Atorvastatin in Treating Patients With Stage IIb-III Triple Negative Breast Cancer Who Did Not Achieve a Pathologic Complete Response After Receiving Neoadjuvant Chemotherapy

Study Overview
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Brief Summary
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This phase II trial studies how well atorvastatin works in treating patients with stages IIb-III triple negative breast cancer who did not achieve a pathologic complete response to neoadjuvant chemotherapy. Pathologic complete response is the lack of all signs of cancer in tissue samples removed during surgery after upfront chemotherapy. Atorvastatin is used for the treatment of high cholesterol and may reduce the risk of triple negative breast cancer from coming back. Triple-negative breast cancer is a type of breast malignancy that is comprised of cancer cells that do not have estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein. Patients with TNBC do not have established systemic therapies such as anti-estrogens or HER2-targeting agents to reduce recurrence after surgery, and residual cancer found at surgery is associated with higher relapse rate.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the proportion of patients with undetectable circulating tumor cells (CTCs) at 6 months in patients with stage IIB/III triple negative breast cancer (TNBC) who did not achieve a pathologic complete response a (pCR) or Residual Cancer Burden-I (RCB-I) after receiving neoadjuvant chemotherapy (NAC) with and without atorvastatin therapy. SECONDARY OBJECTIVES: I. To determine if baseline fasting lipid profile level (low density lipoprotein cholesterol [LDL-C]) and/or change in serum lipid levels are a predictive biomarker of change in the proportion of patients with CTCs. II. To assess effect of biomarkers on atorvastatin treatment response, defined as CTCs, circulating tumor deoxyribonucleic acid (DNA) (ctDNA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum Interleukin-6 (IL-6) and other inflammatory cytokines, for the purpose of identifying the optimal patient population for future larger scale adjuvant studies. III. To determine if baseline fasting lipid profile level (LDL-C) and/or change in serum lipid levels are associated with 2-year relapse free survival (RFS) rate. IV. To determine if baseline CRP and/or change in serum lipid levels are a predictive biomarker of change in the proportion of patients with CTCs. V. To determine if baseline C-reactive protein (CRP) and/or change in CRP are associated with 2-year RFS rate. VI. To determine if baseline absolute number of CTCs and/or CTC change are associated with 2-year RFS rate. VII. To estimate the 2-year RFS rate of patients with TNBC who did not achieve pCR with and without atorvastatin therapy. VIII. To describe the toxicity and adverse events profile of atorvastatin treatment when given concurrently with standard doses of radiotherapy to the chest wall and regional nodes. EXPLORATORY OBJECTIVES: I. To evaluate the correlation between multiplexed imaging biomarkers in the normal or tumor tissue taken at the time of surgery, and response to atorvastatin-induced CTC changes or with measured outcomes. OUTLINE: Patients are assigned to 1 of 2 groups. GROUP I: Patients receive standard of care atorvastatin orally (PO) once daily (QD) for up to 24 months. A physical exam is performed, and blood drawn at 3, 6, 12, 18 and 24 months after starting standard of care treatment or at any time the disease appears to get worse. GROUP II: Patients not eligible to receive atorvastatin, will be enrolled into non-statin observation group with/without capecitabine treatment.

Official Title
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Atorvastatin in Triple-Negative Breast Cancer (TNBC) Patients Who Did Not Achieve a Pathologic Complete Response (pCR) After Receiving Neoadjuvant Chemotherapy, a Multicenter Pilot Study

Conditions
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Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Estrogen Receptor Negative, HER2/Neu Negative, Inflammatory Breast Carcinoma, Progesterone Receptor Negative, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8, Stage IIB Breast Cancer AJCC v6 and v7, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Triple-Negative Breast Carcinoma

Intervention / Treatment
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* Drug: Atorvastatin
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is willing and able to provide written informed consent for the trial Diagnosis of TNBC (including patients with a clinical diagnosis of triple negative inflammatory breast cancer) Has histological confirmation of breast carcinoma Have stage IIB or III disease as defined by the American Joint Committee on Cancer version 7 or 8 Has confirmed TNBC, defined as having estrogen and progesterone receptor < 10% positivity by immunohistochemistry (IHC) and HER2 normal, which is 0 or 1+ by IHC and negative by fluorescence in situ hybridization (FISH) if performed or HER2 2+ by IHC and negative by FISH or HER2 negative by FISH if IHC is not performed Received neoadjuvant chemotherapy and did not achieve pCR nor had an RCB-I (we will enroll patients with an RCB-II or RCB-III) following neoadjuvant chemotherapy. Since the RCB index has not been validated in IBC, any amount of residual disease will be allowed. pCR is defined as: a) the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0 in the current American Joint Committee on Cancer [AJCC] staging system). Or b) the absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 in the current AJCC staging system) Has a performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) performance scale Absolute neutrophil count (ANC) >= 1,500/mcL Platelets >=100,000 /mcL Hemoglobin (Hgb) >= 8 g/dL Creatinine levels < 2.0 x upper limit of normal (ULN) Total bilirubin =< 1.5 x ULN Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN Subjects of childbearing potential should be willing to use effective methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through at least 4 months after the last dose of study drug; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year; effective methods of birth control include 1). Use of hormonal birth control methods: pills, shots/injections, implants (placed under the skin by a health care provider), or patches (placed on the skin); 2). Intrauterine devices (IUDs); 3). Using 2 barrier methods (each partner must use 1 barrier method) with a spermicide. Males must use the male condom (latex or other synthetic material) with spermicide. Females must choose either a diaphragm with spermicide, or cervical cap with spermicide, or a sponge (spermicide is already in the contraceptive sponge) Within 3 months from completion of definitive surgery after neoadjuvant chemotherapy Willing to take statin for minimum of two years Exclusion Criteria: Has not recovered from adverse events due to prior therapies, i.e. monoclonal antibody, chemotherapy, targeted small molecule therapy, radiation therapy, or surgery Note: Subjects with =< grade 2 neuropathy, alopecia and general disorders and administration site conditions are an exception to this criterion and may qualify for the study Has a known malignancy (other than breast cancer) except basal cell carcinoma or squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy Has known psychiatric or substance abuse disorders and assessed by attending physician that would interfere with cooperation with the requirements of the trial Has received prior therapy with a statin within past 6 months or is currently receiving statin therapy; patients who previously received a statin more than 6 months prior to beginning study therapy and who discontinued treatment for reasons other than severe toxicity or allergic reaction are eligible Is currently receiving another anti-lipidemic agent other than statin: fibric acid derivatives (i.e. fenofibrate, gemfibrozil), bile acid sequestrants (i.e. cholestyramine, colestipol), ezetimibe, niacin, lovaza (omega-3-acid ethyl esters), red yeast rice, orlistat, phytosterol, and lomitapide Known hypersensitivity to statin or any component of the formulation Active liver disease or unexplained persistent elevations of serum transaminases, defined as elevated transaminases > 3 x ULN on at least 2 separate occasions 1 week apart Pregnancy or women who may become pregnant and not on acceptable form of contraception; lactating women Has evidence of distant metastasis Record of myocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication Chronic steroid use as this may prevent any immunomodulatory roles of statin treatment, defined as anticipating need of supraphysiologic dose of steroids for at least 12 weeks while on study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (atorvastatin)<br>Patients receive standard of care atorvastatin PO QD for up to 24 months. | Drug: Atorvastatin<br>* Patients will receive Atorvastatin per ASCVD guidelines dosed as either a moderate intensity (20mg/day) or high intensity statin (80mg/day). Tablets are available in either 20mg or 80mg and will be dispensed as per standard of care for up to 24 months as part of the study. Patients may also receive capecitabine concurrently with Atorvastatin per physician discretion as standard of care. Standard of care dosing of Capecitabine is a 21 day cycle consisting 14 days on and 7 days off. The starting dosing will be per physician discretion, but may be up to 2500mg/m2 per day.<br>|
| Active Comparator: Group II (capecitabine)<br>Patients not eligible to receive atorvastatin, will be enrolled into non-statin observation group with/without capecitabine treatment. | Drug: Capecitabine<br>* Patients not eligible to receive atorvastatin in group II will be enrolled into non-statin observation group with/without capecitabine treatment. Capecitabine administration will be dosed as per standard of care. Standard of care dosing of Capecitabine is a 21 day cycle consisting 14 days on and 7 days off. The starting dosing will be per physician discretion, but may be up to 2500mg/m2 per day.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportions of patients with undetectable circulating tumor cells (CTC) | Will estimate the proportion of patients with negative CTC at 6 months with 95% confidence interval, will also describe the patterns of the change in CTC (from negative to positive [any CTC count in blood], positive to negative, positive to positive or negative to negative) in those who receive statin and those who do not receive statin, separately. Will also explore any pattern of CTC counts at baseline and at follow-ups in patient subgroup, including patients treated with different adjuvant therapies. | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline fasting lipid profile level (low density lipoprotein cholesterol [LDL-C]) and/or change in serum lipid levels | Will determine if baseline fasting lipid profile level (LDL-C) and/or change in serum lipid levels are associated with 2-year relapse free survival (RFS) rate. | Baseline up to 2 years | 
| Biomarkers on atorvastatin treatment response | Defined as CTCs, circulating tumor deoxyribonucleic acid (DNA) (ctDNA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum Interleukin-6 (IL-6) and other inflammatory cytokines, for the purpose of identifying the optimal patient population for future larger scale adjuvant studies. | Up to 2 years | 
| Baseline C-reactive protein (CRP) and/or change in serum lipid levels | Will determine if baseline CRP and/or change in serum lipid levels associated with 2-year RFS rate. Will be summarized for each group (statin versus [vs] no statin) using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, and frequency and proportion for categorical variables. | Baseline up to 2 years | 
| Baseline absolute number of circulating tumor cells (CTCs) and/or CTC change | Will determine if baseline absolute number of CTCs and or CTC change are associated with 2-year RFS rate. Will be summarized for each group (statin vs no statin) using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, and frequency and proportion for categorical variables. | Baseline up to 2 years | 
| Recurrence-free survival (RFS) | RFS from the time of surgery will be estimated with 95% confidence intervals using the Kaplan-Meier method and compared between the treatment groups or CTC response groups using log-rank test. | At 2 years | 
| Incidence of adverse events | Adverse events, grade and relationship will be tabulated by treatment arms. | Up to 24 months |