Lymphangioleiomyomatosis
Conditions
Keywords
VEGF-D, Imatinib mesylate, Sirolimus
Brief summary
This is a phase 1 clinical trial comparing imatinib mesylate to placebo for individuals with lymphangioleiomyomatosis (LAM).
Detailed description
This is a double blind, adjusted parallel design, randomized clinical trial comparing imatinib mesylate 400 mg daily or matching placebo on the primary outcome of log transformed serum VEGF-D level in patients with LAM. Sirolimus using patients will have co-administration of Imatinib mesylate or placebo for 28 days prior to sirolimus discontinuation. The duration of 400 mg imatinib mesylate or placebo will be 56 days, a dose reduction is allowed for toxicity. The primary endpoint will be the change in the log transformed VEGF-D one month after monotherapy imatinib mesylate or placebo. Total trial duration is 2 months of drug administration.
Interventions
DRUGImatinib Mesylate 400Mg Capsule
Sirolimus or everolimus will be withdrawn after 28 days if used at baseline
Sirolimus or everolimus will be withdrawn after 28 days if used at baseline
Sponsors
Columbia University
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Definite or Probable LAM * FVC or Postbronchodilator FEV1 \<90% predicted
Exclusion criteria
* Current or planned pregnancy or lactation * Unwillingness to discontinue sirolimus * Change in the dose or use of sirolimus within the past month * Inability to perform spirometry * Allergy or intolerance of albuterol and/or ipratropium * Other serious illness that would impact the outcome of the study including cancer that has not received curative therapy, Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study), uncontrolled diabetes, chronic renal disease, chronic liver disease, or active uncontrolled infection * Current lung transplant * Known diagnosis of human immunodeficiency virus (HIV) infection * Current cigarette smoking * Required use of warfarin, ketoconazole, itraconazole, clarithromycin, or rifampin during the 2 months of the study. * Unwillingness to avoid grapefruit juice or St. Johns Wort during the study. * Planned surgery during the 2 months of the study. * Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent. * Patient has received and other investigational agents within 28 days of first day of study drug dosing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum VEGF-D | Before and 1 month after initiation of monotherapy imatinib mesylate or placebo | Change in the square root of the intrasubject plasma VEGF-D |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | 3 months | Adverse event and Serious Adverse Event numbers using the CTCAE Version 4.03 definitions |
Other
| Measure | Time frame | Description |
|---|---|---|
| Lung Function | 2 months | FEV1 % predicted change |
| SGRQ | 2 months | Saint Georges Respiratory Questionnaire change |
Countries
United States
Participant flow
Recruitment details
18 Subjects signed consent, 2 subjects failed baseline evaluation and were not randomized. 1 subject was randomized, took 4 placebo pills and stopped (without side effects) and is deemed not evaluable.
Participants by arm
| Arm | Count |
|---|---|
| Imatinib Mesylate 400mg Capsule 56 days of Imatinib mesylate 400 mg oral daily with or without co-administration of an mTOR inhibitor for 28 days. A dose reduction to 200 mg daily is allowed for toxicity.
Imatinib Mesylate 400Mg Capsule: Sirolimus or everolimus will be withdrawn after 28 days if used at baseline | 8 |
| Placebo Capsule 56 days of Placebo with or without co-administration of an mTOR inhibitor for 28 days. A dose reduction is allowed for toxicity.
Placebo - Capsule: Sirolimus or everolimus will be withdrawn after 28 days if used at baseline | 7 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Imatinib Mesylate 400mg Capsule | Placebo Capsule | Total |
|---|---|---|---|
| Age, Continuous | 45 years STANDARD_DEVIATION 12 | 50 years STANDARD_DEVIATION 11 | 47.7 years STANDARD_DEVIATION 12 |
| Forced Expiratory Volume in 1 Second | 59 Percent predicted STANDARD_DEVIATION 23.1 | 60 Percent predicted STANDARD_DEVIATION 15.4 | 59.5 Percent predicted STANDARD_DEVIATION 18.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 7 |
| other Total, other adverse events | 8 / 8 | 5 / 7 |
| serious Total, serious adverse events | 0 / 8 | 0 / 7 |
Outcome results
Primary
Serum VEGF-D
Change in the square root of the intrasubject plasma VEGF-D
Time frame: Before and 1 month after initiation of monotherapy imatinib mesylate or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib Mesylate 400mg Capsule | Serum VEGF-D | 0.05 Log transformed VEGF-D change pg/dL | Standard Deviation 0.1 |
| Placebo Capsule | Serum VEGF-D | 0.07 Log transformed VEGF-D change pg/dL | Standard Deviation 0.13 |
Secondary
Adverse Events
Adverse event and Serious Adverse Event numbers using the CTCAE Version 4.03 definitions
Time frame: 3 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib Mesylate 400mg Capsule | Adverse Events | Adverse Events | 10 number of events |
| Imatinib Mesylate 400mg Capsule | Adverse Events | Serious Adverse Events | 0 number of events |
| Placebo Capsule | Adverse Events | Adverse Events | 12 number of events |
| Placebo Capsule | Adverse Events | Serious Adverse Events | 0 number of events |
Other Pre-specified
Lung Function
FEV1 % predicted change
Time frame: 2 months
Other Pre-specified
SGRQ
Saint Georges Respiratory Questionnaire change
Time frame: 2 months