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Detection and Prevention of Anthracycline-Related Cardiac Toxicity With Concurrent Simvastatin

Primary Purpose

Breast Cancer, Stage I Breast Cancer, Stage II Breast Cancer

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Simvastatin
Doxorubicin/cyclophosphamide
Sponsored by
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring Breast cancer, Adriamycin, Simvastatin, Statin, Echocardiogram

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Female Sex (Note: Patients may be pre-menopausal or post-menopausal)
  • Age 18 years or older
  • Histologically confirmed invasive breast carcinoma, stage I-III (Note: Estrogen Receptor (ER), Progesterone Receptor (PR) and HER2 status must be known. In newly diagnosed patients planning neoadjuvant treatment, a formal assessment of axillary lymph nodes is not required.)
  • Planning to initiate adjuvant or neoadjuvant AC (adriamycin and cytoxan) chemotherapy (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2-3 weeks x 4 cycles). (Note: Participants may be planning to receive adjuvant taxane therapy after the completion of AC chemotherapy. HER2 positive patients must be planning to initiate trastuzumab therapy after AC chemotherapy.)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Normal organ function and marrow function as defined by:

    • Absolute neutrophil count (ANC) ≥ 1,000
    • Platelet count ≥ 100,000
    • Total bilirubin less than or equal to the upper limit of normal
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times the upper limit of normal
    • Creatinine ≤1.5 times the upper limit of normal
    • Creatine kinase (CK) ≤2.5 times the upper limit of normal
  • Left ventricular ejection fraction (LVEF) as assessed by baseline echocardiogram at or above the lower limit of normal
  • Women of childbearing potential must agree to use adequate contraception (non-hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of participation. Should a woman become pregnant or suspect she is pregnant while participating in the study, she should inform her treating physician immediately
  • Ability to understand the study regimen and the willingness to sign a written informed consent document
  • Negative pregnancy test (women of childbearing potential only)

Exclusion Criteria:

  • Prior anthracycline therapy
  • Currently pregnant or lactating
  • Currently receiving investigational agents
  • Known active liver disease (cirrhosis, chronic viral hepatitis, autoimmune liver disease or other known clinically significant active liver disease)
  • Known myopathy or history of rhabdomyolysis
  • Uncontrolled hypothyroidism
  • History of allergic reaction or intolerance to statin treatment
  • Currently receiving statin therapy or have received any statin therapy within the last 3 months
  • Known history of ischemic cardiac disease (including angina requiring anti-anginal medications, myocardial infarction, coronary artery disease documented on cardiac catheterization or ischemia documented on stress test), congestive heart failure, clinically significant arrhythmia or conduction system abnormalities, clinically significant valvular disease, clinically significant pericardial effusion or EF below the lower limit of normal
  • Uncontrolled inter-current illness including, but not limited to, ongoing or active serious infection, other active cardiac disease or psychiatric illness/social situations which would limit compliance with study requirements
  • Inability to swallow tablets or use of a feeding tube
  • Gastrointestinal disease, surgery or malabsorption that could potentially impact the absorption of the study drug
  • Daily consumption of alcohol exceeding 3 standard drinks a day (defined as 10 grams of alcohol, which is equivalent to 285 mL of beer, 530 mL of light beer, 100 mL of wine or 30 mL of liquor)
  • Women currently taking drugs which are strong inhibitors or inducers of CYP3A4 are not eligible. These may be found at the Indiana University Clinical Pharmacology website at http://medicine.iupui.edu/clinpharm/ddis/main-table/.
  • Women taking associated with a substantial risk of myopathy when co-administered with simvastatin are not eligible. These drugs are listed in the simvastatin package insert (available at: http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf).
  • Women taking medications for which interaction with simvastatin may result in increased levels are not eligible. Such drugs are listed in the simvastatin package insert (available at: http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf).
  • Any medical condition which, in the opinion of the investigator, puts the patient at risk of potentially serious complications while on study treatment

Sites / Locations

  • Kimmel Cancer Center at Johns Hopkins at Sibley Memorial Hospital
  • Kimmel Cancer Center at Johns Hopkins

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Simvastatin

No drug

Arm Description

Simvastatin will be administered on an outpatient basis orally at a dose of 40 mg once daily. Treatment will start 7 days prior to the planned doxorubicin/cyclophosphamide chemotherapy initiation and will continue for a total of 25 weeks.

Participant not randomized to simvastatin will participate in all aspects of the study, including planned doxorubicin/cyclophosphamide chemotherapy, with the exception of simvastatin administration.

Outcomes

Primary Outcome Measures

Change in Echocardiographic Global Longitudinal Strain (GLS)
To compare the absolute change in echocardiographic GLS (Global Longitudinal Strain) from baseline (T0) to 2-3 weeks after (T2) completion of 4 cycles of (neo)adjuvant anthracycline-based chemotherapy in early stage breast cancer patients who do and do not receive concurrent simvastatin therapy

Secondary Outcome Measures

Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Number of participants with concurrent administration of simvastatin with (neo)adjuvant anthracycline-based chemotherapy in early stage breast cancer patients who experience adverse events as defined by NCI CTCAE v4.0.
Recurrence Free Survival (RFS) With Concurrent Simvastatin
To describe the recurrence free survival (RFS) in early stage breast cancer patients treated with anthracycline-based chemotherapy with and without concurrent simvastatin

Full Information

First Posted
March 14, 2014
Last Updated
July 7, 2023
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
Avon Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT02096588
Brief Title
Detection and Prevention of Anthracycline-Related Cardiac Toxicity With Concurrent Simvastatin
Official Title
Detection and Prevention of Anthracycline-Related Cardiac Toxicity With Concurrent Simvastatin
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
May 20, 2014 (Actual)
Primary Completion Date
April 25, 2017 (Actual)
Study Completion Date
March 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
Avon Foundation

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Doxorubicin (Adriamycin), one of the drugs commonly used for the treatment of breast cancer, is in a class of medications called anthracyclines. Anthracyclines may cause heart damage that can lead to weakening of the heart muscle. This heart damage may happen right away or may occur many years after the anthracycline is given Simvastatin is an oral medication approved by the FDA to lower cholesterol. Simvastatin is in a class of medications called statins. Some research has shown that statins may prevent heart damage that can be caused by anthracyclines like Doxorubicin (Adriamycin). The purpose of this study is to determine if taking simvastatin while receiving the chemotherapy Doxorubicin (Adriamycin) will minimize damage to the heart. This study is for women who will be receiving the anthracycline doxorubicin (Adriamycin) as part of their breast cancer treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Stage I Breast Cancer, Stage II Breast Cancer, Stage III Breast Cancer
Keywords
Breast cancer, Adriamycin, Simvastatin, Statin, Echocardiogram

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
34 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Simvastatin
Arm Type
Experimental
Arm Description
Simvastatin will be administered on an outpatient basis orally at a dose of 40 mg once daily. Treatment will start 7 days prior to the planned doxorubicin/cyclophosphamide chemotherapy initiation and will continue for a total of 25 weeks.
Arm Title
No drug
Arm Type
Active Comparator
Arm Description
Participant not randomized to simvastatin will participate in all aspects of the study, including planned doxorubicin/cyclophosphamide chemotherapy, with the exception of simvastatin administration.
Intervention Type
Drug
Intervention Name(s)
Simvastatin
Other Intervention Name(s)
Zocor
Intervention Description
Simvastatin will be administered on an outpatient basis orally at a dose of 40 mg once daily.
Intervention Type
Drug
Intervention Name(s)
Doxorubicin/cyclophosphamide
Other Intervention Name(s)
Adriamycin/Cytoxan
Intervention Description
The standard chemotherapy regimen that must be planned for all participants in order to take part in this study. The regimen is given every 2 or 3 weeks per standard of care, at the direction of the treating physician.
Primary Outcome Measure Information:
Title
Change in Echocardiographic Global Longitudinal Strain (GLS)
Description
To compare the absolute change in echocardiographic GLS (Global Longitudinal Strain) from baseline (T0) to 2-3 weeks after (T2) completion of 4 cycles of (neo)adjuvant anthracycline-based chemotherapy in early stage breast cancer patients who do and do not receive concurrent simvastatin therapy
Time Frame
up to 15 weeks
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Description
Number of participants with concurrent administration of simvastatin with (neo)adjuvant anthracycline-based chemotherapy in early stage breast cancer patients who experience adverse events as defined by NCI CTCAE v4.0.
Time Frame
52 weeks
Title
Recurrence Free Survival (RFS) With Concurrent Simvastatin
Description
To describe the recurrence free survival (RFS) in early stage breast cancer patients treated with anthracycline-based chemotherapy with and without concurrent simvastatin
Time Frame
5 years

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Female Sex (Note: Patients may be pre-menopausal or post-menopausal) Age 18 years or older Histologically confirmed invasive breast carcinoma, stage I-III (Note: Estrogen Receptor (ER), Progesterone Receptor (PR) and HER2 status must be known. In newly diagnosed patients planning neoadjuvant treatment, a formal assessment of axillary lymph nodes is not required.) Planning to initiate adjuvant or neoadjuvant AC (adriamycin and cytoxan) chemotherapy (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2-3 weeks x 4 cycles). (Note: Participants may be planning to receive adjuvant taxane therapy after the completion of AC chemotherapy. HER2 positive patients must be planning to initiate trastuzumab therapy after AC chemotherapy.) Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Normal organ function and marrow function as defined by: Absolute neutrophil count (ANC) ≥ 1,000 Platelet count ≥ 100,000 Total bilirubin less than or equal to the upper limit of normal Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times the upper limit of normal Creatinine ≤1.5 times the upper limit of normal Creatine kinase (CK) ≤2.5 times the upper limit of normal Left ventricular ejection fraction (LVEF) as assessed by baseline echocardiogram at or above the lower limit of normal Women of childbearing potential must agree to use adequate contraception (non-hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of participation. Should a woman become pregnant or suspect she is pregnant while participating in the study, she should inform her treating physician immediately Ability to understand the study regimen and the willingness to sign a written informed consent document Negative pregnancy test (women of childbearing potential only) Exclusion Criteria: Prior anthracycline therapy Currently pregnant or lactating Currently receiving investigational agents Known active liver disease (cirrhosis, chronic viral hepatitis, autoimmune liver disease or other known clinically significant active liver disease) Known myopathy or history of rhabdomyolysis Uncontrolled hypothyroidism History of allergic reaction or intolerance to statin treatment Currently receiving statin therapy or have received any statin therapy within the last 3 months Known history of ischemic cardiac disease (including angina requiring anti-anginal medications, myocardial infarction, coronary artery disease documented on cardiac catheterization or ischemia documented on stress test), congestive heart failure, clinically significant arrhythmia or conduction system abnormalities, clinically significant valvular disease, clinically significant pericardial effusion or EF below the lower limit of normal Uncontrolled inter-current illness including, but not limited to, ongoing or active serious infection, other active cardiac disease or psychiatric illness/social situations which would limit compliance with study requirements Inability to swallow tablets or use of a feeding tube Gastrointestinal disease, surgery or malabsorption that could potentially impact the absorption of the study drug Daily consumption of alcohol exceeding 3 standard drinks a day (defined as 10 grams of alcohol, which is equivalent to 285 mL of beer, 530 mL of light beer, 100 mL of wine or 30 mL of liquor) Women currently taking drugs which are strong inhibitors or inducers of CYP3A4 are not eligible. These may be found at the Indiana University Clinical Pharmacology website at http://medicine.iupui.edu/clinpharm/ddis/main-table/. Women taking associated with a substantial risk of myopathy when co-administered with simvastatin are not eligible. These drugs are listed in the simvastatin package insert (available at: http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf). Women taking medications for which interaction with simvastatin may result in increased levels are not eligible. Such drugs are listed in the simvastatin package insert (available at: http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf). Any medical condition which, in the opinion of the investigator, puts the patient at risk of potentially serious complications while on study treatment
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Karen Smith, MD, MPH
Organizational Affiliation
SKCCC at Johns Hopkins
Official's Role
Principal Investigator
Facility Information:
Facility Name
Kimmel Cancer Center at Johns Hopkins at Sibley Memorial Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20016
Country
United States
Facility Name
Kimmel Cancer Center at Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287-0013
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Detection and Prevention of Anthracycline-Related Cardiac Toxicity With Concurrent Simvastatin

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