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

Sponsor

Zymeworks Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03821233

Collaborator

(none)

174

Enrollment

Locations

Arm

75.6

Anticipated Duration (Months)

10.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HER2-expressing Cancers	Drug: ZW49	Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

174 participants

Allocation:

N/A

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Apr 15, 2019

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Aug 1, 2025

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Incidence of dose-limiting toxicities (DLTs) [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 [Up to 7 months]
Number of participants who experienced an adverse event
Incidence of lab abnormalities [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 [Up to 7 months]
Number of participants who experienced an abnormal ECG or LVEF
Incidence of dose reductions of ZW49 [Up to 7 months]
Number of doses reduced and number of participants who require a dose reduction

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Moffitt Cancer Center	Tampa	Florida	United States	33612
3	University of Chicago Medicine	Chicago	Illinois	United States	60637
4	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
5	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
6	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
7	NEXT Oncology	San Antonio	Texas	United States	78229
8	Virginia Cancer Specialists, PC	Fairfax	Virginia	United States	22031
9	Flinders Medical Centre	Adelaide		Australia	5042
10	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
11	Jewish General Hospital	Montreal	Quebec	Canada	H3T1E2
12	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of	13620
13	Korea University Anam Hospital	Seoul		Korea, Republic of	02841
14	Seoul National University Hospital	Seoul		Korea, Republic of	03080
15	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
16	Asan Medical Center	Seoul		Korea, Republic of	05505