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

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ClinicalTrials.gov Identifier: NCT03821233
Recruitment Status : Recruiting
First Posted : January 29, 2019
Last Update Posted : May 13, 2019
Sponsor:
Information provided by (Responsible Party):
Zymeworks Inc.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 69 participants
Intervention Model: Single Group 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 : January 24, 2019
Estimated Primary Completion Date : May 30, 2021
Estimated Study Completion Date : April 30, 2023


Arm Intervention/treatment
Experimental: ZW49 Drug: ZW49
  • Dose Escalation: ZW49 administration IV every 2 weeks (Q2W) and dose levels determined by the SMC
  • Expansion: MTD or RD identified in the dose-escalation part of the study




Primary Outcome Measures :
  1. 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.

  2. Incidence of adverse events [ Time Frame: Up to 7 months ]
    Number of participants who experienced an adverse event

  3. 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.

  4. 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

  5. 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 :
  1. Serum concentrations of ZW49 [ Time Frame: Up to 7 months ]
    End of infusion concentration, maximum serum concentration, and trough concentration of ZW49

  2. Incidence of anti-drug antibodies (ADAs) [ Time Frame: Up to 7 months ]
    Number of participants who develop ADAs

  3. 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

  4. 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

  5. Duration of response [ Time Frame: Up to 2 years ]
    Median duration of response (in months) and range (minimum, maximum)

  6. Progression-free survival [ Time Frame: Up to 2 years ]
    Median progression-free survival (in months) and range (minimum, maximum)

  7. Overall survival [ Time Frame: Up to 2 years ]
    Median overall survival (in months) and range (minimum, maximum)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

  • 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).
  • Known leptomeningeal disease (LMD)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03821233


Contacts
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Contact: Zymeworks Clinical Trial Resource (206) 237-1030 medinfo@zymeworks.com

Locations
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United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Principal Investigator: Komal Jhaveri, MD         
United States, Tennessee
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Principal Investigator: Erika Hamilton, MD         
United States, Texas
NEXT Oncology Recruiting
San Antonio, Texas, United States, 78229
Principal Investigator: Anthony Tolcher, MD         
Sponsors and Collaborators
Zymeworks Inc.
Investigators
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Study Director: Neil Josephson, MD Zymeworks Inc.

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Responsible Party: Zymeworks Inc.
ClinicalTrials.gov Identifier: NCT03821233     History of Changes
Other Study ID Numbers: ZWI-ZW49-101
First Posted: January 29, 2019    Key Record Dates
Last Update Posted: May 13, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Zymeworks Inc.:
Gastric cancers
Esophageal cancers
Gastroesophageal junction (GEJ) cancers
Breast cancer
Ovarian cancer
Non-small cell lung cancer
Colorectal cancer
HER2
Bispecific antibody
Biparatopic antibody
Immunotherapy
Cholangiocarcinoma

Additional relevant MeSH terms:
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Antibodies
Immunologic Factors
Physiological Effects of Drugs