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.
