Utomilumab 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 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines * Cohort 1 subjects must have received prior trastuzumab and a taxane separately or in combination * Subjects in Cohort 2 must have received at least 1 prior therapy in the advanced/metastatic setting * 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 formalin-fixed paraffin-embedded (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 Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Performance status 0-1 (by Eastern Cooperative Oncology Group [ECOG] scale)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 /uL)
• Platelet count >= 100 x 10^9/L (>= 100,000 /uL)
• 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 (e.g., on Coumadin with an international normalized ratio [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 x the upper limit of normal (ULN) or calculated creatinine clearance (by Cockcroft-Gault formula) >= 60 mL/min
• Aspartate aminotransferase (AST) =< 2.5 x ULN
• Alanine aminotransferase (ALT) =< 2.5 x ULN
• Bilirubin =< 1.5 x 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 who has not been naturally postmenopausal for at least 24 consecutive months (i.e., 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 60 days and on a stable corticosteroid dose of =< 4 mg/day decadron (or equivalent steroid regimen) for at least 1 month; subjects with a history of CNS metastases that are both treated and stably controlled are eligible if all of the following apply * Therapy has been administered (surgery and/or radiation therapy) * There is no additional treatment planned for brain metastases * The subject is clinically stable * The subject is on a stable corticosteroid dose of =< 4 mg/day decadron (or equivalent steroid regimen) for at least 1 month
• Prior malignancy (other than in situ cervical cancer, or basal cell or squamous cell carcinoma of the skin), unless treated with curative intent and without evidence of disease for 3 years or longer
• Administration of other prior anticancer therapies within 4 weeks of enrollment, except ongoing administration of a bisphosphonate drug or denosumab as treatment for bone metastasis
• Toxicities related to prior anticancer treatment (except alopecia) that have not resolved to =< grade 1 according to common terminology criteria for adverse events (CTCAE version [v] 5) before registration or prior to start of therapy
• Currently receiving systemic antibiotic, antiviral, or antifungal therapy for the treatment of an active infection
• Systemic corticosteroid therapy at doses of greater than prednisone 5 mg daily (or dose-equivalent chronic steroid regimen) for therapeutic and not adrenal replacement indications (maintenance steroid use for adrenal insufficiency is permitted); acute emergency administration, topical applications, inhaled sprays, eye drops or local injections of corticosteroids are allowed
• History of bleeding diathesis
• Any co-morbid medical condition deemed by the treating or principal investigator to possibly put the subject at significant risk for toxicity
• Subject has known sensitivity to any of the products to be administered during dosing
• Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• History of venous thromboembolism within prior 6 months; chronic, systemic corticosteroid use for palliative or supportive purpose is not permitted; use of corticosteroids as symptomatic treatment may be allowed on individual basis and upon discussion with the sponsor; acute emergency administration, topical applications, inhaled sprays, eye drops or local injections of corticosteroids are allowed
• Subject with reproductive potential who will not agree to use, during the study and for 60 days after the last dose of utomilumab or 6 months for ado-trastuzumab emtansine or trastuzumab two highly effective method of contraceptive such a: * Implants * Injectables * Intrauterine devices (IUDs) such as copper T or levonorgestrel-releasing intrauterine system (LNG-IUS * Sexual abstinence * Vasectomized partner * Condom or occlusive cap (diaphragm or cervical/vault cap) supplemented with the use of a spermicide during treatment