Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

14 participants

Study Classification

INTERVENTIONAL

Study Start Date

2012-09-30

Study Completion Date

2015-08-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Lymphangioleiomyomatosis

Study Design

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Intervention Model

SEQUENTIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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"Sirolimus" and "Hydroxychloroquine"

Subjects will take 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 for 6 months. Once safety is established at the lower dose ("Sirolimus" and "Hydroxychloroquine" 200 mg), subjects enrolled henceforth will receive Sirolimus and Hydroxychloroquine 400 mg (200 mg twice a day) for 6 months.

Group Type EXPERIMENTAL

"Sirolimus" and "Hydroxychloroquine" 200 mg

Intervention Type DRUG

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.

"Sirolimus" and "Hydroxychloroquine" 400 mg

Intervention Type DRUG

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.

Interventions

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"Sirolimus" and "Hydroxychloroquine" 200 mg

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.

Intervention Type DRUG

"Sirolimus" and "Hydroxychloroquine" 400 mg

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 Type DRUG

Other Intervention Names

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sirolimus(rapamune), hydroxychloroquine (plaquenil) Sirolimus (Rapamune), Hydroxychloroquine (plaquenil)

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Maximum Eligible Age

85 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No