Gemcitabine Hydrochloride or Pemetrexed Disodium and Carboplatin With or Without Celecoxib in Treating Patients With Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pemetrexed disodium and celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving gemcitabine hydrochloride or pemetrexed disodium together with carboplatin is more effective with or without celecoxib in treating non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying gemcitabine hydrochloride, pemetrexed disodium, and carboplatin to compare how well they work when given together with celecoxib or a placebo in treating patients with advanced non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary To confirm the beneficial effect of gemcitabine hydrochloride or pemetrexed disodium in combination with carboplatin with or without celecoxib in patients with advanced non-small cell lung cancer that expresses COX-2. Secondary To describe the response rate in patients treated with these regimens. To describe the distribution of progression-free survival (PFS) and overall survival of patients treated with these regimens. To compare the PFS of patients with COX-2 index ≥ 2 (adjusting for CYP2C9 genotype and celecoxib trough concentrations as covariates) treated with these regimens. To correlate urinary PGE-M level with COX-2 expression, COX-2 inhibition, and outcome. To evaluate the association between the -765G/C polymorphism in PTGS2 and COX-2 expression in non-small cell lung cancer specimens. To characterize a trough plasma celecoxib concentration which will be used as a measure of patient adherence to study treatment and which may be used in future studies for correlations with genotype and pharmacodynamic outcomes. OUTLINE: This is a multicenter study. Patients are stratified according to gender, disease stage (IIIB vs IV), histology (squamous cell carcinoma vs non-squamous cell carcinoma), smoking status (never/former light smoker [defined as ≤ 10 pack years AND quit ≥ 1 year ago] vs smoker), and COX-2 expression status (COX-2 index ≥ 4 vs COX-2 index ≥ 2 but < 4). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive gemcitabine hydrochloride* IV on days 1 and 8 OR pemetrexed disodium* IV on day 1. Patients also receive carboplatin IV on day 1 and oral celecoxib twice daily on days 1-21. Arm II: Patients receive gemcitabine hydrochloride* OR pemetrexed disodium* and carboplatin as in arm I. Patients also receive oral placebo twice daily on days 1-21. NOTE: *Patients with squamous cell carcinoma receive gemcitabine hydrochloride; patients with non-squamous cell carcinoma receive pemetrexed disodium. In both arms, treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients with responding or stable disease may continue to receive celecoxib or placebo alone in the absence of disease progression or unacceptable toxicity. Patients may undergo blood and urine sample collection periodically for correlative laboratory studies. After completion of study therapy, patients are followed up every 2 months for 2 years and then every 6 months for 3 years.

Official Title
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A Randomized Phase III Double Blind Trial Evaluating Selective COX-2 Inhibition in COX-2 Expressing Advanced Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: celecoxib
* Drug: gemcitabine hydrochloride
* Drug: pemetrexed disodium
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed non-small cell carcinoma of the lung, including the following cell types: Adenocarcinoma Large cell carcinoma Squamous cell carcinoma Mixture of these types A tissue block must be available at the time of registration Tumor expresses COX-2 (COX-2 index ≥ 2) Stage IIIB disease with malignant pleural effusion, supraclavicular node involvement, or contralateral hilar node involvement OR stage IV disease Patients with stage IIIB disease who are eligible for clinical trials that involve combined chemotherapy and chest irradiation are not eligible for this study Patients with stage IV disease are eligible Patients with recurrent disease, not amenable to (or refusing) a potentially curative therapy, are eligible Measurable or non-measurable disease Measurable disease is defined as lesions that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm with spiral CT scan Non-measurable disease is defined as all other lesions, including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and truly nonmeasurable lesions, including any of the following: Bone lesions Leptomeningeal disease Ascites Pleural/pericardial effusion Inflammatory breast disease Lymphangitis cutis/pulmonis Abdominal masses that are not confirmed and followed by imaging techniques Cystic lesions Patients with symptomatic CNS metastases are eligible provided they received prior therapy (e.g., surgery, radiotherapy, or gamma knife), are neurologically stable, and are off steroids for ≥ 14 days before study entry Patients with asymptomatic CNS metastases without associated edema, shift, or requirement for steroids or antiseizure medications may be eligible after discussion with the Study Chair Patients should be off steroids at least 7 days before preregistration No leptomeningeal disease or carcinomatous meningitis PATIENT CHARACTERISTICS: ECOG performance status 0-2 Granulocytes ≥ 1,500/μL Platelet count ≥ 100,000/μL Creatinine clearance ≥ 45 mL/min Bilirubin ≤ 1.5 mg/dL AST and ALT ≤ 2.0 times upper limit of normal (ULN) (≤ 5.0 times ULN if liver metastases are present) Serum albumin ≥ 2.5 mg/dL Not pregnant or nursing Negative pregnancy test No currently active second malignancy other than non-melanoma skin cancer Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at < 30% risk of relapse No known hypersensitivity to aspirin, NSAIDs, or sulfonamides No active ulcer disease No history of gastrointestinal bleeding within the past three years None of the following cardiovascular conditions within the past 6 months: Myocardial infarction Unstable angina Symptomatic congestive heart failure Serious uncontrolled cardiac arrhythmia Cerebrovascular accident or transient ischemic attack Pulmonary embolism Symptomatic carotid artery or peripheral vascular disease Deep vein thrombosis Other significant thromboembolic event PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior chemotherapy, immunotherapy, or other systemic therapy for non-small cell lung cancer, including adjuvant therapy At least 2 weeks since prior surgery and recovered At least 7 days since prior radiotherapy At least 14 days since prior NSAIDs (other than low-dose aspirin [≤ 325 mg daily]), including any of the following: Celecoxib Choline Mg Trisalicylate (Trilisate®) Ibuprofen (Advil® or Motrin®) Naproxen (Aleve®, Naprosyn® or Anaprox®) Etodolac (Lodine®) Oxaprozin (Daypro®) Diflunisal (Dolobid®) Nabumetone (Relafen®) Tolmetin (Tolectin®) Valdecoxib (Bextra®) No chronic use of NSAIDs (i.e., > 4 weeks of daily use) Patients on low-dose aspirin are eligible No other concurrent chemotherapy or hormonal therapy (other than megestrol acetate [Megace] for appetite stimulation) No other concurrent investigational therapy

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive gemcitabine hydrochloride* IV on days 1 and 8 OR pemetrexed disodium* IV on day 1. Patients also receive carboplatin IV on day 1 and oral celecoxib twice daily on days 1-21. | Drug: carboplatin<br>* Given IV<br>Drug: celecoxib<br>* Given orally<br>Drug: gemcitabine hydrochloride<br>* Given IV<br>Drug: pemetrexed disodium<br>* Given IV<br>|
| Active Comparator: Arm II<br>Patients receive gemcitabine hydrochloride* OR pemetrexed disodium* and carboplatin as in arm I. Patients also receive oral placebo twice daily on days 1-21. | Drug: carboplatin<br>* Given IV<br>Drug: gemcitabine hydrochloride<br>* Given IV<br>Drug: pemetrexed disodium<br>* Given IV<br>Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | Time between randomization and disease relapse or death from any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | Time between randomization and death from any cause, assessed up to 5 years | 
| Response Rate | The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. Response rates (including complete and partial response) will be tested using Fisher's exact test | Up to 5 years | 
| Incidence of Toxicities as Assessed by NCI CTCAE v. 4.0 | The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment | Up to 5 years | 
| Prognostic Value of Urinary Prostaglandin Metabolites (PGE-M) Levels for Worse PFS for Patients Who Had Baseline Urinary PGE-M Above/Below the First Quartile (Q1) | Prognostic value of urinary prostaglandin metabolites (PGE-M) levels for worse PFS for patients who had baseline urinary PGE-M above/below the first quartile (Q1, 10.09). Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | Up to 5 years | 
| Prognostic Value of Urinary Prostaglandin Metabolites (PGE-M) Levels for Worse PFS for Patients Who Had Baseline Urinary PGE-M Above/Below the Median Quartile (Q2) | prognostic value of urinary prostaglandin metabolites (PGE-M) levels for worse PFS for patients who had baseline urinary PGE-M above/below the median quartile (Q2, 15.38). Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | Up to 5 years | 
| Prognostic Value of Urinary Prostaglandin Metabolites (PGE-M) Levels for Worse PFS for Patients Who Had Baseline Urinary PGE-M Above/Below the Third Quartile (Q3) | Prognostic value of urinary prostaglandin metabolites (PGE-M) levels for worse PFS for patients who had baseline urinary PGE-M above/below the median quartile (Q3, 27.86). Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the lung, adenosquamous cell lung cancer, large cell lung cancer, squamous cell lung cancer, recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer