Neoadjuvant IRESSA As Single Agent PreopTherapy for NSCLC With Molecular Correlates

Study Overview
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Brief Summary
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RATIONALE: Gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving gefitinib before surgery may shrink the tumor so it can be removed. PURPOSE: This phase II trial is studying how well gefitinib works in treating patients who are undergoing surgery for stage I, stage II, or stage III non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary Determine the effects of neoadjuvant gefitinib on downstream signaling pathways, including Src-Stat3, PI3K/Akt, ERK activity, and Bcl-2 family members in patients with resectable stage I-IIIA non-small cell lung cancer. Determine the effects of this drug on cell cycle and apoptosis within the primary tumor, by measuring changes in pre- and post-treatment Ki-67, Mcm2, cleaved caspase-3, and ApoTag, in these patients. Secondary Determine the clinical response rate in patients treated with this drug. Determine the pathological response rate, defined as > 95% necrosis or fibrosis in the pathological specimen, in patients treated with this drug. Determine the metabolic activity of this drug in these patients. Determine the safety, tolerability, and feasibility of this drug, in terms of toxicity and post-treatment resectability, in these patients. Correlate plasma and tumor concentrations of this drug with changes in post-treatment molecular markers in these patients. Identify a gene profile that predicts response to this drug in these patients. OUTLINE: This is an open-label, pilot study. Patients receive oral gefitinib once daily for 4 weeks in the absence of disease progression or unacceptable toxicity. Within 3 days after completion of gefitinib, patients undergo restaging evaluation. Patients whose disease is still considered resectable proceed to surgery. Patients undergo thoracotomy with lobectomy or pneumonectomy OR sleeve resection. Patients also undergo mediastinal lymph node dissection. After surgical resection, treatment with gefitinib may continue off study at the discretion of the principal investigator. After completion of study therapy, patients are followed at 30 days, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study within 12.5 months.

Official Title
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Pilot Neoadjuvant Study of ZD1839 (IRESSA®) as Single Agent Preoperative Therapy for Clinical Stage 1A and 1B (T1-2N0), II (T1-2N1, T3N0) and Selected IIIA (T3N1) Non-Small Cell Lung Cancer (NSCLC) With Molecular Correlates

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: ZD1839


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed resectable non-small cell lung cancer (NSCLC), meeting 1 of the following clinical staging criteria: Stage IA or IB (T1-2, N0) Stage II (T1-2, N1 with negative mediastinoscopy or T3, N0) Stage IIIA (T3, N1 with negative mediastinoscopy) Level 10 hilar nodes may be positive provided mediastinoscopy is negative The following are not allowed (as evidenced by clinical staging criteria [CT scan, positron-emission tomography (PET) scan, or mediastinoscopy): Positive N2 lymph nodes (ipsilateral/subcarinal mediastinal lymph nodes) Positive N3 lymph nodes (contralateral mediastinal/hilar and supraclavicular/scalene lymph nodes) T4 primary tumor (malignant pleural effusion or mediastinal invasion) Symptomatic tumors (T3, N0-1) involving the superior sulcus (i.e., Pancoast tumors) Measurable disease by contrast-enhanced CT scan No metastatic disease (except peribronchial or hilar lymph node involvement [N1]) by fludeoxyglucose F 18 PET scan No malignant pleural effusion by preoperative evaluation Pleural effusions visible only on CT scan that are not large enough for safe thoracentesis are allowed No exudative effusions (even if cytologically negative), as evidenced by any of the following: Ratio of pleural fluid protein to serum protein > 0.5 Ratio of pleural fluid lactic dehydrogenase (LDH) to serum LDH ≥ 0.6 Pleural fluid LDH > 200 IU/L No superior vena cava syndrome No spinal cord compression PATIENT CHARACTERISTICS: Age 18 and over Performance status Eastern Cooperative Oncology Group (ECOG) 0-1 Life expectancy Not specified Hematopoietic WBC ≥ 4,000/mm^3 Absolute granulocyte count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST or ALT ≤ 2 times ULN Alkaline phosphatase ≤ 2 times ULN Renal Creatinine < 1.5 times ULN Cardiovascular No uncontrolled ventricular arrhythmia No myocardial infarction within the past 3 months Pulmonary Pre-resection FEV_1 > 2.0 L OR Predicted post-resection FEV_1 > 1.0 L No clinically active interstitial lung disease Chronic stable asymptomatic radiographic changes allowed No post-obstructive pneumonia Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Willing to provide tumor biopsy pre- and post-gefitinib administration AND undergo PET scan No known severe hypersensitivity to study drug or any of its excipients No uncontrolled major seizure disorder No unstable or uncontrolled diabetes mellitus No serious infection requiring IV antibiotics No grade 3 neuropathy No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix No other unstable or serious medical condition that would preclude study treatment or surgery No psychiatric disorder that would preclude giving informed consent No psychological, familial, sociological, or geographical condition that would preclude study compliance and follow up No other significant clinical disorder or laboratory finding that would preclude study participation PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior or concurrent systemic chemotherapy for NSCLC Endocrine therapy Not specified Radiotherapy No prior or concurrent radiotherapy for NSCLC Surgery Recovered from prior oncologic or other major surgery At least 5 years since prior resection of lung disease No prior surgery for NSCLC No concurrent ophthalmic surgery Other More than 30 days since prior non-approved or investigational drugs No other concurrent therapy for NSCLC No other concurrent investigational therapy No concurrent use of any of the following medications: Phenytoin Carbamazepine Barbiturates (e.g., phenobarbital) Rifampin Hypericum perforatum (St. John's wort)

Ages Eligible for Study
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Minimum Age: 18 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: Neoadjuvant ZD1839 Preoperative Therapy<br>The ZD1839 250-mg tablet will be taken once a day, every day about the same time. It can be taken with or without food. At the time of surgery, investigators will collect tissue from the participant's tumor once it has been removed. This tissue will be used to study the effect of ZD1839 on tumor growth. | Drug: ZD1839<br> <br> * Other names: gefitinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Objective Response Rate according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Investigators planned to use this pilot study of neoadjuvant ZD1839 in patients with resectable NSCLC to specifically correlate molecular parameters to the primary clinical study endpoint clinical response assessed by CT response and PET scan response of the primary tumor. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Toxicity Related to Study Treatment | Review of adverse events utilizing Common Toxicity Criteria (CTC) V3. To estimate the safety, tolerability, and feasibility of preoperative ZD1839 in patients with resectable Stage IA/IB, II and selected IIIA NSCLC by evaluating toxicity and operability after preoperative ZD1839. | 3 years | 

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