Clinical trial NCT03821233: A Dose Finding Study of ZW49 in Patients With HER2-Positive Cancers
Official title: A Phase 1 Study of ZW49 in Patients With Locally Advanced (Unresectable) or Metastatic HER2-Expressing Cancers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HER2-expressing Cancers
Keywords: 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
Lead sponsor: Zymeworks BC Inc.
Sponsor class: INDUSTRY
First posted: 2019-01-29
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Incidence of dose-limiting toxicities (DLTs)
timeFrame: Up to 4 weeks
measure: Incidence of adverse events
timeFrame: Up to 7 months
measure: Incidence of lab abnormalities
timeFrame: Up to 7 months
measure: Incidence of electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) abnormalities
timeFrame: Up to 7 months
measure: Incidence of dose reductions of ZW49
timeFrame: Up to 7 months
Secondary outcomes:
measure: Serum concentrations of ZW49
timeFrame: Up to 7 months
measure: Incidence of anti-drug antibodies (ADAs)
timeFrame: Up to 7 months
measure: Objective response rate (ORR)
timeFrame: Up to 6 months
measure: Disease control rate
timeFrame: Up to 6 months
measure: Duration of response
timeFrame: Up to 2 years
measure: Progression-free survival
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: San Antonio
country: United States
facility: NEXT Oncology
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Adelaide
country: Australia
facility: Flinders Medical Centre
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
Study officials:
affiliation: Zymeworks BC Inc.
name: Joseph Woolery, PharmD, BCOP
role: STUDY_DIRECTOR
References: