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

Tracking Information

• First Submitted Date: August 2, 2012
• First Posted Date: September 18, 2012
• Results First Submitted Date: March 30, 2017
• Results First Posted Date: October 11, 2018
• Last Update Posted Date: October 11, 2018
• Study Start Date: September 2012
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 13, 2018)

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".

Original Primary Outcome Measures (submitted: September 13, 2012)

safety of everolimus and hydroxychloroquine [ Time Frame: 4 years ]

We will conduct a two-center phase I trial of sirolimus (mTOR inhibitor) in combination with hydroxychloroquine (autophagy inhibitor 200-400mg) administered daily for 24 weeks. Eligible subjects will receive 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 or twice a day for 6 months, depending on time of enrollment into the study, following a standard phase I dose escalation design. All adverse events will be captured.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis
• Official Title: Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus

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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Lymphangioleiomyomatosis

Intervention

• 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)

Study Arms

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.

Interventions:

• Drug: "Sirolimus" and "Hydroxychloroquine" 200 mg
• Drug: "Sirolimus" and "Hydroxychloroquine" 400 mg

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 11, 2016): 14
• Original Estimated Enrollment (submitted: September 13, 2012): 18
• Actual Study Completion Date: August 2015
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01687179
• Other Study ID Numbers: SAIL-1100; 1ZIAHL002541-21 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Elizabeth Henske, Brigham and Women's Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Brigham and Women's Hospital
• Original Study Sponsor: Same as current
• Collaborators: 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)

• PRS Account: Brigham and Women's Hospital
• Verification Date: September 2018