Atezolizumab, Pertuzumab, and High-Dose Trastuzumab in Treating Patients with Her2-Positive Breast Cancer with Central Nervous System Metastases

Inclusion Criteria

• Histologically confirmed metastatic breast cancer
• Histologically confirmed HER-2 positive by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) 2013 guidelines by local laboratory. Central confirmation of HER-2 status is not required. * Immunohistochemistry (IHC) 3+ based on circumferential membrane staining that is complete, intense -AND/OR- * Fluorescence in situ hybridization (FISH) positive based on one of the three following criteria: ** Single-probe average HER2 copy number >= 6.0 signals/cell; OR ** Dual-probe HER2/CEP17 ratio >= 2.0 OR ** Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell
• At least one measurable CNS lesion, defined as >= 10 mm in at least one dimension
• Unequivocal evidence of new and/or progressive brain metastases, and at least one of the following scenarios: * Treated with stereotactic radiosurgery (SRS) or surgery with residual un-treated lesions remaining; such participants are eligible for immediate enrollment on this study providing that at least one untreated lesion is measurable * Participants who have had prior whole- brain radiation therapy and/or SRS and then whose lesions have subsequently progressed are also eligible; in this case, lesions which have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression following SRS * Participants who have not previously been treated with cranial radiation (e.g., WBRT or SRS) are eligible to enter the study, but such participants must be asymptomatic from their CNS metastases and not requiring corticosteroids for symptom control * Both participants who present with systemic stable/absent or progressive disease are eligible to this trial, as long as they fulfill one of the above criteria
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan (within 28 days prior to start of protocol)
• Stable dose of dexamethasone 2 mg or less for at least 7 days prior to initiation of treatment
• Concurrent administration of other anti-cancer therapy during the course of this study is not allowed; note that concurrent use of supportive care medications (e.g. anti-resorptive agents, pain medications) is allowed
• Absolute neutrophil count >= 1,000/ul (within 8 days prior to initiating protocol therapy)
• Platelets >= 75,000/ul (within 8 days prior to initiating protocol therapy)
• Hemoglobin >= 9 g/dL (within 8 days prior to initiating protocol therapy)
• Total bilirubin =< 1.5 mg/dL x institutional upper limit of normal except subject with documented Gilbert's syndrome (=< 5 x upper limit of normal [ULN]) or liver metastasis, who must have a baseline total bilirubin =< 3.0 mg/dL (within 8 days prior to initiating protocol therapy)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN OR =< 5.0 x institutional ULN for patients with documented liver metastases (within 8 days prior to initiating protocol therapy)
• Albumin > 2.5 mg/dL (within 8 days prior to initiating protocol therapy)
• Serum creatinine =< 1.5 x ULN (or glomerular filtration rate >= 60 ml/min as determined by the Cockcroft-Gault equation) (within 8 days prior to initiating protocol therapy)
• Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 8 days of initiating protocol therapy; childbearing potential is defined as pre-menopausal women with intact uterus and ovaries
• Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 4 months after completion of atezolizumab administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Visceral crisis or impending visceral crisis at time of screening
• CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt placement)
• Known leptomeningeal metastases (defined as positive CSF cytology and/or unequivocal radiological evidence of clinically significant leptomeningeal involvement; CSF sampling is not required in the absence of suggestive symptoms to exclude leptomeningeal involvement)
• Treatment with high dose systemic corticosteroids defined as dexamethasone > 2 mg/day or bioequivalent within 7 days of treatment initiation
• Patients unable to undergo gadolinium contrast-enhanced magnetic resonance imaging (MRI) or receive IV contrast for any reason (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme obesity, hypersensitivity)
• Chemotherapy or targeted therapy within 14 days prior to planned treatment start
• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
• No washout is required for endocrine therapy; if a patient has been on endocrine therapy within 28 days of study entry, that same endocrine therapy is permitted to be continued during protocol therapy, at the investigator’s discretion, as is continuation of ovarian suppression in premenopausal women; starting a new endocrine therapy during protocol therapy is not permitted
• Current use or history of receiving a non-approved, investigational treatment within 14 days prior to planned treatment start
• Subjects with a history of hypersensitivity to compounds of similar biologic composition to atezolizumab or any constituent of the product
• Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, chronic liver or renal disease, or severe malnutrition
• Pregnant women or women who are lactating/breastfeeding due to the teratogenic potential of the study drugs
• Active, second potentially life-threatening cancer
• Major surgery within 21 days of planned treatment start
• Active infection requiring iv antibiotics at treatment initiation
• Medical condition that requires chronic systemic steroid therapy or on any other form of immunosuppressive medication; for example, patients with autoimmune disease that requires systemic steroids or immunosuppression agents should be excluded; replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest
• Known human immunodeficiency virus (HIV), hepatitis B surface antigen (HepBsAg), or hepatitis C (HCV) ribonucleic acid (RNA); HIV-positive participants on combination antiretroviral therapy are ineligible because of the unclear effects of immune checkpoint inhibitors in this setting
• Live vaccines within 28 days of first dose of trial therapy and during trial treatment
• Known intolerance to trastuzumab or pertuzumab or atezolizumab