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

Sponsor

Peking Union Medical College Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT01749072

Collaborator

(none)

120

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer Effects of Chemotherapy	Drug: Gefitinib group Drug: Vinorelbine, Ifosfamide, Mesna	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Dec 1, 2012

Anticipated Primary Completion Date :

Dec 1, 2016

Anticipated Study Completion Date :

Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Other: Gefitinib Gefitinib group Gefitinib (Iressa) 250mg once per day until progression disease or intolerant side effects	Drug: Gefitinib group Gefitinib 250mg once per day until the progression disease or intolerant side effects Other Names: Gefitinib (Iressa)
Other: Vinorelbine-Ifosfamide 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 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; Other Names: VI group

Arm

Intervention/Treatment

Other: Gefitinib

Gefitinib group Gefitinib (Iressa) 250mg once per day until progression disease or intolerant side effects

Drug: Gefitinib group

Gefitinib 250mg once per day until the progression disease or intolerant side effects

Other Names:

Gefitinib (Iressa)

Other: Vinorelbine-Ifosfamide

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

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;

Other Names:

VI group

Outcome Measures

Primary Outcome Measures

Progression free survival [up to 52 weeks (about one year)]
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.

Secondary Outcome Measures

Overall survival [Up to 100 weeks]
From date of randomization until the date of death from any cause, assessed up to 100 weeks.
objective response rate [up to 9 weeks]
The objective response rate includes the complete remission and partial remission rate.
the score of functional assessment of cancer treatment-lung (FACT-L) [Up to 100 weeks]
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)
Number of participants with adverse events [Up to six months]
The adverse events are assessed by National Cancer Institute-Common Toxicity Criteria (Version 3.0) (NCI-CTC).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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;