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.
Primary Objectives * To test if cancers with high chromosomal instability (CIN) respond to paclitaxel better than low CIN cancers. Secondary Objectives * To identify patient-specific differences in tumor levels and distribution of paclitaxel at 20 hours after first dose and patient-specific differences in peripheral non-tumor tissue (skin or plasma) paclitaxel levels 20 ± 4 hours after first dose. * To determine if paclitaxel levels are higher at 20h after the 3rd dose than after the first dose, and if levels are higher at 20h after the 10th, 11th, or 12th dose than the 1st and 3rd dose. * Compare pre-existing versus post-treatment antimitotic effects at 20h after the 1st dose, 20h after the 3rd dose, and 20h after the 10th, 11th, or 12th dose. * Correlate drug levels and distribution with biomarkers including mitotic index, aneuploidy, chromosomal instability, and Ki67. * Correlate pathologic response and clinical response with biomarkers including mitotic index, aneuploidy, CIN and Ki67. * To test if CIN increases in patient tumors in response to paclitaxel and to evaluate the feasibility of these measurements by genomic analysis. Initial Actual Primary and Study Completion Date registered as 8/16/2022 with 24 participants enrolled. Per a Protocol Amendment dated 5/7/24, this study will re-open to enroll up to 50 participants. NCI funding and data sharing information added.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Paclitaxel is an FDA approved medication for treatment of curable breast cancer and is available by prescription at pharmacies throughout the United States.
University of Iowa Health Care/Holden Comprehensive Cancer Center
Iowa City, Iowa, United States
NOT_YET_RECRUITINGUniversity of Wisconsin Carbone Cancer Center
Madison, Wisconsin, United States
RECRUITINGResponse 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
Time frame: Up to 3 months
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 79 days
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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.
Time frame: Baseline and 20 hours post-first dose
Correlate Drug Levels With Aneuploidy of Tumor
Correlate pathologic response and clinical response with biomarkers including aneuploidy
Time frame: Up to 3 months
Correlate Drug Levels With Chromosomal Instability of Tumor
Correlate pathologic response and clinical response with biomarkers including CIN
Time frame: 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.
Time frame: 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.
Time frame: Baseline and 20 hours post-first dose