COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC

Study Overview
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Brief Summary
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The investigators will perform a two-center phase I trial of celecoxib (COX-2 inhibitor) administered at 200mg by mouth daily for 6 months. Up to 12 adult women with LAM will be recruited (between 4-8 at each site). The Specific Aims are: Aim 1: To investigate whether, in LAM patients, celecoxib is safe and well tolerated, and has evidence of clinical benefit. Aim 2: To investigate the potential value of a novel biomarker of LAM, quantitative measurement of the number of TSC2 mutant LAM cells per ml of blood, to assess disease severity.

Detailed Description
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Background: Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction, kidney angiomyolipomas (AMLs), and LAM cell growth within the axial lymphatics and multiple other organs and surfaces. LAM occurs both sporadically and in association with tuberous sclerosis complex (TSC). Sirolimus (rapamycin), an mTORC1 inhibitor, has been shown to stabilize lung function decline and decrease angiomyolipoma tumor size in both TSC and sporadic LAM patients. However, cessation of rapamycin therapy results in recurrent decline in lung function, and regrowth of angiomyolipoma, suggesting that continuous use may be required to maintain its beneficial effects. Recently the investigators have discovered that cyclo-oxygenase (COX) function is altered in cells lacking TSC2, including in a LAM patient-derived angiomyolipoma cell line. COX-2 levels are increased, prostaglandin metabolite levels are increased, and treatment with COX-2 inhibitors are effective in reducing tumor size in two different Tsc mouse models, one a native tumor, and the other a xenograft model. Furthermore, rapamycin does not affect these differences in COX-2 expression or prostaglandin metabolites. Objectives/Hypothesis: Our preclinical studies indicate that celecoxib (a COX-2 specific inhibitor) decreases the size of TSC2-deficient tumors in Tsc models. Hence the investigators propose this Pilot Clinical Trial to test the safety and tolerability of celecoxib in patients with LAM, with preliminary assessment of potential benefit using multiple approaches. Specific aims: The primary endpoint of this pilot trial is to test the safety and tolerability of treatment with celecoxib in patients with mild-to-moderate LAM, who are not currently on sirolimus; and to assess the potential benefit of this treatment using the following: 1. Spirometry, 2. MRI measurement of angiomyolipoma size, 3. St. George's Respiratory Questionnaire, 4. VEGF-D serum levels. The investigators will assess Exhaled breath condensate prostaglandin metabolites to confirm effects of celecoxib. The investigators will also develop a novel biomarker of LAM to assess response, quantitative measurement of the number of TSC2 mutant circulating LAM cells, by next generation sequencing. Study design: The investigators will perform a pilot clinical trial to investigate the safety and tolerability of celecoxib therapy as a single agent for patients with LAM. LAM subjects who are not taking everolimus or rapamycin will be treated with celecoxib at 200mg PO QD for 6 months. They will be monitored for respiratory function and angiomyolipoma size. At the end of the 6 month period, celecoxib will be discontinued, and subjects will be monitored for another 6 months. Clinical Impact: Sirolimus is the only medical therapy shown to reduce tumor size and stabilize lung function in patients with LAM and TSC-LAM. Although sirolimus has clear benefits, results from the MILES trial suggest that continuous therapy in some form is required, as the rate of decline in lung function resumed when sirolimus was discontinued. The investigators hope that celecoxib will show benefit with minimal toxicity in this trial, and provide an alternative approach for the long term prophylactic/preventive treatment of patients with mild-to-moderate LAM. Our study will include patients with TSC LAM, which often appears to be more slowly progressive than sporadic LAM, and hence long term therapy with celecoxib may have particular benefit in the TSC LAM population. In addition, the investigators will develop a quantitative measure of circulating LAM cell levels as part of this trial.

Official Title
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COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC

Conditions
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Lymphangioleiomyomatosis (LAM)

Intervention / Treatment
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* Drug: Celecoxib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female of age 18 to 69 Ability to give informed consent Definite diagnosis of LAM Typical cystic change on CT scan of the chest plus one of the following i) biopsy or cytology of any tissue demonstrating LAM, ii) angiomyolipoma, chylothorax, clinical or genetic diagnosis of tuberous sclerosis, iii) serum VEGF-D > 800pg/ml post-bronchodilator forced expiratory volume in one second ≥ 70% of predicted and DLCO ≥ 70% predicted during baseline visit. Women of childbearing potential must agree to use two forms of barrier contraception after screening visit, for the duration of study participation and for 30 days after last dose. Exclusion Criteria: History of intolerance to non-steroidal anti-inflammatory drugs (NSAIDs) History of current regular use (daily most days of the week) of NSAIDs History of use of rapamycin or everolimus Uncontrolled intercurrent illness Pregnant, breast feeding or planning to become pregnant in the next 2 years Significant hematological (platelet count <100.000/µl or hepatic abnormalities (Liver function tests >2 times normal). Use of an investigational drug within 30 days of study start Inability to attend scheduled clinic visits Inability to give informed consent Inability to perform spirometry Creatinine > 1.0 mg/dl or eGFR < 60 ml/min Pneumothorax within past 8 weeks History of malignancy in the last 2 years other than basal cell skin cancer Use of estrogen containing medication within 30 days of enrolment Currently taking doxycycline, metformin, lupron or simvastatin Unable to undergo MRI History of seizure within the last year History of hepatitis or known active hepatitis B or C, or HIV positive serology Angiomyolipoma of diameter > 4 cm History of vascular disease, including myocardial infarction or stroke History of ulcers or GI bleeding Allergy to sulfonamides, unless subject has previously used Celocoxib without any adverse reactions. Age older than 70

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: celecoxib<br>Celecoxib 200mg PO QD for 6 months | Drug: Celecoxib<br>* We will perform a pilot clinical trial to investigate the safety and tolerability of celecoxib therapy as a single agent for patients with LAM. LAM subjects who are not taking everolimus or rapamycin will be treated with celecoxib at 200mg PO QD for 6 months. They will be monitored for respiratory function and angiomyolipoma size. At the end of the 6 month period, celecoxib will be discontinued, and subjects will be monitored for another 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Number of Participants with Adverse Events as a Measure of Safety and Tolerability in LAM patients | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 | Forced expiratory volume in 1 second | 1 year | 
| Angiomyolipoma Size Measured Volumetrically on MRI | We are reporting the number of participants in this trial who had angiomyolipoma either at the beginning or end of the study. | 1 year | 
| St. George's Respiratory Questionnaire | St. George's Respiratory Questionnaire is a commonly used questionnaire to assess the respiratory function of an individual. The minimum and maximyum socres on this Questionnaire are: 0 and 100. A higher score shows more limitations, so a lower score is better in terms of respiratory function. There are no subscales. Below we are providing mean scores for all 9 participants in this trial. | 1 year | 
| VEGF-D Serum Levels | VEGF-D serum levels | 6 months | 
| EBC Prostaglandin Metabolites | We had intended to perform Exhaled breath condensate prostaglandin metabolites. However, this proved to be impossible, and no data was obtained. | 1 year | 
| Circ LAM Cell Count | We had planned to determine a circulating LAM cell count. However, this proved to be impossible. Therefore, no data was collected. | 1 year |