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

Non-small Cell Lung Cancer Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00503971
• Other study ID #: TARZO
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: July 18, 2007
• Last updated: October 19, 2012
• Start date: December 2007
• Est. completion date: December 2011

Study information

• Verified date: April 2008
• Source: Spanish Lung Cancer Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 50
• Est. completion date: December 2011
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Histologically confirmed NSCLC

2. Diagnosis of advanced stage IIIB with pleural effusion or IV NSCLC

3. Previous disease progression after >= 3 months treatment with Erlotinib. Must tolerate erlotinib dose of 150 mg daily during the prior month.

4. 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).

5. At least 18 years old.

6. 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.

7. At least 4 weeks from any prior major surgery or radiation therapy and have adequately recovered from the toxicities and/or complications

8. ECOG performance status 0 to 2

9. Adequate bone marrow function without the current use of colony stimulating factors.

10. Adequate coagulation function.

11. Adequate liver function

12. Adequate renal function

13. 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.

14. 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:

1. Patient has been treated with any investigational agent for any indication within 4 weeks of study treatment.

2. Patient previously treated with Vorinostat or any other HDAC inhibitor for any indication in the previous 30 days.

3. Patient has history of hypersensitivity or intolerance to Erlotinib.

4. Patient has an active infection or has received intravenous antibiotic, antiviral or antifungal medications with 2 weeks

5. Patient with symptomatic central nervous system metastases with or without corticosteroids treatment.

6. Inability to take and/or tolerate oral medications.

7. Patient has known active hepatitis B or C infection,(HIV) HIV-related malignancy.

8. Pregnant or breastfeeding.

9. Patient with a history of gastrointestinal disease, surgery

10. Patient with uncontrolled undercurrent illness or circumstances that could limit compliance with the study.

11. 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.

12. 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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Non-small Cell Lung Cancer

Intervention

Drug:
• Vorinostat plus Erlotinib
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

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Spanish Lung Cancer Group	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.		First cycle	Yes
Secondary	Efficacy: Objective response rate; Time to progression; Time to response Response duration;Progression free survival;Clinical Benefict Rate		Along the study	No
Secondary	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)		baseline, after cycle 3 and at the end of treatment	No