PURPOSE:    

• To assess, in comparison with placebo, the impact of adjuvant therapy with two years of daily oral ZD1839 (IRESSA) on the overall survival of patients with completely resected   (T1N1-2, T2NO-2, T3N0-2) non-small cell lung cancer (NSCLC).

BACKGROUND:     

• Lung cancer is the second most common cancer in both men and women in North America, but is the most common cause of cancer-related mortality in both sexes.   It accounts for approximately 30% of all cancer deaths, with 180,000 individuals in North America expected to develop lung cancer in year 2000 and 172,000 expected to die from this disease.  
• With intensive efforts being devoted to the improvement of early detection techniques, however, the percentage of early stage NSCLC patients is expected to increase.  Stage is the most important determinant of survival in NSCLC.  The 5-year survival rate for completely resected Stage I is ~70% (60% for Stage IB), but falls to 40% for patients who have first level nodal involvement (Stage II).  At this time, patients with Stages I and II NSCLC do not receive adjuvant therapy after surgery. 
• There is convincing evidence that EGFR (Epithelial Growth Factor Receptor) is over-expressed in many human cancers, including NSCLC.  Furthermore, over-expression of EGFR has been correlated with poor prognostic features, such as increased angiogenesis (development of blood vessels by the tumor, to feed it) and metastatic potential (potential for spreading to other parts of the body) of tumors.  Pre-clinical work showed ZD1839 (IRESSA)’s inhibition of epidermal growth factor receptor (EGFR), and Phase I clinical trials confirmed its anti-tumor activity and mild toxicity profile.  Although ZD1839 (IRESSA) was expected to be cytostatic rather than cytotoxic there were some durable partial responses (decreases in tumor size by >50% overall) in these studies.
• The evidence of activity of ZD1839 coupled with an acceptable toxicity profile and an oral route of administration, a study of the compound in the adjuvant setting for patients with resected NSCLC appears appropriate.                                             

CRITERIA FOR INCLUSION OF SUBJECTS: 

• Patients must have histological proof of a primary non-small cell lung cancer (Bronchoalveolar carcinomas presenting as a discrete solitary radiological mass or nodule are eligible).   
• Patients must be classified post-operatively as Stage IB, II or IIA on the basis of pathologic criteria.  At the time of resection a complete mediastinal lymph node resection or at least a lymph node sampling should have been attempted. 
• If a complete mediastinal lymph node resection or lymph node sampling was not undertaken, any mediastinal lymph node which measured 1.5cm or more on the pre-surgical CT/MRI scan must have been biopsied and found to be free of metastatic involvement on histopathological examination. 
• Surgery may consist of lobectomy, sleeve resection, bilobectomy or pneumonectomy as determined by the attending surgeon based on the intraoperative findings. 
• Patients must sign informed consent and agree to submit representative formalin fixed paraffin block of tumor at the request of the Central Tumor Bank in order that the specific EGFR correlative marker assays may be conducted. 
• The patient must have an ECOG performance status of 0, 1 or 2. Chest x-ray, EKG must be completed 14 days prior to randomization. MRI, CT scan of the chest must be completed within 42 days prior to surgical resection. 
• Hematology and Biochemistry lab work must be done and completed within a certain time frame. 
• The patient’s age will be 18 years old or greater.  Patients must have completed radiation at least 3 weeks prior to randomization and have recovered from all radiation-induced toxicity. 
• Patients who have received radiation therapy should also be randomized within 16 weeks of surgery.     

CRITERIA FOR EXCLUSION OF SUBJECTS: 

• Prior or concurrent malignancies;
• A diagnosis of a combination of small cell and non-small cell carcinomas or a pulmonary carcinoid tumor;    
• More than one discrete area of apparent primary cancer;   
• Clinically significant or untreated ophthalmologic or gastrointestinal conditions;  
• Any active pathological condition that would render the protocol treatment dangerous such as: uncontrolled congestive heart failure, angina, or arrhythmias, active uncontrolled infection;  
• A history of psychiatric or neurological disorder that would make the obtainment of informed consent problematic or that would limit compliance with study requirements;  
• A pregnant or breast-feeding patient;   
• Prior or concurrent adjuvant or neoadjuvant chemotherapy or immunotherapy for NSCLC.  Specifically full dose pre-operative radiotherapy of curative intent;
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used on the trial
• Patients with ongoing use of phenytoin, carbamazepine, barbiturates, rifampicin, or St John’s Wort;
• Incomplete healing from previous oncologic or other major surgery    

RECRUITMENT OF SUBJECTS: 

• Investigator’s will recruit patients from St. Paul University hospital, and Parkland Health & Hospital System.   

For more information, please contact Nicklett Johnston, R.N. at 214-645-7728.