COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC
Condition: Lymphangioleiomyomatosis (LAM)
MeSH terms: Lymphangioleiomyomatosis
Study type: Interventional
Phase: Phase 2

Summary: 
      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: 
      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.
    

Intervention name(s): Celecoxib
Intervention type(s): Drug
Intervention description(s): 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.
Intervention MeSH terms: Celecoxib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment