safety study of sirolimus and hydroxychloroquine in women with lymphangioleiomyomatosis

Conditions: Lymphangioleiomyomatosis

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.

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.

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

Keywords: lam tsc lymphangioleiomyomatosis