• MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT. [ Time Frame: First cycle ] [ Designated as safety issue: Yes ]
  

• Efficacy: Objective response rate; Time to progression; Time to response Response duration;Progression free survival;Clinical Benefict Rate [ Time Frame: Along the study ] [ Designated as safety issue: No ]
  
• Exploratory Endpoints: Molecular analysis (EGFR mutations; thioredoxin; Hsp70; methylation of 14-3-3 sigma and CHFR, EGFR mutation at serum (in blood samples from patients) [ Time Frame: baseline, after cycle 3 and at the end of treatment ] [ Designated as safety issue: No ]
  

Drug: Vorinostat
Dose level 1: 300 mg d1-7 every 21 days Dose level 2: 400 mg d1-7 every 21 days Dose level 2b: 300 mg d1-7 and 15-21 every 28 days Dose level 3: 400 mg d1-7 and 15-21 every 28 days
Drug: Erlotinib
Dose level 1, 2, 2b and 3: 100 mg Dose level E1, E2, E2b and E3: 150 mg

SAMPLE:

Patients must have histologically-confirmed diagnosis of stage IIIB or IV NSCLC, with prior treatment with Erlotinib. In the phase I study the upper expected number of patients will be eighteen. In the phase II thirty two eligible patients will be included in the study. The enrollment period will be approximately 1.5 years. All patients will be treated with Erlotinib and Vorinostat regimen. Participating hospitals will be those of the Spanish Lung Cancer Group (SLCG).

For the phase I portion, there will be 3 sites: Dr. Noemi Reguart and Dr. Rafael Rosell, Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Badalona (Barcelona, Spain), Dr. Felip Cardenal, Institut Catalan d'Oncologia. Centre Sanitari i Universitari de Bellvitge (CSUB), Hospitalet de Llobregat (Barcelona, Spain) and Dr. Lola Isla, Hospital Clinico Lozano Blesa, (Zaragoza, Spain) For the phase II portion, 10 hospitals (adding 7 to the first 3) from the Spanish Lung Cancer Group (SLCG) will be involved. Hospitals will be included during phase I study.

OBJECTIVES AND HYPOTHESES Primary Phase I

(1) To determine the MTD of oral vorinostat in combination with erlotinib and to ensure that this treatment is sufficiently safe and tolerable to permit further study.

Phase II (1) To determine the objective response rate (RR) of patients with stage IIIB or IV NSCLC treated with Vorinostat plus Erlotinib.

Hypothesis: administration of Vorinostat to Erlotinib to patients with stage IIIB or IV NSCLC obtains a response rate >= 20%.

Secondary

(1) To determine the CBR (clinical benefit rate), time to progression, time to response, response duration, and progression free survival in patients treated with vorinostat and erlotinib in combination.

Hypothesis: CBR should be of at least 25% and it will include stable disease for at least 3 months and objective RECIST response for at least 4 weeks.

Exploratory endpoints

Molecular analysis:

Main Objective: analysis of EGFR mutations (in exons 19, 20 and 21) in serum samples at baseline (before treatment), at three months of treatment and at the end of the treatment.

Secondary Objectives: retrospective analysis of molecular markers potentially related to drug sensitivity such as E-catherin protein expression, thioredoxin serum levels; Hsp70; methylation of 14-3-3r and CHFR.