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

NCT ID: NCT04224272

Last Updated: 2025-08-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 51 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-06-10
• Study Completion Date: 2025-06-30

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.

Conditions

HER2+/HR+ Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

ZW25 (zanidatamab) + palbociclib + fulvestrant

ZW25 (zanidatamab) plus palbociclib, fulvestrant

Group Type: EXPERIMENTAL

ZW25 (Zanidatamab)

Intervention Type: DRUG

Administered intravenously

Palbociclib

Intervention Type: DRUG

Administered orally

Fulvestrant

Intervention Type: DRUG

Administered as an intramuscular injection

Interventions

ZW25 (Zanidatamab)

Administered intravenously

Intervention Type: DRUG

Palbociclib

Administered orally

Intervention Type: DRUG

Fulvestrant

Administered as an intramuscular injection

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Jazz Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

UCLA Hematology/Oncology Parkside

Santa Monica, California, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

Seattle Cancer Care Alliance

Seattle, Washington, United States

Tom Baker Cancer Centre

Calgary, Alberta, Canada

The Ottawa Hospital Cancer Centre

Ottawa, Ontario, Canada

Sunnybrook Research Institute

Toronto, Ontario, Canada

Jewish General Hospital

Montreal, Quebec, Canada

Hospital General Universitario de Elche

Elche, Alicante, Spain

Hospital Universitario Vall d'Hebrón

Barcelona, , Spain

Hospital Ruber Internacional

Madrid, , Spain

Hospital Universitario Virgen de la Victoria

Málaga, , Spain

Hospital Universitario Virgen del Rocío

Seville, , Spain

Hospital Clínico Universitario de Valencia

Valencia, , Spain

Countries

United States; Canada; Spain

References

Escriva-de-Romani S, Cejalvo JM, Alba E, Friedmann J, Rodriguez-Lescure A, Savard MF, Pezo RC, Gion M, Ruiz-Borrego M, Hamilton E, Pluard T, Webster M, Beeram M, Linden H, Saura C, Shpektor D, Salim B, Harvey P, Hurvitz SA. Zanidatamab plus palbociclib and fulvestrant in previously treated patients with hormone receptor-positive, HER2-positive metastatic breast cancer: primary results from a two-part, multicentre, single-arm, phase 2a study. Lancet Oncol. 2025 Jun;26(6):745-758. doi: 10.1016/S1470-2045(25)00140-8. Epub 2025 May 5.

Reference Type: DERIVED

PMID: 40339592 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2019-002956-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ZWI-ZW25-202

Identifier Type: -

Identifier Source: org_study_id