Back to resultsA 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 (ABC-SE)
Primary Purpose
Breast Cancer
Status
Recruiting
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Letrozole
Letrozole and atorvastatin
Fulvestrant
Sponsored by
About this trial
This is an interventional treatment trial for Breast Cancer focused on measuring 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
Eligibility Criteria
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.
-
Sites / Locations
- Lund University Hospital, Department of OncologyRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Experimental
Other
Arm Label
Letrozole
Letrozole+Atorvastatin
Fulvestrant
Arm Description
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.
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.
Fulvestrant will be used as second line endocrine treatment upon progression on first line with letrozole +/- atorvastatin.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
Duration of Clinical benefit.
Duration of Clinical Benefit (DCB) includes complete response, partial response and disease stabilization assessed through study completion.
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.
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.
Full Information
NCT ID
NCT02958852
First Posted
October 5, 2016
Last Updated
September 1, 2020
Sponsor
Lund University Hospital
Collaborators
South Sweden Breast Cancer Group
1. Study Identification
Unique Protocol Identification Number
NCT02958852
Brief Title
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
Acronym
ABC-SE
Official Title
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 Type
Interventional
2. Study Status
Record Verification Date
September 2020
Overall Recruitment Status
Recruiting
Study Start Date
November 2016 (Actual)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
April 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Lund University Hospital
Collaborators
South Sweden Breast Cancer Group
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer
Keywords
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
126 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Letrozole
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Letrozole+Atorvastatin
Arm Type
Experimental
Arm Description
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.
Arm Title
Fulvestrant
Arm Type
Other
Arm Description
Fulvestrant will be used as second line endocrine treatment upon progression on first line with letrozole +/- atorvastatin.
Intervention Type
Drug
Intervention Name(s)
Letrozole
Intervention Type
Drug
Intervention Name(s)
Letrozole and atorvastatin
Intervention Type
Drug
Intervention Name(s)
Fulvestrant
Intervention Description
Fulvestrant will be used as second line treatment upon progression on first line treatment with letrozole +/- atorvastatin.
Primary Outcome Measure Information:
Title
Clinical benefit rate.
Description
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.
Time Frame
6 months after the last patient has been randomly assigned.
Secondary Outcome Measure Information:
Title
Progression free survival.
Description
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.
Time Frame
6 months after the last patient has been randomly assigned. Data cut off, 15th October 2020.
Title
Objective response rate.
Description
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.
Time Frame
6 months after the last patient has been randomly assigned. Data cut off, 15th October 2020.
Title
Time to progression.
Description
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.
Time Frame
From date of treatment start until the date of first documented progression. Data cut off, 15th October 2020.
Title
Duration of Clinical benefit.
Description
Duration of Clinical Benefit (DCB) includes complete response, partial response and disease stabilization assessed through study completion.
Time Frame
6 months after the last patient has been randomly assigned. Data cut off, 15th October 2020.
Title
Overall survival.
Description
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.
Time Frame
6 months after the last patient has been randomly assigned. Data cut off, 15th October 2020.
Title
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0.
Description
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.
Time Frame
From date of treatment start, until 1 month after the last patient in the study has finished the trial.
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
-
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Signe Borgquist, MD, PhD
Phone
+46 46 17 85 57
Email
signe.borgquist@med.lu.se
First Name & Middle Initial & Last Name or Official Title & Degree
Ana Bosch Campos, MD, PhD
Phone
+46 46 17 75 20
Email
ana.bosch_campos@med.lu.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Signe Borgquist, MD, PhD
Organizational Affiliation
Lund University Hospital, Department of Oncology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Lund University Hospital, Department of Oncology
City
Lund
ZIP/Postal Code
221 85
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Signe Borgquist, MD, PhD
Phone
+46 46 17 75 20
Email
signe.borgquist@med.lu.se
First Name & Middle Initial & Last Name & Degree
Jan Sundberg, RN
Phone
+46 46 17 70 34
Email
jan.sundberg@skane.se
First Name & Middle Initial & Last Name & Degree
Signe Borgquist, MD, PhD
First Name & Middle Initial & Last Name & Degree
Ana Bosch Campos, MD, PhD
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
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
We'll reach out to this number within 24 hrs