Lymphangioleiomyomatosis
Conditions
Keywords
LAM, TSC, lymphangioleiomyomatosis
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.
Interventions
DRUGSirolimus 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.
DRUGSirolimus 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.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Brigham and Women's Hospital
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | 48 weeks | The Primary endpoint of this study was safety. Safety was assessed based on the adverse events and serious adverse events that occurred in these patients when they were on this combination therapy. Percentage of adverse events in each system at a dose was calculated from the total adverse events at that dose. Subjects were closely monitored and adverse events were classified and graded according to the Common Terminology Criteria for Adverse Events, (CTCAE) Version 4.0. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 or twice a day for 6 months, depending on time of enrollment into the study, following a standard phase I dose escalation.
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. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Sirolimus and Hydroxychloroquine |
|---|---|
| 6 minute walk distance (6MWD) (m) | 442 m STANDARD_DEVIATION 103 |
| Age, Continuous | 49 years |
| Angiomyolipoma | 2 Participants |
| Chylothorax | 1 Participants |
| DLCO (%) | 43 percent predicted STANDARD_DEVIATION 15 |
| DLCO (ml/min/mmhg) | 9.8 ml/min/mmhg STANDARD_DEVIATION 3.1 |
| FEV1 | 1.6 Litres STANDARD_DEVIATION 0.7 |
| FEV1 (%) | 59 Percent predicted STANDARD_DEVIATION 21 |
| FVC (%) | 81 Percent predicted STANDARD_DEVIATION 16 |
| FVC (L) | 2.8 Litres STANDARD_DEVIATION 0.7 |
| Log VEGF-D (Veascular Endothelial Growth factor) | 3.11 log(pg/ml) STANDARD_DEVIATION 0.33 |
| Lung Biopsy | 8 Participants |
| Pneumothorax | 9 Participants |
| Post-Menopause | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 13 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 0 Participants |
| St. George's Respiratory Questionnaire (SGRQ) | 43.8 units on a scale STANDARD_DEVIATION 19.2 |
| Tuberous Sclerois (TSC)- Lymphangioleiomyomatosis (LAM) | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 10 |
| other Total, other adverse events | 3 / 3 | 9 / 10 |
| serious Total, serious adverse events | 0 / 3 | 1 / 10 |
Outcome results
Primary
Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients
The Primary endpoint of this study was safety. Safety was assessed based on the adverse events and serious adverse events that occurred in these patients when they were on this combination therapy. Percentage of adverse events in each system at a dose was calculated from the total adverse events at that dose. Subjects were closely monitored and adverse events were classified and graded according to the Common Terminology Criteria for Adverse Events, (CTCAE) Version 4.0.
Time frame: 48 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Musculoskeletal, connective tissue disorders | 0 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Cardiac Disorders | 2.27 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Eye Disorders | 0 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | GI Disorders | 18.18 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | General Disorders, Administration site condistions | 18.18 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Immune System disorders | 0 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Infections and infestations | 15.91 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Injury, poisoning, procedural complications | 0 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Investigations | 6.82 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Metabolism and nutrition disorders | 0 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Nervous system disorders | 4.55 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Psychiatric disorders | 0 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Renal and urinary disorders | 0 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Reproductive system and breast disorder | 6.82 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Respiratory, thoracic, mediastinal disorders | 2.27 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Skin and Subcutaneous disorders | 25.0 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 200 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Vascular disorders | 0 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Vascular disorders | 1.67 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Metabolism and nutrition disorders | 3.33 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Cardiac Disorders | 1.11 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Musculoskeletal, connective tissue disorders | 4.44 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Eye Disorders | 1.11 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Reproductive system and breast disorder | 1.11 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | GI Disorders | 22.22 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Nervous system disorders | 5.00 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | General Disorders, Administration site condistions | 6.67 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Skin and Subcutaneous disorders | 6.11 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Immune System disorders | 0.56 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Psychiatric disorders | 0.56 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Infections and infestations | 8.33 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Respiratory, thoracic, mediastinal disorders | 9.44 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Injury, poisoning, procedural complications | 0.56 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Renal and urinary disorders | 7.78 Percentage of adverse events |
| Sirolimus and Hydroxychloroquine 400 mg | Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients | Investigations | 20 Percentage of adverse events |