<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03233828</url>
  </required_header>
  <id_info>
    <org_study_id>4387</org_study_id>
    <nct_id>NCT03233828</nct_id>
  </id_info>
  <brief_title>Pre-Treatment of Highly Suspicious Pigmented Skin Lesions With Interleukin-2</brief_title>
  <acronym>IL-2</acronym>
  <official_title>Pre-Treatment of Highly Suspicious Pigmented Skin Lesions With Interleukin-2</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Carman Giacomantonio</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Nova Scotia Health Authority</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Nova Scotia Health Authority</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is meant to assess the use of intralesional IL-2 to modulate the immunological&#xD;
      response to suspected melanoma, or melanoma in situ, in an effort to increase lymphocyte&#xD;
      infiltration and decrease disease metastasis.&#xD;
&#xD;
      Patients that are clinically diagnosed with suspected Melanoma or Melanoma in situ will be&#xD;
      assigned to either a treatment or control arm. The treatment group will be subjected to two&#xD;
      intralesional IL-2 injections, whereas the control group will be subjected to two&#xD;
      intralesional injections of saline.&#xD;
&#xD;
      The proteomic and metabolomic profiles of both groups will be analyzed using urine and blood&#xD;
      samples in an effort to assess the systemic immunological response, if any, to the treatment.&#xD;
      Also, upon disease confirmation and staging by a qualified pathologist, lesions will be&#xD;
      assessed for lymphocyte infiltration using immunohistochemical methods.&#xD;
&#xD;
      This study will determine whether pre-treatment of IL-2 on lesions (clinically diagnosed as&#xD;
      melanoma or melanoma in situ) is effective in generating an adaptive immune response, and&#xD;
      whether that immune response may play a role in preventing disease metastasis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is primarily designed to determine if tumor specific immunity can be generated in&#xD;
      patients with highly suspicious pigmented lesions in response to intralesional IL-2, and&#xD;
      whether that immunity can confer resistance to melanoma metastasis. Patients will be&#xD;
      identified by qualified dermatologists and interviews will be held at the surgery clinic (4th&#xD;
      floor Dickson Center) QEII HSC, NSHA.&#xD;
&#xD;
      The standard wait time from consultation to surgical biopsy is up to 4 weeks. Investigators&#xD;
      will ensure that patients are seen immediately upon notification from participating&#xD;
      dermatologist and all research components of the study are completed within the normally&#xD;
      anticipated wait time. Through utilization of this standard wait time, intralesional IL-2 can&#xD;
      potentially affect an immune response, that otherwise could not be achieved after the biopsy&#xD;
      is completed. Given that the study is conducted within the normal wait time, it doesn't&#xD;
      deviate from the normal standard of care. Following the study protocol, patients will receive&#xD;
      intralesional injections on Day 1(Week 1 Visit) and Day 8 (Week 2 Visit), and excisional&#xD;
      biopsies will be performed on Day 15 (Week 3 Visit), well within the accepted wait time from&#xD;
      consultation to biopsy. The intralesional injections and collection of biospecimens beyond&#xD;
      the biopsy deviate from but does not delay the normal standard of care. Two additional visits&#xD;
      are required in addition to the initial consultation.&#xD;
&#xD;
      This study is a randomized, controlled, double-blind study. Patients with highly suspicious&#xD;
      pigmented lesions will be randomly assigned by an algorithm to one of two groups: 1)&#xD;
      treatment group patients will be treated intralesionally with IL-2 (Proleukin (Aldesleukin),&#xD;
      Novartis Pharmaceuticals Canada Inc.) at a dose of 500,000 International Units (IU) in 0.1ml&#xD;
      of sterilized saline (0.9%, m/v) for 2 treatment cycles 1 week apart (Day 1 and Day 7); 2)&#xD;
      control group patients will be treated intralesionally with sterilized saline (0.9%, m/v) of&#xD;
      the same volume (0.1ml). Randomization will be generated by a Random Block algorithm for each&#xD;
      patient, and instruction preparation for each patient will be sent to pharmacy. IL-2&#xD;
      (Proleukin) will be obtained from Novartis by the pharmacy, paid for by Dr. Carman&#xD;
      Giacomantonio's research services account. The pharmacy will be given instruction to prepare&#xD;
      either IL-2 treatment or injectable control (saline). The pharmacy will assign a codified ID&#xD;
      which will be provided along with the syringe with the patient name labeled as&#xD;
      &quot;Interleukin-2/Placebo&quot; (thus blinding study to clinician and patient). As a pilot study, the&#xD;
      principle of the design is to test the feasibility of proceeding to a larger and more&#xD;
      expensive trial following the methodology and protocol proposed. As such there will be a&#xD;
      minimum of 20 (10 treatment, 10 placebo) participants (up to a maximum of 60). It is&#xD;
      estimated that statistical significance will be reached with 20 patients, however if it is&#xD;
      not reached after 20 patients, an additional 10 (5 treatment, 5 control) patients will be&#xD;
      enrolled. If significance is still not reached after 30 patients, an additional 10 patients&#xD;
      will be enrolled and so on up to a maximum of 60 patients. If after 60 patients, significance&#xD;
      is not achieved then further recruitment under the current protocol would not be logical and&#xD;
      therefore the methodology would need to be revised or study discontinued.&#xD;
&#xD;
      On Day 1 (first treatment) and 15 (excisional biopsy), all patients will have blood (4 vials)&#xD;
      and urine (25-50 ml) samples taken. Local reactions to injections will be monitored for non-&#xD;
      specific signs such as bleeding, arythema, infection, or irritation. Investigators do not&#xD;
      anticipate specific changes in the pigmented lesion related to the injection in this short&#xD;
      time period, however all changes will be noted.&#xD;
&#xD;
      On Day 15, following the second intralesional injection an excisional biopsy will be&#xD;
      performed following standard surgical techniques, as follows: ellipse of skin encompassing&#xD;
      the pigmented lesion extending into the subcutaneous fat will be performed to achieve a&#xD;
      grossly clear but narrow margin of excision. This small defect will be closed primarily with&#xD;
      interrupted sutures. The biopsied specimen will be subsequently evaluated using standard&#xD;
      histological techniques to confirm diagnoses, assess margin status (clear or involved) and&#xD;
      depth of lesion invasion. The depth of lesion invasion will dictate the extent of subsequent&#xD;
      surgical excisions and margin selection according to standard National Comprehensive Cancer&#xD;
      Network (NCCN) guidelines. Pre-biopsy intralesional injections of 0.1ml into the lesion will&#xD;
      not alter dimensions or architecture of the lesion or impact the extent the subsequent biopsy&#xD;
      required. Lesions that are felt to be too large for closure without tissue manipulation or&#xD;
      creation of flaps, will be biopsied using a punch biopsy sampling technique whereby 4mm&#xD;
      diameter discs of tissue from representative areas of the lesion will be taken to confirm the&#xD;
      diagnosis and the depth of invasion. The depth of invasion will dictate the extent and&#xD;
      complexity of subsequent surgery required to remove the lesion and achieve clear margins&#xD;
      according to NCCN guidelines. The biopsied specimen will be processed as follows: using a 22G&#xD;
      needle a fine needle aspiration biopsy will be performed (the needle will be passed through&#xD;
      the center of the lesion two times) for RNA analysis. The remainder of the tissue will be&#xD;
      sent to pathology for standard histological assessment. The pathologist will also report the&#xD;
      extent of observed tumor infiltrating lymphocytes (TILs) associated with treatment compared&#xD;
      to control injections. Blood and urine will be assessed using metabalomic and proteomic&#xD;
      methods to assess systemic immune response to treatment.&#xD;
&#xD;
      All blood, urine, and lesion biopsy samples will be labeled with a codified number (will not&#xD;
      contain any patient identifying information) and will be immediately transported to Dr.&#xD;
      Carman Giacomantonio laboratory at Dalhousie University for storage. Fine needle aspiration&#xD;
      of excised samples will be assessed for tumor genetic and epigeneitic profile. Blood and&#xD;
      urine will be assessed for proteomic and metabolomic profiles, respectively.&#xD;
&#xD;
      All study participants will receive assessments every 4 months for 2 years and biannual&#xD;
      assessments for years 3 to 5 after the initial intervention to assess disease progression, or&#xD;
      the development of new melanoma, to compare between both treatment and control groups. There&#xD;
      is no standardize test or measurable biomarker to assess established or lasting immunity.&#xD;
      This aspect of the study is identical to the patient assessment conducted as per standard of&#xD;
      care for melanoma patients. Again, any publications of study results will be completed devoid&#xD;
      of any information that could be used to identify patients included in the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Low enrollment numbers.&#xD;
  </why_stopped>
  <start_date type="Actual">December 19, 2018</start_date>
  <completion_date type="Actual">September 1, 2022</completion_date>
  <primary_completion_date type="Actual">September 1, 2022</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Patients will be given either intralesional IL-2 or intralesional saline as a control</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Assessment of Number of Patients Needed to Obtain Significance</measure>
    <time_frame>1 year</time_frame>
    <description>Data will be analyzed in order to achieve a statistically significant differentiation between treatment and control outcomes in study measures including tumor infiltrating lymphocytes (TILs) and circulating immunomodulators.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of Metastasis</measure>
    <time_frame>5 years</time_frame>
    <description>All patients will receive assessments every 4 months for 2 years and then biannual assessments for years 3-5 after the initial intervention to assess disease metastasis in treatment and control groups. Both number of new metastases (integer value) and thickness (mm) will be measured as a part of this assessment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assessment of RNA genetic profile</measure>
    <time_frame>5 years</time_frame>
    <description>RNA analysis of excised tissue will be compared to unaffected patient tissue obtained from the clear margins of the excisional biopsy to assess genetic changes resulting from the melanoma and treatment/placebo injections.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Systemic Immune Response: Proteomic Analysis</measure>
    <time_frame>5 years</time_frame>
    <description>Proteomic analysis will be conducted on blood samples to assess systemic immune response to both treatment and control groups. Serum collected from patient blood samples will be used for proteomic analysis to assess protein expression, including circulating immunomodulators (cytokines and chemokines) before, and after, treatment. This study may serve to help develop diagnostic protocols and methods of assessing response to treatments.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Systemic Immune Response: Metabolomic Analysis</measure>
    <time_frame>5 years</time_frame>
    <description>Metabolomic analysis will be conducted on urine samples to assess systemic immune response to both treatment and control groups. All tumor and tissue produce by products in waste that are excreted by the kidneys. Urine samples can be evaluated using techniques, such as Mass Spectrometric, to determine if biological compounds can be identified in association with the presence of a malignant process that would not be produced by normal tissue.This study may serve to help develop diagnostic protocols and methods of assessing response to treatments.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Melanoma (Skin)</condition>
  <condition>Melanoma in Situ</condition>
  <arm_group>
    <arm_group_label>Intralesional IL-2 Injection</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Two subcutaneous intralesional injections of Aldesleukin, prepared by the pharmacy such that the contents will be masked, will be administered by the care provider in a clinic seven days apart.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Saline Injection</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Two subcutaneous intralesional injections of Saline, prepared by the pharmacy such that the contents will be masked, will be administered by the care provider in a clinic seven days apart.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Aldesleukin</intervention_name>
    <description>500,000 IU in 0.1mL</description>
    <arm_group_label>Intralesional IL-2 Injection</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Saline</intervention_name>
    <description>0.1 mL of sterile saline solution (0.9% m/v)</description>
    <arm_group_label>Saline Injection</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  The participant population will include patients characterized by: nodular/polypoid&#xD;
             features, bleeding/ulcerated lesions, excluding face and vulvo-genital lesions.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants who are not: currently immunocompromized, on immuno-therapy for other&#xD;
             diagnosis, have known inflammatory or autoimmune diseases or are otherwise&#xD;
             incapacitated.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carman A Giacomantonio, MD, FRCSC</last_name>
    <role>Principal Investigator</role>
    <affiliation>Surgical Oncologist / General Surgeon / Professor</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Queen Elizabeth II Health Sciences Centre</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <zip>B3H3G1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <link>
    <url>http://www.skincancer.org/skin-cancer-information/melanoma/melanoma-treatments/treatment-of-metastatic-melanoma</url>
    <description>New treatments for metastatic melanoma</description>
  </link>
  <reference>
    <citation>Ranieri JM, Wagner JD, Wenck S, Johnson CS, Coleman JJ 3rd. The prognostic importance of sentinel lymph node biopsy in thin melanoma. Ann Surg Oncol. 2006 Jul;13(7):927-32. doi: 10.1245/ASO.2006.04.023. Epub 2006 May 22.</citation>
    <PMID>16788753</PMID>
  </reference>
  <reference>
    <citation>Sandru A, Voinea S, Panaitescu E, Blidaru A. Survival rates of patients with metastatic malignant melanoma. J Med Life. 2014 Oct-Dec;7(4):572-6.</citation>
    <PMID>25713625</PMID>
  </reference>
  <reference>
    <citation>Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004 Sep 2;351(10):998-1012. doi: 10.1056/NEJMra041245. No abstract available. Erratum In: N Engl J Med. 2004 Dec 2;351(23):2461.</citation>
    <PMID>15342808</PMID>
  </reference>
  <reference>
    <citation>Hersey P, Gallagher S. Intralesional immunotherapy for melanoma. J Surg Oncol. 2014 Mar;109(4):320-6. doi: 10.1002/jso.23494. Epub 2013 Dec 3.</citation>
    <PMID>24301265</PMID>
  </reference>
  <reference>
    <citation>Sloot S, Rashid OM, Sarnaik AA, Zager JS. Developments in Intralesional Therapy for Metastatic Melanoma. Cancer Control. 2016 Jan;23(1):12-20. doi: 10.1177/107327481602300104.</citation>
    <PMID>27009452</PMID>
  </reference>
  <reference>
    <citation>Boyd KU, Wehrli BM, Temple CL. Intra-lesional interleukin-2 for the treatment of in-transit melanoma. J Surg Oncol. 2011 Dec;104(7):711-7. doi: 10.1002/jso.21968. Epub 2011 Jul 8.</citation>
    <PMID>21744347</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 27, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>February 13, 2023</last_update_submitted>
  <last_update_submitted_qc>February 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Nova Scotia Health Authority</investigator_affiliation>
    <investigator_full_name>Carman Giacomantonio</investigator_full_name>
    <investigator_title>Surgical Oncologist / General Surgeon / Professor</investigator_title>
  </responsible_party>
  <keyword>Intralesional Injection</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>Immune Response</keyword>
  <keyword>Interleukin-2 (Aldesleukin)</keyword>
  <keyword>Tumor Infiltration</keyword>
  <keyword>Metastasis Prevention</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Pigmentation Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aldesleukin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03233828
org study id: 4387
nct id: NCT03233828
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This study is meant to assess the use of intralesional IL-2 to modulate the immunological
      response to suspected melanoma, or melanoma in situ, in an effort to increase lymphocyte
      infiltration and decrease disease metastasis.

      Patients that are clinically diagnosed with suspected Melanoma or Melanoma in situ will be
      assigned to either a treatment or control arm. The treatment group will be subjected to two
      intralesional IL-2 injections, whereas the control group will be subjected to two
      intralesional injections of saline.

      The proteomic and metabolomic profiles of both groups will be analyzed using urine and blood
      samples in an effort to assess the systemic immunological response, if any, to the treatment.
      Also, upon disease confirmation and staging by a qualified pathologist, lesions will be
      assessed for lymphocyte infiltration using immunohistochemical methods.

      This study will determine whether pre-treatment of IL-2 on lesions (clinically diagnosed as
      melanoma or melanoma in situ) is effective in generating an adaptive immune response, and
      whether that immune response may play a role in preventing disease metastasis.
This study is primarily designed to determine if tumor specific immunity can be generated in
      patients with highly suspicious pigmented lesions in response to intralesional IL-2, and
      whether that immunity can confer resistance to melanoma metastasis. Patients will be
      identified by qualified dermatologists and interviews will be held at the surgery clinic (4th
      floor Dickson Center) QEII HSC, NSHA.

      The standard wait time from consultation to surgical biopsy is up to 4 weeks. Investigators
      will ensure that patients are seen immediately upon notification from participating
      dermatologist and all research components of the study are completed within the normally
      anticipated wait time. Through utilization of this standard wait time, intralesional IL-2 can
      potentially affect an immune response, that otherwise could not be achieved after the biopsy
      is completed. Given that the study is conducted within the normal wait time, it doesn't
      deviate from the normal standard of care. Following the study protocol, patients will receive
      intralesional injections on Day 1(Week 1 Visit) and Day 8 (Week 2 Visit), and excisional
      biopsies will be performed on Day 15 (Week 3 Visit), well within the accepted wait time from
      consultation to biopsy. The intralesional injections and collection of biospecimens beyond
      the biopsy deviate from but does not delay the normal standard of care. Two additional visits
      are required in addition to the initial consultation.

      This study is a randomized, controlled, double-blind study. Patients with highly suspicious
      pigmented lesions will be randomly assigned by an algorithm to one of two groups: 1)
      treatment group patients will be treated intralesionally with IL-2 (Proleukin (Aldesleukin),
      Novartis Pharmaceuticals Canada Inc.) at a dose of 500,000 International Units (IU) in 0.1ml
      of sterilized saline (0.9%, m/v) for 2 treatment cycles 1 week apart (Day 1 and Day 7); 2)
      control group patients will be treated intralesionally with sterilized saline (0.9%, m/v) of
      the same volume (0.1ml). Randomization will be generated by a Random Block algorithm for each
      patient, and instruction preparation for each patient will be sent to pharmacy. IL-2
      (Proleukin) will be obtained from Novartis by the pharmacy, paid for by Dr. Carman
      Giacomantonio's research services account. The pharmacy will be given instruction to prepare
      either IL-2 treatment or injectable control (saline). The pharmacy will assign a codified ID
      which will be provided along with the syringe with the patient name labeled as
      "Interleukin-2/Placebo" (thus blinding study to clinician and patient). As a pilot study, the
      principle of the design is to test the feasibility of proceeding to a larger and more
      expensive trial following the methodology and protocol proposed. As such there will be a
      minimum of 20 (10 treatment, 10 placebo) participants (up to a maximum of 60). It is
      estimated that statistical significance will be reached with 20 patients, however if it is
      not reached after 20 patients, an additional 10 (5 treatment, 5 control) patients will be
      enrolled. If significance is still not reached after 30 patients, an additional 10 patients
      will be enrolled and so on up to a maximum of 60 patients. If after 60 patients, significance
      is not achieved then further recruitment under the current protocol would not be logical and
      therefore the methodology would need to be revised or study discontinued.

      On Day 1 (first treatment) and 15 (excisional biopsy), all patients will have blood (4 vials)
      and urine (25-50 ml) samples taken. Local reactions to injections will be monitored for non-
      specific signs such as bleeding, arythema, infection, or irritation. Investigators do not
      anticipate specific changes in the pigmented lesion related to the injection in this short
      time period, however all changes will be noted.

      On Day 15, following the second intralesional injection an excisional biopsy will be
      performed following standard surgical techniques, as follows: ellipse of skin encompassing
      the pigmented lesion extending into the subcutaneous fat will be performed to achieve a
      grossly clear but narrow margin of excision. This small defect will be closed primarily with
      interrupted sutures. The biopsied specimen will be subsequently evaluated using standard
      histological techniques to confirm diagnoses, assess margin status (clear or involved) and
      depth of lesion invasion. The depth of lesion invasion will dictate the extent of subsequent
      surgical excisions and margin selection according to standard National Comprehensive Cancer
      Network (NCCN) guidelines. Pre-biopsy intralesional injections of 0.1ml into the lesion will
      not alter dimensions or architecture of the lesion or impact the extent the subsequent biopsy
      required. Lesions that are felt to be too large for closure without tissue manipulation or
      creation of flaps, will be biopsied using a punch biopsy sampling technique whereby 4mm
      diameter discs of tissue from representative areas of the lesion will be taken to confirm the
      diagnosis and the depth of invasion. The depth of invasion will dictate the extent and
      complexity of subsequent surgery required to remove the lesion and achieve clear margins
      according to NCCN guidelines. The biopsied specimen will be processed as follows: using a 22G
      needle a fine needle aspiration biopsy will be performed (the needle will be passed through
      the center of the lesion two times) for RNA analysis. The remainder of the tissue will be
      sent to pathology for standard histological assessment. The pathologist will also report the
      extent of observed tumor infiltrating lymphocytes (TILs) associated with treatment compared
      to control injections. Blood and urine will be assessed using metabalomic and proteomic
      methods to assess systemic immune response to treatment.

      All blood, urine, and lesion biopsy samples will be labeled with a codified number (will not
      contain any patient identifying information) and will be immediately transported to Dr.
      Carman Giacomantonio laboratory at Dalhousie University for storage. Fine needle aspiration
      of excised samples will be assessed for tumor genetic and epigeneitic profile. Blood and
      urine will be assessed for proteomic and metabolomic profiles, respectively.

      All study participants will receive assessments every 4 months for 2 years and biannual
      assessments for years 3 to 5 after the initial intervention to assess disease progression, or
      the development of new melanoma, to compare between both treatment and control groups. There
      is no standardize test or measurable biomarker to assess established or lasting immunity.
      This aspect of the study is identical to the patient assessment conducted as per standard of
      care for melanoma patients. Again, any publications of study results will be completed devoid
      of any information that could be used to identify patients included in the study.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will be given either intralesional IL-2 or intralesional saline as a control
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
measure: Assessment of Number of Patients Needed to Obtain Significance
time frame: 1 year
description: Data will be analyzed in order to achieve a statistically significant differentiation between treatment and control outcomes in study measures including tumor infiltrating lymphocytes (TILs) and circulating immunomodulators.
measure: Assessment of Metastasis
time frame: 5 years
description: All patients will receive assessments every 4 months for 2 years and then biannual assessments for years 3-5 after the initial intervention to assess disease metastasis in treatment and control groups. Both number of new metastases (integer value) and thickness (mm) will be measured as a part of this assessment.
measure: Assessment of RNA genetic profile
time frame: 5 years
description: RNA analysis of excised tissue will be compared to unaffected patient tissue obtained from the clear margins of the excisional biopsy to assess genetic changes resulting from the melanoma and treatment/placebo injections.
measure: Assessment of Systemic Immune Response: Proteomic Analysis
time frame: 5 years
description: Proteomic analysis will be conducted on blood samples to assess systemic immune response to both treatment and control groups. Serum collected from patient blood samples will be used for proteomic analysis to assess protein expression, including circulating immunomodulators (cytokines and chemokines) before, and after, treatment. This study may serve to help develop diagnostic protocols and methods of assessing response to treatments.
measure: Assessment of Systemic Immune Response: Metabolomic Analysis
time frame: 5 years
description: Metabolomic analysis will be conducted on urine samples to assess systemic immune response to both treatment and control groups. All tumor and tissue produce by products in waste that are excreted by the kidneys. Urine samples can be evaluated using techniques, such as Mass Spectrometric, to determine if biological compounds can be identified in association with the presence of a malignant process that would not be produced by normal tissue.This study may serve to help develop diagnostic protocols and methods of assessing response to treatments.
arm group label: Intralesional IL-2 Injection
arm group type: Experimental
description: Two subcutaneous intralesional injections of Aldesleukin, prepared by the pharmacy such that the contents will be masked, will be administered by the care provider in a clinic seven days apart.
arm group label: Saline Injection
arm group type: Placebo Comparator
description: Two subcutaneous intralesional injections of Saline, prepared by the pharmacy such that the contents will be masked, will be administered by the care provider in a clinic seven days apart.
intervention type: Biological
intervention name: Aldesleukin
description: 500,000 IU in 0.1mL
arm group label: Intralesional IL-2 Injection
intervention type: Other
intervention name: Saline
description: 0.1 mL of sterile saline solution (0.9% m/v)
arm group label: Saline Injection
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Carman A Giacomantonio, MD, FRCSC
role: Principal Investigator
affiliation: Surgical Oncologist / General Surgeon / Professor
facility: 
country: Canada
url: http://www.skincancer.org/skin-cancer-information/melanoma/melanoma-treatments/treatment-of-metastatic-melanoma
description: New treatments for metastatic melanoma
citation: Ranieri JM, Wagner JD, Wenck S, Johnson CS, Coleman JJ 3rd. The prognostic importance of sentinel lymph node biopsy in thin melanoma. Ann Surg Oncol. 2006 Jul;13(7):927-32. doi: 10.1245/ASO.2006.04.023. Epub 2006 May 22.
PMID: 16788753
citation: Sandru A, Voinea S, Panaitescu E, Blidaru A. Survival rates of patients with metastatic malignant melanoma. J Med Life. 2014 Oct-Dec;7(4):572-6.
PMID: 25713625
citation: Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004 Sep 2;351(10):998-1012. doi: 10.1056/NEJMra041245. No abstract available. Erratum In: N Engl J Med. 2004 Dec 2;351(23):2461.
PMID: 15342808
citation: Hersey P, Gallagher S. Intralesional immunotherapy for melanoma. J Surg Oncol. 2014 Mar;109(4):320-6. doi: 10.1002/jso.23494. Epub 2013 Dec 3.
PMID: 24301265
citation: Sloot S, Rashid OM, Sarnaik AA, Zager JS. Developments in Intralesional Therapy for Metastatic Melanoma. Cancer Control. 2016 Jan;23(1):12-20. doi: 10.1177/107327481602300104.
PMID: 27009452
citation: Boyd KU, Wehrli BM, Temple CL. Intra-lesional interleukin-2 for the treatment of in-transit melanoma. J Surg Oncol. 2011 Dec;104(7):711-7. doi: 10.1002/jso.21968. Epub 2011 Jul 8.
PMID: 21744347
responsible party type: Sponsor-Investigator
investigator affiliation: Nova Scotia Health Authority
investigator full name: Carman Giacomantonio
investigator title: Surgical Oncologist / General Surgeon / Professor
mesh term: Melanoma
mesh term: Pigmentation Disorders
mesh term: Aldesleukin
sharing ipd: No