<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/NCT02262910</url>
  </required_header>
  <id_info>
    <org_study_id>401</org_study_id>
    <nct_id>NCT02262910</nct_id>
  </id_info>
  <brief_title>Study of ES414 in Metastatic Castration-Resistant Prostate Cancer</brief_title>
  <official_title>A Phase 1 Study of ES414 in Patients Wtih Metastatic Castration-Resistant Prostate Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Aptevo Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Aptevo Therapeutics</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study will be conducted in 2 Stages. The primary objective of Stage 1 of the study is to&#xD;
      identify the maximum tolerated dose (MTD) of ES414 administered intravenously to patients&#xD;
      with mCRPC. Secondary objectives are to evaluate the tolerability, pharmacokinetics (PK),&#xD;
      pharmacodynamics (PD), immunogenicity, cytokine response, and clinical activity of ES414.&#xD;
&#xD;
      The primary objective of Stage 2 of the study is to evaluate the clinical activity of ES414&#xD;
      in patients that have or have not received prior chemotherapy. Secondary objectives are to&#xD;
      further characterize the safety profile, PK, PD, and immunogenicity of ES414.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Stage 1 - Dose Escalation: The dose escalation stage of the study will test weekly doses of&#xD;
      0.2 mcg/kg to 300 mcg/kg over 9 dose levels (cohorts). Cohorts 1 to 3 consist of single&#xD;
      patients and Cohorts 4 - 9 will consist of a minimum of 3 patients; an additional 3 patients&#xD;
      may be added to the cohort if adverse events possibly related to ES414 or dose-limiting&#xD;
      toxicities (DLT) occur. The next dose cohort will only enroll after the patient(s) in the&#xD;
      current dose cohort have completed the first cycle of dosing (4 weeks) with no significant&#xD;
      adverse events or DLTs. Six patients will be enrolled at the maximum tolerated dose (MTD) and&#xD;
      this dose will be used for Stage 2.&#xD;
&#xD;
      Stage 2 - Expansion: The continuous intravenous infusion MTD dose regimen will be further&#xD;
      examined in 2 expansion cohorts; the first cohort are patients that have received prior&#xD;
      chemotherapy, such as docetaxel for mCRPC, and the second cohort are those that have not&#xD;
      received prior chemotherapy for mCRPC. Serum samples will be collected for serial PK&#xD;
      assessment for ES414 drug levels and antibody formation. Response will be assessed every 2&#xD;
      months during the first 6 months of treatment and then every 3 months until progression of&#xD;
      mCRPC, intolerable side effects, or withdrawal of consent.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2015</start_date>
  <completion_date type="Actual">February 18, 2019</completion_date>
  <primary_completion_date type="Actual">December 2018</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>Maximum Tolerated Dose of ES414</measure>
    <time_frame>during first 28 days of treatment</time_frame>
    <description>Identify the maximum tolerated dose in dose-escalation stage (Stage 1) by assessment of dose-limiting toxicities</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety Profile of ES414</measure>
    <time_frame>Patients will be followed for the duration of treatment, an expected average of 6 months, and for 28 days following last treatment</time_frame>
    <description>The safety profile of ES414 will be assessed by monitoring incidence and severity of adverse events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Serum Drug Concentration (Cmax)</measure>
    <time_frame>Pre- and post-infusion at least weekly during first 28-day cycle, and on Days 1 and 15 of subsequent cycles for an expected duration of 6 months, and for up to 8 weeks following last treatment</time_frame>
    <description>Blood samples will be obtained from all patients for determination of the maximum serum concentration of ES414.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration versus time curve (AUC)</measure>
    <time_frame>Pre- and post-infusion at least weekly during first 28-day cycle, and on Days 1 and 15 of subsequent cycles for an expected duration of 6 months, and for up to 8 weeks following last treatment</time_frame>
    <description>Blood samples will be obtained from all patients for determination of the AUC of ES414.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Elimination half-life (T1/2)</measure>
    <time_frame>Pre- and post-infusion at least weekly during first 28-day cycle, and on Days 1 and 15 of subsequent cycles for an expected duration of 6 months, and for up to 8 weeks following last treatment</time_frame>
    <description>Blood samples will be obtained from all patients for determination of the T1/2 of ES414.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune-Related Response Criteria (irRC)</measure>
    <time_frame>Baseline and 6 months</time_frame>
    <description>Investigator measurements of target lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response Evaluation Criteria in Solid Tumors (RECIST 1.1)</measure>
    <time_frame>Baseline and 6 months</time_frame>
    <description>Investigator measurements of target lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamics of ES414</measure>
    <time_frame>Patients will be followed for the duration of treatment, an expected average of 6 months, and for 28 days following last treatment</time_frame>
    <description>Blood samples will be collected from all patients and evaluated by flow cytometry for changes in lymphocytes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PSA Response</measure>
    <time_frame>Baseline and 6 months</time_frame>
    <description>Blood samples will be collected from all patients and tested for PSA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Circulating Tumor Cells</measure>
    <time_frame>Patients will be followed for the duration of treatment, an expected average of 6 months, and for 28 days following last treatment</time_frame>
    <description>Blood samples will be collected from all patients and evaluated for the number of circulating tumor cells</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunogenicity of ES414</measure>
    <time_frame>Patients will be followed for the duration of treatment, an expected average of 6 months, and for 8 weeks following last treatment</time_frame>
    <description>Blood samples will be collected from all patients and tested for antibody formation to ES414.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">35</enrollment>
  <condition>Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>ES414</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cohorts 1-3 of the dose escalation stage of the study (Stage 1) will test weekly doses of 0.2 mcg/kg to 2 mcg/kg. Cohorts 4-9 of the dose escalation stage of the study (Stage 1) will test continuous infusion at flat doses of 25 mcg to 300 mcg per day delivered continuously over 24 hours. The maximum tolerated dose from Stage 1 of the study will be further examined in Stage 2. Patients in cohorts 1-3 will receive ES414 weekly via intravenous (IV) infusion during the first three 28-day cycles and then on Day 1 and 15 of each subsequent cycle until disease progression, intolerable toxicity occurs, or the patient withdraws consent. Patients in cohorts 4-9 will receive ES414 as a continuous IV infusion for 6 months until disease progression, intolerable toxicity occurs, or the patient withdraws consent.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ES414</intervention_name>
    <description>ES414 is a novel humanized bispecific antibody which is designed to treat mCRPC by redirecting T-cell cytotoxicity against prostate cancer cells expressing prostate-specific membrane antigen (PSMA).</description>
    <arm_group_label>ES414</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically confirmed adenocarcinoma of the prostate. No evidence&#xD;
             of neuroendocrine differentiation or small cell features.&#xD;
&#xD;
          -  Surgically or medically castrated, with testosterone ≤ 50 ng/dL (≤ 1.7 nmol/L).&#xD;
&#xD;
          -  Progressive prostate cancer by either serum PSA levels, soft tissue or bone disease as&#xD;
             defined by the PCWG2 criteria.&#xD;
&#xD;
          -  In Stage 1, patients may or may not have received prior chemotherapy for mCRPC. In&#xD;
             Stage 2, patients will be enrolled into two cohorts based on whether or not they have&#xD;
             received prior chemotherapy for mCRPC. Any prior chemotherapy must have been completed&#xD;
             ≥ 4 weeks prior to administration of ES414. Additionally, in countries where&#xD;
             abiraterone or enzalutamide are commercially available, patients in Stage 1 and 2 must&#xD;
             have progressed on abiraterone and/or enzalutamide prior to study entry.&#xD;
&#xD;
          -  ECOG ≤ 1&#xD;
&#xD;
          -  Life expectancy &gt; 6 months per investigator&#xD;
&#xD;
          -  Adequate hematologic, renal, and hepatic parameters&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any chemotherapy, sipuleucel-T, or investigational drug in prior 4 weeks, or&#xD;
             abiraterone or enzalutamide in prior 2 week&#xD;
&#xD;
          -  Any radiation therapy in prior 2 weeks&#xD;
&#xD;
          -  Any prior therapy targeted against PSMA&#xD;
&#xD;
          -  History of seizures&#xD;
&#xD;
          -  History of central nervous system metastasis&#xD;
&#xD;
          -  History of nephrotic syndrome&#xD;
&#xD;
          -  Spot urine total protein:creatinine ratio &gt;1,000 mg/gm&#xD;
&#xD;
          -  Planned palliative procedures for alleviation of bone pain&#xD;
&#xD;
          -  Active infection requiring treatment with systemic anti-infectives or major surgery in&#xD;
             prior 4 weeks.&#xD;
&#xD;
          -  Any prednisone (or equivalent corticosteroids) use within 2 weeks of study entry&#xD;
&#xD;
          -  Chronic immunosuppressive therapy&#xD;
&#xD;
          -  Known history of HIV, hepatitis B, or hepatitis C infection&#xD;
&#xD;
          -  Evidence of severe or uncontrolled systemic diseases&#xD;
&#xD;
          -  History of bleeding disorders or thromboembolic events in prior 3 months&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Scott C Stromatt, MD</last_name>
    <role>Study Director</role>
    <affiliation>Aptevo Therapeutics</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Roswell Park Cancer Institute</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14263</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Texas Veterans Health Care System</name>
      <address>
        <city>Temple</city>
        <state>Texas</state>
        <zip>76504</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Washington/Seattle Cancer Care Alliance</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Vincent's Hospital Sydney</name>
      <address>
        <city>Darlinghurst</city>
        <state>New South Wales</state>
        <zip>2010</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Monash Medical Centre</name>
      <address>
        <city>Clayton</city>
        <state>Victoria</state>
        <zip>3168</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peter MacCallum Cancer Centre</name>
      <address>
        <city>East Melbourne</city>
        <state>Victoria</state>
        <zip>3002</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>September 26, 2014</study_first_submitted>
  <study_first_submitted_qc>October 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 13, 2014</study_first_posted>
  <last_update_submitted>August 22, 2019</last_update_submitted>
  <last_update_submitted_qc>August 22, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 28, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>metastatic castration-resistant prostate cancer</keyword>
  <keyword>CRPC</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_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/NCT02262910
org study id: 401
nct id: NCT02262910
lead sponsor: 
has dmc: No
The study will be conducted in 2 Stages. The primary objective of Stage 1 of the study is to
      identify the maximum tolerated dose (MTD) of ES414 administered intravenously to patients
      with mCRPC. Secondary objectives are to evaluate the tolerability, pharmacokinetics (PK),
      pharmacodynamics (PD), immunogenicity, cytokine response, and clinical activity of ES414.

      The primary objective of Stage 2 of the study is to evaluate the clinical activity of ES414
      in patients that have or have not received prior chemotherapy. Secondary objectives are to
      further characterize the safety profile, PK, PD, and immunogenicity of ES414.
Stage 1 - Dose Escalation: The dose escalation stage of the study will test weekly doses of
      0.2 mcg/kg to 300 mcg/kg over 9 dose levels (cohorts). Cohorts 1 to 3 consist of single
      patients and Cohorts 4 - 9 will consist of a minimum of 3 patients; an additional 3 patients
      may be added to the cohort if adverse events possibly related to ES414 or dose-limiting
      toxicities (DLT) occur. The next dose cohort will only enroll after the patient(s) in the
      current dose cohort have completed the first cycle of dosing (4 weeks) with no significant
      adverse events or DLTs. Six patients will be enrolled at the maximum tolerated dose (MTD) and
      this dose will be used for Stage 2.

      Stage 2 - Expansion: The continuous intravenous infusion MTD dose regimen will be further
      examined in 2 expansion cohorts; the first cohort are patients that have received prior
      chemotherapy, such as docetaxel for mCRPC, and the second cohort are those that have not
      received prior chemotherapy for mCRPC. Serum samples will be collected for serial PK
      assessment for ES414 drug levels and antibody formation. Response will be assessed every 2
      months during the first 6 months of treatment and then every 3 months until progression of
      mCRPC, intolerable side effects, or withdrawal of consent.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose of ES414
time frame: during first 28 days of treatment
description: Identify the maximum tolerated dose in dose-escalation stage (Stage 1) by assessment of dose-limiting toxicities
measure: Safety Profile of ES414
time frame: Patients will be followed for the duration of treatment, an expected average of 6 months, and for 28 days following last treatment
description: The safety profile of ES414 will be assessed by monitoring incidence and severity of adverse events
measure: Maximum Serum Drug Concentration (Cmax)
time frame: Pre- and post-infusion at least weekly during first 28-day cycle, and on Days 1 and 15 of subsequent cycles for an expected duration of 6 months, and for up to 8 weeks following last treatment
description: Blood samples will be obtained from all patients for determination of the maximum serum concentration of ES414.
measure: Area under the concentration versus time curve (AUC)
time frame: Pre- and post-infusion at least weekly during first 28-day cycle, and on Days 1 and 15 of subsequent cycles for an expected duration of 6 months, and for up to 8 weeks following last treatment
description: Blood samples will be obtained from all patients for determination of the AUC of ES414.
measure: Elimination half-life (T1/2)
time frame: Pre- and post-infusion at least weekly during first 28-day cycle, and on Days 1 and 15 of subsequent cycles for an expected duration of 6 months, and for up to 8 weeks following last treatment
description: Blood samples will be obtained from all patients for determination of the T1/2 of ES414.
measure: Immune-Related Response Criteria (irRC)
time frame: Baseline and 6 months
description: Investigator measurements of target lesions
measure: Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
time frame: Baseline and 6 months
description: Investigator measurements of target lesions
measure: Pharmacodynamics of ES414
time frame: Patients will be followed for the duration of treatment, an expected average of 6 months, and for 28 days following last treatment
description: Blood samples will be collected from all patients and evaluated by flow cytometry for changes in lymphocytes
measure: PSA Response
time frame: Baseline and 6 months
description: Blood samples will be collected from all patients and tested for PSA
measure: Circulating Tumor Cells
time frame: Patients will be followed for the duration of treatment, an expected average of 6 months, and for 28 days following last treatment
description: Blood samples will be collected from all patients and evaluated for the number of circulating tumor cells
measure: Immunogenicity of ES414
time frame: Patients will be followed for the duration of treatment, an expected average of 6 months, and for 8 weeks following last treatment
description: Blood samples will be collected from all patients and tested for antibody formation to ES414.
arm group label: ES414
arm group type: Experimental
description: Cohorts 1-3 of the dose escalation stage of the study (Stage 1) will test weekly doses of 0.2 mcg/kg to 2 mcg/kg. Cohorts 4-9 of the dose escalation stage of the study (Stage 1) will test continuous infusion at flat doses of 25 mcg to 300 mcg per day delivered continuously over 24 hours. The maximum tolerated dose from Stage 1 of the study will be further examined in Stage 2. Patients in cohorts 1-3 will receive ES414 weekly via intravenous (IV) infusion during the first three 28-day cycles and then on Day 1 and 15 of each subsequent cycle until disease progression, intolerable toxicity occurs, or the patient withdraws consent. Patients in cohorts 4-9 will receive ES414 as a continuous IV infusion for 6 months until disease progression, intolerable toxicity occurs, or the patient withdraws consent.
intervention type: Biological
intervention name: ES414
description: ES414 is a novel humanized bispecific antibody which is designed to treat mCRPC by redirecting T-cell cytotoxicity against prostate cancer cells expressing prostate-specific membrane antigen (PSMA).
arm group label: ES414
criteria: 
gender: Male
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Scott C Stromatt, MD
role: Study Director
affiliation: Aptevo Therapeutics
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Australia
country: United States
responsible party type: Sponsor
mesh term: Prostatic Neoplasms