A Study of ZW25 (Zanidatamab) With Palbociclib Plus Fulvestrant in Patients With HER2+/HR+ Advanced Breast Cancer

• ClinicalTrials.gov Identifier: NCT04224272
• Recruitment Status: Recruiting
• First Posted: January 13, 2020
• Last Update Posted: February 9, 2021
• Sponsor: Zymeworks Inc.
• Information provided by (Responsible Party): Zymeworks Inc.

Tracking Information

• First Submitted Date: January 7, 2020
• First Posted Date: January 13, 2020
• Last Update Posted Date: February 9, 2021
• Actual Study Start Date: June 10, 2020
• Estimated Primary Completion Date: April 30, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 4, 2020)

• Incidence of dose-limiting toxicities (DLTs; Part 1) [ Time Frame: Up to 4 weeks ]
  Number of participants who experienced a DLT. DLTs include specifically defined adverse events (AEs) considered to be related to ZW25, including combination of ZW25 with palbociclib and/or fulvestrant
• Incidence of AEs (Part 1) [ Time Frame: Up to 3.5 years ]
  Number of participants who experienced AEs, serious adverse events (SAEs), or adverse events of special interest (AESIs)
• Incidence of lab abnormalities (Part 1) [ Time Frame: Up to 3.5 years ]
  Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline lab abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
• Progression-free survival 6 (PFS6; Part 2) [ Time Frame: Up to 6 months ]
  Percent of modified intent to treat patients with PFS greater than or equal to 24 weeks

Original Primary Outcome Measures (submitted: January 8, 2020)

• Incidence of dose-limiting toxicities (DLTs; Part 1) [ Time Frame: Up to 4 weeks ]
  Number of participants who experienced a DLT. DLTs include adverse events (AEs) considered to be related to ZW25, including combination of ZW25 with palbociclib and/or fulvestrant
• Incidence of AEs (Part 1) [ Time Frame: Up to 3.5 years ]
  Number of participants who experienced AEs, serious adverse events (SAEs), or adverse events of special interest (AESIs)
• Incidence of lab abnormalities (Part 1) [ Time Frame: Up to 3.5 years ]
  Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline lab abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
• Progression-free survival 6 (PFS6; Part 2) [ Time Frame: Up to 6 months ]
  Percent of evaluable patients with PFS greater than or equal to 24 weeks

Current Secondary Outcome Measures (submitted: August 4, 2020)

• Maximum serum concentration of ZW25 (Parts 1 and 2) [ Time Frame: Up to 9 months ]
• Trough concentration of ZW25 (Parts 1 and 2) [ Time Frame: Up to 9 months ]
  Minimum observed serum concentration (trough)
• Incidence of anti-drug antibodies (ADAs) (Parts 1 and 2) [ Time Frame: Up to 10 months ]
  Number of participants who develop ADAs
• Objective response rate (Part 2) [ Time Frame: Up to 3.5 years ]
  Number of participants who achieved a best response of either complete response (CR) or partial response (PR) during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and as assessed by the investigator
• Duration of response (Part 2) [ Time Frame: Up to 3.5 years ]
  Time from the first objective response (CR or PR) to documented progressive disease per RECIST 1.1 or death within 30 days of last dose of study drug (ZW25, palbociclib, and/or fulvestrant) from any cause
• Disease control rate (Part 2) [ Time Frame: Up to 3.5 years ]
  Number of participants who achieved a best response of CR, PR, or stable disease during treatment according to the RECIST version 1.1 and as assessed by the investigator
• Progression-free survival (PFS; Part 2) [ Time Frame: Up to 3.5 years ]
  Time from the first dose of ZW25, palbociclib, and/or fulvestrant to the date of documented disease progression (per RECIST 1.1), clinical progression, or death from any cause
• Overall survival (Part 2) [ Time Frame: Up to 3.5 years ]
  Time from the first dose of ZW25, palbociclib, and/or fulvestrant until death from any cause
• Incidence of AEs (Part 2) [ Time Frame: Up to 3.5 years ]
  Number of participants who experienced AEs, SAEs, or AESIs
• Incidence of lab abnormalities (Part 2) [ Time Frame: Up to 3.5 years ]
  Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline lab abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's CTCAE, version 5.0.

Original Secondary Outcome Measures (submitted: January 8, 2020)

• Maximum serum concentration of ZW25 (Parts 1 and 2) [ Time Frame: Up to 9 months ]
• Trough concentration of ZW25 (Parts 1 and 2) [ Time Frame: Up to 9 months ]
  Minimum observed serum concentration (trough)
• Incidence of anti-drug antibodies (ADAs) (Parts 1 and 2) [ Time Frame: Up to 10 months ]
  Number of participants who develop ADAs
• Objective response rate (Part 2) [ Time Frame: Up to 3.5 years ]
  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 and as assessed by the investigator
• Duration of response (Part 2) [ Time Frame: Up to 3.5 years ]
  Median duration of response
• Disease control rate (Part 2) [ Time Frame: Up to 3.5 years ]
  Number of participants who achieved a best response of complete response, partial response, or stable disease during treatment according to the RECIST version 1.1 and as assessed by the investigator
• Progression-free survival (PFS; Part 2) [ Time Frame: Up to 3.5 years ]
  Median PFS
• Incidence of AEs (Part 2) [ Time Frame: Up to 3.5 years ]
  Number of participants who experienced AEs, SAEs, or AESIs
• Incidence of lab abnormalities (Part 2) [ Time Frame: Up to 3.5 years ]
  Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline lab abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's CTCAE, version 5.0.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of ZW25 (Zanidatamab) With Palbociclib Plus Fulvestrant in Patients With HER2+/HR+ Advanced Breast Cancer
• Official Title: Phase 2a Study of ZW25 in Combination With Palbociclib Plus Fulvestrant
• Brief Summary: This is a multicenter, Phase 2a, open-label, 2-part study to investigate the safety, tolerability, and anti-tumor activity of ZW25 (zanidatamab) in combination with palbociclib plus fulvestrant. Eligible patients include those with locally advanced (unresectable) and/or metastatic human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor (HR)-positive breast cancer.
• Detailed Description: Part 1 of the study will first evaluate the safety and tolerability of ZW25 in combination with palbociclib plus fulvestrant and will confirm the recommended doses (RDs) of ZW25 and palbociclib in this combination. Part 2 of the study will evaluate the anti-tumor activity of the combination of ZW25 with palbociclib plus fulvestrant at the RD level in patients with HER2-positive, HR-positive advanced breast cancer.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HER2+/HR+ Breast Cancer

Intervention

• Drug: ZW25 (Zanidatamab)
  Administered intravenously
• Drug: Palbociclib
  Administered orally
• Drug: Fulvestrant
  Administered as an intramuscular injection

Study Arms

Experimental: ZW25 (zanidatamab) + palbociclib + fulvestrant

ZW25 (zanidatamab) plus palbociclib, fulvestrant

Interventions:

• Drug: ZW25 (Zanidatamab)
• Drug: Palbociclib
• Drug: Fulvestrant

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 4, 2020): 86
• Original Estimated Enrollment (submitted: January 8, 2020): 76
• Estimated Study Completion Date: June 30, 2023
• Estimated Primary Completion Date: April 30, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Pathologically-confirmed diagnosis of breast cancer with evidence of locally advanced (unresectable) and/or metastatic disease. All patients in both Parts 1 and 2 must have HER2-positive and HR-positive disease.
• Received prior treatment with trastuzumab, pertuzumab, AND ado-trastuzumab emtansine (T-DM1); disease progression during or after the most recent prior therapy. Patients in any part of the study who did not receive pertuzumab or T-DM1 because of lack of access (e.g., due to insurance coverage or because they were treated prior to regulatory agency approval of the agent in a relevant indication) or due to medical ineligibility for treatment with T-DM1 (e.g., history of severe infusion reactions to trastuzumab, >/= Grade 2 peripheral neuropathy, or platelet count < 100 x 10^9/L) may be eligible for the study. Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, and/or metastatic setting is permitted.
• Sites of disease assessible per RECIST version 1.1 (both measurable and non-measurable disease allowed)
• An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
• Adequate organ function
• Adequate cardiac left ventricular function, as defined by left ventricular ejection fraction (LVEF) >/= institutional standard of normal

Exclusion Criteria:

• Prior treatment with trastuzumab, pertuzumab, lapatinib, T-DM1, or other anti-HER2-targeted therapy </= 3 weeks before the first dose of ZW25
• Prior treatment with chemotherapy, other anti-cancer therapy not otherwise specified, or hormonal cancer therapy </= 3 weeks before the first dose of ZW25
• Prior treatment with palbociclib or any other CDK4/6 inhibitor, including experimental agents
• 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)
• QTc Fridericia (QTcF) > 470 ms
• Grade 2 or greater pneumonitis and/or interstitial lung disease, including pulmonary fibrosis, or other clinically significant infiltrative pulmonary disease not related to lung metastases
• Active hepatitis B or hepatitis C infection
• Acute or chronic uncontrolled renal disease, pancreatitis, or severe liver disease (Child-Pugh Class C)
• Known infection with Human Immunodeficiency Virus (HIV)-1 or HIV-2 (Exception: patients with well controlled-HIV [e.g., cluster of differentiation 4 (CD4)-positive T-cell count > 350 mm3 and undetectable viral load] are eligible.)
• Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• Brain metastases: Untreated central nervous system (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 neurologically stable for at least 1 month at the time of screening).
• History of or ongoing leptomeningeal disease
• Grade 3 or greater peripheral neuropathy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Canada, Spain, United States

Administrative Information

• NCT Number: NCT04224272
• Other Study ID Numbers: ZWI-ZW25-202; 2019-002956-18 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Zymeworks Inc.
• Study Sponsor: Zymeworks Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Elaina Gartner, MD; Zymeworks Inc.

• PRS Account: Zymeworks Inc.
• Verification Date: February 2021