<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/NCT01715077</url>
  </required_header>
  <id_info>
    <org_study_id>CA184-181</org_study_id>
    <nct_id>NCT01715077</nct_id>
  </id_info>
  <brief_title>Study of Ipilimumab in the Immune System</brief_title>
  <official_title>A Correlative Study of Melanoma Tumor-Infiltrating Lymphocytes (TILs) and Response to Ipilimumab</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Participants will be taking 3 mg/kg ipilimumab intravenously over a 90-minute period every 3&#xD;
      weeks for a total of four doses. Tumor-infiltrating lymphocytes (TILs)will be analyzed for&#xD;
      functional characteristics.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      STUDY DESIGN&#xD;
&#xD;
        -  Screening&#xD;
&#xD;
           - Assessment of the subject's eligibility to participate as determined by the&#xD;
           inclusion/exclusion criteria.&#xD;
&#xD;
        -  Biopsy schedule&#xD;
&#xD;
           - Subjects will be biopsied according to the schedule in Section 7.&#xD;
&#xD;
        -  Induction&#xD;
&#xD;
             -  The recommended induction dose of ipilimumab is 3 mg/kg administered intravenously&#xD;
                over a 90-minute period every 3 weeks for a total of four doses, as tolerated.&#xD;
&#xD;
             -  Laboratory evaluations should be performed and the results examined before&#xD;
                administration of each ipilimumab dose.&#xD;
&#xD;
             -  As durable disease stabilization and/or objective tumor response can be seen after&#xD;
                early progression before Week 12, it is recommended that, in the absence of&#xD;
                dose-limiting toxicities (eg, serious immune-mediated adverse reactions), all four&#xD;
                doses of ipilimumab be administered over the initial 12 weeks even in the setting&#xD;
                of apparent clinical progression, providing the subject's performance status&#xD;
                remains stable.&#xD;
&#xD;
             -  All subjects who enter the induction period, including those who may have&#xD;
                discontinued treatment for drug-related AEs and/or who have evidence of clinical&#xD;
                progression during the induction period, should obtain a 12-week tumor assessment.&#xD;
&#xD;
             -  Based on clinical experience in the ongoing and completed melanoma studies, the&#xD;
                following recommendations apply for subject management in light of the Week 12 or&#xD;
                later tumor assessments:&#xD;
&#xD;
        -  The appearance of new lesions in subjects with other stable or shrinking baseline tumor&#xD;
           burden may be experiencing clinical benefit and should continue in follow-up and/or&#xD;
           maintenance therapy before alternative anti-cancer agents are considered. These subjects&#xD;
           can be seen to have continued tumor shrinkage in follow-up scans.&#xD;
&#xD;
        -  As long as overall tumor burden is stable or decreasing, subjects should remain in&#xD;
           follow-up and/or maintenance (see below), even in the presence of new lesions.&#xD;
&#xD;
        -  Clinical progression warranting alternative anti-cancer treatment should be considered&#xD;
           only in subjects whose overall tumor burden appears to be substantially increased and/or&#xD;
           in subjects whose performance status is decreased.&#xD;
&#xD;
        -  Patients are eligible for retreatment treatments with ipilimumab on this protocol&#xD;
&#xD;
        -  Follow-up&#xD;
&#xD;
           - Subjects will be required to attend a follow-up visit within 90 days of the last&#xD;
           ipilimumab treatment.&#xD;
&#xD;
        -  Re-treatment&#xD;
&#xD;
      Patients who received ipilimumab at any dose in a prior/parent study and have met each of the&#xD;
      following criteria:&#xD;
&#xD;
        -  Had no unacceptable toxicity requiring ipilimumab discontinuation; OR&#xD;
&#xD;
        -  Patients who permanently discontinued treatment due to select irAEs as follows:&#xD;
&#xD;
             1. Reversible autoimmune hepatitis&#xD;
&#xD;
             2. Medically manageable endocrinopathy&#xD;
&#xD;
             3. Reversible dermatological toxicity AND&#xD;
&#xD;
        -  Have experienced documented disease progression after demonstrating expanded clinical&#xD;
           benefit.&#xD;
&#xD;
      Expanded clinical benefit is defined as:&#xD;
&#xD;
        -  Patients whose disease is responding (partial response, complete response); or&#xD;
&#xD;
        -  Patients whose disease was stable more than or equal to 3 months.&#xD;
&#xD;
        -  Patients who demonstrated mixed or delayed response.&#xD;
&#xD;
      The mixed or delayed response is defined as follows:&#xD;
&#xD;
      Patients with Mixed Response: defined as at least 50% reduction in the bidimensional size of&#xD;
      one or more non-cystic lesions, even in the presence of any new lesions.&#xD;
&#xD;
      Patients with Delayed Response: defined as objective response (PR or CR) following&#xD;
      progressive disease, occurring any time after Week 12 in the prior/parent protocol, in&#xD;
      patients who have not received therapy with a non ipilimumab anti-cancer agent (approved or&#xD;
      experimental) between the PD and objective response.&#xD;
&#xD;
      Patients with select irAEs related to ipilimumab that have completely resolved with&#xD;
      immunosuppressive therapy or are adequately controlled with hormone therapy, may be&#xD;
      considered for further re-treatment with ipilimumab under this study, at the time of disease&#xD;
      progression. The list of completely reversible or medically managed immune-related adverse&#xD;
      events (irAEs) eligible for consideration are:&#xD;
&#xD;
        -  Reversible autoimmune hepatitis&#xD;
&#xD;
        -  Medically managed endocrinopathy&#xD;
&#xD;
        -  Reversible dermatological toxicity All other irAEs are not considered eligible for&#xD;
           re-treatment, including, but not limited to, greater or equal Grade 3 colitis or&#xD;
           diarrhea, or uveitis of any grade.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">October 2017</completion_date>
  <primary_completion_date type="Actual">October 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>TILs characteristics</measure>
    <time_frame>2 years</time_frame>
    <description>Tumor-infiltrating lymphocytes (TILs)will be observed before and after 3 mg/kg Ipilimumab is administered on patients with Stage III (unresectable) or Stage IV melanoma.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) and Overall Survival (OS)</measure>
    <time_frame>2 years on average</time_frame>
    <description>To evaluate the Progression Free Survival (PFS) and Overall Survival (OS) in patients with previously untreated, metastatic melanoma.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">4</enrollment>
  <condition>Previously Untreated and Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma</condition>
  <arm_group>
    <arm_group_label>Ipilimumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The recommended induction dose of ipilimumab is 3 mg/kg administered intravenously over a 90-minute period every 3 weeks for a total of four doses, as guided by laboratory tests and patient assessment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab at 3 mg/kg dose</intervention_name>
    <arm_group_label>Ipilimumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Willing and able give written informed consent.&#xD;
&#xD;
          2. Previously untreated (adjuvant interferon is acceptable), and histologically confirmed&#xD;
             Stage III (unresectable) or Stage IV melanoma with at least 2 metastatic lesions, (one&#xD;
             amenable to resection that measures over 0.75 cm3 by volume AND another amenable to 3&#xD;
             X core biopsy OR resection that measures over 0.5 cm3) at study entry AND at least 1&#xD;
             additional RECIST measurable lesion must be present for study entry, other than the 2&#xD;
             identified for resection/biopsy, defined as a lesion that can be accurately measured&#xD;
             in two perpendicular diameters, as per RECIST by CT scan, MRI, or calipers by clinical&#xD;
             exam.&#xD;
&#xD;
          3. Subjects with asymptomatic or previously treated brain metastases are only eligible&#xD;
             for enrollment provided they have evidence of 30 day stability of the brain metastasis&#xD;
             prior to the date of registration. &quot;Stability&quot; being no change in the imaging modality&#xD;
             used (CT or MRI) at the baseline and 30 day time point. (Systemic steroids should be&#xD;
             avoided if possible, or the subject should be stable on the lowest clinically&#xD;
             effective dose of steroids as they may interfere with the activity of ipilimumab if&#xD;
             administered at the time of the first ipilimumab dose.)&#xD;
&#xD;
          4. Must be at least 28 days since treatment with surgery or radiation, or immunotherapy&#xD;
             (IFN-alpha), and recovered from any clinically significant toxicity experienced during&#xD;
             treatment.&#xD;
&#xD;
          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.&#xD;
&#xD;
          6. Life expectancy of ≥ 16 weeks.&#xD;
&#xD;
          7. Subjects must have the complete set of baseline (screening/baseline) radiographic&#xD;
             images, including but not limited to brain, chest, abdomen, pelvis, and bone scans (if&#xD;
             applicable). The images can be accepted if obtained 6 weeks before initiation of&#xD;
             ipilimumab.&#xD;
&#xD;
          8. Required values for initial laboratory tests: WBC &gt; 2.0 x 109/L; ANC &gt; 1.0 x 109/L;&#xD;
             Platelets &gt; 100 x 109/L; Hemoglobin &gt; 90 g/L (&gt; 80 g/L; may be transfused); Creatinine&#xD;
             &lt; 2.0 x ULN; AST/ALT &lt; 2.5 x ULN for patients without liver metastasis, &lt; 5 times for&#xD;
             liver metastases; Bilirubin &lt; 2.0 x ULN, (except patients with Gilbert's Syndrome, who&#xD;
             must have a total bilirubin less than 51.3 µmol/L); INR &lt; 1.3&#xD;
&#xD;
          9. No active or chronic infection HIV, Hepatitis B, or Hepatitis C.&#xD;
&#xD;
         10. Men and women, ≥ 18 years of age.&#xD;
&#xD;
         11. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L&#xD;
             or equivalent units of HCG) within 72 hours before the start of ipilimumab.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Sex and Reproductive Status: a) WOCBP and men of fathering potential who are unwilling&#xD;
             or unable to use an acceptable method to avoid pregnancy for the entire study and for&#xD;
             up to 26 weeks after the last dose of investigational product. Adequate contraception&#xD;
             for women is defined as oral contraceptives, other hormonal contraceptives or&#xD;
             mechanical products such as an intrauterine device or barrier methods (diaphragm,&#xD;
             condoms, spermicides), abstinence or sterile partner (eg, vasectomy). Adequate&#xD;
             contraception for men is defined as abstinence, sterile partner, condoms, or&#xD;
             vasectomy. b) Women who are pregnant or breastfeeding.&#xD;
&#xD;
          2. Target Disease Exceptions: a) Subjects on any other systemic therapy for cancer,&#xD;
             including any other experimental treatment. b) Prior treatment with an anti-CTLA-4&#xD;
             antibody if treatment failure was due to irAEs. If a subject was discontinued from the&#xD;
             prior anti-CTLA-4 treatment due to an AE or SAE, regardless of the type of event, that&#xD;
             discontinuation constitutes an exclusion criterion. If irAEs were serious enough to&#xD;
             require a subject's withdrawal from prior treatment, the subject should be excluded&#xD;
             from this study. c) Prior treatment with chemotherapy/biochemotherapy/immunotherapy&#xD;
             for systemic disease for melanoma (prior treatment with IFN-alpha immunotherapy is&#xD;
             allowed)..&#xD;
&#xD;
          3. Primary ocular and mucosal melanomas are not allowed.&#xD;
&#xD;
          4. Medical History and Concurrent Diseases: a) Autoimmune disease: subjects with a&#xD;
             documented history of inflammatory bowel disease, including ulcerative colitis and&#xD;
             Crohn's disease are excluded from this study as are subjects with a history of&#xD;
             symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis&#xD;
             [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [eg, Wegener's&#xD;
             Granulomatosis]). Subjects with motor neuropathy considered of autoimmune origin (eg,&#xD;
             Guillain-Barre Syndrome and Myasthenia Gravis) are excluded from this study. b) Any&#xD;
             subject who has a life-threatening condition that requires high-dose&#xD;
             immunosuppressant(s). c) Presence of known HIV, hepatitis B or hepatitis C infection,&#xD;
             regardless of control on antiviral therapy. d) Subjects with melanoma who have another&#xD;
             active, concurrent, malignant disease with the exception of subjects with adequately&#xD;
             treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma&#xD;
             in situ of the cervix.&#xD;
&#xD;
          5. Other Exclusion Criteria: a) Prisoners or subjects who are involuntarily incarcerated.&#xD;
             b) Subjects who are compulsorily detained for treatment of either a psychiatric or&#xD;
             physical (eg, infectious disease) illness. c) Any underlying medical or psychiatric&#xD;
             condition that, in the opinion of the investigator, could make the administration of&#xD;
             ipilimumab hazardous or could obscure the interpretation of adverse events. d) Any&#xD;
             non-oncology vaccine therapy used for prevention of infectious diseases for up to 4&#xD;
             weeks before or after any dose of ipilimumab, with the exceptions of amantadine and&#xD;
             flumadine.&#xD;
&#xD;
          6. Any acute or chronic treatment with warfarin or anti-platelet agent (aspirin is&#xD;
             allowed up to a dose of 300 mg daily) including clopidogrel. Heparin, low molecular&#xD;
             weight heparin, any heparinoid are allowed after appropriate cessation (usually 24&#xD;
             hours prior to induction).&#xD;
&#xD;
          7. Any known or suspected bleeding diathesis on the basis or personal or family history&#xD;
             (including diagnoses of von Willebrands disease or other familial factor deficiency).&#xD;
&#xD;
          8. The risk of the excision involves a significant risk of morbidity or mortality due to&#xD;
             its size, location or vascularity (at the discretion of the principal investigators).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anthony Joshua, M.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>UHN-Princess Margaet Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Princess Margaret Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233-58. doi: 10.1146/annurev.immunol.14.1.233.</citation>
    <PMID>8717514</PMID>
  </reference>
  <reference>
    <citation>Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065-8. doi: 10.1016/s0092-8674(05)80055-8. No abstract available.</citation>
    <PMID>1335362</PMID>
  </reference>
  <reference>
    <citation>Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA, McGowan P, Linsley PS. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell. 1992 Dec 24;71(7):1093-102. doi: 10.1016/s0092-8674(05)80059-5.</citation>
    <PMID>1335364</PMID>
  </reference>
  <reference>
    <citation>Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996 Apr 1;77(7):1303-10. doi: 10.1002/(SICI)1097-0142(19960401)77:73.0.CO;2-5.</citation>
    <PMID>8608507</PMID>
  </reference>
  <reference>
    <citation>Hamid, O., Chasalow, S. D., Tsuchihashi, Z., Alaparthy, S., Galbraith, S., and Berman, D. Association of baseline and on-study tumor biopsy markers with clinical activity in patients (pts) with advanced melanoma treated with ipilimumab. J Clin Oncol 27, 15s. 2009.</citation>
  </reference>
  <reference>
    <citation>Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch MT, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, Dranoff G. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3005-10. doi: 10.1073/pnas.0712237105. Epub 2008 Feb 19.</citation>
    <PMID>18287062</PMID>
  </reference>
  <reference>
    <citation>Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4712-7. doi: 10.1073/pnas.0830997100. Epub 2003 Apr 7.</citation>
    <PMID>12682289</PMID>
  </reference>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>October 12, 2012</study_first_submitted>
  <study_first_submitted_qc>October 23, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 26, 2012</study_first_posted>
  <last_update_submitted>August 10, 2018</last_update_submitted>
  <last_update_submitted_qc>August 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 13, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>melanoma</keyword>
  <keyword>stage IV</keyword>
  <keyword>stage III</keyword>
  <keyword>unresectable</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01715077
org study id: CA184-181
nct id: NCT01715077
lead sponsor: 
has dmc: Yes
Participants will be taking 3 mg/kg ipilimumab intravenously over a 90-minute period every 3
      weeks for a total of four doses. Tumor-infiltrating lymphocytes (TILs)will be analyzed for
      functional characteristics.
STUDY DESIGN

        -  Screening

           - Assessment of the subject's eligibility to participate as determined by the
           inclusion/exclusion criteria.

        -  Biopsy schedule

           - Subjects will be biopsied according to the schedule in Section 7.

        -  Induction

             -  The recommended induction dose of ipilimumab is 3 mg/kg administered intravenously
                over a 90-minute period every 3 weeks for a total of four doses, as tolerated.

             -  Laboratory evaluations should be performed and the results examined before
                administration of each ipilimumab dose.

             -  As durable disease stabilization and/or objective tumor response can be seen after
                early progression before Week 12, it is recommended that, in the absence of
                dose-limiting toxicities (eg, serious immune-mediated adverse reactions), all four
                doses of ipilimumab be administered over the initial 12 weeks even in the setting
                of apparent clinical progression, providing the subject's performance status
                remains stable.

             -  All subjects who enter the induction period, including those who may have
                discontinued treatment for drug-related AEs and/or who have evidence of clinical
                progression during the induction period, should obtain a 12-week tumor assessment.

             -  Based on clinical experience in the ongoing and completed melanoma studies, the
                following recommendations apply for subject management in light of the Week 12 or
                later tumor assessments:

        -  The appearance of new lesions in subjects with other stable or shrinking baseline tumor
           burden may be experiencing clinical benefit and should continue in follow-up and/or
           maintenance therapy before alternative anti-cancer agents are considered. These subjects
           can be seen to have continued tumor shrinkage in follow-up scans.

        -  As long as overall tumor burden is stable or decreasing, subjects should remain in
           follow-up and/or maintenance (see below), even in the presence of new lesions.

        -  Clinical progression warranting alternative anti-cancer treatment should be considered
           only in subjects whose overall tumor burden appears to be substantially increased and/or
           in subjects whose performance status is decreased.

        -  Patients are eligible for retreatment treatments with ipilimumab on this protocol

        -  Follow-up

           - Subjects will be required to attend a follow-up visit within 90 days of the last
           ipilimumab treatment.

        -  Re-treatment

      Patients who received ipilimumab at any dose in a prior/parent study and have met each of the
      following criteria:

        -  Had no unacceptable toxicity requiring ipilimumab discontinuation; OR

        -  Patients who permanently discontinued treatment due to select irAEs as follows:

             1. Reversible autoimmune hepatitis

             2. Medically manageable endocrinopathy

             3. Reversible dermatological toxicity AND

        -  Have experienced documented disease progression after demonstrating expanded clinical
           benefit.

      Expanded clinical benefit is defined as:

        -  Patients whose disease is responding (partial response, complete response); or

        -  Patients whose disease was stable more than or equal to 3 months.

        -  Patients who demonstrated mixed or delayed response.

      The mixed or delayed response is defined as follows:

      Patients with Mixed Response: defined as at least 50% reduction in the bidimensional size of
      one or more non-cystic lesions, even in the presence of any new lesions.

      Patients with Delayed Response: defined as objective response (PR or CR) following
      progressive disease, occurring any time after Week 12 in the prior/parent protocol, in
      patients who have not received therapy with a non ipilimumab anti-cancer agent (approved or
      experimental) between the PD and objective response.

      Patients with select irAEs related to ipilimumab that have completely resolved with
      immunosuppressive therapy or are adequately controlled with hormone therapy, may be
      considered for further re-treatment with ipilimumab under this study, at the time of disease
      progression. The list of completely reversible or medically managed immune-related adverse
      events (irAEs) eligible for consideration are:

        -  Reversible autoimmune hepatitis

        -  Medically managed endocrinopathy

        -  Reversible dermatological toxicity All other irAEs are not considered eligible for
           re-treatment, including, but not limited to, greater or equal Grade 3 colitis or
           diarrhea, or uveitis of any grade.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: TILs characteristics
time frame: 2 years
description: Tumor-infiltrating lymphocytes (TILs)will be observed before and after 3 mg/kg Ipilimumab is administered on patients with Stage III (unresectable) or Stage IV melanoma.
measure: Progression Free Survival (PFS) and Overall Survival (OS)
time frame: 2 years on average
description: To evaluate the Progression Free Survival (PFS) and Overall Survival (OS) in patients with previously untreated, metastatic melanoma.
arm group label: Ipilimumab
arm group type: Experimental
description: The recommended induction dose of ipilimumab is 3 mg/kg administered intravenously over a 90-minute period every 3 weeks for a total of four doses, as guided by laboratory tests and patient assessment.
intervention type: Drug
intervention name: Ipilimumab at 3 mg/kg dose
arm group label: Ipilimumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Anthony Joshua, M.D
role: Principal Investigator
affiliation: UHN-Princess Margaet Hospital
facility: 
country: Canada
citation: Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233-58. doi: 10.1146/annurev.immunol.14.1.233.
PMID: 8717514
citation: Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065-8. doi: 10.1016/s0092-8674(05)80055-8. No abstract available.
PMID: 1335362
citation: Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA, McGowan P, Linsley PS. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell. 1992 Dec 24;71(7):1093-102. doi: 10.1016/s0092-8674(05)80059-5.
PMID: 1335364
citation: Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996 Apr 1;77(7):1303-10. doi: 10.1002/(SICI)1097-0142(19960401)77:73.0.CO;2-5.
PMID: 8608507
citation: Hamid, O., Chasalow, S. D., Tsuchihashi, Z., Alaparthy, S., Galbraith, S., and Berman, D. Association of baseline and on-study tumor biopsy markers with clinical activity in patients (pts) with advanced melanoma treated with ipilimumab. J Clin Oncol 27, 15s. 2009.
citation: Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch MT, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, Dranoff G. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3005-10. doi: 10.1073/pnas.0712237105. Epub 2008 Feb 19.
PMID: 18287062
citation: Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4712-7. doi: 10.1073/pnas.0830997100. Epub 2003 Apr 7.
PMID: 12682289
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Ipilimumab