Celecoxib and Radiation Therapy in Treating Patients With Locally Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Celecoxib may stop the growth of tumor cells by stopping blood flow to the tumor and may make the tumor cells more sensitive to radiation therapy. PURPOSE: Phase I/II trial to study the effectiveness of combining celecoxib with radiation therapy in treating patients who have locally advanced non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose and the recommended phase II dose of concurrent celecoxib and limited-field radiotherapy in intermediate-prognosis patients with locally advanced non-small cell lung cancer. Determine the efficacy and toxicity of this regimen in these patients. Determine how the predictors of mortality in the general population (i.e., comorbid conditions, functional status, quality of life, and psychological status) influence prognosis, toxicity, and outcomes of therapy in patients treated with this regimen. Correlate circulating levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and interleukin-8 (IL8) with survival in patients treated with this regimen. Correlate circulating levels of interleukin-1 (IL1), interleukin-6 (IL6), and transforming growth factor-beta (TGFB) with pulmonary toxicity in patients treated with this regimen. OUTLINE: This is a phase I dose-escalation study of celecoxib followed by a phase II, multicenter study. Phase I: Patients receive oral celecoxib twice daily. Beginning on day 6, patients undergo thoracic radiotherapy 5 days a week for 3-6.5 weeks . Patients continue to receive celecoxib for up to 2 years in the absence of disease progression or unacceptable toxicity. Phase II: If fewer than 3 of the first 6 patients experience dose-limiting toxicity, then the dose of celecoxib is escalated for all patients in the study, including those in the first cohort. Quality of life is assessed at baseline and at 3, 6, and 12 months after start of therapy. Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 6-12 patients will be accrued for the phase I portion of this study and a total of 116 patients will be accrued for the phase II portion of this study within 25 months.

Official Title
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A Phase I/II Trial of a COX-2 Inhibitor, Celebrex (Celecoxib), [National Screening Committee# 719627] With Limited Field Radiation for Intermediate Prognosis Patients With Locally Advanced Non-Small Cell Lung Cancer, With Analysis of Prognostic Factors

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: celecoxib
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed non-small cell lung cancer Inoperable stage IIB OR Unresectable stage IIIA or IIIB No evidence of hematogenous metastases PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 2 AND more than 5% weight loss over the past 3 months OR Zubrod 0-1 AND less than 5% weight loss over the past 3 months and refuses chemotherapy or are medically unable to tolerate combined modality therapy Life expectancy Not specified Hematopoietic Not specified Hepatic Bilirubin no greater than 2 times upper limit of normal International Normalized Ratio (INR) no greater than 3.0 if taking warfarin Renal Creatinine clearance at least 50 mL/min Other No active gastrointestinal ulcers or bleeding within the past 3 months No other malignancy within the past 3 years except nonmelanoma skin cancer No known hypersensitivity to celecoxib No prior allergic-type reactions to sulfonamides No prior asthma, urticaria, or allergic-type reactions to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior neoadjuvant chemotherapy No concurrent chemotherapy Endocrine therapy No concurrent corticosteroids Radiotherapy No prior thoracic radiotherapy Surgery No prior complete or subtotal tumor resection Other No concurrent NSAIDs, lithium, furosemide, or angiotensin-converting enzyme inhibitors Concurrent aspirin (325 mg/day) for cardioprotection allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: Celecoxib 200mg BID + RT<br>COX-2 Inhibitor: Celecoxib 200 mg b.i.d, 7 days/week begins 5 days prior to start of radiation therapy (RT). Once RT begins, Celecoxib a.m. dose 1-2 hours prior to RT. Administer for 2 years or until disease progression. Concurrent Radiation Therapy: 2 Gy daily, 30-33 fractions, 5 days/week for 6-7 weeks, for a total dose of 60-66 Gy; or 3 Gy daily, 15 fractions, 5 days/week for 3-4 weeks for a total dose of 45 Gy. | Drug: celecoxib<br> <br> * Other names: COX-2 Inhibitor;Radiation: radiation therapy<br> <br> |
| Experimental: Phase I: Celecoxib 400mg BID + RT<br>COX-2 Inhibitor: Celecoxib 400 mg b.i.d, 7 days/week begins 5 days prior to start of radiation therapy (RT). Once RT begins, Celecoxib a.m. dose 1-2 hours prior to RT. Administer for 2 years or until disease progression. Concurrent Radiation Therapy: 2 Gy daily, 30-33 fractions, 5 days/week for 6-7 weeks, for a total dose of 60-66 Gy; or 3 Gy daily, 15 fractions, 5 days/week for 3-4 weeks for a total dose of 45 Gy. | Drug: celecoxib<br> <br> * Other names: COX-2 Inhibitor;Radiation: radiation therapy<br> <br> |
| Experimental: Phase II: Celecoxib 400mg BID + RT<br>COX-2 Inhibitor: Celecoxib 400 mg b.i.d, 7 days/week begins 5 days prior to start of radiation therapy (RT). Once RT begins, Celecoxib a.m. dose 1-2 hours prior to RT. Administer for 2 years or until disease progression. Concurrent Radiation Therapy: 2 Gy daily, 30-33 fractions, 5 days/week for 6-7 weeks, for a total dose of 60-66 Gy; or 3 Gy daily, 15 fractions, 5 days/week for 3-4 weeks for a total dose of 45 Gy. | Drug: celecoxib<br> <br> * Other names: COX-2 Inhibitor;Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Celecoxib Combined With Radiation Therapy (RT) | Patients were followed for at least 90 days from start of RT and carefully evaluated with respect to treatment morbidity. A dose limiting toxicity (DLT) was defined as grade 3 or 4 nonhematologic (excluding nausea, vomiting, and alopecia) and grade 4 hematologic toxicities. Six patients were to be accrued at each dose level. If no more than three of the six patients experienced a DLT then that dose level was considered acceptable and dose escalation occurred by accruing six more patients at the next dose level. Otherwise, the preceding dose level, if any, would be declared the MTD. The MTD would be used for the Phase II arm. At a given dose, the probability of halting dose escalation when the true toxicity is 50% or higher is at least 66% (power). In addition, if the true DLT rate is instead 20%, there will still be a 10% probability of halting dose escalation at a given dose level (type I error). Rating scale: 0 = not the MTD, 1 = MTD | Start of treatment to 90 days | 
| Overall Survival | Because only 21 patients (18 analyzable) out of 128 planned were accrued on this study, all analyzable patients were combined to report overall survival. The original study design planned for a comparison to a historical control, but due to the small number of patients, survival time is only reported, not tested. | From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II non-small cell lung cancer, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer