Vinorelbine and Ifosfamide as Third-line Treatment for Refractory Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
Although fist-line therapy with Cisplatin and etoposide(EP)or Carboplatin and etoposide(CE)and second-line therapy with topotecan has been given, patients with ED-SCLC still relapse and 2-year survival is less than 10%. There is no standard treatment recommendation for this group of patients who failed to second-line therapy and had good performance status. Some cytotoxic drugs for the treatment of non-small cell lung cancer, i.e. vinorelbine, paclitaxel, and ifosfamide, were used in refractory or recurrent SCLC patients. Recently, a retrospective study showed the overall response rate was 30%, the median progression free survival (PFS) was 6.5 months, and the median overall survival was 10.4 months in advanced combined SCLC patients treated with first-line regimen of vinorelbine, ifosfamide and cisplatin (NIP). Because of the previous platinum administration and patient's performance status, only vinorelbine and ifosfamide (NI) are combined and used as third-line therapy for refractor or recurrent ED-SCLC in our lung cancer center. And this clinical trial is designed to prospectively investigate the efficacy and safety of NI regimen in refractory or recurrent ED-SCLC patients in our center.

Detailed Description
-----------------
Small cell lung cancer (SCLC) is a highly aggressive disease characterized by its rapid doubling time, high growth fraction, early development of disseminated disease, and dramatic response to first-line chemotherapy and radiation. Small cell lung cancer accounts for approximately 20%-25% lung cancer patients. SCLC patients are categorized as limited disease, defined as disease that is confined to the ipsilateral hemithorax that can be encompassed within a tolerable radiation port, or extensive disease (ED), defined as the presence of overt metastatic disease determined by imaging or physical examination. Two third of patients are diagnosed with ED at presentation. Despite the development of novel cytotoxic drugs, the therapeutic approach to SCLC has been stagnant for more than twenty years. Standard treatment for ED-SCLC remains EP or CE, a regimen that yield a median survival of approximately 9 months and a 5-year survival of less than 1%. Most patients are destined to relapse, and the prognosis for this group of patients who relapse is poor. Patients who relapse < 3 months after first-line therapy are commonly called refractory, and patients who relapse 3 months after therapy are labeled as sensitive. In a randomized multicenter study, von Pawel et al compared cyclophosphamide, adriamycin, and vincristine (CAV) with topotecan as a single agent in patients who had relapse at least 60 days (2 months) after initial therapy. The response rates were 24.3% in patients treated with topotecan and 18.3% in patients treated with CAV (P=0.285). Median times to progression were 13.3 weeks for the topotecan arm and 12.3 weeks for the CAV arm. Median survival times were 25 weeks for topotecan and 24.7 weeks for CAV. The proportion of patients with symptom improvement was greater in the topotecan arm than in the CAV arm. The authors concluded that topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC. So in some guidelines for SCLC, topotecan is recommended as the standard second-line treatment in patients who relapse less than 3 months. As for patients who relapse more than six months after the end of initial treatment, EP or CE regimen is recommended to be used again.

Official Title
-----------------
A Phase Ⅱ Single-arm Clinical Trial to Investigate the Efficacy and Safety of Vinorelbine-ifosfamide Regimen as Third-line Treatment in Refractory or Recurrent Extensive Small Cell Lung Cancer Patients

Conditions
-----------------
Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: NI group


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: histologically or cytologically confirmed ED-SCLC; age>18 and <75; measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST); previous treatments including first-line therapy with EP or CE and second-line therapy with topotecan; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2; life expectancy > 3 months; neutrophil count > 1500/ul; platelet count > 100,000ul; hemoglobin level > 9g/dl; bilirubin level < 1.5mg/dL; creatinine level < 2mg/dl; alanine transaminase (AST) levels < 2.5× upper limit of normal (ULN)(or < 5× ULN if liver metastases were present); Exclusion Criteria: previous anticancer therapy including vinorelbine or ifosfamide; newly diagnosed central nervous system (CNS) metastasis and not treated by radiotherapy or surgery; additional malignancies; uncontrolled systemic disease; pregnancy or breast feeding phase;

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| refractory SCLC<br>NI group vinorelbine 25mg/m2 d1,d8; Ifosfamide 1.25g/m2 d1-d3; Mesna 400mg iv 0,4,8 hours after ifosfamide administration for 3 days; every 3 weeks; up to the maximum cycles (total:6); | Drug: NI group<br>* vinorelbine 25mg/m2 d1,d8; ifosfamide 1.25g/m2 d1-d3; Mesna 400mg iv 0,4,8 hours after ifosfamide administration for 3 days<br>* Other names: Mesna;;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the disease control rate | The disease control rate includes the rate of progression disease,partial remission and stable disease. | up to 9 weeks | 

Secondary 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) | 
| Overall survival | From date of randomization until the date of death from any cause, assessed up to 100 weeks. | Up to 100 weeks | 
| the score of functional assessment of cancer treatment-lung (FACT-L) | FACT-L ia assessed at different time points. (Date of randomization, 1 weeks after chemotherapy, every cycle of chemotherapy, every month after chemotherapy,up to 52 weeks) | up to 52 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
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
small cell lung cancer, chemotherapy, vinorelbine, ifosfamide, third-line treatment