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

A Phase 1 Study of ZW49 in Patients With Locally Advanced (Unresectable) or Metastatic HER2-Expressing Cancers

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.

Study Overview

• Status: Active, not recruiting
• Conditions: HER2-expressing Cancers
• Intervention / Treatment: Drug: ZW49

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
• Enrollment (Estimated): 174
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5042
    • Flinders Medical Centre
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H3T1E2
      • Jewish General Hospital
• Korea, Republic of
  • Seongnam-si, Korea, Republic of, 13620
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 02841
    • Korea University Anam Hospital
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medicine
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • San Antonio, Texas, United States, 78229
      • Next Oncology
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists, PC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZW49	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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2019
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: January 28, 2019
• First Submitted That Met QC Criteria: January 28, 2019
• First Posted (Actual): January 29, 2019

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Colorectal cancer; HER2; Immunotherapy; Non-small cell lung cancer; Breast cancer; Ovarian cancer; Cholangiocarcinoma; Bispecific antibody; Biparatopic antibody; Gastric cancers; Esophageal cancers; Gastroesophageal junction (GEJ) cancers
• Other Study ID Numbers: ZWI-ZW49-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No