Lung Cancer Clinical Trial
Gemcitabine Hydrochloride or Pemetrexed Disodium and Carboplatin With or Without Celecoxib in Treating Patients With Advanced Non-Small Cell Lung Cancer
Summary
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.
Full Description
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.
Eligibility Criteria
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
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