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

NCT04224272 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: ZWI-ZW25-2022019-002956-18
• Study Type: interventional
• Target: 51
• Locations: 3 countries
• Sites: 13

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.

Conditions

HER2+/HR+ Breast Cancer

Keywords

HER2; HR; Bispecific antibody; Biparatopic antibody; Immunotherapy; Breast cancer; Chemotherapy; Palbociclib; Fulvestrant

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (10)

• Number of Participants Reporting Any Treatment-emergent Adverse Event, Serious Adverse Event, and Adverse Event of Special Interest

  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

Study Arms (1)

ZW25 (zanidatamab) + palbociclib + fulvestrant

EXPERIMENTAL

ZW25 (zanidatamab) plus palbociclib, fulvestrant

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

Interventions

ZW25 (Zanidatamab) DRUG

Administered intravenously

ZW25 (zanidatamab) + palbociclib + fulvestrant

Palbociclib DRUG

Administered orally

ZW25 (zanidatamab) + palbociclib + fulvestrant

Fulvestrant DRUG

Administered as an intramuscular injection

ZW25 (zanidatamab) + palbociclib + fulvestrant

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Jazz Pharmaceuticals: lead

Study Sites (13)

UCLA Hematology/Oncology Parkside

Santa Monica, California, 90404, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

Tom Baker Cancer Centre

Calgary, Alberta, T2N4N2, Canada

Location

The Ottawa Hospital Cancer Centre

Ottawa, Ontario, K1H 8L6, Canada

Location

Sunnybrook Research Institute

Toronto, Ontario, M4N3M5, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T1E2, Canada

Location

Hospital General Universitario de Elche

Elche, Alicante, 03203, Spain

Location

Hospital Universitario Vall d'Hebrón

Barcelona, 08035, Spain

Location

Hospital Ruber Internacional

Madrid, 28034, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain

Location

Related Publications (1)

• 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.

  PMID: 40339592 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

zanidatamab; palbociclib; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Clinical Trial Disclosure & Transparency
• Organization: Jazz Pharmaceuticals Inc.

ClinicalTrialDisclosure@JazzPharma.com

215-832-3750

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: January 7, 2020
• First Posted: January 13, 2020
• Study Start: June 10, 2020
• Primary Completion: April 28, 2023
• Study Completion: June 30, 2025
• Last Updated: August 1, 2025
• Results First Posted: August 14, 2024

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (3); CA (4); ES (6)