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

HER2-expressing Cancers Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03821233
• Other study ID #: ZWI-ZW49-101
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: April 15, 2019
• Est. completion date: August 2025

Study information

• Verified date: December 2023
• Source: Zymeworks Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 174
• Est. completion date: August 2025
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• 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

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Adelaide
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
United States	University of Chicago Medicine	Chicago	Illinois
United States	City of Hope	Duarte	California
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	NEXT Oncology	San Antonio	Texas
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Zymeworks Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Incidence of adverse events	Number of participants who experienced an adverse event	Up to 7 months
Primary	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
Primary	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
Primary	Incidence of dose reductions of ZW49	Number of doses reduced and number of participants who require a dose reduction	Up to 7 months
Secondary	Serum concentrations of ZW49	End of infusion concentration, maximum serum concentration, and trough concentration of ZW49	Up to 7 months
Secondary	Incidence of anti-drug antibodies (ADAs)	Number of participants who develop ADAs	Up to 7 months
Secondary	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
Secondary	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
Secondary	Duration of response	Median duration of response (in months) and range (minimum, maximum)	Up to 2 years
Secondary	Progression-free survival	Median progression-free survival (in months) and range (minimum, maximum)	Up to 2 years
Secondary	Overall survival	Median overall survival (in months) and range (minimum, maximum)	Up to 2 years