Neoadjuvant Weekly Paclitaxel and Biomarkers of Therapy Response

Study Overview
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Brief Summary
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The hypothesis of this study is that paclitaxel levels increase chromosomal instability (CIN) in tumors and this is lethal to tumors that have pre-existing CIN. Treatment will be administered on an outpatient basis. Paclitaxel will be initiated as standard infusions on days 1, 8, and 15 of a 21-day cycle. Participants will continue with paclitaxel for cycles 2-4 prior to surgery.

Official Title
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Neoadjuvant Weekly Paclitaxel and Biomarkers of Therapy Response

Conditions
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Breast Neoplasm Female

Intervention / Treatment
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* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with pathologically demonstrated breast cancer Patients must be candidates for neoadjuvant paclitaxel chemotherapy by their treating oncologist. No other investigational or commercial therapeutic agents may be given concurrently with the paclitaxel. Patients must not have metastatic disease on staging work-up with CBC and liver function studies. A formalin-fixed paraffin embedded tumor block (preferred) or unstained slides must be available from a prior biopsy of the primary tumor or lymph node. A minimum of 8 slides must be available. The primary tumor or lymph node must be readily biopsied by surgery or radiology teams. The primary tumor must be measurable by an imaging modality prior to treatment. This imaging modality is to be repeated after completion of 4 cycles of paclitaxel and prior to surgery. Such imaging modalities may include ultrasound, CT, mammography, or MRI. MRI will be the preferred imaging modality if available because it has the highest accuracy and positive predictive value for predicting pathologic complete response.All imaging will be performed per standard of care at the discretion of the treating physicians. Subjects may not have had prior systemic chemotherapy regimens administered for treatment of their current breast cancer. However, studies (window studies, for example) that are deemed non-therapeutic, including those that utilize agents that are not FDA approved for the treatment of the patient's current breast cancer, are permitted. Patients must have adequate organ and marrow function as determined by the treating oncologist. Patient must be willing to undergo additional biopsy of breast tumor or lymph node. Patient must have the ability and willingness to sign a written informed consent document. Women of childbearing potential (per UWCCC policy definition) must agree to use effective contraception as discussed with treating oncologist for the duration of the study. Exclusion Criteria: History of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel including to other drugs formulated in Cremophor(R) EL (polyoxyethylated castor oil). Patients with known HIV due to concern that chemotherapy may cause further immunosuppression and potential infectious complications. Patients on non-aspirin anti-coagulation (Coumadin, heparins, or clopidogrel) or with documented bleeding disorders will be excluded due to risk of bleeding with biopsy. Uncontrolled intercurrent illness including, but not limited to, ongoing or active severe infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, other malignancies requiring therapy or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because paclitaxel is a pregnancy category D drug and may cause deleterious effects to the fetus. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with paclitaxel, breastfeeding should be discontinued if the mother is enrolled in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Weekly Paclitaxel<br>Paclitaxel 80 mg/m2 will be initiated as standard infusion on days 1, 8, 15 of a 21-day cycle. Participants will continue with paclitaxel 80 mg/m2 for cycles 2-4 prior to surgery. | Drug: Paclitaxel<br>* Paclitaxel is an FDA approved medication for treatment of curable breast cancer and is available by prescription at pharmacies throughout the United States.<br>* Other names: Taxol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Paclitaxel | To test if high cancers with high chromosomal instability (CIN) respond to paclitaxel better than low CIN cancers. Response determined by the percent decrease in linear measurement of tumor size on the greatest dimension per RECIST-like criteria | Up to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Level Difference of Paclitaxel | Identify patient-specific differences in tumor levels of paclitaxel at 20 hours after first dose. This is measured by high-performance liquid chromatography of tumor and plasma samples and comparing variability between patients with descriptive statistics. | Up to 1 day | 
| Non-Tumor Level Difference of Paclitaxel | Identify patient-specific differences in non-tumor (plasma) levels of paclitaxel at 20 hours after first dose. This is measured by high-performance liquid chromatography of tumor and plasma samples and comparing variability between patients with descriptive statistics. | Up to 1 day | 
| Paclitaxel Levels | Paclitaxel levels at the first dose, 20 hours after the 3rd dose, and 20 hours after the 12th dose. This is measured by high-performance liquid chromatography of tumor and plasma samples and comparing difference at two time points within the same patient with paired statistics. | Up to 79 days | 
| Antimitotic Effects | Compare pre-existing versus post-treatment antimitotic effects at 20 hours after the 1st dose, 20 hours after the 3rd dose, and 20 hours after the 12th dose. This is measured by tissue analysis of tumor samples with phospho-histone H3 and stains for spindle morphology to quantify mitotic index and mitotic characteristics at two time points using paired statistical analysis. | Up to 79 days | 
| Mitotic Index | The mitotic index is a measure of cells arresting in mitosis, previously thought to be the major mechanism of taxol action. It is defined as the percentage of cells undergoing mitosis in a given population of cells. An elevated mitotic index indicates more cells are at this phase of the cell cycle at the time of sampling. | Baseline and 20 hours post-first dose | 
| Correlate Drug Levels With Aneuploidy of Tumor | Correlate pathologic response and clinical response with biomarkers including aneuploidy | Up to 3 months | 
| Correlate Drug Levels With Chromosomal Instability of Tumor | Correlate pathologic response and clinical response with biomarkers including CIN | Up to 3 months | 
| Ki67 of Tumor | The Ki-67 protein is a cellular marker for proliferation. Ki-67 is an excellent marker to determine the growth fraction of a given cell population. The fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) is often correlated with the clinical course of cancer. | Up to 3 months | 
| Change in CIN Levels | There are many proposed ways to measure CIN. Here, we used # of multipolar spindles as a surrogate of CIN measures. | Baseline and 20 hours post-first dose |