Clinical trial NCT01687179: Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis
Official title: Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphangioleiomyomatosis
Keywords: LAM
TSC
lymphangioleiomyomatosis
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2012-09-18
Enrollment: 14
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients
timeFrame: 48 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Elizabeth P Henske, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Joel Moss, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tang Y, El-Chemaly S, Taveira-Dasilva A, Goldberg HJ, Bagwe S, Rosas IO, Moss J, Priolo C, Henske EP. Alterations in Polyamine Metabolism in Patients With Lymphangioleiomyomatosis and Tuberous Sclerosis Complex 2-Deficient Cells. Chest. 2019 Dec;156(6):1137-1148. doi: 10.1016/j.chest.2019.05.038. Epub 2019 Jul 9.
citation: Lamattina AM, Taveira-Dasilva A, Goldberg HJ, Bagwe S, Cui Y, Rosas IO, Moss J, Henske EP, El-Chemaly S. Circulating Biomarkers From the Phase 1 Trial of Sirolimus and Autophagy Inhibition for Patients With Lymphangioleiomyomatosis. Chest. 2018 Nov;154(5):1070-1082. doi: 10.1016/j.chest.2018.08.1029. Epub 2018 Aug 23.
citation: El-Chemaly S, Taveira-Dasilva A, Goldberg HJ, Peters E, Haughey M, Bienfang D, Jones AM, Julien-Williams P, Cui Y, Villalba JA, Bagwe S, Maurer R, Rosas IO, Moss J, Henske EP. Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis: Results of a Phase I Clinical Trial. Chest. 2017 Jun;151(6):1302-1310. doi: 10.1016/j.chest.2017.01.033. Epub 2017 Feb 10.