GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases

Inclusion Criteria: Cohort A: * At least one measurable CNS metastasis, 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 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 WBRT and/or SRS and then whose lesions have subsequently progressed or who have new lesions 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. * 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. Cohort B: * New and/or progressive brain metastasis(es) with clinical indication for resection. * All Cohorts: * Pathologically confirmed HER2-positive MBC by local laboratory with the following requirements: HER2 overexpressed or amplified (immunohistochemistry of 3+ or HER2 gene amplification by in situ hybridization with a ratio of HER2-gene signals to centromere 17 signals ≥ 2.0 or average HER2 copy number ≥ 6.0 signals/cells). * Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. * Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan. * Stable or decreasing corticosteroid dose 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. * The participant is ≥18 years old. * Participants must have normal organ and marrow function as defined below: * Absolute neutrophil count ≥1,000/μl * Platelets ≥75,000/μl * Hemoglobin ≥9 g/dL * Total bilirubin ≤1.5mg/dL (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(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN OR ≤ 5.0 × institutional ULN for patients with documented liver metastases. * Serum creatinine ≤ 1.5 mg/dL (or glomerular filtration rate ≥ 30 ml/min as determined by the Cockcroft-Gault equation) * Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 8 days of initiating protocol therapy. * The effects of GDC-0084 on the developing human fetus are unknown and radiotherapy has known teratogenic effects so women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 7 months after completion of Trastuzumab administration per recommendations from the Trastuzumab package insert. * The subject is capable of understanding and complying with the protocol and has signed the informed consent document. * Participant must be able to swallow and retain oral medication. 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 \[Defined as positive CSF cytology and/or unequivocal radiological evidence of clinically significant leptomeningeal involvement. CSF sampling is not required in the absence of suggestive symptoms to exclude leptomeningeal involvement\]. * Patients with known contraindication to MRI (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme obesity, hypersensitivity, etc.). However, head CT with contrast may be used in place of MRI at baseline and throughout the trial if MRI is contraindicated and a participant's brain metastases are clearly measurable by head CT. * Chemotherapy or targeted therapy within 14 days prior to initiation of protocol therapy. No washout is required for trastuzumab. * Has received prior therapy with a PI3K or mTOR inhibitor. * No washout is required for endocrine therapy. If a patient has been on ovarian suppression for at least 28 days prior to initiation of study treatment, continuation of ovarian suppression is permitted on protocol. 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 initiation of protocol therapy. * Subjects with a history of hypersensitivity to compounds of similar biologic composition to GDC-0084 or any constituent of the product. * The subject has an 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 (DM), gastric or duodenal ulceration diagnosed within the previous 6 months, chronic liver or renal disease, or severe malnutrition. If a participant has controlled DM but is unable to monitor blood sugars at home, they will be excluded from the trial. * The subject is pregnant or breast-feeding. * No active, second potentially life-threatening cancer. * Has had major surgery within 21 days before initiation of protocol therapy. * Active infection requiring IV antibiotics at the time of protocol therapy initiation. * Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest. * Known intolerance to trastuzumab. * QT interval time of ≥ 470 msec. * Participants receiving any medications or substances that are strong inhibitors or strong inducers of CYP3A4 are ineligible. Should a participant be taking one of these agents and is able to discontinue the therapy or switch to a different agent, no washout will be required prior to starting study medication. Please see Appendix M for the list of medications. Corticosteroids, which are weak CYP3A4 inducers are allowed. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product