Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis

• Status: Completed
• Trial end date: 2015-08-01
• Target enrollment: 0
• Participant gender: Female

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Brigham and Women's Hospital
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Treatments: Everolimus; Hydroxychloroquine; Sirolimus

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