Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus
18 Years
85 Years
Female
Lymphangioleiomyomatosis
Trial Information
Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus
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.
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
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
safety of everolimus and hydroxychloroquine
Outcome Description:
We will conduct a two-center phase I trial of sirolimus (mTOR inhibitor) in combination with hydroxychloroquine (autophagy inhibitor 200-400mg) administered daily for 24 weeks. Eligible subjects will receive 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 or twice a day for 6 months, depending on time of enrollment into the study, following a standard phase I dose escalation design. All adverse events will be captured.
Outcome Time Frame:
4 years
Safety Issue:
Yes
Principal Investigator
Elizabeth P Henske, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Brigham and Women's Hospital
Authority:
United States: Federal Government
Study ID:
SAIL-1100
NCT ID:
NCT01687179
Start Date:
September 2012
Completion Date:
June 2016
Related Keywords:
- Lymphangioleiomyomatosis
- LAM
- TSC
- lymphangioleiomyomatosis
- Lymphangioleiomyomatosis
Name | Location |
|---|---|
| Brigham and Women's Hospital | Boston, Massachusetts 02115 |
