Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis

Lymphangioleiomyomatosis Clinical Trial

— SAIL  

Official title:

Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01687179
• Other study ID #: SAIL-1100
• Secondary ID: 1ZIAHL002541-21
• Status: Completed
• Phase: Phase 1
• Start date: September 2012
• Est. completion date: August 2015

Study information

• Verified date: September 2018
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: August 2015
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• 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.
• "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.

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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".	48 weeks