Phase Ib/II Study of Zanidatamab Plus Tucatinib and Chemotherapy in HER2-Positive Advanced Breast Cancer

Inclusion Criteria:

1. Participants must be capable of understanding the purpose of the Study and have signed a written informed consent form (ICF) prior to beginning specific protocol procedures.
2. Female or male participants ≥ 18 years of age at the time of signing the ICF.
3. ECOG PS of 0-1.
4. Minimum life expectancy of ≥ 12 weeks at screening.
5. Unresectable locally advanced or metastatic disease documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent.
6. Locally confirmed HER2-positive breast cancer (immunohistochemistry \[IHC\] score of 3+ or ICH score of 2+ with confirmation of HER2 amplification by in situ hybridization \[ISH\]) per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2018 criteria on the most recent analyzed biopsy.
7. Evaluable disease by RECIST v.1.1.
8. All participants need to have experienced disease progression after at least one line, but no more than 3 lines, of anti-HER2-therapy for advanced disease.
9. Able to provide the most recently available FFPE tumor tissue blocks at the time of inclusion.

   Note: If no archived sample is available participant eligibility should be discussed with the Medical Monitor.
10. Able to provide blood samples at the established time points.
11. Participant must have adequate bone marrow, coagulation, liver, and renal function:

    * Absolute neutrophil count (ANC) ≥ 1.5 × 103/μL, platelet count ≥ 100 x 103/μL, and hemoglobin (Hgb) ≥ 9 g/dL. Transfusion must be ≥ 14 days prior to starting therapy to establish adequate hematologic parameters independent of transfusion support. Participants with chronic anemia (other than autoimmune hemolytic anemia) that is supported by intermittent red blood cell transfusions are eligible.
    * International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × the upper limit of normal (ULN), unless on medication known to alter INR and aPTT (Note: Warfarin and other coumarin derivatives are prohibited).
    * Total bilirubin ≤ 1.5 × ULN or ≤ 3.0 × ULN for participants with Gilbert's disease (if the conjugated bilirubin is ≤ 1.5 × ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN (for participants with liver metastases, AST and ALT ≤ 5.0 × ULN are acceptable).
    * Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min calculated per institutional guidelines.
12. Female participants of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of Study treatments.

    Note: A woman is considered of childbearing potential, i.e., fertile, following menarche until post-menopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. For participants with a hormonal profile compatible with menopausal status, they will be discussed with the medical monitor.
13. Female participants of childbearing potential and male participants with a partner of childbearing potential must agree to use two methods of birth control with a failure rate of less than 1% per year starting at the screening, throughout the study, and for 12 months after the last dose of Study treatments.

    Note: See Section 8.4.2 for allowed contraceptive methods.
14. Female participants must refrain from oocyte donation and breastfeeding, and male participants must not donate or bank sperm starting at the screening, throughout the study, and for 12 months after the last dose of Study treatments.
15. Participants must be accessible for treatment and follow-up visits.

Specific inclusion criteria for BMs:

1. Stable BMs were defined as BMs radiographically stable for ≥4 weeks since completion of treatment.
2. Untreated BM without immediate need for local therapy. For participants with untreated CNS lesions \> 2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment.
3. BMs that had progressed since local CNS therapy, with no clinical indication for immediate retreatment with local therapy.
4. Washout periods before the first day of dosing were \>7 days for SRS or gamma knife, and \>24 days for WBRT, respectively. The use of systemic corticosteroids for control of symptoms of BM is not permitted if the total daily dose is \> 2 mg of dexamethasone (or equivalent). However, participants on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible following discussion and approval by the medical monitor. Participants receiving an anticonvulsant therapy must be on stable dosing regimen for ≥ 14 days prior to the first dose of Study treatment.

Specific inclusion criteria for phase II At least 50% of participants enrolled in phase II must have BMs.

Exclusion Criteria:

1. Participation in another clinical trial, interventional or observational, until the Study's safety visit.

   Note: Participation in retrospective studies or data analysis is allowed.
2. Have received treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS radiation, or experimental agent within ≤ 3 weeks prior to the first dose of Study treatments.

   Note: For palliative non-CNS radiotherapy, a shorter washout period may be acceptable. This should be evaluated on a case-by-case basis and discussed with the medical monitor.
3. Prior treatment with capecitabine and eribulin.
4. Known or suspected leptomeningeal disease (LMD) as documented by the investigator.
5. Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term (including massive uncontrolled effusions \[pleural, pericardial, peritoneal\] or pulmonary lymphangitis).
6. Receipt of a live vaccine within 4 weeks prior to enrollment.
7. History of prior allogeneic bone marrow, stem cell, or solid organ transplantation.
8. The washout periods for prior anticancer therapies before randomization are as follows:

   * Prior therapies with chemotherapy and/or monoclonal antibodies including ADCs: washout period up to 3 weeks.
   * Prior therapies with small molecule targeted therapies: washout period of ≤ 2 weeks or 5 half-lives, whichever is shorter.
   * No washout period needed for endocrine therapy.
   * No washout period for gonadotropin-releasing hormone agonists.
9. Requirement for ongoing therapy with any prohibited medications listed in the protocol.

   Note: Refer to the prescribing information for each of the Study drugs for any additional prohibited concomitant medications.
10. Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances, including life-threatening hypersensitivity to monoclonal antibodies or excipients in zanidatamab.
11. Ongoing, clinically significant toxicity associated with prior cancer therapies that has not resolved to ≤ Grade 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities not considered a safety risk for the participant at the investigator's discretion).
12. Has a concurrent malignancy or malignancy within 5 years of Study enrollment except for carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor's medical monitor is required.
13. Major surgical procedure or significant traumatic injury within 4 weeks before the first dose of Study treatment or anticipation of the need for major surgery within the course of the Study treatment.
14. Have clinically significant cardiac disease such as:

    * Ventricular arrhythmia requiring therapy.
    * Uncontrolled hypertension (defined as persistent systolic blood pressure \> 150 mm Hg and/or diastolic blood pressure \> 100 mm Hg on antihypertensive medications).
    * Any history of symptomatic congestive heart failure (CHF) classified as New York Heart Association (NYHA) Class II to IV, or any Grade ≥2 CHF related to prior therapy. Participants with Grade 1 CHF from prior treatment are eligible only if the condition has fully resolved at the time of screening.
    * Presence of ≥ Grade 2 QTc prolongation on screening electrocardiogram (ECG).
    * Conditions potentially resulting in drug-induced prolongation of the QT interval or torsade de pointes:

      1. Congenital or acquired long QT syndrome.
      2. Family history of sudden death.
      3. History of previous drug induced QT prolongation.
      4. Current use of medications with known and accepted associated risk of QT prolongation.
    * Myocardial infarction or unstable angina within 6 months prior to first dose of study treatment.
    * Left ventricular ejection fraction (LVEF) \< 50% as determined by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of Study treatments.
15. Having a history of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
16. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of the Study enrolment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, pleural effusion, post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
17. Having peripheral neuropathy ≥ Grade 2.
18. Known history of clinically significant bleeding, thrombosis, intestinal obstruction, or gastrointestinal perforation within 3 months of study initiation.
19. Known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Participants with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen \[HBsAg\] test and a positive hepatitis B core antibody \[HBcAb\] test, accompanied by a negative HBV DNA test) are eligible. Participants positive for HCV antibody are eligible only if the polymerase chain reaction (PCR) is negative for HCV RNA.
20. Known infection with Human Immunodeficiency Virus (HIV). I. Note: Participants with HIV on antiretroviral therapy (ART) with well-controlled HIV infection/disease are allowed.

    II. Participants on ART must have a CD4+ T-cell count ≥ 350 cells/mm3 at time of screening.

    III. Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening.

    IV. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to Study entry.

    V. The combination of the ART regimen must not contain any medications that may interfere with the Study treatments.
21. Other systemic uncontrolled infection at the time of enrollment.
22. Having known dihydropyridine dehydrogenase deficiency (DPD). This must be checked before treatment with capecitabine, according to current guidelines.
23. Having an inability to swallow pills or significant gastrointestinal disease, which would preclude the adequate oral absorption of medications.
24. Any other serious medical condition and/or abnormality in clinical laboratory tests that, in the Investigator's judgment, precludes the participant's safe participation in and completion of the Study.

Specific exclusion criteria for phase II

• Prior treatment with HER2 tyrosine kinase inhibitors (TKIs).