Cisplatin/Vinorelbine/Bevacizumab Followed by Docetaxel/Gemcitabine/Bevacizumab Versus the Cisplatin/Docetaxel/Bevacizumab Combination in Locally Advanced or Metastatic NSCLC

An unanswered question in first line treatment of non small cell lung cancer (NSCLC) is whether the administration of more than 2 active drugs provides greater efficacy than a two-drug combination. Docetaxel/gemcitabine combination is a well tolerated regimen, which has comparable efficacy to docetaxel/cisplatin or vinorelbine/cisplatin. In a recent phase II study in first line treatment of advanced or metastatic NSCLC, the sequential administration of vinorelbine/cisplatin followed by docetaxel/gemcitabine produced a response rate of 45.8% and a 1-year survival rate of 51%. The addition of bevacizumab to a platinum-based regimen provided a survival benefit in patients with advanced or metastatic NSCLC.

Inclusion criteria

• Histologically confirmed, unresectable locally advanced (stage IIIB with pleural effusion) or metastatic (stage IV) non-squamous NSCLC
• Performance status (WHO) 0-1
• Adequate bone marrow (ANC ≥ 1,500/mm3, PLT ≥ 100,000/mm3, Hgb ≥ 11 g/dL), liver (Bilirubin ≤ 1.5 UNL, SGOT/SGPT ≤ 2.5 UNL, ALP ≤ 5 UNL), and renal function (Creatinine ≤ UNL - if borderline, creatinine clearance should be ≥ 60 mL/min)
• No previous chemotherapy or immunotherapy for advanced/metastatic NSCLC is allowed

--Previous radiotherapy is allowed provided that the measurable lesions are outside the radiation fields

• Measurable disease, defined as at least 1 bidimensionally measurable lesion ≥ 20 X 10 mm
• Patient able to take oral medication
• Absence of active CNS disease
• Paraffin embedded sample of primary or metastatic tumor diagnostic specimen must be available
• Patients must be able to understand the nature of this study and give written informed consent

Exclusion criteria

• Pregnant or lactating women
• Women of child-bearing age unable or unwilling to take effective contraceptive measures
• Active CNS disease, brain metastases, or leptomeningeal involvement
• Symptomatic neuropathy > grade1 according to the NCI CTCAE (version 3.0)
• Cardiovascular disease (class II-IV NYHA congestive heart failure, myocardial infarction within the previous 4 months, LVEF < normal, uncontrolled hypertension, ventricular arrhythmia), anticoagulation treatment or thrombotic event within the previous 6 months
• Active infection, requiring IV antibiotic treatment, within the previous 2 weeks
• Long-term oxygen therapy
• Second primary malignancy, except for non-melanoma skin cancer and in situ cervical cancer
• Radiotherapy within the previous 4 weeks
• Previous radiotherapy to the only measurable lesion
• Concurrent treatment with other anti-cancer drug
• Uncontrolled hypercalcemia
• Known allergy to drugs with similar chemical structure to study drugs. Concurrent corticosteroids, except for chronic therapy with methylprednisolone ≤ 20 mgr daily (or equivalent) for more than one month