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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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HER2-expressing Cancers

Intervention / Treatment
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* Drug: ZW49


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZW49<br> | Drug: ZW49<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, Bispecific antibody, Biparatopic antibody, Immunotherapy, Gastric cancers, Esophageal cancers, Gastroesophageal junction (GEJ) cancers, Breast cancer, Ovarian cancer, Non-small cell lung cancer, Colorectal cancer, Cholangiocarcinoma