A Trial for Treatment of Stage IIIB or IV Non-Small Cell Lung Cancer

This is a randomized, open-label, multicenter study for patients with advanced or metastatic non-small cell lung cancer (stage IIIB or IV). The objective of this study is progression-free survival of bevacizumab and pemetrexed compared to pemetrexed monotherapy during second-line treatment of Stage IIB or IV non-small cell lung cancer.

This phase II trial will address the issues of bevacizumab treatment duration and treatment safety by incorporating bevacizumab into a variation of the ECOG reference regimen as first-line therapy for patients with non-squamous non-small cell lung cancer. Following disease progression or treatment failure, the potential benefit of continued bevacizumab therapy will be tested by randomizing patients to two treatment arms, including second-line chemotherapy with or without further bevacizumab.

For first-line treatment, a regimen of carboplatin, docetaxel, and bevacizumab followed by maintenance bevacizumab therapy will be given to all patients. Upon disease progression or treatment failure, patients will be randomized to one of two second-line regimens: pemetrexed plus bevacizumab or pemetrexed monotherapy.

• Drug: First-Line Treatment
  Docetaxel 75 mg/m2, Carboplatin AUC=6,Bevacizumab 15 mg/kg administered in 21-day cycles on day 1 of each cycle.
  Other Name: Avastin
• Drug: Maintenance
  Bevacizumab 15 mg/kg maintenance in 21 day cycles for up to 18 cycles.
  Other Name: Avastin
• Drug: Second-Line Treatment
  Arm A: Pemetrexed 500 mg/m2 plus Bevacizumab 15 mg/kg administered in 21 day cycles on Day 1 of each cycle. Arm B: Pemetrexed 500 mg/m2 administered in 21 day cycles on Day 1 of each cycle.
  Other Names:

  • Avastin
  • Alimta

• Experimental: First Line Treatment
  All patients will receive first-line treatment in 21-day cycles for up to 6 cycles. All first-line medications are administered intravenously on Day 1 of each cycle. Response is assessed every 2 cycles until disease progression.
  Intervention: Drug: First-Line Treatment
• Experimental: Maintenance
  Patients who have not progressed will continue on bevacizumab maintenance
  Intervention: Drug: Maintenance
• Experimental: Second-Line Treatment
  Upon disease progression, eligible patients will be randomized for second-line treatment to one of two treatment arms. All second line medications are administered intravenously on Day 1 of each 21 day cycle until disease progression. Response is assessed every 2 cycles.
  Intervention: Drug: Second-Line Treatment

Inclusion Criteria:

• Age ≥ 18 years
• Histologically or cytologically confirmed stage IIIB with malignant pleural effusion or stage IV NSCLC except squamous-cell carcinoma.
• Measurable disease defined by RECIST.
• Adequate organ function
• Peripheral neuropathy ≤ grade 1
• ECOG Performance Status 0-1
• Estimated survival of ≥ 12 weeks
• Provide written informed consent

Exclusion Criteria:

• Prior chemotherapy for advanced NSCLC
• Neoadjuvant or adjuvant treatment within 6 months of registration
• Prior radiation therapy within 3 weeks of registration. All side effects must have resolved by registration
• Prior treatment with an investigational or marketed agent that acts by antiangiogenesis mechanisms
• Large ( > 4 cm) centrally located lesions or large lesions in close proximity to major blood vessels unless treated with palliative radiation
• Brain metastases or leptomeningeal disease, except for patients who have had a resection and/or completed a course of cranial irradiation, have no worsening CNS symptoms, and have discontinued all corticosteroids for that indication for at least 1 month prior to registration
• History of gross hemoptysis (defined as bright red blood of at least ½ teaspoon or 2.5 mL per episode) within 3 months of registration unless definitively treated with surgery, radiation, arteriographic embolization, or endobronchial interventions at least 4 weeks prior to registration
• Presence of cavitary lesion
• Presence of squamous histology (mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible; sputum cytology alone is not acceptable)
• Major surgery, open biopsy or significant traumatic injury within 4 weeks of registration or anticipation of need for major surgical procedure during the course of the study

• Minor surgical procedures, fine needle aspirations or core biopsies within

  1 week prior to registration

• Current, ongoing therapeutic anticoagulation with full-dose warfarin or its equivalent
• Current or recent (within 10 days of the first dose of study treatment) use of aspirin (at least 325 mg/day) or other NSAIDs with anti-platelet activity or treatment with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix), or cilostazol (Pletal)
• History of prior malignancy within the past 3 years except for curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or treated localized prostate cancer with a current PSA of < 1.0 mg/dL on two successive evaluations, at least 3 months apart, with the most recent evaluation no more than 4 weeks prior to registration
• History of serious systemic disease
• Pregnancy or women who are breast-feeding. Women of child-bearing potential and non-vasectomized men must agree to use effective methods of birth control during and 3 months following treatment period. Women of child- bearing potential must have a negative pregnancy test.
• History of severe hypersensitivity reaction to docetaxel or any other drugs formulated with polysorbate 80
• Any other medical condition, including mental illness or substance abuse, which in the judgment of the investigator, is likely to interfere with a patient's ability to provide informed consent, cooperate, and participate in the study, or to interfere with the interpretation of the results
• Use of any investigational agent within 4 weeks prior to registration