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Aminolevulinic Acid

Photosensitizing Agents

Patients in this arm will receive the placebo orally approximately 3 hrs prior to anesthesia followed by standard of care BCS. Fluorescence imaging will be performed on tissue specimens resected prior to completion of standard of care resection. Fluorescence-guided resection will not be performed in patients in this arm.

Patients in this arm will receive PD G 506 A orally approximately 3 hrs prior to anesthesia followed by standard of care BCS. Fluorescence imaging will be performed on tissue specimens resected prior to completion of standard of care resection. Fluorescence imaging performed after SoC BCS is complete will guide the resection of additional tissue.

PD G 506 A for oral solution (aminolevulinic acid \[ALA\] hydrochloride \[HCl\] granules for oral solution) is administered as a single dose (20 mg/kg body weight) approximately 3 hours (min 2 hours, max 4 hours) prior to anesthesia.

Aminolevulinic Acid Hydrochloride

Fluorescence imaging camera and associated accessories used to view and capture fluorescence and white light images and videos of the surgical cavity and excised tissue specimens during the surgical procedure.

Eagle V1.2 Imaging System

Oral placebo is administered as a single dose approximately 3 hours (min 2 hours, max 4 hours) prior to anesthesia.

Placebo

Maeve Richmond

Jagapreetha Visweswaran

Jennifer Durand, RN

Melinda Porter, RN

Terry P. Mamounas, MD

Melissa Suarez

Linda Castellanos

Sheldon M. Feldman, MD

Christian Donahoe, RN

Nicole Zaremba, MD

Ralph DaCosta, PhD

Breast conserving surgery (BCS) is performed on patients with breast cancer to resect and completely remove the cancer while conserving as much of the surrounding healthy tissue as possible. Current methods do not allow surgeons to determine the completeness of surgical resection in real-time. This often results in the need for a second surgical procedure, or in some cases more than two surgical procedures in order to have confidence that all cancer has been removed.

This Phase 3 study will evaluate the safety and efficacy of the fluorescent imaging agent PD G 506 A for the real-time visualization of cancer during standard of care breast conserving surgery. PD G 506 A is an investigational drug which is converted in the body into a fluorescent molecule that accumulates in cancer cells. Patients receiving PD G 506 A will undergo standard of care breast conserving surgery followed by fluorescence imaging and removal of any potentially cancerous tissue left behind in the surgical cavity.

Re-operations due to positive margins following breast conserving surgery (BCS) increase poor cosmesis, complications, discomfort, stress, adjuvant delay, medical costs and risk of local recurrence. Reducing positive margin rates can be achieved through optimizing surgical procedures. This study evaluates a new method for surgeons to visualize carcinoma in real-time, both in the surgical cavity and on the margins of excised specimen(s) during the index BCS procedure.

The active ingredient of PD G 506A is aminolevulinic acid hydrochloride (ALA HCl). ALA HCl is a prodrug that is metabolized intracellularly to form the fluorescent molecule protoporphyrin IX (PpIX). The exogenous application of ALA HCl leads to a highly selective accumulation of PpIX in malignant tissues.

This Phase 3, 2-part, single-blind \[pathologist(s)-blinded\] randomized placebo-controlled trial study is designed to evaluate the efficacy and safety of PD G 506 A to aid in the visualization of carcinoma during BCS. The Eagle V1.2 Imaging System will be used in this trial to visualize PpIX fluorescence.

Part A is an open-label training phase of the study to optimize workflow and Part B of the study is randomized and single-blind and will serve as the pivotal portion of the study.

Part A of the study is open-label. All patients in Part A will receive the investigational drug and will undergo standard of care breast conserving surgery (BCS) followed by fluorescence-guided resection. Part B of the study is randomized and placebo controlled; patients will be randomized to receive placebo + standard of care BCS alone or PD G 506 A + SoC BCS followed by fluorescence-guided resection.

In Part B, the participant and pathologist will be blind to treatment arm allocation for the duration of the study. The surgeon will be blind to treatment arm allocation up until the time that standard of care resection is complete. The blind will be broken during the surgical procedure after the surgeon declares standard of care resection complete.

Fluorescence Imaging of Carcinoma During Breast Conserving Surgery

A Prospective Multi-center Clinical Study Evaluating the Use of PD G 506 A and the Eagle V1.2 Imaging System for the Visualization of Carcinoma During Breast Conserving Surgery

Percentage of patients with negative-margins following fluorescence-guided resection (FGR) among patients with positive margins following standard of care (SoC)

Patient-level specificity to identify residual carcinoma

Patient-level sensitivity to identify residual carcinoma

Orientation-level diagnostic performance of PD G 506 A-induced fluorescence to determine the presence or absence of cancer in the surgical cavity as compared to margin histopathology.

Percentage of patients with at least one histopathology-positive margin following SoC who then have ALL histopathology-negative margins following FGR, among all patients imaged.

Patient-level sensitivity, specificity, NPV, PPV of PD G 506 A-induced fluorescence to determine the presence or absence of residual cancer

Patient-level sensitivity, specificity, PPV and NPV to determine the presence or absence of residual cancer in the surgical cavity at the end of FGR (using modified patient-level definitions)

Patient-level sensitivity, specificity, PPV and NPV to determine the presence or absence of cancer in the surgical cavity after SoC BCS.

Patient-level sensitivity, specificity, PPV and NPV to determine the presence or absence of cancer in the surgical cavity after SoC (using modified patient-level definitions).

Percentage of patients assessed as residual tumor negative at the end of FGR who had positive final margins on histopathology

Percentage of patients in whom SOC final margins were carcinoma negative and all FL-driven shave specimens are carcinoma-negative

Percentage of patients with histopathology-negative margins at the end of SoC who have at least one orientation that was both FL-positive and histopathology-positive among (1) patients with histopathology negative final margins after SOC and (2) all patients imaged

Percentage of patients with no fluorescence identified at the end of SoC in whom all final margins after SoC are histopathologically confirmed to be negative for carcinoma.

Patient-level in vivo diagnostic performance of PD G 506 A-induced fluorescence to determine the presence or absence of residual cancer in the surgical cavity at the end of FGR as compared to the final margin histopathology.

Percentage of orientations where in vivo and ex vivo fluorescence assessments are discordant.

Percentage of patients receiving a 2nd surgery on the ipsilateral breast within 1 year of index BCS to remove suspected residual disease.

Percentage of patients receiving an early 2nd surgery (planned or actual) on the ipsilateral breast related to positive final margins.

Weight (mg) of all tissue removed based on SoC and/of FGR

Patient satisfaction with the cosmetic outcome of breast conserving surgery performed based on SoC in combination with PD G 506 A and the Eagle V1.2 Imaging System

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