Lung Cancer in Women Treated With Anti-oestrogens anD Inhibitors of EGFR

Study Overview
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Brief Summary
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Lung Cancer is to become the first cause of death related to cancer in France as it's already the case in United States. At Present, Lung Cancer in women and in men is treated similarly. Nevertheless, numerous studies shows that lung cancer in women has specificities : at the time of the diagnosis female patients are younger, there are less clinical signs, clinical stages are earlier, histology is often adenocarcinoma. The link with tabagism is weaker . Sensitivity to tabagism is higher (more cancer in women with the same tabagism). Response rate to chemotherapy is better. Prognosis is better Numerous hypotheses have been put forward to account for the specific characteristics of female lung cancer described above. One hypothesis is that there are different genetic anomalies in women. Some studies show an increase of EGFR mutation and HER2 expression and a decrease of expression of repair enzymes (ERCC1, RRM1, BRCA) which can explain the increase sensitivity to tabagism and to chemotherapy. Another hypothesis is that hormones play a role in oncogenesis. Indeed, lung cancer presents hormonal risk factors : pre-menopause, less than 3 kids, short menstrual cycle, hormone replacement therapy. Estrogens would have a deleterious effect on cancer incidence and on survival of lung cancer in women. Cellular and animal models show that ER pathway is activated in lung cancer and participates in oncogenesis. Moreover an interaction between RE and EGFR pathway has been demonstrated on lung cancer cell lines and mouse models. EGFR-TKI have shown benefit in women with wild type EGFR or unknown status (with erlotinib) and in women with EGFR mutations (with gefitinib). In this study, the use of these two treatment will be in accordance with their market authorisations. The objective of this study is to test the addition of an anti-estrogen (fulvestrant) to EGFR-TKI. Fulvestrant is a pure anti-oestrogen that binds to ER, blocks it and accelerates its breakdown. It has a market authorisation in breast cancer. Furthermore the association between EGFR-TKI and anti-estrogen could have a synergetic effect due to interaction between RE and EGFR pathways .

Official Title
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Phase II Randomised Clinical Trial Evaluating an EGFR Tyrosine Kinase Inhibitor (EGFR-TKI) Versus an EGFR-TKI Combined With an Anti-oestrogen Treatment (Fulvestrant) in Women With Advanced Stage Non-squamous Lung Cancer

Conditions
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Stage IV Lung Cancer

Intervention / Treatment
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* Drug: Gefitinib
* Drug: Fulvestrant
* Drug: Erlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed predominant non-squamous, non-small cell lung cancer The presence of analysable tissue for the research of EGFR activating mutation. Analysis must be performed in INCa-labelled laboratories or platforms according to a validated technique Not suitable for radiation, inoperable stage III or stage IV Patients with an EGFR mutation must never have taken chemotherapy or must be in progression after only one previous line of chemotherapy (including maintenance). Patients without an EGFR mutation must have received one or two lines of chemotherapy beforehand. Maintenance chemotherapy is not considered to be a treatment line. Adjuvant chemotherapy is not considered to be a first line of treatment if it dates back to over a year Female Menopausal: older than 60 years of age or history of ovariectomy or younger than 60 years old with amenorrhoea for more than 12 months or an FSH rate that corresponds to a post-menopausal rate (according to the laboratory) Exclusion Criteria: History of cancer except for skin cancer or cancer dating from over five years ago and considered to be cured Known or suspected Cerebral metastases or spinal cord compression unless they are asymptomatic without treatment or stable after being treated by surgery and/or radiation therapy. Corticosteroid treatments for symptoms must have discontinued for more than four weeks Pregnancy and breast-feeding Patient taking hormone replacement therapy for menopause that has not been stopped two weeks before the start of the trial treatment A change in bone marrow, kidney and liver functions inconsistent with treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Gefinitib + Fulvestrant (patient with EGFR mutations)<br> | Drug: Gefitinib<br>* 250 mg per day (oral)<br>Drug: Fulvestrant<br>* 500 mg (2 x 250 mg), IV by month with an additional 500 mg dose two weeks after the initial dose<br>|
| Active Comparator: Erlotinib (wild type patients)<br> | Drug: Erlotinib<br>* 150 mg per day (oral)<br>|
| Experimental: Erlotinib + Fulvestrant (wild type patients)<br> | Drug: Fulvestrant<br>* 500 mg (2 x 250 mg), IV by month with an additional 500 mg dose two weeks after the initial dose<br>Drug: Erlotinib<br>* 150 mg per day (oral)<br>|
| Active Comparator: Gefinib (patient with EGFR mutations)<br> | Drug: Gefitinib<br>* 250 mg per day (oral)<br>|

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 progression for EGFR mutated patient | Around nine months | 
| Progression free survival | From date of randomization until the date of first progression for EGFR wild type patients | Around three months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| toxicity of EGFR-TKI and fulvestrant | The number of patients for whom at least an adverse event will have been reported, the number of events, according to the relation to the treatment, the intensity, and the cycle of appearance for EGFR WT patients | Around three months | 
| Response rate | For EGFR WT patients | Around three months | 
| Overall survival | For all patients | Up to 18 months | 
| toxicity of EGFR-TKI and fulvestrant | The number of patients for whom at least an adverse event will have been reported, the number of events, according to the relation to the treatment, the intensity, and the cycle of appearance for EGFR mutated patients | Around Nine months | 
| Response rate | For EGFR-Mutated patients | Around nine months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung cancer, women