Neoadjuvant Weekly Paclitaxel and Biomarkers of Therapy Response

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.

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.

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 per institutional guidelines.
• A formalin-fixed paraffin embedded tumor block (preferred) or unstained slides must be available from a prior biopsy of the primary tumor (preferred) 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 institutional policy) 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 as determined by treatment physician.
• 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.