Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis
Condition: Lymphangioleiomyomatosis
MeSH terms: Lymphangioleiomyomatosis
Intervention: "Sirolimus" and "Hydroxychloroquine" 200 mg; "Sirolimus" and "Hydroxychloroquine" 400 mg
Intervention 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 taken orally daily.; 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.
Intervention MeSH terms: Sirolimus; Hydroxychloroquine; Temsirolimus; MTOR Inhibitors
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: Female
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: LAM; TSC; 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.
    

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