Multicenter, Predictive, Prospective, Phase III, Open, Randomized, Pharmacogenomic Study in Patients With Advanced Lung Carcinoma (BREC)

Primary objective:

· Time to progression.

Secondary objectives:

• Assess Overall survival of both treatment groups.
• Assess Tumor response rate using RECIST criteria
• Assess Toxicity profile of patients enrolled in the study.
• Exploratory evaluation of potential genetic markers of response or resistance to chemotherapy.

Study population:

Patients with advanced non-small-cell lung cancer who have not received treatment for the disease at this stage and who have a good performance status (ECOG 0-1) and measurable disease (at least one target lesion according to RECIST criteria).

Duration of treatment:

Six chemotherapy cycles will be given. The duration of every cycle will be 21 days. If the treatment is beneficial, it may be prolonged to a total of 8 cycles at the discretion of the investigator.

Calendar and planned finalization date:

The approximate duration of the study is 3 years of recruitment followed by 1 year of follow-up.

• Drug: Cisplatin, Docetaxel
  Docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both on day 1, every 21 days. Total number of cycles: 6
• Drug: Gemcitabine, Cisplatin
  Gemcitabine 1250 mg/m2, days 1 and 8, and Cisplatin 75 mg/m2, day 1. 21-day cycles. Total number of cycles: 6
• Drug: Docetaxel, Cisplatin
  Docetaxel 75 mg/m2 and Cisplatin 75 mg/m2, both administered on day 1, every 21 days. Total number of cycles: 6
• Drug: Docetaxel
  Docetaxel 75 mg/m2, day 1. 21-day cycles. Total number of cycles: 6

• Active Comparator: A
  Docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both on day 1, every 21 days. Total number of cycles: 6
  Intervention: Drug: Cisplatin, Docetaxel
• Experimental: B1
  Low RAP expression and any levels of BRCA1 expression: Gemcitabine 1250 mg/m2, days 1 and 8, and Cisplatin 75 mg/m2, day 1. 21-day cycles. Total number of cycles: 6
  Intervention: Drug: Gemcitabine, Cisplatin
• Experimental: B2
  Intermediate or high RAP expression and low or intermediate BRCA1 expression: Docetaxel 75 mg/m2 and Cisplatin 75 mg/m2, both administered on day 1, every 21 days. Total number of cycles: 6
  Intervention: Drug: Docetaxel, Cisplatin
• Experimental: B3
  Intermediate or high RAP expression and high BRCA1 expression: Docetaxel 75 mg/m2, day 1. 21-day cycles. Total number of cycles: 6
  Intervention: Drug: Docetaxel

INCLUSION CRITERIA:

1. Patients age 18 years or more.
2. Histologically confirmed diagnosis of non-small-cell lung carcinoma.
3. Only patients with advanced disease defined as stage IV or IIIB with or without pleural effusion will be included. In the event of IIIB disease without pleural effusion those patients, who for some reason (respiratory disease, large radiation volume...) may not be candidates to have chemotherapy and radiotherapy treatment and may only be treated with chemotherapy, will be considered.
4. Tumor specimen available (according to the criterion of the specimen-processing laboratory) for the analysis of RAP80 and BRCA1 expression in mRNA.
5. A measurable lesion, as defined by RECIST criteria.
6. Karnofsky score 80% or more (ECOG < 2).
7. No previous treatment with chemotherapy or other agents for disseminated disease. Chemotherapy is allowed if the patient's initial diagnosis is limited disease and the patient has received adjuvant or neoadjuvant treatment, as long as a minimum of 6 months has passed since the end of the adjuvant and/or neo-adjuvant chemotherapy.
8. Patients with cerebral disease may be included without any time limitations after holocranial irradiation or complementary antiedema treatment, as long as there is correct control of the clinical symptoms arising from the brain disease or is symptomatic.

9. Patients with the following hematologic values:

   ANC ≥ 1.5 x 109/L Hb ≥ 10 g/dl Platelets ≥ 100 x 109/L

10. Patients with the following biochemical values:

    Bilirubin ≤ 1.5 mg/dL AST and ALT < 1.5 upper limit of normality Creatinine clearance ≥ 60 ml/min.

11. Patients of childbearing age of either sex must use effective contraceptive methods (barrier methods or other birth control methods) before entering the study and while participating in the study.
12. Patients should sign an informed consent form before inclusion in the study that specifies that the clinical trial treatment entails consent for the analysis of biological specimens of tumor and blood.
13. Patients must be available for clinical follow-up.

EXCLUSION CRITERIA

1. Previous chemotherapy treatment, except the supposition reflected in inclusion criterion 7.
2. Patients diagnosed of another neoplasm, with the exception of cervical carcinoma in situ, treated squamous cell carcinomas or superficial bladder tumors (Ta and TIS), or other malignant tumors that have received curative treatment within the last 5 years before inclusion in the study.
3. Patients with serious active bacterial or fungal infective processes from a clinical vantage point (= grade 2 of NCI-CTC, Version 3).
4. Patients who have received an investigational medicinal product in the 21 days before inclusion in the study.
5. Patients with HIV infection, HCV infection, coronary artery disease or uncontrolled arrhythmia, uncontrolled cerebrovascular disease, or other clinical conditions that, in the judgment of the investigator, contraindicate the patient's participation in the study.
6. Patients who are pregnant or breastfeeding. Women of childbearing age must have a negative pregnancy test performed within 7 days before the onset of treatment.
7. Substance abuse and clinical, psychological or social conditions that can undermine the validity of the informed consent or protocol compliance.
8. Patients who present any contraindication or suspected allergy to the products under investigation in the study
9. Impossibility to comply with chemotherapy treatment due to cultural or geographic circumstances.
10. Significant weight loss (= 10% of body weight) in the 6 weeks before inclusion in the study.
11. Any condition that is unstable or could endanger the patient's safety and/or the patient's compliance with the study.
12. Contraindication for steroid use.