4-1BB Agonist Monoclonal Antibody PF-05082566 With Trastuzumab Emtansine or Trastuzumab in Treating Patients With Advanced HER2-Positive Breast Cancer

INCLUSION CRITERIA

• History of biopsy proven HER2 overexpressing breast cancer and radiographic evidence of metastatic disease, or locally recurrent unresectable disease. The HER2 status can be determined either by immunohistochemistry (IHC) [IHC score, 3+] or by fluorescence in situ hybridization (FISH) [as defined by HER2/CEP 17 ratio ≥ 2.0, or HER2 copy number ≥ 6], or as otherwise defined by 2018 ASCO/CAP guidelines.
• Cohort 1 subjects must have received trastuzumab and a taxane separately or in combination (those who previously received ado-trastuzumab emtansine may accrue to Cohort 2).
• Subjects in Cohort 2 must have received at least 1 prior therapy including ado-trastuzumab emtansine.
• Subjects who discontinued prior trastuzumab or ado trastuzumab emtansine due to progressive or refractory disease are eligible for enrollment
• Available tumor samples. For eligibility, if no unstained slides remain, stained pathology slides may be reviewed at the treating institution. However, a tumor sample is required for research evaluations per the following (any of Item 1; 2; or 3, in order of preference).
• A FFPE tumor tissue block from a de novo fresh tumor biopsy obtained during screening will be requested, though not mandated.
• A recently obtained archival FFPE tumor tissue block (or 10 to 15 unstained slides) from a primary or metastatic tumor resection or biopsy if the following criteria are met:
• The biopsy or resection was performed within 1 year of enrollment OR
• The subject has not received any intervening systemic anti cancer treatment from the time the tissue was obtained and enrolled onto the current study. OR
• Any archival FFPE tumor tissue block (or unstained slides) from primary tumor resection specimen (if not provided per above). The archival sample may have been collected at any time prior to the current study, regardless of any intervening therapy. If an FFPE tissue block cannot be provided, a minimum of 10 unstained slides (15 preferable) will be acceptable.
• Subjects must have evaluable OR measurable disease, as defined by RECIST v1.1.
• Performance status 0 to 1 (by Eastern Cooperative Oncology Group [ECOG] scale).
• Laboratory parameters (must satisfy all): Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (≥ 1500/µL) Platelet count ≥ 100 × 109/L (≥ 100,000 /µL) Hemoglobin ≥ 9.0 g/dL; subjects on therapeutic anticoagulation are eligible if there is no bleeding and they are on a stable dose of anticoagulation therapy (eg, on Coumadin with an INR of 2 to 3) for at least 7 days before registration (prior to the start of therapy, or stable heparin or Factor Xa inhibitor dose) Serum creatinine ≤ 1.5 × the ULN or calculated creatinine clearance (by Cockcroft Gault formula) ≥ 60 mL/min Aspartate aminotransferase (AST) ≤ 2.5 × ULN Alanine aminotransferase (ALT) ≤ 2.5 × ULN Bilirubin ≤ 1.5 × ULN
• Subjects must not be pregnant or breastfeeding. A pregnancy test will be obtained if the subject is a woman of child bearing potential, defined as a sexually mature woman who has not undergone a hysterectomy or and/or bilateral oophorectomy or who has not been naturally postmenopausal for at least 24 consecutive months (ie, who has had menses at any time in the preceding 24 consecutive months) with 2 pregnancy tests, one at screening, and another immediately preceding the initiation of treatment.
• Subjects must have signed an informed consent document stating that they understand the investigational nature of the proposed treatment
• Left ventricular ejection fraction determined by echocardiogram or multiple gated acquisition scan (MUGA) (cardiac scan) must be 50% or higher.

EXCLUSION CRITERIA

• Previously discontinued either trastuzumab or ado trastuzumab emtansine due to intolerance.
• Received any other investigational agents within 30 days of registration.
• Central nervous system (CNS) metastases, unless previously treated by either radiation therapy and/or surgical resection, clinically stable for at least