A Dose Finding Study of ZW49 in Patients With HER2-Positive Cancers

• ClinicalTrials.gov Identifier: NCT03821233
• Recruitment Status: Recruiting
• First Posted: January 29, 2019
• Last Update Posted: April 6, 2021
• Sponsor: Zymeworks Inc.
• Information provided by (Responsible Party): Zymeworks Inc.

Tracking Information

• First Submitted Date: January 28, 2019
• First Posted Date: January 29, 2019
• Last Update Posted Date: April 6, 2021
• Actual Study Start Date: April 15, 2019
• Estimated Primary Completion Date: May 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 3, 2019)

• Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Up to 4 weeks ]
  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.
• Incidence of adverse events [ Time Frame: Up to 7 months ]
  Number of participants who experienced an adverse event
• Incidence of lab abnormalities [ Time Frame: Up to 7 months ]
  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.
• Incidence of electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) abnormalities [ Time Frame: Up to 7 months ]
  Number of participants who experienced an abnormal ECG or LVEF
• Incidence of dose reductions of ZW49 [ Time Frame: Up to 7 months ]
  Number of doses reduced and number of participants who require a dose reduction

Original Primary Outcome Measures (submitted: January 28, 2019)

• Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Up to 4 weeks ]
  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.
• Incidence of adverse events [ Time Frame: Up to 7 months ]
  Number of participants who experienced an adverse event
• Incidence of lab abnormalities [ Time Frame: Up to 7 months ]
  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.
• Incidence of electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) abnormalities [ Time Frame: Up to 7 months ]
  Number of participants who experienced an abnormal ECF or LVEF
• Incidence of dose reductions of ZW49 [ Time Frame: Up to 7 months ]
  Number of doses reduced and number of participants who require a dose reduction

Current Secondary Outcome Measures (submitted: January 28, 2019)

• Serum concentrations of ZW49 [ Time Frame: Up to 7 months ]
  End of infusion concentration, maximum serum concentration, and trough concentration of ZW49
• Incidence of anti-drug antibodies (ADAs) [ Time Frame: Up to 7 months ]
  Number of participants who develop ADAs
• Objective response rate (ORR) [ Time Frame: Up to 6 months ]
  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
• Disease control rate [ Time Frame: Up to 6 months ]
  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
• Duration of response [ Time Frame: Up to 2 years ]
  Median duration of response (in months) and range (minimum, maximum)
• Progression-free survival [ Time Frame: Up to 2 years ]
  Median progression-free survival (in months) and range (minimum, maximum)
• Overall survival [ Time Frame: Up to 2 years ]
  Median overall survival (in months) and range (minimum, maximum)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Dose Finding Study of ZW49 in Patients With HER2-Positive Cancers
• Official Title: A Phase 1 Study of ZW49 in Patients With Locally Advanced (Unresectable) or Metastatic HER2-Expressing Cancers
• Brief Summary: 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.
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HER2-expressing Cancers

Intervention

Drug: ZW49

• 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

Study Arms

Experimental: ZW49

Intervention: Drug: ZW49

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 16, 2020): 174
• Original Estimated Enrollment (submitted: January 28, 2019): 69
• Estimated Study Completion Date: April 30, 2023
• Estimated Primary Completion Date: May 30, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Pathologically-confirmed diagnosis of breast cancer, gastroesophageal adenocarcinoma (GEA), or other HER2-expressing cancer with evidence of locally advanced (unresectable) and/or metastatic disease.

  • Dose-escalation (Cohort 1): HER2-high advanced solid tumors
  • Expansion (Cohort 2): HER2-high breast cancer
  • Expansion (Cohort 3): HER2-high GEA
  • Expansion (Cohort 4): HER2-high other non-breast and non-GEA cancers

• Progressive disease that has progressed on or been refractory to all standard of care. Patients who were intolerant to or ineligible for standard therapy may be eligible if the reasons are carefully documented and approval is provided by the sponsor medical monitor

  • Patients with HER2-high breast cancer must have received prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1)
  • Patients with HER2-high GEA must have received prior treatment with trastuzumab

• Sites of disease assessible per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

  • Dose-escalation: measurable or non-measurable disease
  • Expansion: measurable disease
• ECOG performance status score of 0 or 1
• Adequate organ function
• Adequate cardiac left ventricular function, as defined by a LVEF >/= institutional standard of normal

Exclusion Criteria:

• History of myocardial infarction or unstable angina within 6 months prior to enrollment, troponin levels consistent with myocardial infarction, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic congestive heart failure (CHF)
• Clinically significant infiltrative pulmonary disease not related to lung metastases
• Active hepatitis B or hepatitis C infection or other known chronic liver disease
• Acute or chronic uncontrolled renal disease, pancreatitis, or liver disease (with exception of patients with Gilbert's Syndrome, asymptomatic gall stones, liver metastases, or stable chronic liver disease per investigator assessment)
• Known history of human immunodeficiency virus (HIV) infection
• Brain metastases: Untreated CNS metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of start of study treatment. Stable, treated brain metastases are allowed (defined as patients who are off steroids and anticonvulsants and are stable for at least 1 month at the time of screening).
• Known leptomeningeal disease (LMD)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Zymeworks Clinical Trial Resource; (206) 237-1030; medinfo@zymeworks.com

• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT03821233
• Other Study ID Numbers: ZWI-ZW49-101
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Zymeworks Inc.
• Study Sponsor: Zymeworks Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Joseph Woolery, PharmD, BCOP; Zymeworks Inc.

• PRS Account: Zymeworks Inc.
• Verification Date: April 2021