Intercalating and Maintenance Use of Iressa Versus Chemotherapy in Selected Advanced Non Small Cell Lung Cancer

Study Overview
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Brief Summary
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Platinum-based combination chemotherapy, such as gemcitabine-carboplatin, is one of the standard first-line therapy for advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have clinical efficacy, as compared with the best supportive care or standard chemotherapy, when given as second-line or third-line therapy for advanced NSCLC. Treatment with EGFR-TKI is most effective in female, never-smoker, or patients with adenocarcinoma, and patients of Asian origin. In these populations, such treatment is associated with favorable objective response rates, progression-free survival, and overall survival. These populations also have a relatively high incidence of somatic mutations in the region of the EGFR gene that encodes the tyrosine kinase domain. The recent study(IPASS) by Tony S. Mok showed gefitinib was superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia . In the subgroup of 261 patients who were positive for the EGFR gene mutation, PFS was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel(HR= 0.48,P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, PFS was significantly longer among those who received carboplatin-paclitaxel(HR=2.85,P<0.001). Gefitinib treatment was well tolerated, with lower in hematologic toxicity, and no treatment-related interstitial lung disease.In this study(IPASS), only patients with a mutation of the EGFR gene in the tumor could get benefit from gefitinib as first line treatment. Tony S. Mok and his colleague also found that intercalating and maintenance administration of erlotinib(another EGFR-TKI)following gemcitabine/platinum chemotherapy as first line therapy led to a significant improvement in PFS .

Detailed Description
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Nowadays,EGFR mutation status is unknown for most of the advanced NSCLC patients in clinical practice.Those patients with high probability of EGFR mutation maybe could get benefit from gefitinib as first-line treatment. For this reason, the investigators need more investigation to focus on EGFR mutation unknown patients. In the previous study (including FAST-ACT), the patients enrolled trial received EGFR-TKI plus chemotherapy nearly simultaneously,so the investigators could not know whether those patients gained benefit from EGFR-TKI or chemotherapy, maybe chemotherapy alone was enough. If the patients with EGFR mutation status unknown could get stable disease(SD) after two cycles of chemotherapy,those patients may be optimal for the investigation of intercalating and maintenance administration of gefitinib. The reasons are that chemotherapy may be enough for those with objective response after two cycles chemotherapy, of course, those with disease progression (PD) should be excluded from the study. On the basis of these and other studies, the investigators hypothesized that in a selected population,first-line chemotherapy(gemcitabine +carboplatin) with intercalating and maintenance use of gefitinib would be more efficacious than chemotherapy alone. In this study, the investigators compared the efficacy, safety, and adverse-event profile of chemotherapy plus gefitinib with those of chemotherapy alone, when these drugs were used as first-line treatment in nonsmokers or former light smokers in China, who had lung adenocarcinoma with EGFR gene mutation unknown.

Official Title
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Intercalating and Maintenance Use of Iressa vs. Chemotherapy in Selected Advanced NSCLC: a Randomised Study

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Gefitinib
* Drug: Gemcitabine +Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: After two cycles chemotherapy(gemcitabine plus carboplatin), patients with stable disease(SD) by RECIST1.1. Patients between 18 and 75 years of age. Present with histologically proven or cytological diagnosis of adenocarcinoma NSCLC Stage IIIB or IV as defined by the American Joint Committee on Cancer Staging Criteria for Lung Cancer, that is not amenable to curative therapy,such as surgery or radiotherapy and so on. No prior systemic chemotherapy or targeted therapy for lung cancer before screening. Never smokers(defined as having smoked less than 100 cigarettes in their lifetime ) or light ex-smokers (defined as having ceased smoking at least 15 years before Day 1 of study treatment and having smoked 10 pack-years or fewer). EGFR mutation status unknown. ECOG performance status of 0 or 1. Adequate organ function. Prior radiation therapy allowed to <25% of the bone marrow . Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study enrollment. Patients must have recovered from the acute toxic effects of the treatment prior to study enrollment. Signed informed consent document on file. Estimated life expectancy of ≥12 weeks. Patient compliance and geographic proximity that allow adequate follow up. Exclusion Criteria: Known severe hypersensitivity to gefitinib. Sympotomatic patients with brain metastases. Pleural effusion or pericardiac effusion that cannot be controlled by drainage or other procedures. Inability to comply with protocol or study procedures. A serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient's ability to complete the study. A serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease. Second primary malignancy that is clinically detectable at the time of consideration for study enrollment. Interstitial pneumonia.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine +Carboplatin +Gefitinib<br>Arm A: Gemcitabine 1250mg/m2+Carboplatin AUC=5, every 4 weeks, maximum 4 cycles, Gefitinib 250mg/d every cycle d15-25, and Gefitinib 250mg/d from d15 of last cycle until disease progression | Drug: Gefitinib<br>* Gefitinib 250mg/d every cycle d15-25,and Gefitinib 250mg/d from d15 of last cycle until disease progression<br>* Other names: Iressa;Drug: Gemcitabine +Carboplatin<br>* Gemcitabine 1250mg/m2+Carboplatin AUC=5, every 4 weeks, maximum 4 cycles<br>|
| Active Comparator: Gemcitabine +Carboplatin<br>Arm B: Gemcitabine 1250mg/m2+Carboplatin AUC=5, every 4 weeks, maximum4 cycles, observation until disease progression | Drug: Gemcitabine +Carboplatin<br>* Gemcitabine 1250mg/m2+Carboplatin AUC=5, every 4 weeks, maximum 4 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter ever recorded since study treatment started, or progression in existing non-target lesions,or the appearance of one or more new lesions . | The evaluation of disease is demanded every two months for the patients receiving maintenance use of Gefitinib or patients in observation after chemotherapy,until disease progression occured | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chemotherapy, maintenance therapy, gefitinib