A Study of U3-1402 (Patritumab Deruxtecan) in Subjects With Metastatic Breast Cancer

Eligibility Criteria:

Inclusion criteria for Part A and B (HER2-negative) and Part Z (HER2-positive) cohorts:

• Written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses
• Women and men at least 18 years-of-age at the time of signature of the informed consent form (ICF)
• Histologically documented locally advanced or metastatic breast cancer
• Triple-negative breast cancer (TNBC) patients should have received at least 1 but no more than 5 prior lines of chemotherapy in the metastatic setting
• Parts A and B patients only: Patients with HR+ HER2-negative MBC should have received prior treatment with endocrine therapy +CDK 4/6 inhibitor. No limit to prior endocrine therapy regimens, but no more than 2 prior chemotherapy regimens in the metastatic setting are allowed. HR+ = Estrogen receptor (ER) and/or Progesterone (PgR) positivity that are defined as ≥1% of cells expressing HR via IHC analysis. HER2 negativity is defined as either of the following: IHC 0, IHC 1+, or IHC 2+/in situ hybridization (ISH) negative.
• Part B patients only: Patients with HER2-negative MBC will be included into one of the following 2 subgroups: 1) MBC HR+, HER2-, regardless of HER3 expression, who have received trastuzumab deruxtecan and/or sacituzumab govitecan, or, 2) mTNBC, regardless of HER3 expression, who have received sacituzumab govitecan and/or datopotamab deruxtecan.
• Part Z patients only: should have documented HER2-positive expression as per American Society of Clinical Oncology - College of American Pathologists guidelines based on local testing.
• Part Z patients only: should have had prior treatment with at least 2 anti-HER2 therapies, 1 of which must be trastuzumab deruxtecan. These patients must have experienced disease progression after receiving trastuzumab deruxtecan.
• At least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (bone-only disease excluded)
• Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed ≥4 weeks prior to initiation of study treatment (2 weeks for patients who received palliative radiation therapy), there is no evidence of central nervous system disease progression on a scan or mild neurologic symptoms, and there is no requirement for chronic corticosteroid therapy for the treatment of brain metastases
• Willingness to undergo pre-treatment biopsy and on-treatment biopsies; must have a tumor amenable to pre-treatment biopsy (unless archived tissue is available and was obtained within 2 months prior to starting treatment) and on-treatment biopsy (excludes bone lesions and previously irradiated lesions)
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
• Has adequate organ function within 7 days before the start of study treatment, defined as:
• Platelet count ≥100 × 109/L
• Hemoglobin (Hb) ≥9 g/dL (transfusion and/or growth factor support allowed)
• Absolute neutrophil count ≥1.5 × 109/L
• Prothrombin time (PT) and partial thromboplastin time (PTT) ≤1.5 × the upper limit of normal (ULN), except for patients on coumadin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-international normalized ratio (INR) within therapeutic range as deemed appropriate by the Investigator
• Serum creatinine ≤1.5 × ULN, or creatinine clearance ≥50 mL/min as calculated using the modified Cockcroft-Gault equation; confirmation of creatinine clearance is only required when creatinine is >1.5 × ULN
• AST/ALT ≤3 × ULN (if liver metastases are present, ≤5 × ULN)
• Total bilirubin ≤1.5 × ULN if no liver metastases or 470 ms for females and >450 ms for males in three successive screening measurements
• Patients with a left ventricular ejection fraction (LVEF) 180 mmHg or diastolic blood pressure >110 mmHg).
• Documented myocardial infarcti