HER2+/HR+ Breast CancerPhase 2NCT04224272
Phase 2a Study of ZW25 in Combination With Palbociclib Plus Fulvestrant
A Phase 2 study testing ZW25 (Zanidatamab), Palbociclib and Fulvestrant in people with HER2+/HR+ Breast Cancer, run by Jazz Pharmaceuticals at 13 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HER2+/HR+ Breast Cancer
- What is being tested?
- ZW25 (Zanidatamab), Palbociclib and Fulvestrant
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 51 participants
- Where
- 13 sitesin 3 countries
- Study dates
- 10 Jun 2020to 30 Jun 2025
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
13 sites in 3 countries.
13 sites in 3 countries
Spain6 sites
Hospital Universitario Vall d'Hebrón
Barcelona, 08035
Hospital General Universitario de Elche
Elche, Alicante, 03203
Hospital Ruber Internacional
Madrid, 28034
Hospital Universitario Virgen de la Victoria
Málaga, 29010
Hospital Universitario Virgen del Rocío
Seville, 41013
Hospital Clínico Universitario de Valencia
Valencia, 46010
Canada4 sites
Tom Baker Cancer Centre
Calgary, Alberta, T2N4N2
Jewish General Hospital
Montreal, Quebec, H3T1E2
The Ottawa Hospital Cancer Centre
Ottawa, Ontario, K1H 8L6
Sunnybrook Research Institute
Toronto, Ontario, M4N3M5
United States3 sites
Sarah Cannon Research Institute
Nashville, Tennessee, 37203
UCLA Hematology/Oncology Parkside
Santa Monica, California, 90404
Seattle Cancer Care Alliance
Seattle, Washington, 98109
About this study
Official title: A Study of ZW25 (Zanidatamab) With Palbociclib Plus Fulvestrant in Patients With HER2+/HR+ Advanced Breast Cancer
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.
Read the 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
- Being tested
- ZW25 (Zanidatamab), Palbociclib, Fulvestrant
- Keywords
- HER2, HR, Bispecific antibody, Biparatopic antibody, Immunotherapy, Breast cancer, Chemotherapy, Palbociclib, Fulvestrant
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZW25 (Zanidatamab)Drug
Administered intravenously
PalbociclibDrug
Administered orally
FulvestrantDrug
Administered as an intramuscular injection
| Study group | Role | What they receive |
|---|---|---|
| ZW25 (zanidatamab) + palbociclib + fulvestrant | Experimental | Participants who received intravenous dose of 20 mg/kg ZW25 (zanidatamab) every 2 weeks (Q2W) in combination with an oral administration of 125 mg palbociclib once daily from Days 1 to 21, and an intramuscular injection of 500 mg fulvestrant Q2W for 3 doses (Cycle 1 Days 1 and 15 and Cycle 2 Day 1), and every 4 weeks (Q4W) thereafter. Receives: Drug: ZW25 (Zanidatamab); Drug: Palbociclib; Drug: Fulvestrant |
What is being measured
The primary outcome is the main question the study is designed to answer.
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; and 2) meet the criteria as specified in the protocol.
Measured: 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.
Measured: From the start of dosing of any study drug up until 30 days after last study dose, up to approximately 5 years 20 days.
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).
Measured: 6 months from first dose of all study drugs 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
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 decrease in LVEF greater than or equal to 10 percentage points from baseline and LVEF value less than 50% post-baseline or LVEF value greater than or equal to 20% to less than or equal to 39% post 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.
Measured: From the start of dosing of any study drug up until 30 days after last study dose, up to approximately 5 years 20 days
Maximum Serum Concentration Steady State of ZW25
Pharmacokinetics (PK) were evaluated using noncompartmental analysis (NCA).
Measured: End of ZW25 infusion on Cycle 4 Day 1 (steady state) (each cycle is 28 days)
Trough Concentration Steady State of ZW25
Pharmacokinetics (PK) were evaluated using noncompartmental analysis (NCA).
Measured: Predose at Cycle 4 Day 1 (steady state) (each cycle is 28 days)
Number of Participants With Anti-drug Antibodies (ADAs) Post-baseline
Participants were considered to be ADA positive if they were initially ADA negative at baseline and tested positive for ADAs following study drug exposure ("treatment-induced ADA response"), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater than the titer of the baseline sample ("treatment-enhanced ADA response").
Participants were considered to be ADA negative if they were ADA negative at baseline and all post-baseline samples were negative, or if they were ADA positive at baseline but did not have any post-baseline samples with a titer that was at least 4-fold greater than the titer of the baseline sample ("treatment-unaffected ADA").
Measured: Predose at Cycle 1 Days 1 and 15; Cycle 2 Days 1 and 15; Cycle 4 Day 1 and subsequent ADA assessment visits; end of treatment; 30 days post last dose (safety FU); and every 8 weeks (efficacy FU) (each cycle, 28 days), up to approximately 5 years 20 days.
Objective Response Rate
Confirmed objective response rate is defined as the number of patients with confirmed complete response (CR) and confirmed partial response (PR). CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions as assessed by the Investigator per RECIST v1.1.
Measured: From first dose of treatment up to end of study, approximately 5 years 20 days
Duration of Response
DOR is defined as the time from the first confirmed objective response (CR or PR) to documented PD per RECIST 1.1 or death within 30 days of last dose of study drug (ZW25, palbociclib, and/or fulvestrant) from any cause. Only participants who achieved a confirmed objective response were included in the analysis.
Measured: From first dose of treatment up to end of study, approximately 5 years 20 days
Disease Control Rate
Disease control is defined as a best response of CR, PR, non-CR/non-PD (for participants who have only non-target lesions), or SD per RECIST 1.1. The proportion of participants who achieve a disease control response was calculated.
Measured: From first dose of treatment up to end of study, approximately 5 years 20 days
Progression-free Survival
Progression-free survival (PFS) time is defined as the time from first dose of ZW25, palbociclib, and/or fulvestrant to the date of first documented disease progression (per RECIST 1.1) or death from any cause, whichever occurs first.
Measured: From first dose of treatment up to end of study, approximately 5 years 20 days
Overall Survival
OS is defined as time from first dose of ZW25, palbociclib, and/or fulvestrant until death from any cause.
Measured: From first dose of treatment up to end of study, approximately 5 years 20 days
Incidence of Abnormal Hepatic Lab Values
Measured: From first dose of treatment up to end of study, approximately 5 years 20 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2020
- Study start10 Jun 2020
- Primary completion28 Apr 2023
- Study completion30 Jun 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HER2+/HR+ Breast CancerStudies of the same condition, open and under way.
- More trials run by Jazz PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 51 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jazz Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04224272
- Sponsor's protocol ID
- ZWI-ZW25-202
- Other IDs
- 2019-002956-18, 2019
- Status last verified
- Aug 2026
- First submitted
- 7 Jan 2020
- Last updated
- 24 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 40339592