Clinical Trials

Inclusion Criteria:

• Is 18 years of age or of the legal adult age per local standard at the time of signing the informed consent.
• Has histologically confirmed HER2-positive breast cancer according to ASCO–CAP Guidelines as evaluated by a central laboratory (Wolff, 2018).
  • The testing of HER2 status must be performed within 6 months prior to C1D1 by a sponsor-designated central laboratory.
  • Most recently available tissue blocks or freshly cut slides from all participants must be submitted to confirm HER2 positivity by a sponsor-designated central laboratory. If archived tissue is not available, a fresh biopsy is required. If a participant meets all other inclusion/exclusion criteria, but the participant’s HER2-status is not yet confirmed by the sponsor designated central laboratory prior to randomization, the following procedure should be implemented:
    • Participants who were previously assessed as having IHC 3+ HER2 positive status will be randomized directly while the most recently available tissue blocks or freshly cut slides will be submitted to a sponsor-designated central laboratory to confirm HER2 positivity.
    • Participants who were previously assessed as having IHC 2+ HER2 positive status will not be randomized directly until their most recently available tissue blocks or freshly cut slides are confirmed for HER2 positivity by a sponsor-designated central laboratory.
• Participants with unresectable or metastatic HER2 positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.
  • Must have received at least 2 lines of HER2-directed therapy for their metastatic disease.
    • 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.
  • 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.
  • Participants must not have received more than 4 lines of HER2-directed therapy in the metastatic setting.
• Has measurable disease per RECIST version 1.1.
• Is eligible to receive one of the chemotherapy options listed in the physician’s choice of chemotherapy (eribulin, gemcitabine, vinorelbine, or capecitabine). 
• Participants with history of treated or clinically inactive CNS metastases are eligible, provided the following criteria are met:
  • Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants, may be included in the study if they have recovered to ≤ Grade 1 or baseline from the acute toxic effect associated with the treatment ≥ 7 days prior to randomization of the participant in the study.
  • Prior stereotactic radiosurgery or stereotactic radiotherapy should be completed ≥ 7 days before the randomization of the participant. A minimum of ≥ 14 days must have elapsed between the end of whole brain radiotherapy and the study randomization of the participant in the study. 
• Has a life expectancy of at least 6 months, in the opinion of the investigator.
•  Has adequate hematologic parameters defined as follows: 
  • Absolute neutrophil count ≥ 1000/mm .
  • Platelet count ≥ 100,000/mm ; participants with stable platelet count from 75,000 to 100,000/mm may be included with approval from the medical monitor.
  • Hemoglobin ≥ 8 g/dL; participants with chronic anemia (other than autoimmune hemolytic anemia) that is supported by intermittent red blood cell transfusions are eligible. 
• Has adequate hepatic function defined as follows:
  • Total serum bilirubin ≤ 1.5 × ULN or < 3 × ULN in the presence of Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastasis at baseline
  • Aspartate aminotransferase ≤ 3.0 × ULN per institutional values
  • Alanine aminotransferase ≤ 3.0 × ULN per institutional values (≤ 5.0 × ULN if liver metastases are present)
• Has creatinine clearance ≥ 30 mL/minute as calculated per local institutional guidelines.
•  Has LVEF ≥ 50% as determined by either echocardiogram or MUGA obtained within 4 weeks before the first dose of study intervention.
• Has ECOG performance status of 0 or 1.
• Participant agrees to the following based on sex assigned at birth.
  • Male participants:
    • Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 5 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice, whichever is longer:
    • Refrain from donating fresh unwashed semen
    • Use contraception as follows:
      • Use a male condom and should also be advised of the benefit of a female partner using a highly effective method of contraception, as a condom may break or leak, when having sexual intercourse with a WOCBP who is not currently pregnant.
      • Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person.
  • 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 WONCBP Contraceptive and Barrier Guidance. OR
      • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, Contraceptive and Barrier Guidance, during the study intervention period and for at least 5 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice, whichever is longer. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first 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.
      • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    • Additional requirements for pregnancy testing during and after study intervention are provided
    • 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 
• Is capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

• Has known or suspected leptomeningeal disease.
• Has uncontrolled or significant cardiovascular disease, including any of the following: 
  • History of myocardial infarction within 6 months before randomization
  • Troponin levels consistent with myocardial infarction as defined by the manufacturer’s specifications within 28 days prior to randomization
  • History of symptomatic congestive heart failure (New York Heart Association Class II to IV)
  • Left ventricular ejection fraction <40% at any time while receiving previous anti-HER2 based therapy e. Ventricular arrhythmia requiring therapy
• Has toxicity related to prior cancer therapy that has not resolved to ≤ Grade 1, with the following exceptions: 
  • Alopecia
  • Neuropathy resolved to ≤ Grade 2
  •  Congestive heart failure that was ≤ Grade 1 in severity at the time of occurrence and resolved completely 
• Has uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
• Has known HIV infection.
• Has active hepatitis B or C infection. 
  • Participants who are HBsAg positive are eligible if they have hepatitis B virus DNA less than 500 IU/mL.
  • Participants positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for hepatitis C RNA 
• Has an active SARS-CoV-2 infection. Participants with prior infection that has resolved per local institutions’ requirements and screening guidance are eligible.
• Has a history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of zanidatamab.
• Is unable to receive trastuzumab treatment due to medical contraindications.
• 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.
• Has any condition that would prevent treatment with the physician’s choice of chemotherapy.
• 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. 
• Has a history of prior allogeneic bone marrow, stem cell, or solid organ transplantation.
• Was treated with any local or systemic antineoplastic therapy (including hormonal therapies for breast cancer) or any investigational therapy within 4 weeks or 5 half-lives (whichever is longer) prior to randomization.
• Has a history of trauma or major surgery within 4 weeks prior to randomization. 
• Has a known hypersensitivity to any components of the study drugs, including chemotherapy.
• Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 5/8/2024. Questions regarding updates should be directed to the study team contact.