<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/NCT02983006</url>
  </required_header>
  <id_info>
    <org_study_id>15-00906</org_study_id>
    <nct_id>NCT02983006</nct_id>
  </id_info>
  <brief_title>Study of DS-8273a With Nivolumab in Unresectable Stage III or Stage IV Melanoma</brief_title>
  <official_title>A Phase 1 Study of TRAIL-DR5 Antibody DS-8273a Administered in Combination With Nivolumab in Subjects With Unresectable Stage III or Stage IV Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NYU Langone Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Daiichi Sankyo, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>NYU Langone Health</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety profile, tolerability, and&#xD;
      immunoregulatory (pharmacodynamic; PD) activity of DS-8273a administered in combination with&#xD;
      nivolumab (anti-PD-1 antibody) to subjects with unresectable Stage III or Stage IV melanoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Principal investigator hypothesize that TRAIL D5 antibody DS-8273a administered in&#xD;
      combination with nivolumab will be well tolerated and that the addition of DS-8273a will&#xD;
      augment the clinical efficacy of nivolumab.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2016</start_date>
  <completion_date type="Actual">January 1, 2021</completion_date>
  <primary_completion_date type="Actual">December 23, 2019</primary_completion_date>
  <phase>Phase 1</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>Safety (adverse events) of the protocol therapy</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Safety will be evaluated for all treated subjects using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Anti-tumor activity of the protocol therapy</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Tumor response will be determined for all subjects by RECIST 1.1 as well as by immune-related response criteria</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>DS-8273a &amp; Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient groups (cohorts) will receive a single dose level of DS 8273a &amp; Nivolumab; DS 8273a will be increased in subsequent cohorts.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>DS-8273a</intervention_name>
    <description>Starting Dose: 4 mg/ kg IVQ 3 weeks (Cohort 1)&#xD;
Dose Escalation: 8 mg/kg IV Q 3 weeks (Cohort 2), 16 mg/kg IV Q 3 weeks (Cohort 3), 24 mg/kg IV Q 3 weeks (Cohort 4), 2 mg/kg IV Q 3 weeks (Cohort -1), 4 mg/kg IV Q 3 weeks (Cohort -2)</description>
    <arm_group_label>DS-8273a &amp; Nivolumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>5 mg/kg IV Q 3 weeks</description>
    <arm_group_label>DS-8273a &amp; Nivolumab</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1) Signed Written Informed Consent The signed informed consent form prior to the&#xD;
             performance of any study related procedures that are not considered part of standard&#xD;
             of care.&#xD;
&#xD;
             2) Target Population&#xD;
&#xD;
               1. Subjects who are ipilimumab naïve with progressive unresectable Stage III or&#xD;
                  Stage IV melanoma; eligible patients may have had prior adjuvant therapy, but not&#xD;
                  including ipilimumab, and been treated with up to 3 prior treatments for&#xD;
                  metastatic melanoma [eg, chemotherapy, other biologic or targeted therapy or&#xD;
                  Interleukin-2 (IL-2)].&#xD;
&#xD;
               2. Histologic or cytologic confirmation of stage III or stage IV melanoma&#xD;
&#xD;
               3. Measurable disease at baseline as assessed by CT and/or MRI&#xD;
&#xD;
               4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1&#xD;
&#xD;
               5. Screening laboratory values must meet the following criteria and should be&#xD;
                  obtained within 7 days prior to registration • White blood cell (WBC) ≥ 2000/μL •&#xD;
                  Neutrophils ≥ 1500/μL&#xD;
&#xD;
                    -  Platelets ≥ 100 x103/μL&#xD;
&#xD;
                    -  Hemoglobin &gt; 9.0 g/dL&#xD;
&#xD;
                    -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance&#xD;
                       (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):&#xD;
&#xD;
                    -  Female CrCl = (140 - age in years) x weight in kg x 0.85&#xD;
&#xD;
                    -  72 x serum creatinine in mg/dL&#xD;
&#xD;
                    -  Male CrCl = (140 - age in years) x weight in kg x 1.00&#xD;
&#xD;
                    -  72 x serum creatinine in mg/dL&#xD;
&#xD;
                    -  Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤ 3 x ULN&#xD;
                       Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can&#xD;
                       have total bilirubin &lt; 3.0 mg/dL)&#xD;
&#xD;
                       3) Age and Reproductive Status Men and women ≥ 18 years old&#xD;
&#xD;
               1. Men and women of childbearing potential (WOCBP) must be using an acceptable&#xD;
                  method of contraception to avoid pregnancy throughout the study, and for women at&#xD;
                  least 23 weeks after the last dose of investigational product and for men at&#xD;
                  least 31 weeks after the last dose of investigational product in such a manner&#xD;
                  that the risk of pregnancy is minimized. See Section 3.3.3 for the definition of&#xD;
                  WOCBP.&#xD;
&#xD;
               2. Women must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or&#xD;
                  equivalent units of HCG) within 24 hours prior to the start of investigational&#xD;
                  product.&#xD;
&#xD;
                  Exclusion Criteria:&#xD;
&#xD;
          -  1) Target Disease Exceptions&#xD;
&#xD;
             a) Subjects with known or suspected brain metastasis, or brain as the only site of&#xD;
             disease are excluded with the following exceptions.&#xD;
&#xD;
             i) Subjects with controlled brain metastasis (no radiographic progression at least 4&#xD;
             weeks following radiation and/or surgical treatment, off steroids for at least 4&#xD;
             weeks, and have no new or progressing neurological signs or symptoms) will be allowed.&#xD;
&#xD;
             b) Subjects with a history of prior malignancy with the exception of carcinoma in situ&#xD;
             of the cervix or other malignancy diagnosed &gt; 2 years ago that has undergone&#xD;
             potentially curative therapy with no evidence of disease for the last ≥ 2 years and&#xD;
             that is deemed by the investigator to be at a low risk of recurrence.&#xD;
&#xD;
             2) Medical History and Concurrent Diseases&#xD;
&#xD;
             a) Active autoimmune disease or a history of known or suspected autoimmune disease&#xD;
             with the exception of subjects with isolated vitiligo, treated thyroiditis or resolved&#xD;
             childhood asthma/atopy.&#xD;
&#xD;
             b) Known human immunodeficiency virus (HIV), active hepatitis A, or hepatitis B or C&#xD;
             infection.&#xD;
&#xD;
             c) Evidence of active infection that requires anti-bacterial, anti-viral, or&#xD;
             anti-fungal therapy ≤ 7 days prior to initiation of study drug therapy d) History of&#xD;
             acute diverticulitis within the last 6 months, or current chronic diarrhea e) Active&#xD;
             peptic ulcer disease even if asymptomatic f) Prior organ allograft or allogenic bone&#xD;
             marrow transplantation g) Uncontrolled or significant cardiovascular disease&#xD;
             including, but not limited to, any of the following: i) Myocardial infarction within&#xD;
             the past 6 months ii) Uncontrolled angina within the past 6 months iii) Any history of&#xD;
             clinically significant ventricular arrhythmias (such as ventricular tachycardia,&#xD;
             ventricular fibrillation or Torsades de pointes). Controlled atrial fibrillation by&#xD;
             itself is not an exclusion criterion.&#xD;
&#xD;
             h) Baseline toxicities from prior anti-cancer treatments &gt; Grade 1. i) Inability to be&#xD;
             venipunctured and/or tolerate venous access. j) Any major surgery within 4 weeks or a&#xD;
             diagnostic procedure (eg incision, needle biopsy) within 1 day of study drug&#xD;
             administration.&#xD;
&#xD;
             k) Known drug or alcohol abuse. l) Presence of underlying medical condition that in&#xD;
             the opinion of the Investigator or Sponsor could adversely affect the ability of the&#xD;
             subject to comply with or tolerate study procedures and/or study therapy, or confound&#xD;
             the ability to interpret the tolerability of combined administration of DS-8273A and&#xD;
             nivolumab in treated subjects.&#xD;
&#xD;
             3) Allergies and Adverse Drug Reaction&#xD;
&#xD;
             a) History of allergy to components of nivolumab or DS-8273A, or known allergy to&#xD;
             other antibody therapies.&#xD;
&#xD;
             4) Sex and Reproductive Status&#xD;
&#xD;
               1. WOCBP who are unwilling or unable to use an acceptable method to minimize the&#xD;
                  risk of pregnancy for the entire study period and for at least 23 weeks after the&#xD;
                  last dose of investigational product.&#xD;
&#xD;
               2. Women who are pregnant or breastfeeding.&#xD;
&#xD;
               3. Women with a positive pregnancy test on enrollment or prior to investigational&#xD;
                  product administration.&#xD;
&#xD;
               4. Sexually active fertile men not using effective birth control if their partners&#xD;
                  are WOCBP.&#xD;
&#xD;
                  5) Prohibited Prior Treatments and/or Therapies&#xD;
&#xD;
             a) Exposure to any investigational drug within 4 weeks of study drug administration.&#xD;
&#xD;
             b) Any anti-cancer therapy (eg, chemotherapy, biologics, radiotherapy, or hormonal&#xD;
             treatment) within 4 weeks or at least 5 half-lives (whichever is longer) of study drug&#xD;
             administration.&#xD;
&#xD;
             c) Prior therapy with an anti-PD-1/PD-L1 antibody or a TRAIL-DR5 antibody d)&#xD;
             Concurrent chemotherapy, hormonal therapy, immunotherapy regimens, or radiation&#xD;
             therapy, standard or investigational.&#xD;
&#xD;
             6) Other Exclusion Criteria&#xD;
&#xD;
               1. Prisoners or subjects who are involuntarily incarcerated&#xD;
&#xD;
               2. Subjects who are compulsorily detained for treatment of either a psychiatric or&#xD;
                  physical (eg, infectious disease) illness&#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>Jeffrey Weber, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NYU Perlmutter Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Laura and Isaac Perlmutter Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>December 2, 2016</study_first_submitted>
  <study_first_submitted_qc>December 2, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 6, 2016</study_first_posted>
  <last_update_submitted>October 8, 2021</last_update_submitted>
  <last_update_submitted_qc>October 8, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 18, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>TRAIL-DR5</keyword>
  <keyword>DS-8273a</keyword>
  <keyword>Immunoglobulin gamma-1 (IgG1)</keyword>
  <keyword>Cell mediated cytotoxicity (ADCC)</keyword>
  <keyword>Complement dependent cytotoxicity (CDC)</keyword>
  <keyword>DR5</keyword>
  <keyword>Immunoglobulin G4 (IgG4)</keyword>
  <keyword>Monoclonal antibody</keyword>
  <keyword>Programmed Cell Death 1 (PD-1)</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>Nivolumab</mesh_term>
    <mesh_term>DS-8273a</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/NCT02983006
org study id: 15-00906
nct id: NCT02983006
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to evaluate the safety profile, tolerability, and
      immunoregulatory (pharmacodynamic; PD) activity of DS-8273a administered in combination with
      nivolumab (anti-PD-1 antibody) to subjects with unresectable Stage III or Stage IV melanoma.
Principal investigator hypothesize that TRAIL D5 antibody DS-8273a administered in
      combination with nivolumab will be well tolerated and that the addition of DS-8273a will
      augment the clinical efficacy of nivolumab.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety (adverse events) of the protocol therapy
time frame: Up to 2 years
description: Safety will be evaluated for all treated subjects using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
measure: Anti-tumor activity of the protocol therapy
time frame: Up to 2 years
description: Tumor response will be determined for all subjects by RECIST 1.1 as well as by immune-related response criteria
arm group label: DS-8273a & Nivolumab
arm group type: Experimental
description: Patient groups (cohorts) will receive a single dose level of DS 8273a & Nivolumab; DS 8273a will be increased in subsequent cohorts.
intervention type: Biological
intervention name: DS-8273a
description: Starting Dose: 4 mg/ kg IVQ 3 weeks (Cohort 1)
Dose Escalation: 8 mg/kg IV Q 3 weeks (Cohort 2), 16 mg/kg IV Q 3 weeks (Cohort 3), 24 mg/kg IV Q 3 weeks (Cohort 4), 2 mg/kg IV Q 3 weeks (Cohort -1), 4 mg/kg IV Q 3 weeks (Cohort -2)
arm group label: DS-8273a & Nivolumab
intervention type: Biological
intervention name: Nivolumab
description: 5 mg/kg IV Q 3 weeks
arm group label: DS-8273a & Nivolumab
other name: Opdivo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jeffrey Weber, MD, PhD
role: Principal Investigator
affiliation: NYU Perlmutter Cancer Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Nivolumab
mesh term: DS-8273a