<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/NCT03821233</url>
  </required_header>
  <id_info>
    <org_study_id>ZWI-ZW49-101</org_study_id>
    <nct_id>NCT03821233</nct_id>
  </id_info>
  <brief_title>A Dose Finding Study of ZW49 in Patients With HER2-Positive Cancers</brief_title>
  <official_title>A Phase 1 Study of ZW49 in Patients With Locally Advanced (Unresectable) or Metastatic HER2-Expressing Cancers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Zymeworks Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Zymeworks Inc.</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a first-in-human, Phase 1, multicenter, open-label, dose-escalation study to&#xD;
      establish the maximum-tolerated dose (MTD) or recommended dosage (RD) of ZW49, the&#xD;
      investigational agent under study, and to assess the safety and tolerability of ZW49.&#xD;
      Eligible patients include those with locally advanced (unresectable) or metastatic&#xD;
      HER2-expressing cancers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will use a 3+3 dose-escalation study design to evaluate the safety and tolerability&#xD;
      of ZW49 and to determine the MTD or RD of ZW49 for further study. Selected expansion cohorts&#xD;
      will be subsequently opened based upon Safety Monitoring Committee (SMC) recommendation and&#xD;
      sponsor approval to further evaluate the safety and tolerability of ZW49 at the MTD or RD and&#xD;
      to assess preliminary anti-tumor activity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 15, 2019</start_date>
  <completion_date type="Anticipated">August 2025</completion_date>
  <primary_completion_date type="Anticipated">August 2023</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of dose-limiting toxicities (DLTs)</measure>
    <time_frame>Up to 4 weeks</time_frame>
    <description>Number of participants who experienced a DLT. DLTs are events that occur following administration of any amount of ZW49 and are considered related to ZW49 per the investigator. DLTs will include only events considered related to ZW49.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 7 months</time_frame>
    <description>Number of participants who experienced an adverse event</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of lab abnormalities</measure>
    <time_frame>Up to 7 months</time_frame>
    <description>Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline laboratory abnormality, including either hematology and chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) abnormalities</measure>
    <time_frame>Up to 7 months</time_frame>
    <description>Number of participants who experienced an abnormal ECG or LVEF</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of dose reductions of ZW49</measure>
    <time_frame>Up to 7 months</time_frame>
    <description>Number of doses reduced and number of participants who require a dose reduction</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Serum concentrations of ZW49</measure>
    <time_frame>Up to 7 months</time_frame>
    <description>End of infusion concentration, maximum serum concentration, and trough concentration of ZW49</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of anti-drug antibodies (ADAs)</measure>
    <time_frame>Up to 7 months</time_frame>
    <description>Number of participants who develop ADAs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>Up to 6 months</time_frame>
    <description>Number of participants who achieved a best response of either complete or partial response during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate</measure>
    <time_frame>Up to 6 months</time_frame>
    <description>Number of participants who achieved a best response of complete response, partial response, or stable disease during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Median duration of response (in months) and range (minimum, maximum)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Median progression-free survival (in months) and range (minimum, maximum)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Median overall survival (in months) and range (minimum, maximum)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">174</enrollment>
  <condition>HER2-expressing Cancers</condition>
  <arm_group>
    <arm_group_label>ZW49</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZW49</intervention_name>
    <description>Dose Escalation: ZW49 administered intravenously at dose levels determined by the SMC&#xD;
Expansion: MTD or RD identified in the dose-escalation part of the study</description>
    <arm_group_label>ZW49</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pathologically-confirmed diagnosis of breast cancer, gastroesophageal adenocarcinoma&#xD;
             (GEA), or other HER2-expressing cancer with evidence of locally advanced&#xD;
             (unresectable) and/or metastatic disease.&#xD;
&#xD;
               -  Dose-escalation (Cohort 1): HER2-high advanced solid tumors&#xD;
&#xD;
               -  Expansion (Cohort 2): HER2-high breast cancer&#xD;
&#xD;
               -  Expansion (Cohort 3): HER2-high GEA&#xD;
&#xD;
               -  Expansion (Cohort 4): HER2-high other non-breast and non-GEA cancers&#xD;
&#xD;
          -  Progressive disease that has progressed on or been refractory to all standard of care.&#xD;
             Patients who were intolerant to or ineligible for standard therapy may be eligible if&#xD;
             the reasons are carefully documented and approval is provided by the sponsor medical&#xD;
             monitor&#xD;
&#xD;
               -  Patients with HER2-high breast cancer must have received prior treatment with&#xD;
                  trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1)&#xD;
&#xD;
               -  Patients with HER2-high GEA must have received prior treatment with trastuzumab&#xD;
&#xD;
          -  Sites of disease assessible per Response Evaluation Criteria in Solid Tumors (RECIST)&#xD;
             version 1.1&#xD;
&#xD;
               -  Dose-escalation: measurable or non-measurable disease&#xD;
&#xD;
               -  Expansion: measurable disease&#xD;
&#xD;
          -  ECOG performance status score of 0 or 1&#xD;
&#xD;
          -  Adequate organ function&#xD;
&#xD;
          -  Adequate cardiac left ventricular function, as defined by a LVEF &gt;/= institutional&#xD;
             standard of normal&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of myocardial infarction or unstable angina within 6 months prior to&#xD;
             enrollment, troponin levels consistent with myocardial infarction, or clinically&#xD;
             significant cardiac disease, such as ventricular arrhythmia requiring therapy,&#xD;
             uncontrolled hypertension, or any history of symptomatic congestive heart failure&#xD;
             (CHF)&#xD;
&#xD;
          -  Clinically significant infiltrative pulmonary disease not related to lung metastases&#xD;
&#xD;
          -  Active hepatitis B or hepatitis C infection or other known chronic liver disease&#xD;
&#xD;
          -  Acute or chronic uncontrolled renal disease, pancreatitis, or liver disease (with&#xD;
             exception of patients with Gilbert's Syndrome, asymptomatic gall stones, liver&#xD;
             metastases, or stable chronic liver disease per investigator assessment)&#xD;
&#xD;
          -  Known history of human immunodeficiency virus (HIV) infection&#xD;
&#xD;
          -  Brain metastases: Untreated CNS metastases, symptomatic CNS metastases, or radiation&#xD;
             treatment for CNS metastases within 4 weeks of start of study treatment. Stable,&#xD;
             treated brain metastases are allowed (defined as patients who are off steroids and&#xD;
             anticonvulsants and are stable for at least 1 month at the time of screening).&#xD;
&#xD;
          -  Known leptomeningeal disease (LMD)&#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>Joseph Woolery, PharmD, BCOP</last_name>
    <role>Study Director</role>
    <affiliation>Zymeworks Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>City of Hope</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Chicago Medicine</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fox Chase Cancer Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sarah Cannon Research Institute</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NEXT Oncology</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Virginia Cancer Specialists, PC</name>
      <address>
        <city>Fairfax</city>
        <state>Virginia</state>
        <zip>22031</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Flinders Medical Centre</name>
      <address>
        <city>Adelaide</city>
        <zip>5042</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Princess Margaret Cancer Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jewish General Hospital</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3T1E2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seoul National University Bundang Hospital</name>
      <address>
        <city>Seongnam-si</city>
        <zip>13620</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Korea University Anam Hospital</name>
      <address>
        <city>Seoul</city>
        <zip>02841</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seoul National University Hospital</name>
      <address>
        <city>Seoul</city>
        <zip>03080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Severance Hospital, Yonsei University Health System</name>
      <address>
        <city>Seoul</city>
        <zip>03722</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Asan Medical Center</name>
      <address>
        <city>Seoul</city>
        <zip>05505</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Canada</country>
    <country>Korea, Republic of</country>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 28, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 29, 2019</study_first_posted>
  <last_update_submitted>May 9, 2023</last_update_submitted>
  <last_update_submitted_qc>May 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HER2</keyword>
  <keyword>Bispecific antibody</keyword>
  <keyword>Biparatopic antibody</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>Gastric cancers</keyword>
  <keyword>Esophageal cancers</keyword>
  <keyword>Gastroesophageal junction (GEJ) cancers</keyword>
  <keyword>Breast cancer</keyword>
  <keyword>Ovarian cancer</keyword>
  <keyword>Non-small cell lung cancer</keyword>
  <keyword>Colorectal cancer</keyword>
  <keyword>Cholangiocarcinoma</keyword>
  <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/NCT03821233
org study id: ZWI-ZW49-101
nct id: NCT03821233
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is a first-in-human, Phase 1, multicenter, open-label, dose-escalation study to
      establish the maximum-tolerated dose (MTD) or recommended dosage (RD) of ZW49, the
      investigational agent under study, and to assess the safety and tolerability of ZW49.
      Eligible patients include those with locally advanced (unresectable) or metastatic
      HER2-expressing cancers.
The study will use a 3+3 dose-escalation study design to evaluate the safety and tolerability
      of ZW49 and to determine the MTD or RD of ZW49 for further study. Selected expansion cohorts
      will be subsequently opened based upon Safety Monitoring Committee (SMC) recommendation and
      sponsor approval to further evaluate the safety and tolerability of ZW49 at the MTD or RD and
      to assess preliminary anti-tumor activity.
allocation: N/A
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of dose-limiting toxicities (DLTs)
time frame: Up to 4 weeks
description: Number of participants who experienced a DLT. DLTs are events that occur following administration of any amount of ZW49 and are considered related to ZW49 per the investigator. DLTs will include only events considered related to ZW49.
measure: Incidence of adverse events
time frame: Up to 7 months
description: Number of participants who experienced an adverse event
measure: Incidence of lab abnormalities
time frame: Up to 7 months
description: Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline laboratory abnormality, including either hematology and chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
measure: Incidence of electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) abnormalities
time frame: Up to 7 months
description: Number of participants who experienced an abnormal ECG or LVEF
measure: Incidence of dose reductions of ZW49
time frame: Up to 7 months
description: Number of doses reduced and number of participants who require a dose reduction
measure: Serum concentrations of ZW49
time frame: Up to 7 months
description: End of infusion concentration, maximum serum concentration, and trough concentration of ZW49
measure: Incidence of anti-drug antibodies (ADAs)
time frame: Up to 7 months
description: Number of participants who develop ADAs
measure: Objective response rate (ORR)
time frame: Up to 6 months
description: Number of participants who achieved a best response of either complete or partial response during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
measure: Disease control rate
time frame: Up to 6 months
description: Number of participants who achieved a best response of complete response, partial response, or stable disease during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
measure: Duration of response
time frame: Up to 2 years
description: Median duration of response (in months) and range (minimum, maximum)
measure: Progression-free survival
time frame: Up to 2 years
description: Median progression-free survival (in months) and range (minimum, maximum)
measure: Overall survival
time frame: Up to 2 years
description: Median overall survival (in months) and range (minimum, maximum)
arm group label: ZW49
arm group type: Experimental
intervention type: Drug
intervention name: ZW49
description: Dose Escalation: ZW49 administered intravenously at dose levels determined by the SMC
Expansion: MTD or RD identified in the dose-escalation part of the study
arm group label: ZW49
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Joseph Woolery, PharmD, BCOP
role: Study Director
affiliation: Zymeworks Inc.
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
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facility: 
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country: Australia
country: Canada
country: Korea, Republic of
country: United States
responsible party type: Sponsor
sharing ipd: No