Breast and Melanoma Trial With Lymphoseek to Identify Lymph Nodes

Data from this pivotal clinical trial will be used to support a marketing application (i.e., NDA) of Navidea's Lymphoseek for use in anatomical delineation of lymphoid tissue (nodes) in the lymphatic pathway draining the primary site of a tumor.

Multicenter, open-label, within-patient comparative study of Lymphoseek and vital blue dye in the detection of excised lymph nodes in patients with known melanoma and breast cancer. All patients will receive a single dose of 50 µg Lymphoseek radiolabeled with 0.5 or 2.0 mCi Tc 99m and vital blue dye.

In patients with primary melanoma and breast cancer, lymph node status is often a strong predictor of outcome and influences the course of treatment a patient may follow after surgery. In an effort to reduce the morbidity and costs of detection of lymph node metastases, surgical oncologists have developed a method by which the sentinel lymph node (SLN; the first node in a draining basin) is identified intraoperatively and removed. This technique, called sentinel node biopsy, has extremely high negative predictive values for melanoma metastases and breast cancer metastases. The two largest trials for melanoma, Morton, et al (2005) and Rossi, et al (2006), reported false negative rates of 6.3% and 14.7%, respectively. Morton, et al (2006), in perhaps the most mature trial reported to date, showed a false negative rate of 3.4%. There is growing evidence that sentinel node biopsy will have a significant impact on the management of melanoma. Sentinel node biopsy also has extremely high negative predictive values for breast cancer metastases; the false-negative rates range from 0% to 9%. There is growing evidence that sentinel node biopsy will have a significant impact on the management of breast cancer. Although the survival and local recurrence studies have yet to be completed, the technique has emerged into common practice.

Intraoperative lymphatic mapping (ILM) with a radiopharmaceutical is a nuclear medicine examination which identifies for the surgeon the first lymph node to receive lymphatic flow from the primary tumor site. This node is removed and analyzed for the presence of malignant cells. By locating the lymph node prior to surgery, a small incision can be used to remove the node and a smaller dissection can be employed. The high negative predictive value of the technique seems to provide an accurate staging procedure and may spare patients who are lymph node negative the morbidity of a complete lymph node dissection. Consequently, staging of melanoma by lymph node mapping and biopsy may be equivalent to regional node dissection without the attendant post surgical morbidity.

An ideal lymph node imaging agent would exhibit rapid clearance from the injection site, rapid uptake and high retention within the first draining lymph node, and low uptake by the remaining lymph nodes. The ideal agent would also have low radiation absorption; high biological safety; convenient, rapid, and stable technetium-99m labeling; and biochemical purity.

Lymphoseek (Technetium Tc 99m diethylenetriaminepentaacetic acid mannosyl dextran, \[Tc 99m\] DTPA Mannosyl Dextran) is a radiotracer that accumulates in lymphatic tissue by binding to a mannose binding protein that resides on the surface of dendritic cells and macrophages. Lymphoseek is a macromolecule consisting of multiple units of DTPA and mannose, each synthetically attached to a 10 kilodalton dextran backbone. The mannose acts as a substrate for the receptor, and the DTPA serves as a chelating agent for labeling with Tc 99m.

Lymphoseek has a diameter of about 5 nm, which is substantially smaller than current agents used for targeting lymphoid tissue. Lymphoseek's small diameter permits enhanced diffusion into lymph nodes and blood capillaries, resulting in a rapid injection site clearance. Upon entry into the blood, the agent binds to receptors in the liver or is filtered by the kidney and accumulates in the urinary bladder.

Eligibility Criteria:
Inclusion Criteria:

1. The patient has provided written informed consent with HIPAA authorization.
2. The patient is a candidate for surgical intervention, with lymph node mapping being a part of the surgical plan.
3. The patient is at least 18 years of age at the time of consent.
4. The patient has an ECOG performance status of Grade 0 - 2 (see Appendix A).
5. The patient has a clinical negative node status at the time of study entry (i.e. T0-4, N0, M0, see Appendix D and E).
6. If of childbearing potential, the patient has a negative pregnancy test within 72 hours prior to administration of Lymphoseek, has been surgically sterilized, or has been postmenopausal for at least 1 year.

   Melanoma Patients
7. The patient has a diagnosis of primary melanoma. Breast Cancer Patients
8. The patient has a diagnosis of primary breast cancer.
9. Patients with pure ductal carcinoma in situ (DCIS) or non-invasive carcinoma if lymph node biopsy is part of the surgical plan.

Exclusion Criteria:

1. The patient is pregnant or lactating.
2. The patient has clinical or radiological evidence of metastatic cancer including palpably abnormal or enlarged lymph nodes (i.e., all patients should be any T,N0,M0, see Appendix D and E).
3. The patient has a known hypersensitivity to Lymphazurin.
4. The patient has participated in another investigational drug study within 30 days of scheduled surgery.

   Melanoma Patients
5. The patient has a tumor with a Breslow depth less than 0.75mm.
6. Patient has had preoperative chemotherapy, immunotherapy, or radiation therapy.
7. Patient has been diagnosed with a prior invasive melanoma that would occur on the same body region or potentially draining to the same nodal basin or patients with truncal or extremity primary melanoma who has had a prior breast cancer potentially draining to the same axillary nodal basin.
8. Patient has undergone node basin surgery of any type or radiation to the nodal basin(s) potentially draining the primary melanoma.
9. Patient has undergone a wide excision for their primary melanoma (\>1 cm in dimension) or complex reconstruction (rotation, free flap, or skin graft of any type).

   Breast Cancer Patients
10. The patient has bilateral primary breast cancers or multiple tumors within their breast.
11. Patient has had prior surgical procedures such as breast implants, reduction mammoplasty, or axillary surgery.
12. Patient is scheduled for bilateral mastectomy unless for cosmetic reasons and the contraindicated breast will not undergo lymph node mapping.
13. Patient has had preoperative radiation therapy to the affected breast or axilla.