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

Phase 2a Study of ZW25 in Combination With Palbociclib Plus Fulvestrant

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.

Study Overview

• Status: Completed
• Conditions: HER2+/HR+ Breast Cancer
• Intervention / Treatment: Drug: ZW25 (Zanidatamab); Drug: Palbociclib; Drug: Fulvestrant

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
• Enrollment (Actual): 51
• Phase: Phase 2

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N4N2
      • Tom Baker Cancer Centre
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital Cancer Centre
    • Toronto, Ontario, Canada, M4N3M5
      • Sunnybrook Research Institute
  • Quebec
    • Montreal, Quebec, Canada, H3T1E2
      • Jewish General Hospital
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28034
    • Hospital Ruber Internacional
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Alicante
    • Elche, Alicante, Spain, 03203
      • Hospital General Universitario de Elche
• United States
  • California
    • Santa Monica, California, United States, 90404
      • UCLA Hematology/Oncology Parkside
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZW25 (zanidatamab) + palbociclib + fulvestrant; ZW25 (zanidatamab) plus palbociclib, fulvestrant	Drug: ZW25 (Zanidatamab); Administered intravenously; Drug: Palbociclib; Administered orally; Drug: Fulvestrant; Administered as an intramuscular injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-Limiting Toxicities	Dose-limiting toxicities, defined using NCI CTCAE version 5.0, are events that 1) occur following administration of ZW25, palbociclib, and fulvestrant, or any combination of ZW25 and 1 or more of these drugs; and 2) meet the criteria as specified in the protocol.	Cycle 1 Day 1 to Day 28 (each cycle is 28 days)
Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events	A treatment-emergent adverse event occurs after the start of study treatment and is defined as any unfavorable or unintended symptom, sign, or disease (including abnormal lab) temporally associated with the use of treatment that may or may not be considered related to treatment. TEAEs were coded using MedDRA v24.0.	Baseline from the start of dosing of any study drug up until 30 days after last study dose, up to approximately 2 years 10 months.
Progression-free Survival 6	The progression-free survival at 6 months (PFS6) is a binary endpoint variable based on the progression-free survival (PFS) time, defined as the proportion of participants having PFS time greater than or equal to 24 weeks (168 days).	6 months from first dose of any study drug to the date of documented disease progression or death

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Reporting Any Treatment-emergent Adverse Event, Serious Adverse Event, and Adverse Event of Special Interest	A treatment-emergent adverse events (TEAEs) was defined as an adverse event (AE) with onset on or after 1st dose of study treatment through 30 days after final dose of study treatment inclusive. An AE is classified as a serious adverse event (SAE) if fatal, life threatening, requires hospitalization, is disabling/incapacitating, causes congenital anomaly or birth defect, and medically significant. Adverse events of special interest (AESI) include absolute decreases in LVEF greater than or equal to 10 percentage points from baseline, symptomatic heart failure, infusion-related reactions, and all greater than or equal to Grade 2 events of pneumonitis and/or interstitial lung disease, including pulmonary fibrosis.	From the start of dosing of any study drug up until 30 days after last study dose, up to approximately 2 years 10 months
Maximum Serum Concentration of ZW25		Cycle 1, Days 1, 2, 5, 15; Cycle 2, Days 1 and 15; Day 1 of all subsequent cycles (each cycle is 28 days); and end of treatment, up to approximately 5 years 4 months
Trough Concentration of ZW25		Cycle 1, Days 1, 2, 5, 15; Cycle 2, Days 1 and 15; Day 1 of all subsequent cycles (each cycle is 28 days); and end of treatment, up to approximately 5 years 4 months
Incidence of Anti-drug Antibodies (ADAs)		Cycles 1 and 2, Day 15; Day 1 of all subsequent cycles (each cycle is 28 days); end of treatment, 30 days post-last dose (safety follow up), and every 8 weeks (efficacy follow up), up to approximately 5 years 4 months
Objective Response Rate		Baseline up to end of study, approximately 5 years 4 months
Duration of Response		Baseline up to end of study, approximately 5 years 4 months
Disease Control Rate		Baseline up to end of study, approximately 5 years 4 months
Progression-free Survival		Baseline up to end of study, approximately 5 years 4 months
Overall Survival		Baseline up to end of study, approximately 5 years 4 months
Incidence of Lab Abnormalities		Baseline up to end of study, approximately 5 years 4 months

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals
• Investigators: Study Director: Elaina Gartner, MD, Zymeworks Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2020
• Primary Completion (Actual): April 28, 2023
• Study Completion (Actual): June 30, 2025

Study Registration Dates

• First Submitted: January 7, 2020
• First Submitted That Met QC Criteria: January 8, 2020
• First Posted (Actual): January 13, 2020

Study Record Updates

• Last Update Posted (Actual): August 1, 2025
• Last Update Submitted That Met QC Criteria: July 22, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: HER2; Immunotherapy; Breast cancer; Chemotherapy; Fulvestrant; Bispecific antibody; Biparatopic antibody; Palbociclib; HR
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Protein Kinase Inhibitors; Hormone Antagonists; Estrogen Receptor Antagonists; Estrogen Antagonists; Fulvestrant; Palbociclib
• Other Study ID Numbers: ZWI-ZW25-202; 2019-002956-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No