Real-time Intraoperative Breast Cancer Visualization for Margin Assessment

Evaluation of LS301 Uptake in Tumors of Patients Undergoing Partial Mastectomy and Sentinel Lymph Node Biopsy for Breast Cancer

The investigators' preclinical data have demonstrated the feasibility of fluorescence-guided tumor resection by Cancer Vision Goggles (CVG) with LS301 in animal models. In this study, the investigators will conduct intraoperative imaging procedures that have minimal interference with ongoing surgery. The underlying hypothesis is that the accurate detection of all cancer cells highlighted by LS301 during surgery will reduce the number of breast cancer patients with margin positivity to less than 5%, compared to the current surgical paradigm of greater than 20%. The pilot study will obtain critical data required to address the larger question of surgical margin assessment in a full Phase I clinical trial.

Phase 1: to determine the safety and optimal imaging dose of LS301 injected in breast cancer patients.

Phase 2: to determine the ability of this novel fluorescence imaging agent to predict the presence of positive margins around partial mastectomy specimens and positive SLNs during surgical therapy for breast cancer.

A rolling six design which is intended for relatively safe trials and shortening the study duration is proposed for the phase 1 portion 74. In the rolling six design, three to six patients can be enrolled to a dose each time. The dose de-escalation occurs when two or more DLT occur at a dose level while dose escalation occurs when 3/3, 4/4, 5/5, 5/6 or 6/6 patients are evaluated without DLT 75. Three dose levels will be tested in the phase I study, 0.05, 0.075 and 0.10 mg/kg. LS301 will be administered intravenously at a starting dose of 0.05 mg/kg to a cohort of six patients and escalate/de-escalate following the decision rule of the rolling six design. Once six patients have been included at the current dose level, inclusions are suspended until at least five of the six patients have completed the procedure without DLT observed in the evaluation period. MTD is hit where two or more patients out of six at a dose level experience DLT. The investigators do not expect any serious adverse events related to LS301 at the initial Dose Level 1. Once the MTD is determined, an expansion cohort with 9 patients will be tested at the MTD and an optimal imaging dose will be recommended for the subsequent phase II trial.

At the completion of the expansion cohort, a single arm phase 2 trial will be performed at the optimal imaging dose. A breast surgeon will perform breast conserving surgery per standard of care. At the completion of the surgery, a second investigator (to reduce bias in data collection) will wear the cancer vision goggle (CVG) to visualize the excised tissue to determine if there are any positive margins based on the presence of LS301 fluorescence. If any positive margins are observed, the subject will be considered to have a positive margin; otherwise, the margin is considered negative. The excised tissue will later be examined by a breast cancer pathologist. Standard pathologic techniques will be used to determine if there are positive margins. Particular attention will be paid to the sites marked following CVG assessment to confirm whether the margin is positive or negative at any of these sites, or positive at other locations not identified by CVG. No interventions will be allowed based on the CVG results.

This study was initiated at Washington University in St. Louis and is being transferred to UTSW. Phase 1a was initiated at Washington University in St. Louis where 9 subjects were enrolled. The PI is continuing with Phase 1B at UTSW where 9 more subjects will be enrolled. Once completed, the results of Phase 1 (a and b) will be sent to the FDA for review. Phase II will begin once the FDA has reviewed the interim data and authorized Phase II to open. After phase 1 data has been submitted to and discussed with the FDA, an additional cohort of 88 patients will be enrolled to the phase 2 portion of the trial to assess the diagnostic capabilities of LS301 for identification of positive margins at surgery. FDA-approved fluorescence imaging systems may be used to benchmark CVG data.

Inclusion Criteria:

• Newly diagnosed Stage I-II breast cancer patients undergoing breast-conserving therapy and SLN biopsy.
• Negative nodal basin clinical exam.
• At least 18 years of age.
• Able to understand and willing to sign a written informed consent document.

Exclusion Criteria:

• Contraindications for surgery.
• Receiving any investigational agents.
• History of allergic reactions attributed to ICG or other agents used in the study, include known iodide or seafood allergy. The investigators do not expect many of these adverse reactions with LS301 because it is not radioactive and does not possess iodinated counter ions.
• Presence of underlying lung disease
• Pregnant. Female patients of childbearing potential must have a negative serum or urine pregnancy test no more than 7 days before start of participation.
• Breastfeeding. Patients who are breastfeeding are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LS301.