Phase II Anti-PD1 Epigenetic Therapy Study in NSCLC.

Objective response rate to Nivolumab preceded by epigenetic priming. Response will be
assessed by RECIST 1.1 criteria, baseline scans for this assessment will be the baseline
scans done within 4 weeks of enrollment.

Inclusion Criteria:

1. Patients must have histologically proven stage IIIB, IV or recurrent non-small cell
lung cancer. Patients must be willing to undergo a pre-treatment biopsy, either core
needle biopsy or equivalent amount or via excisional specimen. (cytology specimen not
acceptable for this purpose).

2. Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional
techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam. See
Section 11 for the evaluation of measurable disease.

3. Patients must have received at least one platinum based chemotherapy, and not more
than three, prior therapies for stage IIIB/IV disease.

4. Patients who received adjuvant or neoadjuvant platinum-doublet chemotherapy (after
surgery and/or radiation therapy) and developed recurrent or metastatic disease within
6 months of completing therapy are eligible and the adjuvant or neoadjuvant
chemotherapy will count as a line of therapy as above.

5. Subjects with recurrent disease > 6 months after adjuvant or neoadjuvant
platinum-based chemotherapy, who also subsequently progressed during or after a
platinum-doublet regimen given to treat the recurrences, are eligible and do not count
as another line of therapy for advanced disease.

6. Subjects who received pemetrexed, bevacizumab, or erlotinib as maintenance therapy
(nonprogressors with platinum-based doublet chemotherapy) and subsequently progressed
after maintenance therapy) are eligible and do not count as a line of therapy.
However, subject who received a tyrosine kinase inhibitor after failure of a prior
platinum-based therapy, that tyrosine kinase inhibitor therapy would count as an
additional line of therapy.

7. Age >18 years. Because no dosing or adverse event data are currently available on the
use of azacitidine with entinostat, or of Nivolumab, in patients <18 years of age,
children are excluded from this study.

8. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.

9. Life expectancy of greater than 12 weeks.

10. Patients must have adequate organ and marrow function.

11. The effects of entinostat, azacitidine, and Nivolumab, on the developing human fetus
are unknown. For this reason women of child-bearing potential and men must agree to
use adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry and for the duration of study participation and for up to 23
weeks after the last dose of nivolumab. Should a woman become pregnant or suspect she
is pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Men who are sexually active with women of
childbearing potential must also use an adequate contraceptive method for up to 31
weeks after fhe last dose of nivolumab.

12. Ability to understand and the willingness to sign a written informed consent document.

13. Patients with documented EGFR or ALK mutations must have been treated with prior EGFR
or ALK therapy as well as a platinum containing doublet.

14. All adenocarcinoma patients will be tested for ALK rearrangements and EGFR (Exon 19
Deletion and Exon 21 L8585R Substitution) mutations and must have been treated with
prior EGFR or ALK therapy as well as a platinum containing doublet.

15. Patients must have disease amenable to biopsy at the time of enrollment as biopsies
are required for study participation.

Exclusion Criteria:

1. Any active history of a known autoimmune disease. Subjects with vitiligo, type 1
diabetes mellitus, residual hypothyroidism requiring hormone replacement, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll.

2. Subjects with a history of interstitial lung disease. Patients requiring continuous
supplemental oxygen are excluded to avoid possible complications from pneumonitis.

3. Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 2 weeks earlier.

4. Patients who are receiving any other anticancer therapy.

5. Patients with uncontrolled brain metastases. Patients with brain metastases must have
stable neurologic status following local therapy (surgery or radiation) for at least 2
weeks without the use of steroids or on stable or decreasing dose of < 10mg daily
prednisone (or equivalent), and must be without neurologic dysfunction that would
confound the evaluation of neurologic and other adverse events. Patients with a
history of carcinomatous meningitis are not eligible.

6. Patients with advanced malignant hepatic tumors.

7. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to entinostat, azacitidine, or Nivolumab.

8. Known or suspected hypersensitivity to azacitidine or mannitol

9. Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

10. Pregnant women are excluded from this study because entinostat, azacitidine, and
Nivolumab are agents with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with entinostat, azacitidine, or Nivolumab
breastfeeding should be discontinued if the mother is treated on this protocol.

11. HIV-positive patients are excluded.

12. Patients with active hepatitis B or hepatitis C are excluded.

13. Patients with a condition requiring systemic treatment with either corticosteroids
(>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of randomization. Inhaled or topical steroids and adrenal replacement steroid
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
autoimmune disease.

14. Patients with malabsorption in the small intestine or other conditions that would
preclude administration of oral medication.

15. Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody
therapies, any other antibody or drug specifically targeting T-cell co-stimulation or
checkpoint pathways, DNA methyltransferase therapy or HDAC inhibitor therapy.