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
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.
Arms & interventions
- DrugLetrozole
Given PO
- DrugSimvastatin
Given PO
Outcome measures
Primary
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.
Time frame: From pre-surgical baseline to 14 days following preoperative therapy
Secondary
Response per Ki-67
Time frame: Through study completion, an average of 1 year
Change in the level of the following immune biomarkers: Percentage of CD8+ T cells, percentage of FOXp3 Treg cells, ratio of CD8+/Treg ratio
Time frame: Through study completion, an average of 1 year
Patient-Reported Outcomes Measurement Information System (PROMIS) for pain
Time frame: Up to 30 days after surgery
Incidence of adverse events
Time frame: Up to 30 days after surgery
Eligibility criteria
Study locations (4)
Grady Healthcare System
Atlanta, Georgia, 30303
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342