DSMB recommendation

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.

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.

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