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

Summary

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 also undergo collection of blood samples on study. 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 also undergo collection of blood samples on study. 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.