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

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02484664
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 12
• Location: 1
• Arm: 1
• Duration (Months): 29.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Lymphangioleiomyomatosis (LAM)	Drug: Celecoxib	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC
• Study Start Date: Jun 15, 2016
• Actual Primary Completion Date: Nov 19, 2018
• Actual Study Completion Date: Nov 19, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: celecoxib Celecoxib 200mg PO QD for 6 months

Drug: Celecoxib; 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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [1 year]

   Number of Participants with Adverse Events as a Measure of Safety and Tolerability in LAM patients

Secondary Outcome Measures

1. FEV1 [1 year]

   Forced expiratory volume in 1 second

2. Angiomyolipoma Size Measured Volumetrically on MRI [1 year]

   We are reporting the number of participants in this trial who had angiomyolipoma either at the beginning or end of the study.

3. St. George's Respiratory Questionnaire [1 year]

   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.

4. VEGF-D Serum Levels [6 months]

   VEGF-D serum levels

5. EBC Prostaglandin Metabolites [1 year]

   We had intended to perform Exhaled breath condensate prostaglandin metabolites. However, this proved to be impossible, and no data was obtained.

6. Circ LAM Cell Count [1 year]

   We had planned to determine a circulating LAM cell count. However, this proved to be impossible. Therefore, no data was collected.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: David J Kwiatkowski, MD PhD, Brigham and Women's Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 3, 2017

More Information

Publications

None provided.

• Responsible Party: David Kwiatkowski, Professor and Senior Physician, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT02484664
• Other Study ID Numbers: 2015P000954
• First Posted: Jun 30, 2015
• Last Update Posted: Jan 20, 2022
• Last Verified: Jan 1, 2022

• Additional relevant MeSH terms: Lymphangioleiomyomatosis; Celecoxib

Study Results

Participant Flow

Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
Period Title: Overall Study
STARTED	12
COMPLETED	9
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 100%
>=65 years	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	48
Sex: Female, Male (Count of Participants)
Female	12 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	0 0%
Unknown or Not Reported	12 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	12 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	12 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
Measure Participants	12
Count of Participants [Participants]	11 91.7%

2. Secondary Outcome

Title	FEV1
Description	Forced expiratory volume in 1 second
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
Measure Participants	12
Least Squares Mean (Standard Error) [ml]	2583 (166)

3. Secondary Outcome

Title	Angiomyolipoma Size Measured Volumetrically on MRI
Description	We are reporting the number of participants in this trial who had angiomyolipoma either at the beginning or end of the study.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
Measure Participants	12
Count of Participants [Participants]	3 25%

4. Secondary Outcome

Title	St. George's Respiratory Questionnaire
Description	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.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Nine of 12 patients who enrolled on the study stayed on study until the end

Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
Measure Participants	9
Least Squares Mean (Standard Deviation) [score on a scale]	20.2 (4.9)

5. Secondary Outcome

Title	VEGF-D Serum Levels
Description	VEGF-D serum levels
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

those who stayed on study until the end

Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
Measure Participants	9
Median (Full Range) [pg/mL]	656

6. Secondary Outcome

Title	EBC Prostaglandin Metabolites
Description	We had intended to perform Exhaled breath condensate prostaglandin metabolites. However, this proved to be impossible, and no data was obtained.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
Measure Participants	0

7. Secondary Outcome

Title	Circ LAM Cell Count
Description	We had planned to determine a circulating LAM cell count. However, this proved to be impossible. Therefore, no data was collected.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

all participants

Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
Measure Participants	0

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	same as that used by clinicaltrials.gov
Arm/Group Title	Celecoxib
Arm/Group Description	Celecoxib 200mg PO QD for 6 months Celecoxib: 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.
All Cause Mortality
	Celecoxib
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Serious Adverse Events
	Celecoxib
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	Celecoxib
	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)
Gastrointestinal disorders
abdominal pain	3/12 (25%)	6
General disorders
fatigue	3/12 (25%)	3
malaise	2/12 (16.7%)	2
Nervous system disorders
headache	3/12 (25%)	6

Limitations/Caveats

pilot study

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.