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 onedimension.

• Unequivocal evidence of new and/or progressive brain metastases, and at least one ofthe following scenarios:

• Treated with SRS or surgery with residual un-treated lesions remaining. Suchparticipants are eligible for immediate enrollment on this study providing thatat least one untreated lesion is measurable

• Participants who have had prior WBRT and/or SRS and then whose lesions havesubsequently progressed or who have new lesions are also eligible. In thiscase, lesions which have been treated with SRS may be considered as targetlesions if there is unequivocal evidence, in the opinion of the treatingphysician, 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 beasymptomatic from their CNS metastases and not requiring corticosteroids forsymptom control.

• Participants who present with systemic stable/absent or progressive disease areeligible 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 followingrequirements: HER2 overexpressed or amplified (immunohistochemistry of 3+ or HER2gene amplification by in situ hybridization with a ratio of HER2-gene signals tocentromere 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) ormultigated acquisition (MUGA) scan.

• Stable or decreasing corticosteroid dose for at least 7 days prior to initiation oftreatment.

• Concurrent administration of other anti-cancer therapy during the course of thisstudy 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 withdocumented Gilbert's syndrome (≤5 x ULN) or liver metastasis, who must have abaseline total bilirubin ≤3.0 mg/dL;

• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN OR ≤ 5.0 × institutional ULN forpatients with documented liver metastases.

• Serum creatinine ≤ 1.5 mg/dL (or glomerular filtration rate ≥ 30 ml/min asdetermined by the Cockcroft-Gault equation)

• Female subjects of childbearing potential must have a negative serum or urinepregnancy test within 8 days of initiating protocol therapy.

• The effects of GDC-0084 on the developing human fetus are unknown and radiotherapyhas known teratogenic effects so women of child-bearing potential and men must agreeto use adequate contraception (barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation and 7 months aftercompletion of Trastuzumab administration per recommendations from the Trastuzumabpackage insert.

• The subject is capable of understanding and complying with the protocol and hassigned 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 unequivocalradiological evidence of clinically significant leptomeningeal involvement. CSFsampling is not required in the absence of suggestive symptoms to excludeleptomeningeal involvement].

• Patients with known contraindication to MRI (e.g., due to pacemaker, ferromagneticimplants, claustrophobia, extreme obesity, hypersensitivity, etc.). However, head CTwith contrast may be used in place of MRI at baseline and throughout the trial ifMRI is contraindicated and a participant's brain metastases are clearly measurableby head CT.

• Chemotherapy or targeted therapy within 14 days prior to initiation of protocoltherapy. 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 ovariansuppression for at least 28 days prior to initiation of study treatment,continuation of ovarian suppression is permitted on protocol. Starting a newendocrine 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 biologiccomposition 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 AssociationClass III or IV, active ischemic heart disease, myocardial infarction within theprevious six months, uncontrolled diabetes mellitus (DM), gastric or duodenalulceration diagnosed within the previous 6 months, chronic liver or renal disease,or severe malnutrition. If a participant has controlled DM but is unable to monitorblood 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 therapyinitiation.

• 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 orstrong inducers of CYP3A4 are ineligible. Should a participant be taking one ofthese 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 AppendixM for the list of medications. Corticosteroids, which are weak CYP3A4 inducers areallowed. Because the lists of these agents are constantly changing, it is importantto regularly consult a frequently-updated list such ashttp://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such asthe Physicians' Desk Reference may also provide this information. As part of theenrollment/informed consent procedures, the patient will be counseled on the risk ofinteractions with other agents, and what to do if new medications need to beprescribed or if the patient is considering a new over-the-counter medicine orherbal product