Study of Patients With Advanced Non-Small Cell Lung Cancer

• Progression free survival [ Time Frame: Baseline to measured progressive disease, assessed at 3 years. ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: Baseline to date of death from any cause, assessed at 3 years. ] [ Designated as safety issue: No ]
• Overall Tumor Response rate [ Time Frame: Baseline to date of confirmed response, assessed at every other 21 day cycle. ] [ Designated as safety issue: No ]
• Disease control rates defined as complete response, partial response, and stable disease [ Time Frame: Baseline to date of confirmed response, assessed at every other 21 day cycle. ] [ Designated as safety issue: No ]

The purpose of this study is to compare the regimens of pemetrexed, carboplatin with pemetrexed maintenance and paclitaxel, carboplatin, bevacizumab with bevacizumab maintenance in patients with Stage IIIB or IV nonsquamous non-small cell lung cancer.

This is a multicenter, randomized, open-label, Phase III trial. Eligible patients will be randomized in a 1:1 ratio to receive pemetrexed and carboplatin followed by pemetrexed or paclitaxel, carboplatin, and bevacizumab followed by bevacizumab as their study treatment. Patients randomized to Pemetrexed + Carboplatin + Pemetrexed will receive folic acid, vitamin B12, and dexamethasone as stated in the pemetrexed label. Before administration of paclitaxel, patients randomized to Paclitaxel + Carboplatin + Bevacizumab will receive premedication (dexamethasone, diphenhydramine, and cimetidine or ranitidine) as recommended in the paclitaxel label.

• Drug: Pemetrexed
  Induction therapy: 500mg/m2 given intravenously every 21 days X 4 cycles. Maintenance therapy: 500 mg/m2 given intravenously every 21 days until disease progression or treatment discontinuation.
  Other Name: ALIMTA, LY231514
• Drug: Carboplatin
  Induction Therapy (every 21 days X 4 cycles): Area Under the Curve (AUC)6 intravenously infused over 30 minutes.
• Drug: Paclitaxel
  Induction Therapy(every 21 days X 4 cycles): 200 mg/m2 intravenously infused over 3 hours
• Biological: Bevacizumab
  Induction therapy: 15mg/kg given intravenously every 21 days X 4 cycles. Maintenance therapy: 15 mg/kg given intravenously every 21 days until disease progression or treatment discontinuation.

• Experimental: Pemetrexed + Carboplatin + Pemetrexed
  Pemetrexed and Carboplatin followed by Pemetrexed
  Interventions:

  • Drug: Pemetrexed
  • Drug: Carboplatin
• Active Comparator: Paclitaxel + Carboplatin + Bevacizumab
  Paclitaxel, Carboplatin, and Bevacizumab followed by Bevacizumab
  Interventions:

  • Drug: Carboplatin
  • Drug: Paclitaxel
  • Biological: Bevacizumab

Inclusion Criteria:

• a histologic or cytologic diagnosis of advanced NSCLC (Stage IV from the American Joint Committee on Cancer Staging Criteria (AJCC) staging system, version 7.0, including both M1a and M1b), other than predominantly squamous cell histology, that is not amenable to curative therapy. Patients may not have received any prior systemic chemotherapy, immunotherapy, targeted therapy, or biological therapy, including adjuvant therapy, for any stage of NSCLC.
• prior radiation therapy is allowed to < 25% of the bone marrow; however, prior radiation to the whole pelvis not allowed.
• good performance status
• adequate organ function
• estimated life expectancy of at least 12 weeks.

Exclusion Criteria:

• known central nervous system (CNS) disease, other than treated brain metastasis.
• major surgical procedure, open biopsy, open pleurodesis, or significant traumatic injury within 28 days prior to study or have an anticipated need for major surgery during the study.
• core biopsy or other minor surgical procedure, excluding placement of vascular access device, closed pleurodesis, thoracentesis, and mediastinoscopy, within 7 days prior to study.
• history of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis.
• currently receiving ongoing treatment with full-dose warfarin or equivalent
• significant vascular disease within 6 months prior to Day 1 of Cycle 1.
• evidence of bleeding diathesis or coagulopathy.
• serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient's ability to adhere to the protocol.
• serious cardiac condition, such as myocardial infarction, angina, or heart disease.
• inadequately controlled hypertension
• any prior history of hypertensive crisis or hypertensive encephalopathy.
• serious, nonhealing wound, active ulcer, or untreated bone fracture.
• another active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within the last 5 years.
• previously received treatment with paclitaxel, carboplatin, pemetrexed, or bevacizumab (prior intravitreal administration of bevacizumab does not preclude study participation).
• pregnant or breast-feeding.
• history of stroke or transient ischemic attack within 6 months prior to study.
• known sensitivity to any component of paclitaxel, carboplatin, pemetrexed, or bevacizumab.
• history of hemoptysis within 3 months prior to randomization.
• unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs)
• unwilling to take folic acid or vitamin B12 supplementation.
• clinically significant third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage . Patients with M1a disease with pleural effusions are eligible if the effusions can be adequately controlled.