A Clinical Trial to Compare Efficacy and Tolerability of Atorvastatin in Addition to Endocrine Treatment With Focus on Mechanisms of Resistance to Endocrine Treatment (Fulvestrant/Aromatase Inhibitors) in Patients With Advanced Breast Cancer

Study Overview
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Brief Summary
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A Clinical Trial to Compare Efficacy and Tolerability of Atorvastatin in Addition to Endocrine Treatment with Focus on Mechanisms of Resistance to Endocrine Treatment (fulvestrant/aromatase inhibitors) in Patients With Advanced Breast Cancer.

Detailed Description
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A randomized, open-labelled, phase II trial in the first and second-line metastatic treatment setting, comparing standard endocrine treatment (aromatase inhibitor (AI)) with endocrine treatment plus atorvastatin (1:1). Upon progression in the first line setting, and as part of the translational studies on mechanisms of resistance to endocrine therapy, the patients will receive second line endocrine treatment using fulvestrant. Upon progression to first line treatment, patients that were receiving atorvastatin will stop this treatment.

Official Title
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A Clinical Trial to Compare Efficacy and Tolerability of Atorvastatin in Addition to Endocrine Treatment With Focus on Mechanisms of Resistance to Endocrine Treatment (Fulvestrant/Aromatase Inhibitors) in Patients With Advanced Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Letrozole
* Drug: Letrozole and atorvastatin
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with confirmed ER positive/HER2 negative metastatic breast cancer, including locally advanced stage IV disease, requiring systemic endocrine treatment. Age > 18 years. Performance status of Eastern Cooperative Oncology Group (ECOG) ≤ 2. Metastatic disease must be radiologically or clinically assessable, by means of at least one of the following techniques: clinical examination, computerized tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy or positron emission tomography (PET). Bone metastases alone are allowed. Pre-menopausal patients must consent to undergo either surgical or chemical castration during the duration of the treatment and utilize an effective contraception barrier method. Patient not willing to undergo study specific biopsy from the metastatic site should preferably have enough metastatic tumor sample material archived to perform RNA extraction from formalin fixed paraffin embedded (FFPE) material. Patient must be capable and willing to grant signed informed consent prior to any procedure related with this study as well as to allow access to FFPE biopsies for RNA extraction and for serial circulating tumor cells capture. Biopsy of the metastatic site upon progression is not mandatory but desirable. Signed informed consent according to International Conference on Harmonization /Good Clinical Practice, and national/local regulations. Patients currently on first-line treatment with an AI for metastatic breast cancer who cannot participate on the first part of the treatment (taking lowering cholesterol drugs, or already on AIs for metastatic disease when study is opened) can be eligible to enter on the second part to study mechanisms of resistance to fulvestrant once they have progressed to AI. Patients that progress while taking AI as adjuvant treatment, have confirmed hormone receptor+ metastatic breast cancer and are not deemed suitable for first line AI will also be eligible to enter directly in the second part of the study and be treated with fulvestrant up-front. Exclusion Criteria: Previous treatment for metastatic breast cancer (previous systemic treatment for early breast cancer allowed), unless being considered for direct entry to the second part of the study with fulvestrant (see inclusion criteria 9 and 10). Brain as the only site of metastatic breast cancer. Ongoing treatment with statins (e.g. simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin, or rosuvastatin), anion-exchangers (e.g. colestyramin or colesevelam), fibrates (e.g. gemfibrozil), nicotin-acids (or acipimox) or inhibitors of intestinal cholesterol uptake (e.g.ezetimibe ) for the first part of the trial. Evidence of hepatic dysfunction (alanine aminotransferase level more than three times the upper limit of the normal range) or renal dysfunction (creatine kinase level) more than three times the upper limit of the normal range. Known coagulation disorders or treatment with a 4-hydroxycoumarin derivative is an exclusion criterion for the fulvestrant treated patients. Treatment with anticoagulants other than 4-hydroxycoumarin derivatives or antiplatelet drugs. Patients in treatment with heparin can interrupt treatment 24h prior to biopsies and resume treatment 12h after biopsy has been performed. In case of patients treated with clopidogrel or salicylates, they should be able to interrupt treatment 5-7 days before biopsy and resume 24h after. History of hemorrhagic stroke. Pregnancy or breast-feeding. Untreated psychiatric disorders that will impair the patient's ability to comply with study treatment or protocol. History of allergic reactions attributed to compounds of similar chemical or biological composition to either of the study drugs. -

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: Letrozole<br>Confirmed ER positive/HER2 negative metastatic breast cancer, including locally advanced stage IV disease, requiring systemic endocrine treatment, in this case letrozole, 2.5 mg daily until progression of disease. Upon progression of first line, patients will receive second line treatment using fulvestrant. | Drug: Letrozole<br> <br> |
| Experimental: Letrozole+Atorvastatin<br>Confirmed ER positive/HER2 negative metastatic breast cancer, including locally advanced stage IV disease, requiring systemic endocrine treatment, in this case letrozole, 2.5 mg daily, with the addition of atorvastatin, 40 mg daily until progression of disease. Upon progression of first line, patients will receive second line treatment using fulvestrant. | Drug: Letrozole and atorvastatin<br> <br> |
| Other: Fulvestrant<br>Fulvestrant will be used as second line endocrine treatment upon progression on first line with letrozole +/- atorvastatin. | Drug: Fulvestrant<br>* Fulvestrant will be used as second line treatment upon progression on first line treatment with letrozole +/- atorvastatin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rate. | Clinical benefit rate (CBR), defined as the proportion of all randomly assigned patients who have the best overall response a complete response, a partial response, or stable disease up to 24 weeks following first-line letrozole treatment alone or in combination with atorvastatin. | 6 months after the last patient has been randomly assigned. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival. | Progression free survival (PFS) comparing endocrine treatment alone or endocrine treatment in combination with atorvastatin in patients with advanced breast cancer. It is defined as the time elapsing between the time of random assignment to treatment and the date of the earliest evidence of objective disease progression or death of any cause before documented disease-progression assessed through study completion. | 6 months after the last patient has been randomly assigned. Data cut off, 15th October 2020. | 
| Objective response rate. | Objective Response Rate (ORR; the proportion of patients with a best overall response of either a complete response or a partial response) through study completion. | 6 months after the last patient has been randomly assigned. Data cut off, 15th October 2020. | 
| Time to progression. | Time-To-Progression (TTP) defined as time elapsed between date of diagnosis of metastatic disease and date of confirmation of disease progression in the first part of the protocol assessed through study completion. The primary analysis will be performed 6 months after the last patient has been randomly assigned. | From date of treatment start until the date of first documented progression. Data cut off, 15th October 2020. | 
| Duration of Clinical benefit. | Duration of Clinical Benefit (DCB) includes complete response, partial response and disease stabilization assessed through study completion. | 6 months after the last patient has been randomly assigned. Data cut off, 15th October 2020. | 
| Overall survival. | Overall survival defined as the time elapsed from the date of first confirmation of metastatic disease and the date of death from any cause through study completion. | 6 months after the last patient has been randomly assigned. Data cut off, 15th October 2020. | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0. | Information regarding the number of participants with abnormal laboratory values and/or adverse events that are related to treatment is collected continuously during the trial assessed through study completion. Differences between treatment arms in incidence of recorded cardiovascular events and/or incident diabetes mellitus during and after study treatment. | From date of treatment start, until 1 month after the last patient in the study has finished the trial. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Endocrine Treatment, Atorvastatin, Mechanisms of Resistance, Statins, Fulvestrant, Circulating Tumor Cells, Statins and Endocrine Treatment, Tumor Marker Expression, ER+ Metastatic Breast Cancer, Circulating Tumor DNA, Cholesterol