COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC (COLA)
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|ClinicalTrials.gov Identifier: NCT02484664|
Recruitment Status : Active, not recruiting
First Posted : June 30, 2015
Last Update Posted : January 16, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Lymphangioleiomyomatosis (LAM)||Drug: Celecoxib||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC|
|Study Start Date :||January 2016|
|Estimated Primary Completion Date :||June 2019|
|Estimated Study Completion Date :||June 2019|
Celecoxib 200mg PO QD for 6 months
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.
- Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 2 years ]
- FEV1 [ Time Frame: 1 year ]
- angiomyolipoma size measured volumetrically on MRI [ Time Frame: 1 year ]
- St. George's Respiratory Questionnaire [ Time Frame: 1 year ]
- VEGF-D serum levels [ Time Frame: 1 year ]
- Exhaled breath condensate prostaglandin metabolites [ Time Frame: 1 year ]
- circulating LAM cell count [ Time Frame: 1 year ]
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): NCT02484664
|United States, Massachusetts|
|Brigham and Women's Hospital|
|Boston, Massachusetts, United States, 02115|
|Principal Investigator:||David J Kwiatkowski, MD PhD||Brigham and Women's Hospital|