This study will test the safety of the study drug, GDC-0084, in combination with radiation therapy in people who have solid tumor brain metastases or leptomeningeal metastases. All participants will have cancer with a PIK3CA mutation. The researchers will test increasing doses of GDC-0084 to find the highest dose that causes few or mild side effects in participants. The study will also try to find out if the combination of the study drug with radiation is effective against participants' cancer.

Inclusion Criteria:

• Histologically confirmed solid tumor malignancies harboring PIK3CA mutations which include 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 demonstrated by MR imaging of the brain. For patients with brain metastases, measurable lesion by RANO-BM is required28. Patients with spine leptomeningeal metastases are eligible for the study if they have leptomeningeal metastases of the brain demonstrated by MRI 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 < 4mg dexamethasone or equivalent. Patient does not need to be given corticosteroid as prophylaxis if not clinically indicated.

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

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

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

• Patient at reproductive potential must agree to practice an effective contraceptive method

• 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 a treatment plan that respects tissue tolerances
• Patients with brain metastases eligible for single fraction stereotactic radiation therapy
• Serious medical co-morbidities precluding radiotherapy
• Insulin-treated diabetes; subjects with diabetes or impaired glucose tolerance that is not treated with insulin may be enrolled
• QT interval ≥ 450 msec on EKG
• Cardiac dysfunction defined as: myocardial infarction within 6 months of study entry, NYHA Class II/III/IV heart failure, unstable angina or unstable cardiac arrhythmias
• Known hypersensitivity or intolerance to GDC-0084 or to any other inhibitor of the PI3K/ Akt/ mTOR pathway
• Past medical history of interstitial lung disease, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active interstitial lung disease
• Subject receiving any medications or substances that are moderate and/or potent enzyme inducers or inhibitors which may have an effect on the metabolism of GDC-0084.
• Pregnant or lactating women.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.