Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis

Phase 1

Completed

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

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.

Recruitment & 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

Arm && Interventions

Group	Intervention	Description
"Sirolimus" and "Hydroxychloroquine"	"Sirolimus" and "Hydroxychloroquine" 200 mg	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.
"Sirolimus" and "Hydroxychloroquine"	"Sirolimus" and "Hydroxychloroquine" 400 mg	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.

Primary Outcome Measures

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

Secondary Outcome Measures