A Dose Finding Study of ZW49 in Patients With HER2-Positive Cancers
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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.
Condition or disease
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.
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
Secondary Outcome Measures :
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)
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Ages Eligible for Study:
18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Pathologically-confirmed diagnosis of breast cancer, gastroesophageal adenocarcinoma (GEA), or other HER2-expressing cancer with evidence of locally advanced (unresectable) and/or metastatic disease.
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
Prior treatment with ZW25, the investigational HER2-targeted monoclonal antibody
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).