Sequential Phase I/II Trial of Oral Vorinostat in Combination With Erlotinib in Non-small-cell Lung Cancer Patients With Mutations at Epidermal Growth Factor Receptor With Disease Progression After Erlotinib Treatment
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 percentage of patients free of progression at 12 weeks.
Hypothesis: We considered that treatment was effective if we obtained a percentage of
patients free of progression at 12 weeks higher than 60%.
(1) To determine the CBR (clinical benefit rate), response 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.
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.
Teresa Moran, MD
Medical Oncology Service. Institut Catala d'Oncologia- ICO. Hospital Germans Trias i Pujol. Badalona - Barcelona (Spain)
Spain: Spanish Agency of Medicines