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Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis (SAIL)

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ClinicalTrials.gov Identifier: NCT01687179
Recruitment Status : Completed
First Posted : September 18, 2012
Last Update Posted : August 12, 2016
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Elizabeth Henske, Brigham and Women's Hospital

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.


Condition or disease Intervention/treatment Phase
Lymphangioleiomyomatosis Drug: sirolimus and hydroxychloroquine Phase 1

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus
Study Start Date : September 2012
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015


Arm Intervention/treatment
Experimental: Rapamycin 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 or twice a day for 6 months, depending on time of enrollment into the study, following a standard phase I dose escalation.
Drug: sirolimus and hydroxychloroquine
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.
Other Name: sirolimus(rapamune), hydroxychloroquine (plaquenil)




Primary Outcome Measures :
  1. safety of everolimus and hydroxychloroquine [ Time Frame: 4 years ]
    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.



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01687179


Locations
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02120
Sponsors and Collaborators
Brigham and Women's Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Elizabeth P Henske, MD Brigham and Women's Hospital
Principal Investigator: Joel Moss, MD, PhD National Heart, Lung, and Blood Institute (NHLBI)

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Elizabeth Henske, Overall Principal Investigator, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT01687179     History of Changes
Other Study ID Numbers: SAIL-1100
First Posted: September 18, 2012    Key Record Dates
Last Update Posted: August 12, 2016
Last Verified: August 2016

Keywords provided by Elizabeth Henske, Brigham and Women's Hospital:
LAM
TSC
lymphangioleiomyomatosis

Additional relevant MeSH terms:
Lymphangioleiomyomatosis
Lymphangiomyoma
Lymphatic Vessel Tumors
Neoplasms by Histologic Type
Neoplasms
Perivascular Epithelioid Cell Neoplasms
Neoplasms, Connective and Soft Tissue
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Sirolimus
Everolimus
Hydroxychloroquine
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents