Neoadjuvant Weekly Paclitaxel and Biomarkers of Therapy Response

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.

Study Overview

• Status: Completed
• Conditions: Breast Neoplasm Female
• Intervention / Treatment: Drug: Paclitaxel

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Weekly Paclitaxel; 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; Paclitaxel is an FDA approved medication for treatment of curable breast cancer and is available by prescription at pharmacies throughout the United States.; Other Names: Taxol

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Investigators: Principal Investigator: Mark Burkard, University of Wisconsin, Madison

Publications and helpful links

General Publications

• Scribano CM, Wan J, Esbona K, Tucker JB, Lasek A, Zhou AS, Zasadil LM, Molini R, Fitzgerald J, Lager AM, Laffin JJ, Correia-Staudt K, Wisinski KB, Tevaarwerk AJ, O'Regan R, McGregor SM, Fowler AM, Chappell RJ, Bugni TS, Burkard ME, Weaver BA. Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel. Sci Transl Med. 2021 Sep 8;13(610):eabd4811. doi: 10.1126/scitranslmed.abd4811. Epub 2021 Sep 8.

Helpful Links

• UW Carbone Cancer Center Home Page

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2017
• Primary Completion (Actual): August 16, 2022
• Study Completion (Actual): August 16, 2022

Study Registration Dates

• First Submitted: March 16, 2017
• First Submitted That Met QC Criteria: March 23, 2017
• First Posted (Actual): March 30, 2017

Study Record Updates

• Last Update Posted (Actual): October 13, 2023
• Last Update Submitted That Met QC Criteria: October 11, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel
• Other Study ID Numbers: UW16106; A534260 (Other Identifier: UW Madison); SMPH\MEDICINE\HEM-ONC (Other Identifier: UW Madison); 2016-1489 (Institutional Review Board); NCI-2017-00338 (Registry Identifier: NCI CTRP); Protocol Version 8/23/2019 (Other Identifier: UW Madison)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No