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

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.

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