Phase I/II of Oral Vorinostat Combination With Erlotinib in NSCLC Patients With EGFR Mutations With DP After Erlotinib. - Full Text View

Sponsor:	Spanish Lung Cancer Group
Collaborator:	Merck
Information provided by:	Spanish Lung Cancer Group
ClinicalTrials.gov Identifier:	NCT00503971

Purpose

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.

Condition	Intervention	Phase
Non-Small Cell Lung Cancer	Drug: Vorinostat Drug: Erlotinib	Phase I Phase II

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized 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

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: Cancer Lung Cancer

Drug Information available for: Suberoylanilide hydroxamic acid Erlotinib hydrochloride Erlotinib

U.S. FDA Resources

Further study details as provided by Spanish Lung Cancer Group:

Primary Outcome Measures:

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 ]

Secondary Outcome Measures:

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 ]

Estimated Enrollment:	50
Study Start Date:	December 2007
Estimated Study Completion Date:	September 2010
Estimated Primary Completion Date:	December 2008 (Final data collection date for primary outcome measure)

Intervention Details:

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

Dose level 1, 2, 2b and 3: 100 mg Dose level E1, E2, E2b and E3: 150 mg

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Histologically confirmed NSCLC
Diagnosis of advanced stage IIIB with pleural effusion or IV NSCLC
Previous disease progression after >= 3 months treatment with Erlotinib. Must tolerate erlotinib dose of 150 mg daily during the prior month.
Have demonstrated mutations at epidermal growth factor receptor (EGFR) at Exon 19 or Exon 21 (Exon 19 mutations characterized by in-frame deletions (747-750), and Exon 21 mutations resulting in L858R substitutions).
At least 18 years old.
Measurable disease as defined by the presence of at least one lesion that can be accurately measured in at least one dimension using RECIST guidelines.
At least 4 weeks from any prior major surgery or radiation therapy and have adequately recovered from the toxicities and/or complications
ECOG performance status 0 to 2
Adequate bone marrow function without the current use of colony stimulating factors.
Adequate coagulation function.
Adequate liver function
Adequate renal function
Non-sterilized premenopausal female, pregnancy test must be performed and patient must agree to use barrier methods of contraception. Male patients must agree to use an adequate method of contraception.
Available for periodic blood sample analyses, study related assessments 15.Patient has the ability to understand and willingness to sign the informed consent form.

16.Patient is able to read, understand, and complete the study questionnaires.

Exclusion Criteria:

Patient has been treated with any investigational agent for any indication within 4 weeks of study treatment.
Patient previously treated with Vorinostat or any other HDAC inhibitor for any indication in the previous 30 days.
Patient has history of hypersensitivity or intolerance to Erlotinib.
Patient has an active infection or has received intravenous antibiotic, antiviral or antifungal medications with 2 weeks
Patient with symptomatic central nervous system metastases with or without corticosteroids treatment.
Inability to take and/or tolerate oral medications.
Patient has known active hepatitis B or C infection,(HIV) HIV-related malignancy.
Pregnant or breastfeeding.
Patient with a history of gastrointestinal disease, surgery
Patient with uncontrolled undercurrent illness or circumstances that could limit compliance with the study.
History of malignancy except for inactive non-melanoma skin cancer and/or in situ carcinoma of the cervix, or other solid tumor treated curatively and without evidence of recurrence for at least 5 years prior to study enrollment.
Patient has had prescription or non-prescription drugs or other products known to influence CYP3A4 that cannot be discontinued prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study medication.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00503971

Contacts

Contact: Noemi Reguart, MD

+34 93 430 20 06

secretaria@gecp.org

Locations

Spain
Felip Cardenal.	Recruiting
Barcelona, Spain
Contact: Felip Cardenal.
Noemi Reguart	Recruiting
Barcelona, Spain
Dolores Isla	Recruiting
Zaragoza, Spain
Contact: Dolores Isla

Sponsors and Collaborators

Spanish Lung Cancer Group

Merck

Investigators

Study Chair:	Noemi Dr Reguart	Medical Oncology Service. Institut Catala d'Oncologia- ICO. Hospital Germans Trias i Pujol. Badalona - Barcelona (Spain)
Study Chair:	Dolores Dr Isla	Medical Oncology Service. Hospital Clinico Lozano Blesa. Zaragoza. Spain
Study Chair:	Felip Dr Cardenal	Institut Catala d'Oncologia. Centre Sanitari i Universitari de Bellvitge (CSUB). Hospitalet de Llobregat (Barcelona). Spain
Study Chair:	Bertomeu Dr Massutti	Medical Oncology Service. General Hospital. Alicante. Spain
Study Chair:	Rafael Dr Rosell	Medical Oncology Service. Institut Catala d'Oncologia- ICO. Hospital Germans Trias i Pujol. Badalona - Barcelona (Spain)

More Information

No publications provided

Responsible Party:	Noemi Reguart, Spanish Lung Cancer Group
ClinicalTrials.gov Identifier:	NCT00503971 History of Changes
Other Study ID Numbers:	TARZO
Study First Received:	July 18, 2007
Last Updated:	April 4, 2008
Health Authority:	Spain: Spanish Agency of Medicines

Keywords provided by Spanish Lung Cancer Group:

Vorinostat
NSCLC
EGFR
Erlotinib

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases

Vorinostat
Erlotinib
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on February 09, 2012