Vinorelbine-ifosfamide Versus Gefitinib for EGFR Gene Mutation Negative Non-small Cell Lung Cancer Patients

Study Overview
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Brief Summary
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In the National Comprehensive Cancer Network (NCCN) guideline for NSCLC, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is recommended as the third-line treatment for EGFR gene mutation negative NSCLC patients who failed to the first-line platinum doublet chemotherapy [i.e. paclitaxel-carboplatin (PC) or gemcitabine-cisplatin (GP)] and the second-line chemotherapy with docetaxel or pemetrexed. But as we know, if patients had no EGFR gene mutation, EGFR-TKI treatment is not effective. The overall survival is short and the objective response rate is low. As for EGFR gene wild type patients with good performance status, besides EGFR-TKI treatment, other first generation cytotoxic drugs i.e. vinorelbine or ifosfamide maybe an alternative treatment. So the purpose of this clinical trial is to compare the effectiveness and safety of vinorelbine-ifosfamide with gefitinib in advanced or metastatic EGFR gene mutation negative NSCLC patients.

Detailed Description
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Ifosfamide is a first generation cytotoxic drug to treat NSCLC. Phase Ⅱ studies demonstrated that single-agent ifosfamide administrated by various schedules produces response rates of 15-29%, with media survival times of 5-7 months. Ifosfamide has also been used in various combination regimens to treat NSCLC, including platinum based and non-platinum regimens. But in refractory NSCLC patients platinum and some third generation cytotoxic drugs have been used before. So in this study, ifosfamide is combined with vinorelbine. In previous study, Masters reported the objective response rate was 40% and the median survival duration was 50 weeks, with a 1-year survival rate of 48% with vinorelbine-ifosfamide regimen [Vinorelbine 15 mg/m2 on days 1-3, and ifosfamide 2.0g/m2 on days 1-3 with granulocyte-colony stimulating factor (G-CSF) support]. The dose limiting toxicity (DLT) of this regimen is myelosuppression. In our experience, the regimen of vinorelbine 25mg/m2 d1, d8 and ifosfamide 1.25g/m2 d1-d3 with Mesna uroprotection is safe in Chinese population and the objective response rate is about 7% (data not published). Gefitinib is the first small molecule inhibitor that has directed activity towards EGFR and has shown appreciable response rates in phase Ⅱ trials of patients with previously treated advanced NSCLC. In the posterior analysis of Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) and IRESSA Survival Evaluation in Lung Cancer (ISEL) trials, the response rate with gefitinib ranges from 2.6% to 10% in wild-type EGFR gene NSCLC patients.

Official Title
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A Phase Ⅱ Randomized Clinical Trial Comparing Vinorelbine-ifosfamide With Gefitinib as Third-line Treatment in Advanced EGFR Gene Mutation Negative Non-small Cell Lung Cancer Patients

Conditions
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Non-small Cell Lung Cancer, Effects of Chemotherapy

Intervention / Treatment
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* Drug: Gefitinib group
* Drug: Vinorelbine, Ifosfamide, Mesna


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age range:18-70 years old life expectancy more than 12 weeks histologically or cytologically confirmed inoperable NSCLC (stage ⅢB/Ⅳ) ineligible for curative radiotherapy no prior radiotherapy for the target lesions Eastern Cooperative Oncology Group (ECOG) performance score of 0-2; prior treatments include first-line platinum doublet chemotherapy i.e. PC or GP and second-line chemotherapy with docetaxel or pemetrexed; No EGFR gene mutation detected by Scorpions-ARMS; at least one bidimensionally measurable or radiographically assessable lesion; adequate bone marrow reserve; adequate hepatic and renal function; Exclusion Criteria: prior treatments including any of the following drugs:gefitinib,vinorelbine and ifosfamide; additional malignancies; uncontrolled systemic disease; any evidence of clinically active interstitial lung disease; newly diagnosed central nervous system (CNS) metastasis and not treated by radiotherapy or surgery; pregnancy or breast feeding phase;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Other: Gefitinib<br>Gefitinib group Gefitinib (Iressa) 250mg once per day until progression disease or intolerant side effects | Drug: Gefitinib group<br>* Gefitinib 250mg once per day until the progression disease or intolerant side effects<br>* Other names: Gefitinib (Iressa);|
| Other: Vinorelbine-Ifosfamide<br>VI group Vinorelbine 25mg/m2 d1,d8;Ifosfamide 1.25g/m2 d1-d3(Usually Ifosfamide 2g d1-d3 with Mesna 400mg 0,4,8hours after Ifosfamide administration for 3 days);every 3 weeks;at least for 2-6 cycles depending on the progression disease or the patient's physical condition | Drug: Vinorelbine, Ifosfamide, Mesna<br>* Vinorelbine 25mg/m2 d1,d8; Ifosfamide 1.25g/m1 d1-d3 (Usually 2g d1-d3); Mesna 400mg 0,4,8 hours after Ifosfamide administration for uroprotection d1-d3;<br>* Other names: VI group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 52 weeks. | up to 52 weeks (about one year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | From date of randomization until the date of death from any cause, assessed up to 100 weeks. | Up to 100 weeks | 
| objective response rate | The objective response rate includes the complete remission and partial remission rate. | up to 9 weeks | 
| the score of functional assessment of cancer treatment-lung (FACT-L) | FACL-L is assessed at different time points.(Date of randomization, 1 week after chemotherapy/EGFR-TKI, every cycle of chemotherapy/EGFR-TKI, every month of EGFR-TKI treatment/observation, up to 100 weeks) | Up to 100 weeks | 
| Number of participants with adverse events | The adverse events are assessed by National Cancer Institute-Common Toxicity Criteria (Version 3.0) (NCI-CTC). | Up to six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non small cell lung cancer, chemotherapy, gefitinib, vinorelbine, ifosfamide