5-Azacitidine Plus PD-1/PD-L1 Inhibitor With PD-1/PD-L1 Refractory Tumors

This is a Phase I study to determine the optimal biological dose (OBD) of 5-Azacitidine in combination with PD-1/PD-L1 inhibitors in patients with tumors refractory to PD-1/PD-L1 inhibitors, for which such treatments have been approved.

This Phase I study will assess 6 doses of 5-Azacitidine (5, 10, 15, 25, 50 and 75 mg/m2) in combination with a PD1/PD-L1 inhibitor. The PD1/PD-L1 inhibitor will be given at standard of care dosing approved by the FDA for this indication.

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.