Inclusion Criteria:
* Written and voluntary informed consent.
* At least 18 years of age or older.
* Histologically and radiologically confirmed locally advanced or metastatic unresectable solid tumor malignancy for which PD-1 or PD-L1 therapy is already approved by the FDA. Locally advanced is defined as unresectable in the opinion of the treating physician. A repeat biopsy is required if previous biopsy tissue is unavailable.
* At least one Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - defined target lesion.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able to carry on all pre-disease performance without restriction), 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, such as light housework or office work), or 2 (ambulatory and capable of self-care but unable to carry out any work activities, spending more than 50% of waking hours up and about).
* Documented progression on PD1 or PD-L1 inhibitors.
* Recovery from any acute toxicity associated with prior therapy to grade 1.
* Renal function (creatinine level within normal institutional limit, or creatinine clearance \>15 mL/min/1.73 m2 for patients with creatinine levels above institutional normal, calculated using the Cockcroft-Gault formula).
* Liver function (AST/ALT \<3.0 X institutional upper limit of normal OR \<5 X institutional upper limit of normal in cases of liver metastasis; total bilirubin ≤ 1.5 times upper limit of normal).
* Adequate hematological lab values including:
* Absolute Neutrophil Count (ANC) ≥ 1.0 X 109/L
* Platelets ≥ 100X109/L
* Hemoglobin ≥ 7.0 g/dL
* Female subjects of childbearing potential and non-sterilized male subjects who intend to be sexually active during the study must agree to use a highly effective method of contraception from time of screening, throughout the whole duration of the drug treatment, and during the 6-month post-treatment washout period.
* Patients may have previously received a hypomethylating agent, as long as it was not given in combination with ipilimumab.
* Patients may have previously received ipilimumab but must have relapsed or progressed while on therapy.
* Patients must have adequate archival tissue available for the purpose of downstream methylation status assessment, immunohistochemistry, RNA expression (10 slides at 5µM). If archival tissue is not available, a repeat biopsy is required.
Exclusion Criteria:
* Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
* Patients with active, untreated metastases in the central nervous system.
* Patients who are pregnant or breastfeeding.
* Patients who have an active infection.
* Patients with significant hematologic, hepatic, and renal function impairment.
* Patients who are being treated for any concurrent medical condition requiring the use of systemic steroids or history of long-term use of systemic steroids.
* Patients who have a history of inflammatory bowel disease or a history of symptomatic autoimmune disease.
* Patients who have had any major surgical procedure or significant traumatic injury within 28 days prior to study enrollment.
* Patients who have received chemotherapy, immunosuppressive agents or any investigational drug within 28 days prior to starting the study drugs.
* Patients who have any underlying medical condition which, in the treating physician's opinion, will make the administration of study drugs hazardous or obscure the interpretation of adverse events.
