Addition of Aromatase at the Navelbine in Pretreated Metastatic Breast Cancer.

Study Overview
=================
Brief Summary
-----------------
The CHEOPS study aims to confirm the clinical benefit of a combination of an anti-aromatase and metronomic chemotherapy treatment

Detailed Description
-----------------
The CHEOPS study aims to confirm the clinical benefit of a combination of an anti-aromatase and metronomic chemotherapy treatment that would have the theoretical advantage of being well tolerated and more effective than chemotherapy alone even after an anti-aromatase therapy.

Official Title
-----------------
A Randomized Phase II, Multicenter Study Evaluating the Benefit of Adding a Non Steroidal Aromatase Inhibitor to Oral Vinorelbine in Patients With Pretreated Metastatic Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Vinorelbine
* Drug: Letrozole
* Drug: Anastrozole


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 50 years. Histologically proven breast cancer. Progesterone and /or oestrogene receptors positive. HER2 negative on primary tumour. Patient taking hormonotherapy, in progression, already treated by at least one line of anti-aromatase non-steroidal hormonotherapy and by at least on line of chemotherapy. Patient having to begin a second or third line of chemotherapy. Presence of one or several measurable(s) or assessable(s) metastatic lesion(s).In case of isolated bone lesion (s): need to have a non-irradiated with an osteolytic component for be considered as lesion (s) target (s) and having an elevation of the CA15-3. Post menopausal woman. ECOG 0, 1 or 2. Adequate biological function. Neutrophil ≥ 1,5.E9/L Platelets ≥ 100.E9/L Creatinine clearance ≥ 30 mL/min Total bilirubin ≤ 1,5 x the upper limit of normal (ULN) Alkaline phosphatase ≤ 2,5 x ULN ALT, AST ≤ 1,5 x ULN in the absence of liver metastases or ≤ 3 x ULN if liver metastases. Patient with a life expectancy greater than 3 months. Signed informed consent before enrollment. affiliation to a social security scheme Exclusion Criteria: Patient with located or single metastatic tumoral relapse, accessible to a surgical treatment. Patient having already received more 2 lines of chemotherapy for metastatic or advanced decease Patient having already received a treatment by Navelbine® Patient requiring an immediate located radiotherapy for analgesic action Patient with non-irradiated cerebral or symptomatic metastasis, symptomatic pulmonary carcinomatosis lymphangitis Simultaneous administration of another chemotherapy hormonotherapy or anti-tumoral drug Patient having already received another treatment ongoing evaluation within the 30 days before the screening visit Known positive serology HIV Previous cancer within 5 years before the entry in the study, excepted an in situ carcinoma of the cervix or a spino or basal cell carcinoma of the skin or a nonmelanoma skin cancer with an adequate treatment. Any serious concomitant pathology and / or uncontrolled could compromise participation in the study (including uncontrolled diabetes, uncontrolled hypertension, severe infection, profound malnutrition, unstable angina or congestive heart failure - class III or IV according to the New York Heart Association - ventricular arrhythmias, progressive coronary artery disease, myocardial infarction within the last six months, chronic liver or kidney disease, a progressive ulceration of the digestive tract above, CNS disorders). Disorder of gastrointestinal function (GI) or pathology likely to significantly interfere with the absorption of Navelbine, of Letrozole or Anastrozole (eg. Ulcerative disease, uncontrolled nausea, vomiting, diarrhea, syndrome malabsorption, or resection of the small intestine). Known hypersensitivity to letrozole, anastrozole, vinorelbine or other vinco-alkaloids or any other component. Patient with fructose intolerance, galactose, a Lapp lactase deficiency or malabsorption of glucose and galactose (rare hereditary disease). Patient with a history of poor compliance with medical treatment. Patient can not be monitored regularly for family reasons, geographical, social or psychological. Patient with altered mental status would not allow him to understand the study or give informed consent .

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 95 Years

Sexes Eligible for Study
-----------------
Female

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vinorelbine<br>Vinorelbine (metronomic) alone 3 times per week ( mondays, wednesdays, Fridays or Thursdays, Tuesdays, Saturdays) at 50 mg per day, taken orally until progression of disease or toxicity. | Drug: Vinorelbine<br>* Vinorelbine metronomic at 50 mg (1 tablet at 20 mg and 1 tablet at 30mg),per oral, 3 times per week. One dose level reduction is authorized at 30 mg per day.when stopping over 3 consecutive weeks due to toxicity, treatment should be permanently discontinued<br>* Other names: Navelbine;|
| Experimental: Vinorelbine+Anastrozole or Letrozole<br>Vinorelbine metronomic 3 times per week (mondays, wednesdays, Fridays or Thursdays,Tuesdays, Saturdays) at 50 mg per day, taken orally until progression of disease or toxicity. And: Letrozole 2,5 mg every day or Anastrozole 1 mg every day. Until progression of disease or toxicity | Drug: Vinorelbine<br>* Vinorelbine metronomic at 50 mg (1 tablet at 20 mg and 1 tablet at 30mg),per oral, 3 times per week. One dose level reduction is authorized at 30 mg per day.when stopping over 3 consecutive weeks due to toxicity, treatment should be permanently discontinued<br>* Other names: Navelbine;Drug: Letrozole<br>* Lestrozole at 2,5 mg every day , per oral<br>* Other names: ARM A;Drug: Anastrozole<br>* Anastrozole at 1 mg every day, per oral<br>* Other names: ARM B;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Proportion of progression or death | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of partial and complete response rate by RECIST 1.1 | partial and complete response rate by RECIST 1.1 in each arm | up to 6 months | 
| duration of response | duration of response is defined as the time from randomization and the disease progression | up to 6 months | 
| clinical benefit after 24 weeks of treatment | the clinical benefit is defined by the rate of complete response, by the rate of partial response and by the stability of lesions at 24 weeks according to criteria RECIST 1.1 | up to 24 weeks | 
| overall survival | the overall survival of patients randomized is defined as the time from randomization and the date of death | up to 2 years | 
| Toxicity according to criteria NCI CTAEv4.03 | tolerance of the treatment based on AE occurrence according to criteria NCI CTAEv4.03 | up to 2 years | 
| health-related quality of life | health-related quality of life and symptomatic state will be evaluated by filling a questionnaire by patients | up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pretreated metastatic breast cancer