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Trial of Lymphoseek in Intraoperative Localization of Lymph Nodes in Breast Cancer and Melanoma

Sponsor
Navidea Biopharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT00671918
Collaborator
(none)
186
Enrollment
15
Locations
1
Arm
15
Duration (Months)
12.4
Patients Per Site
0.8
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

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 (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.

Lymphatic mapping 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-99m-labeled diethylenetriamine pentaacetic 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
186 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Prospective, Open-Label, Multicenter Comparison Study of Lymphoseek® and Vital Blue Dye as Lymphoid Tissue Targeting Agents in Patients With Known Melanoma or Breast Cancer Who Are Undergoing Lymph Node Mapping
Study Start Date :
Apr 1, 2008
Actual Primary Completion Date :
Jun 1, 2009
Actual Study Completion Date :
Jul 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: Lymphoseek, Lymphatic mapping, Injection

Drug: Lymphoseek
Breast Cancer: Intradermal admin of Lymphoseek: Inject 0.2-0.4 mL in multiple divided injections or a single injection overlying the intact primary tumor or excision biopsy site OR periareolar administration of Lymphoseek: Inject 0.2-.04 mL in multiple divided doses at the margin of the areola OR subareolar administration of Lymphoseek: Inject 0.2-0.4 in multiple divided injections or a single injection in subareolar area as a subcutaneous injection OR peritumor administration of Lymphoseek: Inject 2.0-4.0 mL in multiple divided injections, intraparenchemally surrounding the tumor or biopsy cavity. For melanoma pts intradermal administration of Lymphoseek: Inject 0.2-0.4 mL in multiple divided injections or a single injection overlying the intact primary tumor or excision biopsy site.
Other Names:
  • technetium Tc 99m tilmanocept

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Concordance of Blue Dye and Lymphoseek [Surgery after injections of Lymphoseek and blue dye]

      The proportion of lymph nodes detected intraoperatively by blue dye that were also detected by Lymphoseek.

    Secondary Outcome Measures

    1. Reverse Concordance of Blue Dye and Lymphoseek [Surgery after injections of Lymphoseek and blue dye]

      The proportion of lymph nodes detected intraoperatively by Lymphoseek that were also detected by blue dye.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • The patient has provided written informed consent with HIPAA authorization before participating in the study, as has his/her responsible caregiver, if applicable.

    • The patient is a candidate for surgical intervention, with lymph node mapping being a part of the surgical plan.

    • The patient is at least 18 years of age at the time of consent.

    • The patient has an ECOG performance status of Grade 0 - 2 [8].

    • The patient has a clinical negative node status at the time of study entry.

    • If of child bearing 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.

    • The patient is currently not participating in another investigational drug study.

    Melanoma Patients

    • The patient has a diagnosis of primary melanoma.

    Breast Cancer Patients

    • The patient has a diagnosis of primary breast cancer.

    • Patients with pure ductal carcinoma in situ (DCIS) or non-invasive carcinoma if lymph node biopsy is part of the surgical plan.

    Exclusion Criteria:

    • The patient is pregnant or lactating;

    • 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);

    • The patient has a known hypersensitivity to Lymphazurin or Patent Bleu V.

    Melanoma Patients

    • The patient has a tumor with a Breslow depth less than 0.75mm.;

    • Patients that have had preoperative chemotherapy, immunotherapy or radiation therapy;

    • Patients 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;

    • Patients who have undergone node basin surgery of any type or radiation to the nodal basin(s) potentially draining the primary melanoma;

    • Patients who have 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

    • The patient has bilateral primary breast cancers or multiple tumors within their breast;

    • Patients that have had prior surgical procedures such as breast implants, reduction mammoplasty or axillary surgery;

    • Patients scheduled for bilateral mastectomy for any reason;

    • Patients that have had preoperative radiation therapy to the affected breast or axilla

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Barbara Michna, M.D Alexander City Alabama United States 35010
    2 Helen Krontiras, M.D. Birmingham Alabama United States 35294
    3 Anne Wallace, M.D. La Jolla California United States 92093
    4 Ken Deck, M.D. Laguna Hills California United States 92653
    5 Steve Martinez, M.D. Sacramento California United States 95817
    6 Mark Faries, M.D. Santa Monica California United States 90404
    7 Eli Avisar, M.D. Miami Florida United States 33101
    8 Charles Cox, M.D. Tampa Florida United States 33612
    9 Vernon Sondak, M.D. Tampa Florida United States 33612
    10 Julian Kim, M.D. Cleveland Ohio United States 44106
    11 Bruce Averbook, M.D Cleveland Ohio United States 44109
    12 Stephen Povoski, M.D. Columbus Ohio United States 43210
    13 Thomas Frazier, M.D. Bryn Mawr Pennsylvania United States 19010
    14 Ned Carp, M.D. Philadelphia Pennsylvania United States 19096
    15 Schlomo Schneebaum, M.D. Tel Aviv Israel 64239

    Sponsors and Collaborators

    • Navidea Biopharmaceuticals

    Investigators

    • Study Director: Richard Orahood, M.D., Navidea Biopharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Navidea Biopharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00671918
    Other Study ID Numbers:
    • NEO3-05
    First Posted:
    May 5, 2008
    Last Update Posted:
    Jun 17, 2013
    Last Verified:
    Jun 1, 2013
    Keywords provided by Navidea Biopharmaceuticals
    breast cancer
    lymph nodes
    melanoma
    surgery
    Additional relevant MeSH terms:
    Breast Neoplasms
    Melanoma

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Lymphoseek, Lymphatic Mapping, Injection
    Arm/Group Description Melanoma and breast cancer patients to receive a single dose of 50 μg Lymphoseek radiolabeled with 0.5 or 1.0 mCi Tc-99m and blue dye for lymphatic mapping and surgical resection of lymph nodes.
    Period Title: Overall Study
    STARTED 186
    COMPLETED 169
    NOT COMPLETED 17

    Baseline Characteristics

    Arm/Group Title Lymphoseek
    Arm/Group Description Enrolled patients who were administered any injection of Lymphoseek.
    Overall Participants 179
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    120
    67%
    >=65 years
    59
    33%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    58.5
    (14.1)
    Sex: Female, Male (Count of Participants)
    Female
    128
    71.5%
    Male
    51
    28.5%
    Region of Enrollment (participants) [Number]
    United States
    161
    89.9%
    Israel
    18
    10.1%

    Outcome Measures

    1. Primary Outcome
    Title Concordance of Blue Dye and Lymphoseek
    Description The proportion of lymph nodes detected intraoperatively by blue dye that were also detected by Lymphoseek.
    Time Frame Surgery after injections of Lymphoseek and blue dye

    Outcome Measure Data

    Analysis Population Description
    All enrolled patients who were injected with both Lymphoseek and blue dye, who underwent surgery and had at least one lymph node stained intraoperatively by blue dye, and for whom the tissue type (lymphatic/nonlymphatic) and pathology status (presence/absence of tumor cells) was confirmed.
    Arm/Group Title Intent-To-Treat
    Arm/Group Description Participants received a single dose of 50 μg Lymphoseek radiolabeled with 0.5 or 1.0 mCi Tc 99m and blue dye for lymphatic mapping and surgical resection of lymph nodes.
    Measure Participants 136
    Measure Lymph Nodes 215
    Number (95% Confidence Interval) [Proportion of Lymph Nodes]
    0.9767
    2. Secondary Outcome
    Title Reverse Concordance of Blue Dye and Lymphoseek
    Description The proportion of lymph nodes detected intraoperatively by Lymphoseek that were also detected by blue dye.
    Time Frame Surgery after injections of Lymphoseek and blue dye

    Outcome Measure Data

    Analysis Population Description
    All enrolled patients who were injected with both Lymphoseek and blue dye, who underwent surgery and had at least one lymph node detected by Lymphoseek (at ≥ 3σ count) in vivo, and for whom the tissue type (lymphatic/non-lymphatic) and pathology status (presence/absence of tumor cells) was confirmed.
    Arm/Group Title Reverse Intent-To-Treat
    Arm/Group Description Participants received a single dose of 50 μg Lymphoseek radiolabeled with 0.5 or 1.0 mCi Tc 99m and blue dye for lymphatic mapping and surgical resection of lymph nodes.
    Measure Participants 144
    Measure Lymph Nodes 306
    Number (95% Confidence Interval) [Proportion of Lymph Nodes]
    0.6863

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Lymphoseek
    Arm/Group Description Enrolled patients who were administered any injection of Lymphoseek.
    All Cause Mortality
    Lymphoseek
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Lymphoseek
    Affected / at Risk (%) # Events
    Total 4/179 (2.2%)
    Cardiac disorders
    Myocardial Infarction 1/179 (0.6%) 1
    Gastrointestinal disorders
    Nausea 1/179 (0.6%) 1
    Vomiting 1/179 (0.6%) 1
    Infections and infestations
    Cellulitis 1/179 (0.6%) 1
    Surgical and medical procedures
    Modified Radical Mastectomy 1/179 (0.6%) 1
    Other (Not Including Serious) Adverse Events
    Lymphoseek
    Affected / at Risk (%) # Events
    Total 10/179 (5.6%)
    Gastrointestinal disorders
    Nausea 10/179 (5.6%) 10

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The PI shall not submit a publication to journals or professional societies without the prior written approval of the Sponsor.

    Results Point of Contact

    Name/Title Dr. Frederick Cope
    Organization Navidea Biopharmaceuticals
    Phone 614-793-7500 ext 140
    Email fcope@navidea.com
    Responsible Party:
    Navidea Biopharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00671918
    Other Study ID Numbers:
    • NEO3-05
    First Posted:
    May 5, 2008
    Last Update Posted:
    Jun 17, 2013
    Last Verified:
    Jun 1, 2013