Stereotactic Radiation with Sacituzumab Govitecan and Zimberelimab for the Treatment of Patients with Metastatic Triple Negative Breast Cancer with Brain Metastases, TARGET-TNBC Trial

Inclusion Criteria

• Provision of signed and dated informed consent form (ICF)
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Age ≥ 18
• Triple negative breast cancer; to fulfill the requirement of triple negative disease, a breast cancer must express (≤ 10%), by immunohistochemistry (IHC), of the hormone receptors (estrogen receptor [ER] and progesterone receptor [PR])
• To fulfill the requirement of human epidermal growth factor receptor 2 (HER2) negative disease, a breast cancer must not demonstrate, overexpression of HER2 by either IHC or in-situ hybridization as defined by the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guidelines
• Breast cancer as documented by extracranial tumor biopsy with brain metastases documented from MRI brain imaging or intracranial surgical pathology
• Eligible for SRS to brain metastases or to the post-operative bed
• ≤ 15 brain metastases treated with SRS prior to the start of SG and zimberelimab
• Measurable brain disease per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria that can be measured in at least one dimension as ≥ 0.5 cm for both intact brain metastases and post-operative cavities
• Maximum diameter of the largest intact brain metastases ≤ T 4 cm
• Eastern Cooperative Oncology Group performance status 0 to 2
• Symptomatic patients having undergone surgery or on stable doses of steroids ≤ T 8 mg/day dexamethasone will be enrolled
• Prior treatment with taxane based chemotherapy with anthracyclines (if appropriate)
• A formalin-fixed, paraffin-embedded tumor tissue block or 10 unstained slides of intracranial/extracranial tumor sample (archival or recent) for biomarker evaluation should be made available and submitted to the central lab for correlative studies. If attempts to obtain archival tissue are unsuccessful the patient may be enrolled
• Individuals with prior SRS/fractioned stereotactic radiotherapy (FSRT) treatment will be allowed if active measurable disease has not previously been treated with radiation therapy
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the administration of each dose of study agent
• Male and female patients of childbearing potential who engage in heterosexual intercourse must agree to use specified method(s) of contraception

Exclusion Criteria

• Presence of leptomeningeal disease
• All toxicities attributed to prior anticancer therapy must have been resolved to grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 5) or baseline before administration of study drug(s) other than: * Toxicities attributed to prior anticancer therapy that either are not expected to resolve and/or result in long-lasting sequelae, such as neuropathy after platinum-based therapy * Toxicities that are not expected to interfere with study treatment, such as fatigue, alopecia, or grade 2 hematologic toxicity
• Women who are pregnant or breastfeeding
• Known history of HIV-1 or 2 with detectable viral load
• Active, known, or suspected autoimmune disease. Patients with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment are excluded. Exceptions are: * Patients with type I diabetes mellitus, hypothyroidism only requiring thyroid replacement therapy, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Met any of the following criteria for cardiac disease: * Myocardial infarction or unstable angina pectoris within 6 months of enrollment * History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation * New York Heart Association (NYHA) Class III or greater congestive heart failure or left ventricular ejection fraction of < 40%
• Any patient requiring supplemental oxygen therapy
• Have an active serious infection requiring antibiotics
• Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or gastrointestinal (GI) perforation within 6 months of enrollment
• Patients with prior history of non-breast cancer malignancies are excluded except in the case of adequately treated basal cell cancer, squamous cell skin cancer, chronic lymphocytic leukemia, or other cancers in remission not receiving active therapy for ≥ 2 years
• Known medical condition that, in the investigator’s opinion, would increase the risk associated with study participation or study drug(s) administration or that would interfere with the interpretation of safety results
• Major surgery or significant traumatic injury that has not been recovered from by 14 days before the initiation of study drug
• Current or prior participation in a study of an investigational agent or investigational device within 2 weeks of first dose of study treatment
• Have active hepatitis B virus (HBV) or hepatitis C virus (HCV). In patients with a history of HBV or HCV, patients with detectable viral loads will be excluded
• Absolute neutrophil count < 1,500/mm^3
• Platelet count < 100,000/mm^3, or
• Hemoglobin level < 9.0 g/dL
• Total bilirubin level ≥ 1.5 times the upper limits of normal (ULN), (except patients with Gilbert Syndrome, who are excluded if total bilirubin 3 times ULN), or
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≥ 2.5 times the ULN or ≥ 5 times the ULN if liver metastases are present
• Creatinine clearance < 30 mL/min as assessed by the Cockcroft-Gault equation
• History of allergy or hypersensitivity to any of the study drugs or study drug components
• Prisoners or individuals who are involuntarily incarcerated
• Individuals who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness