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Letrozole With and Without Simvastatin for the Treatment of Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer

Primary Purpose

Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8

Status

Recruiting

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Letrozole

Simvastatin

About this trial

This is an interventional treatment trial for Anatomic Stage I Breast Cancer AJCC v8

Eligibility Criteria

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

Inclusion Criteria:

Age >= 18 years
Biopsy proven hormone receptor positive, HER2 negative stage I-III invasive breast cancer
- Estrogen receptor (ER) and progesterone receptor (PR) positivity are defined as >= 10% of cells expressing hormonal receptors via IHC analysis
- HER2 negativity is defined as either of the following by local laboratory assessment
  - IHC 0, 1+, or 2+ and in situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell)
Minimum primary tumor size 10 mm on any breast imaging (mammogram, ultrasound, magnetic resonance imaging [MRI])
Baseline Ki-67 IHC expression on tumor tissue >= 10%
Post-menopausal women
- Prior bilateral oophorectomy
- Age >= 60 years
- Age < 60 and amenorrheic for 12 months or more in the absence of chemotherapy, endocrine therapy, or ovarian suppression and follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol in the postmenopausal range
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Prior treatment:
- No systemic therapy (chemotherapy, immunotherapy, endocrine therapy, and/or investigational therapy) within 3 months of trial enrollment
No statins, fibrates, or ezetimibe within 3 months of trial enrollment
No active liver disease
Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable) (within 14 days prior to initiation of study treatment)
Absolute neutrophil count (ANC) >= 1,500/mcL (after at least 7 days without growth factor support or transfusion) (within 14 days prior to initiation of study treatment)
Platelets >= 100,000/mcL (within 14 days prior to initiation of study treatment)
Total bilirubin =< 2 institutional upper limit of normal (ULN) (within 14 days prior to initiation of study treatment)
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 institutional ULN (within 14 days prior to initiation of study treatment)
Serum creatinine =< 2 mg/dL (or glomerular filtration rate >= 40 mL/min) (within 14 days prior to initiation of study treatment)
Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions
Be willing and able to provide written informed consent for the trial

Exclusion Criteria:

Patients who are receiving any other investigational agents or an investigational device within 3 months before administration of first dose of study drugs
History of allergic reactions attributed to compounds of similar chemical or biologic composition to simvastatin and/or letrozole
Concomitant use of strong CYP3A4 inhibitors (i.e. clarithromycin, erythromycin, itraconazole, ketroconazole, nefazodone, Posaconazole, voriconazole, protease inhibitors [including boceprevir and telaprevir], telithromycin, cobicistat-containing products), cyclosporine, danazol, and gemfibrozil
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, substance abuse disorders, or psychiatric illness/social situations that would limit compliance with study requirements
Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association class 3 or 4 congestive heart failure; or uncontrolled grade >= 3 hypertension (diastolic blood pressure >= 100 mmHg or systolic blood pressure >= 160 mmHg) despite antihypertensive therapy
Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy

Sites / Locations

Emory University Hospital MidtownRecruiting
Emory University Hospital/Winship Cancer InstituteRecruiting
Emory Saint Joseph's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm I (letrozole, simvastatin)

Arm II (letrozole)

Arm Description

Patients receive letrozole PO QD and simvastatin PO QD for 14 days in the absence of disease progression or unacceptable toxicity.

Patients receive letrozole PO QD for 14 days in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Mean percentage change in Ki-67

Negative change denotes reduction. Ki-67 is a validated surrogate marker for disease-free survival in patients with hormone receptor positive (HR+), HER2- breast cancer. Ki-67 values at 14 days are expressed as geometric mean proportions of the baseline and transformed into percentage change. Geometric mean percentage change of Ki-67 from pre- to post-treatment is calculated and compared between the two treatment arms. A two-sided Mann-Whitney U or Wilcoxon Rank-Sum test is used.

Secondary Outcome Measures

Response per Ki-67

Responders are defined as those with >= 40% pre- to post-treatment decrease in Ki-67, and non-responders are those with < 40% decrease in Ki-67. Descriptive statistics (mean, standard deviation, median, min, max) are applied to biomarkers of interest at 2 designated time points, prior to preoperative therapy (utilizing archival tissue from baseline biopsy) and following completion of 14 days of preoperative therapy. Absolute change or percentage change of biomarkers is calculated and compared between the two treatment arms using the nonparametric Mann-Whitney U test. Correlation among biomarkers is described by Pearson correlation coefficient with 95% confidence interval. The p-value is adjusted by Benjamini-Hochberg procedure to control the false discovery rate.

Change in the level of the following immune biomarkers: Percentage of CD8+ T cells, percentage of FOXp3 Treg cells, ratio of CD8+/Treg ratio

Based on multiplex immunofluorescence. Descriptive statistics (mean, standard deviation, median, min, max) are applied to biomarkers of interest at 2 designated time points, prior to preoperative therapy (utilizing archival tissue from baseline biopsy) and following completion of 14 days of preoperative therapy. Absolute change or percentage change of biomarkers is calculated and compared between the two treatment arms using the nonparametric Mann-Whitney U test. Correlation among biomarkers is described by Pearson correlation coefficient with 95% confidence interval. The p-value is adjusted by Benjamini-Hochberg procedure to control the false discovery rate.

Patient-Reported Outcomes Measurement Information System (PROMIS) for pain

Incidence of adverse events

Evaluated per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 criteria. Adverse events are summarized descriptively using frequencies and percentages of all captured toxicities and grades using CTCAE v.5 criteria.

Full Information

NCT ID

NCT05464810

First Posted

June 24, 2022

Last Updated

November 21, 2022

Sponsor

Emory University

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT05464810

Brief Title

Letrozole With and Without Simvastatin for the Treatment of Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer

Official Title

A Randomized Window of Opportunity Study of Preoperative Letrozole and Simvastatin Versus Letrozole Alone in Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Recruiting

Study Start Date

September 2, 2022 (Actual)

Primary Completion Date

April 15, 2025 (Anticipated)

Study Completion Date

April 15, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Emory University

Collaborators

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This early phase I trial tests whether letrozole with simvastatin works better than letrozole alone to stop tumor cell proliferation in patients with stage I-III hormone receptor positive, HER2 negative invasive breast cancer. Letrozole and simvastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. The addition of simvastatin to letrozole may be more effective at stopping the growth of cancer cells than letrozole alone.

Detailed Description

PRIMARY OBJECTIVE: I. To determine if the addition of simvastatin to letrozole compared to letrozole alone will result in a decrease of Ki67, a biomarker of tumor proliferation, in postmenopausal women with stage I-III, hormone receptor positive, HER2 negative breast cancer following 14 days of pre-surgical therapy. SECONDARY OBJECTIVES: I. To determine if the addition of simvastatin to letrozole compared to letrozole alone will result in increased immune activation from pre- to post-treatment, based on the evaluation of the immune subtype composition in the tissue via multiplex immunofluorescence. II. To determine if changes (from pre- to post-treatment) in immune activation correlate with changes in antiproliferative response, based on Ki-67 (from pre- to post-treatment). III. To identify an association between response defined per percent change in Ki-67 and the percentage of tissue immune biomarkers CD8 and FOXp3. IV. To determine if the addition of simvastatin to letrozole compared to letrozole alone will result in increased pain based on Patient-Reported Outcomes Measurement Information System (PROMIS) from pre- to post-treatment. V. To describe the safety and tolerability of letrozole +/- simvastatin in the pre-surgical setting. EXPLORATORY OBJECTIVES: I. In both arms of the trial, assess the levels of blood-based biomarkers (CRP, IL-6, IL-10, TGF-beta, and TNF-alpha) in pre- and post-treatment blood samples. Ia. Determine if changes (from pre- to post-treatment) in the levels of these blood-based biomarkers correlate with changes in antiproliferative response, based on Ki67 (from pre- to post-treatment). Ib. Determine if changes (from pre- to post-treatment) in the levels of these blood-based biomarkers correlate with changes in immune activation, based on the evaluation of the immune subtype composition in the tissue via multiplex immunofluorescence (from pre- to post-treatment). II. In both arms of the trial, assess fasting total cholesterol levels in pre- and post-treatment blood samples to determine if there is a correlation with changes in antiproliferative response, based on Ki67 (from pre- to post-treatment). III. In both arms of the trial, assess HMG-CoA Reductase immunohistochemistry (IHC) expression in pre- and post-treatment tumor tissue to determine if there is a correlation with changes in antiproliferative response, based on Ki67 (from pre- to post-treatment). OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive letrozole orally (PO) once daily (QD) and simvastatin PO QD for 14 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive letrozole PO QD for 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 30 days.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, HER2-Negative Breast Carcinoma, Hormone Receptor-Positive Breast Carcinoma, Invasive Breast Carcinoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Masking Description

Pathologists are blinded to each other's data and data from earlier analyses of samples.

Allocation

Randomized

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm I (letrozole, simvastatin)

Arm Type

Experimental

Arm Description

Patients receive letrozole PO QD and simvastatin PO QD for 14 days in the absence of disease progression or unacceptable toxicity.

Arm Title

Arm II (letrozole)

Arm Type

Active Comparator

Arm Description

Patients receive letrozole PO QD for 14 days in the absence of disease progression or unacceptable toxicity.

Intervention Type

Drug

Intervention Name(s)

Letrozole

Other Intervention Name(s)

CGS 20267, Femara

Intervention Description

Given PO

Intervention Type

Drug

Intervention Name(s)

Simvastatin

Other Intervention Name(s)

MK 733, Synvinolin, Zocor

Intervention Description

Given PO

Primary Outcome Measure Information:

Title

Mean percentage change in Ki-67

Description

Time Frame

From pre-surgical baseline to 14 days following preoperative therapy

Secondary Outcome Measure Information:

Title

Response per Ki-67

Description

Time Frame

Through study completion, an average of 1 year

Title

Change in the level of the following immune biomarkers: Percentage of CD8+ T cells, percentage of FOXp3 Treg cells, ratio of CD8+/Treg ratio

Description

Time Frame

Through study completion, an average of 1 year

Title

Patient-Reported Outcomes Measurement Information System (PROMIS) for pain

Time Frame

Up to 30 days after surgery

Title

Incidence of adverse events

Description

Time Frame

Up to 30 days after surgery

Other Pre-specified Outcome Measures:

Title

Changes in the level of immune activation in the blood using blood-based biomarkers (CRP, IL-6, IL-10, TGF-beta, TNF-alpha)

Description

Descriptive statistics (mean, standard deviation, median, min, max) are applied to biomarkers of interest at 2 designated time points, prior to preoperative therapy and following completion of 14 days of preoperative therapy. Absolute change or percentage change of biomarkers is calculated and compared between the two treatment arms using the nonparametric Mann-Whitney U test. Correlation among biomarkers is described by Pearson correlation coefficient with 95% confidence interval. The p-value is adjusted by Benjamini-Hochberg procedure to control the false discovery rate.

Time Frame

Through study completion, an average of 1 year

Title

Changes in total cholesterol levels in the blood

Description

Time Frame

Through study completion, an average of 1 year

Title

Changes in HMG-CoA reductase immunohistochemistry (IHC) expression in the tumor tissue

Description

Descriptive statistics (mean, standard deviation, median, min, max) are applied to biomarkers of interest at 2 designated time points, prior to preoperative therapy (utilizing archival tissue from baseline biopsy) and following completion of 14 days of preoperative therapy. Absolute change or percentage change of biomarkers is calculated and compared between the two treatment arms using the nonparametric Mann-Whitney U test. Correlation among biomarkers is described by Pearson correlation coefficient with 95% confidence interval. The p-value is adjusted by Benjamini-Hochberg procedure to control the false discovery rate.

Time Frame

Through study completion, an average of 1 year

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age >= 18 years Biopsy proven hormone receptor positive, HER2 negative stage I-III invasive breast cancer Estrogen receptor (ER) and/or progesterone receptor (PR) positivity are defined as >= 10% of cells expressing hormonal receptors via IHC analysis HER2 negativity is defined as either of the following by local laboratory assessment IHC 0, 1+, or 2+ and in situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell) Minimum primary tumor size 10 mm on any breast imaging (mammogram, ultrasound, magnetic resonance imaging [MRI]) Baseline Ki-67 IHC expression on tumor tissue >= 10% Post-menopausal women Prior bilateral oophorectomy Age >= 60 years Age < 60 and amenorrheic for 12 months or more in the absence of chemotherapy, endocrine therapy, or ovarian suppression and follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol in the postmenopausal range Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Prior treatment: No systemic therapy (chemotherapy, immunotherapy, endocrine therapy, and/or investigational therapy) within 3 months of trial enrollment No statins, fibrates, or ezetimibe within 3 months of trial enrollment No active liver disease Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable) (within 14 days prior to initiation of study treatment) Absolute neutrophil count (ANC) >= 1,500/mcL (after at least 7 days without growth factor support or transfusion) (within 14 days prior to initiation of study treatment) Platelets >= 100,000/mcL (within 14 days prior to initiation of study treatment) Total bilirubin =< 2 institutional upper limit of normal (ULN) (within 14 days prior to initiation of study treatment) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 institutional ULN (within 14 days prior to initiation of study treatment) Serum creatinine =< 2 mg/dL (or glomerular filtration rate >= 40 mL/min) (within 14 days prior to initiation of study treatment) Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions Be willing and able to provide written informed consent for the trial Exclusion Criteria: Patients who are receiving any other investigational agents or an investigational device within 3 months before administration of first dose of study drugs History of allergic reactions attributed to compounds of similar chemical or biologic composition to simvastatin and/or letrozole Concomitant use of strong CYP3A4 inhibitors (i.e. clarithromycin, erythromycin, itraconazole, ketroconazole, nefazodone, Posaconazole, voriconazole, protease inhibitors [including boceprevir and telaprevir], telithromycin, cobicistat-containing products), cyclosporine, danazol, and gemfibrozil Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, substance abuse disorders, or psychiatric illness/social situations that would limit compliance with study requirements Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association class 3 or 4 congestive heart failure; or uncontrolled grade >= 3 hypertension (diastolic blood pressure >= 100 mmHg or systolic blood pressure >= 160 mmHg) despite antihypertensive therapy Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Ruth L. Sacks, MD

Phone

404-778-1345

ruth.lauren.sacks@emory.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ruth L. Sacks, MD

Organizational Affiliation

Emory University Hospital/Winship Cancer Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Emory University Hospital Midtown

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30308

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Nicholas G. Crasta

Phone

404-686-3207

nicholas.gerald.crasta@emory.edu

First Name & Middle Initial & Last Name & Degree

Ruth L. Sacks, MD

Facility Name

Emory University Hospital/Winship Cancer Institute

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ashley Trumbull

Phone

404-778-3969

ashley.lynn.trumbull@emory.edu

First Name & Middle Initial & Last Name & Degree

Ruth L. Sacks, MD

Facility Name

Emory Saint Joseph's Hospital

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30342

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Erica Oberlander

Phone

678-843-6829

erica.oberlander@emoryhealthcare.org

First Name & Middle Initial & Last Name & Degree

Ruth L. Sacks, MD

12. IPD Sharing Statement

Learn more about this trial

Letrozole With and Without Simvastatin for the Treatment of Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer

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