A Study Comparing the Efficacy and Safety of Zanidatamab to Trastuzumab, Each in Combination With Physician's Choice Chemotherapy, for the Treatment of Participants With Metastatic HER2-positive Breast Cancer

A Phase 3, Randomized, Open-label, Multicenter, Controlled Study to Evaluate the Efficacy and Safety of Zanidatamab in Combination With Physician's Choice Chemotherapy Compared to Trastuzumab in Combination With Physician's Choice Chemotherapy for the Treatment of Participants With Metastatic HER2-positive Breast Cancer Who Have Progressed on, or Are Intolerant to, Previous Trastuzumab Deruxtecan Treatment

The efficacy and safety of zanidatamab in combination with physician's choice of chemotherapy compared with trastuzumab in combination with physician's choice of chemotherapy will be evaluated for the treatment of participants with metastatic HER2-positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.

Study Overview

• Status: Recruiting
• Conditions: Metastatic HER2-positive Breast Cancer
• Intervention / Treatment: Drug: Capecitabine; Drug: Trastuzumab; Drug: Zanidatamab; Drug: Eribulin; Drug: Vinorelbine; Drug: Gemcitabine

Detailed Description

Zanidatamab, as a monotherapy or in combination with other antineoplastic agents, has shown clinically meaningful efficacy against multiple HER2-positive advanced/metastatic tumors, including in patients with metastatic breast cancer (mBC). Zanidatamab may offer a viable treatment option for patients with metastatic HER2-positive breast cancer.

The primary objective of the study is to compare the efficacy of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy. The secondary objectives of the study will include further comparing the efficacy, safety and tolerability, patient-reported tolerability, and patient-reported physical functioning of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy. The pharmacokinetics and immunogenicity of zanidatamab in combination with chemotherapy will also be evaluated.

• Study Type: Interventional
• Enrollment (Estimated): 550
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Clinical Trial Disclosure & Transparency; Phone Number: 215-832-3750; Email: ClinicalTrialDisclosure@JazzPharma.com

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Recruiting
    • HPS Pharmacies - Adelaide
  • Mount Kuring-Gai, Australia, 2080
    • Recruiting
    • The Kinghorn Cancer Centre
  • Subiaco, Australia, 6008
    • Recruiting
    • St John of God Hospital Subiaco
  • Queensland
    • Birtinya, Queensland, Australia, 4575
      • Recruiting
      • Sunshine Coast University Private Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3128
      • Recruiting
      • Box Hill Hospital
    • Mount Waverly, Victoria, Australia, 3149
      • Recruiting
      • Peninsula and South Eastern Haematology and Oncology Group
• Austria
  • Innsbruck, Austria, 6020
    • Recruiting
    • Medizinische Universitat Innsbruck
  • Linz, Austria, 4010
    • Recruiting
    • Ordensklinikum Barmherzige Schwestern
  • Vienna, Austria, 1090
    • Recruiting
    • Medizinische Universitat Wien
  • Wels, Austria, 4600
    • Recruiting
    • Klinikum Wels-Grieskirchen GmbH - Abteilung für Innere Medizin IV
• Belgium
  • Anderlecht, Belgium, 1070
    • Recruiting
    • Institute Jules Bordet
  • Edegem, Belgium, 2650
    • Recruiting
    • UZ Antwerpen
  • Gilly, Belgium, 6060
    • Recruiting
    • Grand Hôpital de Charleroi
  • Namur, Belgium, 5000
    • Recruiting
    • CHU Ucl Namur - Site Sainte-Elisabeth
  • Roeselare, Belgium, 8800
    • Recruiting
    • AZ Delta- Campus Rumbeke
• Brazil
  • Brasília, Brazil, 71.635-610
    • Recruiting
    • DASA Hospital Brasilia
  • Ceará, Brazil, 60336-232
    • Recruiting
    • Centro Regional Integrado de Oncologia
  • Itajaí, Brazil, 88301-220
    • Recruiting
    • Catarina Pesquisa Clinica
  • Portalegre, Brazil, 90050-170
    • Recruiting
    • Irmandade da Santa Casa de Misericordia de Porto Alegre
  • Porto Alegre, Brazil, 90610-001
    • Recruiting
    • Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul PUCRS
  • Recife, Brazil, 52.010-075
    • Recruiting
    • Real Hospital Portugues de Beneficiencia Em Pernambuco
  • Salvador, Brazil, 40.170-070
    • Recruiting
    • Nucleo de Oncologia da Bahia
  • São Caetano do Sul, Brazil, 09541-270
    • Recruiting
    • Ceon Pesquisas Ltda
  • São Paulo, Brazil, 01323-030
    • Recruiting
    • Hospital Beneficiencia Portuguesa
  • São Paulo, Brazil, 04062-001
    • Recruiting
    • Onco Star Sp Oncologia Ltda
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 91350-200
      • Recruiting
      • Hospital Nossa Senhora da Conceicao
  • São Paulo
    • Sorocaba, São Paulo, Brazil, 18060-105
      • Recruiting
      • IEPE Unimed Sorocaba
• Canada
  • Montreal, Canada, H3T 1E2
    • Recruiting
    • Jewish General Hospital
  • Ottawa, Canada, K1H 8L6
    • Recruiting
    • The Ottawa Hospital Cancer Centre
  • Québec, Canada, G1S 4L8
    • Recruiting
    • CHU de Québec Université Laval Hôpital du Saint Sacrement
  • Toronto, Canada, M4N 3M5
    • Recruiting
    • Sunnybrook Research Institute
  • Vancouver, Canada, V5Z 4E6
    • Recruiting
    • BC Cancer-Vancouver Center
• France
  • Bordeaux, France, 33076
    • Recruiting
    • Institut Bergonie
  • Caen, France, 14000
    • Recruiting
    • Centre Francois Baclesse
  • Dijon, France, 21000
    • Recruiting
    • Centre Georges Francois Leclerc
  • Le Mans, France, 72000
    • Recruiting
    • Pharmacie Centre de Cancerologie de la Sarthe
  • Lille, France, 59020
    • Recruiting
    • Centre Oscar Lambret
  • Marseille, France, 13009
    • Recruiting
    • Institut Paoli Calmettes
  • Marseille, France, 13005
    • Recruiting
    • AP HM Hopital de La Timone
  • Montpellier, France, 34298
    • Recruiting
    • Pharmacie ICM Val d'Aurelle
  • Strasbourg, France, 67000
    • Recruiting
    • ICANS - Institut de cancérologie Strasbourg Europe
  • Toulouse, France, 31059
    • Recruiting
    • Oncopôle Claudius Regaud Pharmacie
  • Villejuif, France, 94800
    • Recruiting
    • Gustave Roussy
• Germany
  • Berlin, Germany, 13125
    • Recruiting
    • Helios Klinikum Berlin Buch GmbH Klinik für Gynäkologie und Geburtshilfe
  • Dortmund, Germany, 44263
    • Recruiting
    • Marienhospital Bottrop gGmbH
  • Dresden, Germany, 01307
    • Recruiting
    • Universitätsklinikum Carl Gustav Carus an der TU
  • München, Germany, 81377
    • Recruiting
    • LMU Klinikum - Apotheke
  • Ulm, Germany, 89081
    • Recruiting
    • Universitatsklinikum Ulm
• Greece
  • Athens, Greece, 15125
    • Recruiting
    • Athens Medical Center
  • Athens, Greece, 11528
    • Recruiting
    • Aretaieio Hospital
  • Pátrai, Greece, 26504
    • Recruiting
    • University General Hospital of Patras
  • Thessaloniki, Greece, 57001
    • Recruiting
    • European Interbalkan Medical Center
• Italy
  • Aviano, Italy, 33081
    • Recruiting
    • IRCCS Centro di Riferimento Oncologico di Aviano CRO
  • Bergamo, Italy, 24127
    • Recruiting
    • Asst Papa Giovanni XXIII
  • Bologna, Italy, 40138
    • Recruiting
    • Azienda Ospedaliero Universitaria Di Bologna Policlinico S Orsola Malpighi Via Massarenti
  • Milan, Italy, 20141
    • Recruiting
    • Istituto Europeo di Oncologia
  • Milan, Italy, 20132
    • Recruiting
    • Ospedale San Raffaele S.r.l PPDS
  • Modena, Italy, 41124
    • Recruiting
    • Azienda Ospedaliero Universitaria Di Modena
  • Monza, Italy, 20900
    • Recruiting
    • Fondazione IRCCS San Gerardo dei Tintori
  • Padua, Italy, 35128
    • Recruiting
    • Istituto Oncologico Veneto - I.R.C.C.S.
  • Pavia, Italy, 27100
    • Recruiting
    • Fondazione IRCCS Policlinico San Matteo
  • Rome, Italy, 00136
    • Recruiting
    • Fondazione Policlinico Universitario A. Gemelli IRCCS
  • Rozzano, Italy, 20089
    • Recruiting
    • IRCCS Istituto Clinico Humanitas
• Japan
  • Chiba, Japan, 260-8717
    • Recruiting
    • Chiba Cancer Center
  • Chūōku, Japan, 104-0045
    • Recruiting
    • National Cancer Center Hospital
  • Chūōku, Japan, 541-8567
    • Recruiting
    • Osaka International Cancer Institute
  • Fukuoka, Japan, 811-1395
    • Recruiting
    • National Hospital Organization Kyushu Cancer Center
  • Fukushima, Japan, 960-1295
    • Recruiting
    • Fukushima Medical University Hospital
  • Hidaka-shi, Japan, 350-1298
    • Recruiting
    • Saitama Medical University International Medical Center
  • Isesaki-shi, Japan, 259-1193
    • Recruiting
    • Tokai University Hospital
  • Kagoshima, Japan, 892-0833
    • Recruiting
    • Sagara Hospital
  • Kyoto, Japan, 606-8507
    • Recruiting
    • Kyoto University Hospital
  • Nagoya, Japan, 467-8602
    • Recruiting
    • Nagoya City University Hospital
  • Nagoya, Japan, 464-8681
    • Recruiting
    • Aichi Cancer Center
  • Okayama, Japan, 700-8558
    • Recruiting
    • Okayama University Hospital
  • Osaka, Japan, 540-0006
    • Recruiting
    • National Hospital Organization Osaka National Hospital
  • Sapporo, Japan, 003-0804
    • Recruiting
    • National Hospital Organization Hokkaido Cancer Center
  • Tokyo, Japan, 113-8431
    • Recruiting
    • Juntendo University Hospital
  • Tokyo, Japan, 142-8666
    • Recruiting
    • Showa University Hospital
  • Yokohama, Japan, 241-8515
    • Recruiting
    • Kanagawa Cancer Center
• Poland
  • Bialystok, Poland, 15-027
    • Recruiting
    • Białostockie Centrum Onkologii im. Marii Skłodowskiej-Curie w Białymstoku
  • Biała Podlaska, Poland, 21-500
    • Recruiting
    • Wojewódzki Szpital Specjalistyczny W Białej Podlaskiej
  • Krakow, Poland, 30-727
    • Recruiting
    • Pratia MCM Krakow
  • Poznan, Poland, 60-569
    • Recruiting
    • Uniwersytecki Szpital Kliniczny w Poznaniu
  • Poznan, Poland, 60-192
    • Recruiting
    • Pratia Poznań
  • Warsaw, Poland, 02-781
    • Recruiting
    • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy w Warszawie
• South Korea
  • Cheonan-si, South Korea, 330721
    • Recruiting
    • Soon Chun Hyang University Cheonan Hospital
  • Namdong-gu, South Korea, 21565
    • Recruiting
    • Gachon University Gil Medical Center
  • Seongnam-si, South Korea, 13605
    • Recruiting
    • Seoul National University Bundang Hospital
  • Seoul, South Korea, 03080
    • Recruiting
    • Seoul National University Hospital
  • Seoul, South Korea, 06351
    • Recruiting
    • Samsung Medical Center
  • Seoul, South Korea, 03722
    • Recruiting
    • Severance Hospital Yonsei University Health System
  • Seoul, South Korea, 06273
    • Recruiting
    • Gangnam Severance Hospital, Yonsei University Health System
  • Seoul, South Korea, 137-701
    • Recruiting
    • The Catholic University of Korea, Seoul St. Mary's Hospital
• Spain
  • A Coruña, Spain, 15006
    • Recruiting
    • Hospital Universitario A Coruna
  • Badajoz, Spain, 06006
    • Recruiting
    • Hospital Universitario de Badajoz
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall D Hebron
  • Barcelona, Spain, 08916
    • Recruiting
    • ICO Badalona-H.U. Germans Trias i Pujol
  • Elche, Spain, 03203
    • Recruiting
    • Hospital General Universitario de Elche
  • Granada, Spain, 18016
    • Recruiting
    • Hospital Universitario Clínico San Cecilio
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28040
    • Recruiting
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28033
    • Recruiting
    • MD Anderson Cancer Center
  • Madrid, Spain, 28040
    • Recruiting
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28007
    • Recruiting
    • Hospital Beata Maria Ana
  • San Cristóbal de La Laguna, Spain, 38320
    • Recruiting
    • Hospital Universitario de Canarias
  • Seville, Spain, 41013
    • Recruiting
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46010
    • Recruiting
    • Hospital Clínico Universitario de Valencia
  • Vigo, Spain, 36312
    • Recruiting
    • CHUVI - H.U. Alvaro Cunqueiro
• United Kingdom
  • Bath, United Kingdom, BA1 3NG
    • Recruiting
    • Royal United Hospital
  • Glasgow, United Kingdom, G12 0YN
    • Recruiting
    • Beatson West Of Scotland Cancer Centre
  • Leicester, United Kingdom, LE2 7LX
    • Recruiting
    • Leicester Royal Infirmary
  • London, United Kingdom, SE1 9RT
    • Recruiting
    • Guy's Hospital
  • London, United Kingdom, W6 8RF
    • Recruiting
    • Charring Cross Hospital
  • Manchester, United Kingdom, M20 4BX
    • Recruiting
    • The Christie - PPDS
  • Oxford, United Kingdom, OX3 7LJ
    • Recruiting
    • Churchill Hospital
  • Wolverhampton, United Kingdom, WV10 0QP
    • Recruiting
    • New Cross Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic Scottsdale - PPDS
    • Tucson, Arizona, United States, 85719
      • Recruiting
      • University of Arizona Cancer Center
    • Tucson, Arizona, United States, 85711
      • Withdrawn
      • Arizona Oncology Tucson - Wilmot
  • California
    • Cerritos, California, United States, 90703
      • Recruiting
      • The Oncology Institute of Hope and Innovation
    • Glendale, California, United States, 91204
      • Recruiting
      • Los Angeles Hematology Oncology Medical Group Glendale
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC-Norris Comprehensive Cancer Center - Investigational Drug Service IDS
    • San Francisco, California, United States, 94158
      • Recruiting
      • UCSF at Mission Bay MB
  • Colorado
    • Aurora, Colorado, United States, 80045-2517
      • Recruiting
      • University of Colorado-Cancer Center-PPDS
    • Denver, Colorado, United States, 80218
      • Recruiting
      • Rocky Mountain Cancer Centers
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Recruiting
      • MedStar Georgetown University Hospital
    • Washington D.C., District of Columbia, United States, 20010
      • Recruiting
      • Washington Cancer Center
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Recruiting
      • Florida Cancer Specialists Research South
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic Jacksonville - PPDS
    • St. Petersburg, Florida, United States, 33705
      • Recruiting
      • Florida Cancer Specialists Research North
    • West Palm Beach, Florida, United States, 33401
      • Recruiting
      • Florida Cancer Specialists Research East
  • Massachusetts
    • Boston, Massachusetts, United States, 02215-5418
      • Recruiting
      • Dana Farber Cancer Institute
  • Minnesota
    • Coon Rapids, Minnesota, United States, 55433
      • Recruiting
      • Minnesota Oncology Hematology
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic - PPDS
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Recruiting
      • Saint Luke's Cancer Institute
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Recruiting
      • Hackensack Meridian Health
    • New Brunswick, New Jersey, United States, 08901
      • Recruiting
      • Rutgers Cancer Institute of New Jersey
  • New York
    • Long Island City, New York, United States, 11101
      • Recruiting
      • Memorial Sloan Kettering
    • New York, New York, United States, 10029
      • Recruiting
      • The Mount Sinai Hospital
    • New York, New York, United States, 10032-3729
      • Recruiting
      • Columbia University Medical Center 161 Fort Washington
    • New York, New York, United States, 10016-4744
      • Recruiting
      • Perlmutter Cancer Center 160 E 34th St
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Recruiting
      • Messino Cancer Center
    • Durham, North Carolina, United States, 27710-2000
      • Recruiting
      • Duke Cancer Institute
    • Morrisville, North Carolina, United States, 27560
      • Recruiting
      • UNC Central Investigational Drug Services
  • Ohio
    • Cincinnati, Ohio, United States, 45226
      • Recruiting
      • Oncology Hematology Care (OHC)
    • Cleveland, Ohio, United States, 44106-1716
      • Withdrawn
      • University Hospitals Cleveland Medical Center 11100 Euclid Ave
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Abramson Cancer Center of The University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Recruiting
      • Fox Chase Cancer Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Recruiting
      • Rhode Island Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Sarah Cannon Research Institute
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Recruiting
      • Texas Oncology - Fort Worth
    • Houston, Texas, United States, 77030
      • Recruiting
      • U.T. MD Anderson Cancer Center, Investigational Pharmacy Services
    • Houston, Texas, United States, 77090
      • Withdrawn
      • Millennium Research and Clinical Development
    • Irving, Texas, United States, 75063
      • Recruiting
      • Texas Oncology Gulf Coast
    • Irving, Texas, United States, 75063
      • Recruiting
      • Maryland Oncology Hematology Healing Way - USOR
    • Irving, Texas, United States, 75063
      • Recruiting
      • Medical Oncology Hematology Consultants
    • Irving, Texas, United States, 75063
      • Recruiting
      • Nexus Health
    • Irving, Texas, United States, 75063
      • Recruiting
      • Sansum Clinic 540 W - USOR
    • Irving, Texas, United States, 75063
      • Recruiting
      • Texas Oncology West
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Virginia Cancer Specialists
    • Norfolk, Virginia, United States, 23502
      • Recruiting
      • Virginia Oncology Associates, Sentara Health
    • Roanoke, Virginia, United States, 24014
      • Recruiting
      • Blue Ridge Cancer Care
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutchinson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Froedtert and the Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Participants are eligible to be included in the study only if all of the following criteria apply:

1. Is 18 years of age or of the legal adult age per local standard at the time of signing the informed consent.
2. Has histologically confirmed HER2-positive breast cancer according to ASCO-CAP Guidelines as evaluated by a sponsor-designated central laboratory
3. Participants with unresectable or metastatic HER2 positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.

4. Must have received at least 2 lines of HER2-directed therapy for their metastatic disease.

   1. Prior HER2-targeted neo-adjuvant or adjuvant therapy that resulted in relapse within 6 months of the completion of therapy will be considered a line of treatment for metastatic disease.
   2. Based on the physician's choice, participants' eligibility, and institutional and local guidelines, participants may also have received post-T-DXd therapy, for example, a tucatinib-based regimen and/or T-DM1.
   3. Participants must not have received more than 4 lines of HER2-directed therapy in the metastatic setting.
5. Has measurable disease per RECIST version 1.1.
6. Is eligible to receive one of the chemotherapy options listed in the physician's choice of chemotherapy (eribulin, gemcitabine, vinorelbine, or capecitabine).
7. Participants with history of treated or clinically inactive CNS metastases are eligible as specified in the protocol.
8. Has a life expectancy of at least 6 months, in the opinion of the investigator.
9. Has adequate hematologic parameters as defined in the protocol.
10. Has adequate hepatic function as specified in the protocol.
11. Has creatinine clearance ≥ 50 mL/minute as calculated per local institutional guidelines.
12. Has LVEF ≥ 50% as determined by either echocardiogram or MUGA obtained within 4 weeks before the first dose of study intervention.
13. Has ECOG performance status of 0 or 1.

14. Participant agrees to the following based on sex assigned at birth.

    1. Male participants:

       Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 7 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice:

       • Refrain from donating fresh unwashed semen.
       • Use contraception as follows as specified in the protocol

    2. Female participants:

       • A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

         • Is a women of nonchildbearing potential OR
         • Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency during the study intervention period and for at least 7 months after the last dose of study intervention.
       • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 3 days before the first dose of study intervention.
       • Additional requirements for pregnancy testing during and after study intervention are provided in the protocol.
       • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
15. Is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the protocol.

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

1. Has clinically confirmed leptomeningeal disease, in the opinion of the investigator.
2. Has uncontrolled or significant cardiovascular disease.
3. Has toxicity related to prior cancer therapy that has not resolved to ≤ Grade 1, with exceptions as stated in the protocol.
4. Has uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
5. Has an infection with HIV-1 or HIV-2, with the exception of participants with well-controlled HIV.
6. Has active hepatitis B or C infection.
7. Has an active SARS-CoV-2 infection. Participants with prior infection that has resolved per local institutions' requirements and screening guidance are eligible.
8. Has a history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of zanidatamab.
9. Is unable to receive trastuzumab treatment due to medical contraindications.
10. Has any serious underlying medical or psychiatric condition that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site.
11. Has any condition that would prevent treatment with the physician's choice of chemotherapy.

12. Has any issue or condition that in the opinion of the investigator would contraindicate the participant's participation in the study or confound the results of the study.

    Prior/Concomitant Therapy

13. Has a history of prior allogeneic bone marrow, stem cell, or solid organ transplantation.
14. The washout periods for prior anticancer therapies before randomization as specified in the protocol.

15. Has a history of trauma or major surgery within 4 weeks prior to randomization.

    Other Exclusions

16. Has a known hypersensitivity to any components of the study drugs, including chemotherapy.
17. Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zanidatamab plus physician's choice of chemotherapy; Participants with HER2-positive metastatic breast cancer (mBC) who have progressed on, or are intolerant to, previous T-DXd treatment will be randomized to receive intravenous infusion of zanidatamab plus physician's choice of chemotherapy (eribulin, or vinorelbine, or gemcitabine, or capecitabine).	Drug: Capecitabine; Given orally; Drug: Zanidatamab; Administered by intravenous infusion; Drug: Eribulin; Administered by intravenous infusion; Drug: Vinorelbine; Administered by intravenous infusion; Drug: Gemcitabine; Administered by intravenous infusion
Active Comparator: Trastuzumab plus physician's choice of chemotherapy; Participants with HER2-positive metastatic breast cancer (mBC) who have progressed on, or are intolerant to, previous T-DXd treatment will be randomized to receive intravenous infusion of trastuzumab plus physician's choice of chemotherapy (eribulin, or gemcitabine, or vinorelbine, or capecitabine).	Drug: Capecitabine; Given orally; Drug: Trastuzumab; Administered by intravenous infusion; Drug: Eribulin; Administered by intravenous infusion; Drug: Vinorelbine; Administered by intravenous infusion; Drug: Gemcitabine; Administered by intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) Per RECIST Version 1.1 As Assessed by Blinded Independent Central Review (BICR)	PFS is defined as the time in months from randomization to the date of first documented disease progression (as assessed by BICR according to RECIST v1.1) or death from any cause, whichever occurs first.	Until disease progression or death, up to approximately 44 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is defined as the time in months from randomization to the date of death due to any cause.	Until death, up to approximately 80 months
Confirmed Objective Response Rate (ORR) Per RECIST Version 1.1, As Assessed by BICR	The BICR-assessed confirmed ORR is defined as the proportion of participants who had a best overall response of BICR-assessed Complete Response (CR) or Partial Response (PR) after randomization.	Until disease progression or death, up to approximately 44 months
Duration of Response (DOR) Per RECIST Version 1.1, As Assessed by BICR	BICR-assessed DOR is defined as the time in months from the first objective response (CR or PR) that is subsequently confirmed to documented progressive disease (PD) as assessed by BICR per RECIST v1.1 or death from any cause.	Until disease progression or death, up to approximately 44 months
PFS Per RECIST Version 1.1, As Assessed By Investigator	Investigator-assessed PFS is defined as the time in months from randomization to the date of first documented disease progression (as assessed by investigator according to RECIST v1.1) or death from any cause, whichever occurs first	Until disease progression or death, up to approximately 44 months
Confirmed ORR Per RECIST Version 1.1, As Assessed By Investigator	The investigator-assessed confirmed ORR is defined as the proportion of participants who had a best overall response of investigator-assessed confirmed CR or PR after randomization.	Until disease progression or death, up to approximately 44 months
DOR Per RECIST Version 1.1, As Assessed By Investigator	Investigator-assessed DOR is defined as the time in months from the first objective response (CR or PR) that is subsequently confirmed to documented PD as assessed by the investigator per RECIST v1.1 or death from any cause.	Until disease progression or death, up to approximately 44 months
Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events As Graded by NCI CTCAE Version 5.0		Up to approximately 44 months
Number of Participants With Dose Reductions		Up to approximately 44 months
Number of Participants Discontinuing Study Treatment Due to TEAEs		Up to approximately 44 months
Serum Concentrations of Zanidatamab		Up to approximately 44 months
Number of Participants Positive for Anti-drug Antibodies to Zanidatamab		Up to approximately 44 months
Proportion of All Treated Participants, As Treated, Reporting Symptomatic Adverse Events While On Treatment Based on Patient-reported Outcome-Common Terminology Criteria for AEs and European Organisation for Research and Treatment of Cancer Item Library		Up to approximately 44 months
Proportion of All Treated Participants, As Treated, Reporting Overall Side-effect Bother on the Functional Assessment of Chronic Illness Therapy General Physical Item 5 (FACIT-GP5)	The Functional Assessment of Chronic Illness Therapy (FACIT) GP5 Item score ranges from 0 (Not at all) to 4 (Very Much), where higher scores reflect greater bother from treatment side effects.	Up to approximately 44 months
Proportion of Treated Participants, As Treated, With Maintained or Improved Physical Function While On Treatment Based On The Physical Functioning Subscale of the EORTC Quality of Life Questionnaire Core Module (EORTC QLQ-C30)	The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core Module Physical Functioning score ranges from 0 to 100, where higher scores reflect better functioning.	Up to approximately 44 months

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2024
• Primary Completion (Estimated): April 28, 2028
• Study Completion (Estimated): October 18, 2030

Study Registration Dates

• First Submitted: May 24, 2024
• First Submitted That Met QC Criteria: May 24, 2024
• First Posted (Actual): May 30, 2024

Study Record Updates

• Last Update Posted (Actual): February 10, 2026
• Last Update Submitted That Met QC Criteria: February 6, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Trastuzumab; Zanidatamab; Metastatic HER2-positive breast cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Alkaloids; Indoles; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Deoxyribonucleosides; Fluorouracil; Trastuzumab; Capecitabine; Vinorelbine; Gemcitabine; eribulin; zanidatamab
• Other Study ID Numbers: JZP598-303; 2023-508960-31-00 (Other Identifier: EU CTR)

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