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

Primary Purpose

Non-small Cell Lung Cancer

Status

Terminated

Phase

Phase 1

Locations

Spain

Study Type

Interventional

Intervention

Vorinostat plus Erlotinib

About this trial

This is an interventional treatment trial for Non-small Cell Lung Cancer focused on measuring Vorinostat, NSCLC, EGFR, Erlotinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Hospital de la Santa Creu i Sant Pau
Instituto Universitario Dexeus
Hospital Clinic
Institut Catalá d'Oncologia, Centre Sanitari i Universitari de Bellvitge (CSUB)
Institut Catalá d'Oncología, Hospital Germans Trias i Pujol
Hospital La Paz
Hospital Clínico Universitario de Valencia
Hospital Clínico Lozano Blesa

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Vorinostat plus erlotinib

Arm Description

Vorinostat plus erlotinib

Outcomes

Primary Outcome Measures

MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Secondary Outcome Measures

Efficacy: Objective response rate; Time to progression; Time to response Response duration;Progression free survival;Clinical Benefict Rate

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)

Full Information

NCT ID

NCT00503971

First Posted

July 18, 2007

Last Updated

October 19, 2012

Sponsor

Spanish Lung Cancer Group

Collaborators

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT00503971

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2008

Overall Recruitment Status

Terminated

Study Start Date

December 2007 (undefined)

Primary Completion Date

December 2008 (Actual)

Study Completion Date

December 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Spanish Lung Cancer Group

Collaborators

Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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 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%. Secondary (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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Non-small Cell Lung Cancer

Keywords

Vorinostat, NSCLC, EGFR, Erlotinib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Vorinostat plus erlotinib

Arm Type

Experimental

Arm Description

Vorinostat plus erlotinib

Intervention Type

Drug

Intervention Name(s)

Vorinostat plus Erlotinib

Other Intervention Name(s)

Zolinza® and Tarceva®

Intervention Description

Phase I: 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 Phase II: Dose level 3: 400 mg V d1-7 and 15-21 every 28 days plus 150 mg E daily

Primary Outcome Measure Information:

Title

MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Time Frame

First cycle

Secondary Outcome Measure Information:

Title

Efficacy: Objective response rate; Time to progression; Time to response Response duration;Progression free survival;Clinical Benefict Rate

Time Frame

Along the study

Title

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials: