Nelfinavir, Radiation Therapy, Cisplatin, and Etoposide in Treating Patients With Stage III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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RATIONALE: Nelfinavir may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells. Nelfinavir may make tumor cells more sensitive to radiation therapy. Drugs used in chemotherapy, such as cisplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving nelfinavir together with radiation therapy, cisplatin, and etoposide may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of nelfinavir when given together with radiation therapy, cisplatin, and etoposide and to see how well they work in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To determine the dose-limiting toxicities, maximum tolerated dose, and recommended phase II dose of nelfinavir mesylate when administered in combination with concurrent thoracic radiotherapy, cisplatin, and etoposide in patients with unresectable locally advanced non-small cell lung cancer. Secondary To determine the tumor response at 3 months after completion of treatment as measured by RECIST criteria. To assess the inhibition of p-Akt in primary tumor or pathologic lymph nodes and in peripheral blood lymphocytes after 5-10 days of treatment with nelfinavir mesylate. To determine the median overall survival (OS) of patients treated with this regimen. To compare the observed median OS of these patients with the historical median OS of 17 months. OUTLINE: This is a phase I, dose-escalation study of nelfinavir mesylate followed by a phase II study. Phase I: Patients receive oral nelfinavir mesylate twice daily beginning 1-2 weeks before the initiation of chemoradiotherapy and continuing until the completion of radiotherapy. Patients undergo thoracic radiotherapy once daily 5 days a week for 7-8 weeks. Patients also receive cisplatin IV on days 1, 8, 29, and 36 and etoposide IV on days 1-5 and 29-33. After completion of chemoradiotherapy, patients receive two additional courses of cisplatin and etoposide. Phase II: Patients receive nelfinavir mesylate at the maximum tolerated dose determined in phase I and concurrent chemoradiotherapy as in phase I. Patients undergo blood sample collection periodically for correlative laboratory studies. Patients treated in the phase II portion of the study and those with primary tumors or pathologic lymph nodes easily accessible by core biopsy or mediastinoscopy also undergo tumor tissue biopsies. Blood and tumor tissue samples are analyzed for expression of molecular markers (total Akt and p-Akt ) by immunohistochemistry. The molecular markers are correlated with treatment response. After completion of study treatment, patients are followed at 3, 6, and 12 months.

Official Title
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A Phase I/II Trial of Protease Inhibitor, Nelfinavir, Given With Concurrent Thoracic Chemoradiotherapy in Patients With Locally-Advanced Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: etoposide
* Drug: nelfinavir mesylate
* Genetic: protein expression analysis
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis
* Procedure: biopsy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed non-small cell lung cancer Locally advanced (stage III) disease Unresectable disease Candidate for concurrent definitive chemotherapy and thoracic radiotherapy, as determined by the treating physician No malignant pleural effusion PATIENT CHARACTERISTICS: ECOG performance status 0-2 Absolute neutrophil count > 1,500/mm³ Platelet count > 100,000/mm³ Bilirubin ≤ 1.5 mg/dL AST or ALT ≤ 2 times upper limit of normal (ULN) Creatinine ≤ 1.5 times ULN FEV_1 > 600 cc Not pregnant or nursing Negative pregnancy test No weight loss > 10% within the past 6 months No known HIV disease PRIOR CONCURRENT THERAPY: No prior thoracic radiotherapy No prior HIV protease inhibitors More than 5 years since prior chemotherapy At least 3 weeks since prior exploratory thoracotomy No concurrent medications that would preclude nelfinavir administration, including any of the following: Amiodarone Quinidine Rifampin Dihydroergotamine Ergonovine Ergotamine Methylergonovine Hypericum perforatum (St. John's wort) Lovastatin Simvastatin Pimozide Midazolam Triazolam

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>Nelfinavir | Drug: cisplatin<br> <br> Drug: etoposide<br> <br> Drug: nelfinavir mesylate<br> <br> Genetic: protein expression analysis<br> <br> Other: immunohistochemistry staining method<br> <br> Other: laboratory biomarker analysis<br> <br> Procedure: biopsy<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity | Any grade III or higher toxicity during chemoradiation, per CTCAE | 90 days | 
| Maximum Tolerated Dose of Nelfinavir | As determined by dose escalation rules | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response of Tumor | Tumor size as determined by imaging | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, recurrent non-small cell lung cancer