Investigating the Biological Effects of the Addition of Zoledronic Acid to Pre-operative Chemotherapy in Breast Cancer

Study Overview
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Brief Summary
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There is clear preclinical in vitro and in vivo evidence of sequence dependent synergy between chemotherapy agents and zoledronic acid. The aim of the study is to investigate if the synergistic increase in tumour cell apoptosis observed in preclinical studies occurs in patients. The hypothesis for this study is that there may be anti-tumour benefits of the sequential application of chemotherapy agents followed by zoledronic acid in patients with invasive breast cancer.

Official Title
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A Randomised Phase II Feasibility Study Investigating the Biological Effects of the Addition of Zoledronic Acid to Neoadjuvant Combination Chemotherapy on Invasive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: 5-FU, Epirubicin, Cyclophosphamide, Docetaxel
* Drug: 5-FU, Epirubicin, Cyclophosphamide, Docetaxel, Zoledronic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with histological diagnosis of invasive breast cancer requiring neoadjuvant chemotherapy T2 tumour or above WHO Performance status of 0,1 or 2 Must consent to or have undergone a core biopsy for diagnosis of breast cancer AND consent to undergo an additional core biopsy prior to the second cycle of chemotherapy (Day 5 +/- Day 21) Written informed consent Exclusion Criteria: Previous chemotherapy or radiotherapy to treated breast Evidence of metastatic disease or recurrent breast cancer or previous malignancy (some exceptions) Calculated creatinine clearance < 40mls/min Prior treatment with bisphosphonates in last year or known contraindications to bisphosphonate therapy Concurrent tamoxifen or aromatase inhibitor medication Pregnant or lactating women Cardiac dysfunction that precludes use of anthracycline chemotherapy Unwilling to have extra interim biopsy

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 |
| --- | --- |
| Active Comparator: A<br>Neoadjuvant chemotherapy alone | Drug: 5-FU, Epirubicin, Cyclophosphamide, Docetaxel<br>* 3 cycles of FEC q3w, followed by 3 cycles of docetaxel q3w FEC: 5FU 500mg/m2 intravenous bolus D1, Epirubicin 100mg/m2 intravenous bolus D1, Cyclophosphamide 500mg/m2 intravenous bolus D1) every 21 days Docetaxel: (100mg/ m2 intravenous infusion) every 21 days<br>|
| Experimental: B<br>Neoadjuvant chemotherapy + zoledronic acid | Drug: 5-FU, Epirubicin, Cyclophosphamide, Docetaxel, Zoledronic acid<br>* 3 cycles of FEC q3w, followed by 3 cycles of docetaxel q3w FEC: 5FU 500mg/m2 intravenous bolus D1, Epirubicin 100mg/m2 intravenous bolus D1, Cyclophosphamide 500mg/m2 intravenous bolus D1) every 21 days Docetaxel: (100mg/ m2 intravenous infusion) every 21 days Zoledronic acid: 4mg intravenous infusion Day 2, AFTER FIRST CYCLE CHEMOTHERAPY ONLY<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase in apoptotic index between diagnostic core biopsy and repeat core biopsy taken on day 5 |  | Repeat biopsy on day 5 (+/- day 21) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Ki67 immunostaining between preoperative core biopsy, repeat core biopsy on day 5, +/- day 21, and operative specimen |  | Day 5, +/- Day 21, surgical specimen | 
| Changes in serum angiogenesis markers between pre-treatment and operative time points |  | Pre-treatment, Day 5, day 21, pre-surgery | 
| Changes in bone biochemical markers between pre-treatment, treatment and operative timepoints |  | Pre-treatment, Day 5, day 21, pre-surgery | 
| Detection of, and changes in, circulating tumour cells in peripheral blood taken pre-treatment, during treatment and following treatment |  | Pre-treatment, day 5, day 21, pre-surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Zoledronic acid, Neoadjuvant chemotherapy, Synergy, Apoptosis