GDC-0084 With Radiation Therapy for People With PIK3CA-Mutated Solid Tumor Brain Metastases or Leptomeningeal Metastases

Inclusion Criteria:

• Histologically confirmed solid tumor malignancies harboring PIK3CA mutations whichinclude mutations in any of the following genes: PIK3CA, PIK3CB, PIK3CD, PIK3CG,PIK3R1, PIK3R2, PIK3R3, PIK3C2G, PIK3C3, INPP4A, INPP4B, INPPL1, INPP5D, PTEN, AKT1,AKT2, AKT3, and MTOR.

• Brain metastases and/or leptomeningeal metastases involving the brain demonstratedby MR imaging of the brain. For patients with brain metastases, measurable lesion byRANO-BM is required28. Patients with spine leptomeningeal metastases are eligiblefor the study if they have leptomeningeal metastases of the brain demonstrated byMRI imaging of the brain.

• KPS ≥ 70

• Age ≥ 18 years

• Able to provide informed consent.

• If a patient is on corticosteroid, he/she must be on a stable daily dose of < 4mgdexamethasone or equivalent. Patient does not need to be given corticosteroid asprophylaxis if not clinically indicated.

• No limit to prior therapies with the last systemic therapy ≥ 1 week from initiationof protocol therapy. Systemic therapy can resume after completion of protocol DLTassessment period.

• Patients with prior SRS are eligible, provided that there are new, non-irradiatedbrain lesions or leptomeningeal metastases. Patients must be ≥ 3 months post priorcranial radiation therapy.

• Patients with seizure history related to brain metastases or leptomeningealmetastases controlled on antiepileptic medications are eligible.

• Patient at reproductive potential must agree to practice an effective contraceptivemethod

• Patient must be able to swallow and retain oral medication

• Adequate organ function as assessed by laboratory tests.

• Adequate bone marrow function

• Hemoglobin ≥ 8g/dL

• Absolute neutrophil count ≥1,000/mm^3

• Platelet count ≥ 100,000/mm^3

• Adequate liver function

• Bilirubin ≤1.5 times upper limit normal (ULN)

• AST and ALT ≤ 2.5 times ULN

• Alkaline phosphatase ≤ 2 times ULN

• Adequate renal function ° BUN and Creatinine ≤ 1.5 times ULN

Exclusion Criteria:

• Previous radiotherapy to the intended treatment site that precludes developing atreatment plan that respects tissue tolerances

• Patients with brain metastases eligible for single fraction stereotactic radiationtherapy

• Serious medical co-morbidities precluding radiotherapy

• Insulin-treated diabetes; subjects with diabetes or impaired glucose tolerance thatis not treated with insulin may be enrolled

• QT interval ≥ 450 msec on EKG

• Cardiac dysfunction defined as: myocardial infarction within 6 months of studyentry, NYHA Class II/III/IV heart failure, unstable angina or unstable cardiacarrhythmias

• Known hypersensitivity or intolerance to GDC-0084 or to any other inhibitor of thePI3K/ Akt/ mTOR pathway

• Past medical history of interstitial lung disease, drug-induced ILD, radiationpneumonitis that required steroid treatment, or any evidence of clinically activeinterstitial lung disease

• Subject receiving any medications or substances that are moderate and/or potentenzyme inducers or inhibitors which may have an effect on the metabolism ofGDC-0084.

• Pregnant or lactating women.