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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

Phase 1/Phase 2
18 Years
Not Enrolling
Non-small Cell Lung Cancer

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Trial Information

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.


(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.

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.

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.

Type of Study:


Study Design:

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

Outcome Measure:

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

Outcome Time Frame:

First cycle

Safety Issue:


Principal Investigator

Teresa Moran, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Medical Oncology Service. Institut Catala d'Oncologia- ICO. Hospital Germans Trias i Pujol. Badalona - Barcelona (Spain)


Spain: Spanish Agency of Medicines

Study ID:




Start Date:

December 2007

Completion Date:

December 2011

Related Keywords:

  • Non-Small Cell Lung Cancer
  • Vorinostat
  • EGFR
  • Erlotinib
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms