Fluorescence Imaging of Carcinoma During Breast Conserving Surgery

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.

Eligibility Criteria:
Inclusion Criteria:

1. Female, 18 years or older
2. Histologically or cytologically confirmed primary breast cancer (includes invasive lobular carcinoma, invasive ductal carcinoma, inflammatory breast cancer, papillary breast cancer, adenoid cystic carcinoma of the breast, mucinous breast cancer, metaplastic breast cancer, cribriform carcinoma and ductal carcinoma in situ, alone or in combination with invasive disease)
3. Scheduled for a lumpectomy (including bilateral lumpectomy) of a breast malignancy (eligibility for breast conserving surgery/partial mastectomy based on clinical staging using TNM staging system (AJCC Cancer Staging Manual: Breast Cancer, 8th Edition70).
4. Patient must have normal organ and bone marrow function and be appropriate surgical candidate per site standard of care
5. Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) starting the day entering the study, and for the duration of the study period (until the Week 2 visit)

Exclusion Criteria:

1. Currently on (neo)adjuvant therapy to treat another cancer
2. Receiving or intended to receive neoadjuvant therapy to treat the primary breast cancer (including chemotherapy, endocrine therapy and radiotherapy)
3. Stage 4 cancer, inclusive of metastatic disease
4. Non-invasive diseases of the breast (includes lobular carcinoma in situ, phyllodes and Paget's disease of the breast)
5. Patients who have had the following procedures performed on the involved breast:

   1. Surgery for a benign lesion(s) within 1 year of the BCS date
   2. Breast implants inserted within 1 year of the BCS date
   3. Breast reduction, surgery for malignant disease or mastectomy (at any time prior to the BCS date)
   4. Surgery for a benign lesion(s) or insertion of implants \>1 year prior to the BCS date and who have signs of ongoing inflammation, active tissue healing and/or extensive scarring
   5. Radiation at any time prior to the BCS date and who have signs of ongoing inflammation, active tissue healing and/or extensive scarring
6. Patients for whom intraoperative frozen section analysis is planned
7. Patients who have not recovered from adverse events due an investigational pharmaceutical or diagnostic agents administered more than 30 days prior to their scheduled surgical procedure
8. History of hypersensitivity to ALA HCl or porphyrins
9. Known or documented personal or family history of porphyria
10. Patient has a recording of any parameter as defined below:

    1. Bilirubin: Above upper limit of normal
    2. Aspartate aminotransferase (SGOT): \> 2.5 X institutional upper limit of normal
    3. Alanine aminotransferase ( (SGPT): \> 2.5 X institutional upper limit of normal
11. Patient has serum creatinine \>1.5 times institutional upper limit of normal, OR calculated creatinine clearance \> 60 mL/min/1.73 m² for patients with creatinine levels above institutional normal.
12. Uncontrolled concurrent illness, that in the opinion of the Investigator would prevent the patient from participation in the study, including but not limited to:

    1. Ongoing or active infection;
    2. Cardiovascular disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia).
13. Patients who have the following collagen vascular diseases:

    1. Lupus
    2. Scleroderma
14. Use of an investigational drug within 30 days of their scheduled surgical procedure
15. Simultaneous use of other potentially phototoxic substances (such as St. John's wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones and tetracyclines), and topical preparations containing ALA for 24 hours during the perioperative period.
16. Social or medical situations including uncontrolled psychiatric illnesses that would in the opinion of the Investigator limit compliance with study requirements (e.g. ability to travel for follow-up)
17. Patients who are pregnant or become pregnant (it is unknown if ALA HCl is teratogenic or has abortifacient effects)
18. Patients who are breast feeding (there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ALA HCl, breastfeeding should be discontinued if the mother is treated with ALA HCl)
19. Inability to consent