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

Abramson Cancer Center at Penn Medicine

Status and phase: Completed; Phase 2; Phase 1

Conditions: Lung Cancer

Treatments: Drug: etoposide; Drug: cisplatin; Genetic: protein expression analysis; Other: laboratory biomarker analysis; Radiation: radiation therapy; Procedure: biopsy; Drug: nelfinavir mesylate; Other: immunohistochemistry staining method

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00589056

UPCC 04507

CDR0000582319

IRB-806285

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 55 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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55 participants in 1 patient group

Single arm

Experimental group

Description:

Nelfinavir

Treatment:

Drug: nelfinavir mesylate

Radiation: radiation therapy

Other: immunohistochemistry staining method

Procedure: biopsy

Drug: cisplatin

Genetic: protein expression analysis

Other: laboratory biomarker analysis

Drug: etoposide