Anti Cancer Stem Cell Activity of Pre-operative Bevacizumab and Chemotherapy in Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate anti-cancer stem cell (CSC) activity (measured by the amount of Aldehyde dehydrogenase 1/ALDH1+ cells before and after treatment) of pre-operative bevacizumab in combination with conventional chemotherapy in breast cancer receiving neo-adjuvant treatment, compared to a control arm receiving chemotherapy alone.

Official Title
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Phase II Proof of Concept  Trial Evaluating Anti Cancer Stem Cell Activity of Pre-operative Bevacizumab in Combination With Chemotherapy in Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: bevacizumab
* Drug: no bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women older than 18 ys Primary breast cancer treated in the neoadjuvant setting (synchronous metastatic disease are eligible) Primary breast tumor accessible to initial biopsy White Blood Count > 3.000/µl and Absolute neutrophil count ≥ 1.500/µl AND platelets ≥ 100 x 109/L AND Hemoglobin ≥ 9 g/dL, Serum creatinine ≤ 150µm/l• Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours, Total bilirubin ≤ 1.5 ULN and ASAT < 2.5 ULN AND ALAT < 1.5 ULN (2.5 if liver metastasis), Adequate coagulation function: International normalized ratio (INR) ≤ 1.5 and TCA ≤ 1.5 x ULN Left ventricular ejection fraction (LVEF) ≥ 55% (isotopic or ultrasound methods) Karnofsky Index > 1 ; Performance status 0 to 1 Patients must have signed a written informed consent form prior to any study specific screening procedures Patient affiliated to the national Social Security regimen or beneficiary of this regimen. Exclusion Criteria: Previous history of cancer (other than curatively treated basal and squamous cell carcinoma of the skin and/or in-situ carcinoma of the cervix) relapsing within the 5 years before study entry Known contra-indication to anticancer compounds used Uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or history of hypertensive encephalopathy History of inherited diathesis or recent thrombotic events Non-healing wound, active peptic ulcer or bone fracture. Major surgery or significant traumatic injury within 28 days prior to study treatment start History of abdominal fistula, trachea-oesophageal fistula or urinary fistula Use of Non Steroid Anti Inflammatory or full dose anticoagulants or antiaggregation treatments within 10 days Pregnancy and breast feeding, premenopausal patient and no effective contraception Brain metastasis. Any unstable severe disease such as : uncontrolled cardiac or vascular disease, uncontrolled hemorrhagy, uncontrolled neuropsychiatric disorders, including dementia, uncontrolled infection or any severe disorders that may preclude study participation Patient considered geographically, socially or psychologically unable to comply with the treatment and the required medical follow-up.

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: WITH bevacizumab<br>bevacizumab 15 mg/kg on day 1 of each cycle : 4 cycles of 5-fluorouracil 500 mg/m² IV + epirubicin 100 mg/m² IV + cyclophosphamide 500 mg/m² IV (FEC100) every 21 days and 4 cycles of docetaxel 100 mg/m² IV every 21 days. Patients with HER2+ disease will receive trastuzumab (8 mg/kg (IV then 6 mg/kg, every 21 days), which will be started with docetaxel and administered for a total duration of 54 weeks, 18 injections. | Drug: bevacizumab<br>* Patients receive on day 1 of each cycle : bevacizumab 15 mg/kg (8 injections in total).<br>* Other names: avastin;|
| Active Comparator: without bevacizumab<br>4 cycles 5-fluorouracil 500 mg/m² IV + epirubicin 100 mg/m² IV + cyclophosphamide 500 mg/m² IV of (FEC100) every 21 days and 4 cycles of docetaxel 100 mg/m² IV every 21 days. Patients with HER2+ disease will receive trastuzumab (8 mg/kg (IV then 6 mg/kg, every 21 days), which will be started with docetaxel and administered for a total duration of 54 weeks, 18 injections. | Drug: no bevacizumab<br>* no bevacizumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of the anti-cancer stem cell activity | The anti-cancer stem cell (CSC) activity is measured by the amount of Aldehyde dehydrogenase 1/ALDH1+ cells after 4 cycles of treatment compared to the amount before treatment | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the safety of the treatment | Evaluation of the safety of the treatment at each cycle, estimated by the number of patients with clinical and biological adverse events coded according to the CTCAE | 8 months | 
| Evaluation of the disease-free survival, recurrence-free survival and overall survival | The disease-free survival, recurrence-free survival and overall survival are calculated from the inclusion to the time of the event | 5 years | 
| Evaluation of the pathological complete response rate | Evaluation of the pathological complete response rate according to the classification of Sataloff | 8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer