Letrozole with and without Simvastatin for the Treatment of Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer
18 Years and older, Female
WINSHIP5524-22 (primary)
NCI-2022-02545
STUDY00004257
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 simvastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Adding simvastatin to letrozole may be more effective at stopping the growth of cancer cells than letrozole alone.
Objectives
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 myalgias (muscle 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. Patients undergo mammogram and/or magnetic resonance imaging (MRI) during screening and blood sample collection throughout the study.
ARM II: Patients receive letrozole PO QD for 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo mammogram and/or MRI during screening and blood sample collection throughout the study.
After completion of study treatment, patients are followed for 30 days.
Eligibility
- 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 5 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 >= 55 years
* Age < 55 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 60 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 60 days prior to initiation of study treatment)
- Platelets >= 100,000/mcL (within 60 days prior to initiation of study treatment)
- Total bilirubin =< 2 institutional upper limit of normal (ULN) (within 60 days prior to initiation of study treatment)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 institutional ULN (within 60 days prior to initiation of study treatment)
- Serum creatinine =< 2 mg/dL (or glomerular filtration rate >= 40 mL/min) (within 60 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
Treatment Sites in Georgia
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