Phase I/II of Oral Vorinostat Combination With Erlotinib in NSCLC Patients With EGFR Mutations With DP After Erlotinib.
This is an open label, non-randomized, sequential, phase I/II trial in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) with EGFR mutations after progression to Erlotinib. The study will have two parts. The first part (phase I) will be a dose finding (MTD) study to be implemented at three hospitals. The second part of the study (phase II) will asses the safety and efficacy of the combination. In this second part (phase II) patients will be treated with oral Erlotinib 150 mg P.O daily plus oral Vorinostat administered according to the results of the phase I. The study endpoints to be evaluated will include safety and response rate (RR) as primary endpoints and clinical benefit rate (CBR), time to progression, time to response, response duration and progression free survival as secondary endpoints. All the patients (phase I and II) will be treated until progression disease, unacceptable toxicity or withdrawal of the consent, and will be treated at the discretion of the principal investigator.
Non-small Cell Lung Cancer
Drug: Vorinostat plus Erlotinib
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- 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 ]
|Study Start Date:||December 2007|
|Study Completion Date:||December 2011|
|Primary Completion Date:||December 2008 (Final data collection date for primary outcome measure)|
Experimental: Vorinostat plus erlotinib
Vorinostat plus erlotinib
Drug: Vorinostat plus Erlotinib
Dose level 1: 300 mg V d1-7 every 21 days plus 100 mg E daily Dose level 2: 400 mg V d1-7 every 21 days plus 100 mg E daily Dose level 2b: 300 mg V d1-7 and 15-21 every 28 days plus 100 mg E daily Dose level 3: 400 mg V d1-7 and 15-21 every 28 days plus 150 mg E daily
Dose level 3: 400 mg V d1-7 and 15-21 every 28 days plus 150 mg E daily
Other Name: Zolinza® and Tarceva®
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.
|Instituto Universitario Dexeus|
|Barcelona, Spain, 08028|
|Institut Catalá d'Oncologia, Centre Sanitari i Universitari de Bellvitge (CSUB)|
|Barcelona, Spain, 08907|
|Barcelona, Spain, 08036|
|Hospital de la Santa Creu i Sant Pau|
|Barcelona, Spain, 08025|
|Institut Catalá d'Oncología, Hospital Germans Trias i Pujol|
|Barcelona, Spain, 08916|
|Hospital La Paz|
|Madrid, Spain, 28046|
|Hospital Clínico Universitario de Valencia|
|Valencia, Spain, 46010|
|Hospital Clínico Lozano Blesa|
|Zaragoza, Spain, 50009|
|Principal Investigator:||Teresa Moran, MD||Medical Oncology Service. Institut Catala d'Oncologia- ICO. Hospital Germans Trias i Pujol. Badalona - Barcelona (Spain)|
|Study Chair:||Dolores Isla, MD||Medical Oncology Service. Hospital Clinico Lozano Blesa. Zaragoza. Spain|
|Study Chair:||Felip Cardenal, MD||Institut Catala d'Oncologia. Centre Sanitari i Universitari de Bellvitge (CSUB). Hospitalet de Llobregat (Barcelona). Spain|
|Study Chair:||Bertomeu Massutti, MD||Medical Oncology Service. General Hospital. Alicante. Spain|
|Study Chair:||Rafael Rosell, MD||Medical Oncology Service. Institut Catala d'Oncologia- ICO. Hospital Germans Trias i Pujol. Badalona - Barcelona (Spain)|
|Study Chair:||Noemi Reguart, MD||Medical Oncology Service. Hospital Clinic - Barcelona (Spain)|
|Principal Investigator:||Amelia Insa, MD||Medical Oncology Service. Hospital Clínico Universitario - Valencia (Spain)|
|Principal Investigator:||Cinta Pallarés, MD||Medical Oncology Service. Hospital de la Santa Creu i Sant Pau - Barcelona (Spain)|