Brain Irradiation and Tremelimumab in Metastatic Breast Cancer

Inclusion Criteria

• Diagnosis of CNS metastases for whom SRS or WBRT is indicated, as determined by radiation oncologist assessment
• Age 18 and older at the time of consent
• Written informed consent and authorization obtained from the subject/HIPAA-appointed legal representative prior to performing any protocol-related procedures including screening evaluations
• ECOG performance of 0-2 with anticipated life expectancy of ≥12 weeks
• Histologically or cytologically confirmed invasive breast cancer that is HER2-positive (3+ by IHC and/or >2.0 by FISH) if concurrent HER2-directed therapy is planned;
• Non-CNS progression of disease as assessed by the investigator/treating physician, for which a change in systemic therapy is planned OR achievement of stable or responsive non-CNS disease for which a holiday from the current systemic therapy is planned, as assessed by the investigator/treating physician.
• Measurable non-CNS disease, defined by RECIST1.1 criteria
• Recovered from all toxicities associated with prior treatment, to acceptable baseline status or grade 1 or less (for lab toxicities see below limits for inclusion,), except for toxicities not considered a safety risk, such as alopecia or vitiligo. Peripheral neuropathy must be grade 2 or less
• Adequate organ and marrow function, as defined below:
• platelets ≥ 75x 103/μL;
• absolute neutrophil count (ANC) ≥ 1,000/μL;
• hemoglobin ≥ 9.0 g/dL;
• total bilirubin ≤1.5 x ULN (upper limit of normal) except subject with documented Gilbert's syndrome (≤5 x ULN) or liver metastasis, who must have a baseline total bilirubin ≤3.0 mg/dL;
• AST and ALT ≤ 3 x ULN, unless associated with hepatobiliary metastases, in that case ≤5 x ULN
• serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 50 ml/min as determined by the Cockcroft-Gault equation);
• Negative hepatitis B serologic tests. If positive results are not indicative of active or chronic infection, the subjects can enter the study at the investigator's discretion
• Females of childbearing potential who are sexually active with a non-sterilized male partner must use a highly effective method of contraception prior to the first dose of investigational product, and must agree to continue using such precautions for 6 months after the final dose of investigational product; cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. They must also refrain from egg cell donation for 6 months after the final dose of investigational product;
• Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause);
• A highly effective method of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. The acceptable methods of contraception
• Non-sterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from Days 1 through 90 post last dose. In addition, they must refrain from sperm donation for 90 days after the final dose of investigational product
• LVEF ≥50% for patients enrolling in the HER2 directed therapy arm
• Willing to attempt a baseline tumor biopsy procedure

Exclusion Criteria

• CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt placement)
• Known leptomeningeal metastases not amenable to radiotherapy. Patients receiving radiotherapy for leptomeningeal metastases are eligible
• Received any prior monoclonal antibody against CTLA-4, programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PD-L1)
• Subjects with a history of hypersensitivity to compounds of similar biolog