirolimus" and "Hydroxychloroquine" 400 mg
Sponsored by
Brigham and Women's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphangioleiomyomatosis focused on measuring LAM, TSC, lymphangioleiomyomatosis

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Brigham and Women's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

"Sirolimus" and "Hydroxychloroquine"

Arm Description

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.

Outcomes

Primary Outcome Measures

Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients
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".

Secondary Outcome Measures

Full Information

First Posted
August 2, 2012
Last Updated
September 13, 2018
Sponsor
Brigham and Women's Hospital
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT01687179
Brief Title
Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis
Acronym
SAIL
Official Title
Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
September 2012 (undefined)
Primary Completion Date
August 2015 (Actual)
Study Completion Date
August 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Brigham and Women's Hospital
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphangioleiomyomatosis
Keywords
LAM, TSC, lymphangioleiomyomatosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
"Sirolimus" and "Hydroxychloroquine"
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
"Sirolimus" and "Hydroxychloroquine" 200 mg
Other Intervention Name(s)
sirolimus(rapamune), hydroxychloroquine (plaquenil)
Intervention 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 taken orally daily.
Intervention Type
Drug
Intervention Name(s)
"Sirolimus" and "Hydroxychloroquine" 400 mg
Other Intervention Name(s)
Sirolimus (Rapamune), Hydroxychloroquine (plaquenil)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients
Description
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".
Time Frame
48 weeks

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elizabeth P Henske, MD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Joel Moss, MD, PhD
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02120
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31299246
Citation
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.
Results Reference
derived
PubMed Identifier
30144422
Citation
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.
Results Reference
derived
PubMed Identifier
28192114
Citation
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.
Results Reference
derived

Learn more about this trial

Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis

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