Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Lymphangioleiomyomatosis

Intervention / Treatment
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* Drug: Sirolimus and Hydroxychloroquine 200 mg
* Drug: Sirolimus and Hydroxychloroquine 400 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus and Hydroxychloroquine<br>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<br>* 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.<br>* Other names: sirolimus(rapamune), hydroxychloroquine (plaquenil);Drug: Sirolimus and Hydroxychloroquine 400 mg<br>* 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.<br>* Other names: Sirolimus (Rapamune), Hydroxychloroquine (plaquenil);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LAM, TSC, lymphangioleiomyomatosis