A Study of NIVO Plus IPI and Guadecitabine or NIVO Plus IPI in Melanoma and NSCLC Resistant to Anti-PD1/PDL1

Inclusion Criteria:

1. Target Population Melanoma cohort A

   1. Histologic diagnosis of malignant melanoma
   2. Unresectable Stage III/Stage IV melanoma patients with resistance to anti-PD-1/PD-L1 and measurable lesions by CT or MRI per iRECIST/RECIST criteria that can be amenable to biopsy
   3. Only one line of immunotherapy for advanced (unresectable Stage III or Stage IV) disease with anti-PD-1/PD-L1 and its combinations; if BRAF mutant one line of targeted therapy is allowed prior to anti-PD-1/PD-L1therapy.
2. Target Population NSCLC cohort B

   1. Histologic or cytologic diagnosis of NSCLC lackingEGFR-sensitizing mutation and/or ALK/ROS1 translocation.
   2. Stage IV NSCLC patients with primary resistance to anti-PD-1/PD-L1 and measurable lesions by CT or MRI per iRECIST/RECIST criteria that can be amenable to biopsy.
   3. Only one line of immunotherapy for advanced (unresectable Stage III or Stage IV) disease with anti-PD-1/PD-L1 or its combinations; one line of chemotherapy is allowed prior to anti-PD-1/PDL-1 therapy.
3. confirmed PD
4. 4 weeks or greater since last treatment and
5. Must have recovered from any acute toxicity associated with prior therapy
6. Life expectancy greater than 16 weeks
7. Subjects with adequate organ function defined as:

   1. WBC ≥3500/uL
   2. ANC ≥2000/uL
   3. Platelets ≥ 100 x 103/uL
   4. Hemoglobin ≥ 9 g/dL
   5. Creatinine \< or \<= 2.5 x ULN
   6. AST

      * \< or \<= 2.5 x ULN for patients without liver metastasis
      * \< or \<= 5 x ULN for patients with liver metastasis
   7. Bilirubin

      * \< or \<= 3 x ULN for patients with liver metastasis
      * \<3.0 mg/mL for patients with Gilbert's Syndrome
      * 1.5 x ULN for patients without liver metastasis
8. Negative screening tests for HIV, HepB, and HepC. If positive results are not indicative of true active or chronic infection, the patient can enter the study after discussion and agreement between the Investigator and the Medical Monitor.
9. Women of child-bearing potential must not be pregnant or breastfeeding, must have a negative pregnancy test at Screening and all men must be practicing two medically acceptable methods of birth control. Men should not father a child while receiving treatment with guadecitabine+ ipilimumab, and for 2 months following completion of treatment. Men with female partners of childbearing potential should use effective contraception during this time.

Exclusion Criteria:

1. Sex and Reproductive Status

   1. Women who are pregnant or breastfeeding;
   2. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 23 weeks after the study;
   3. Women with a positive pregnancy test on enrollment or prior to investigational product administration;
   4. Sexually active fertile men not using effective birth control if their partners are WOCBP
2. Target Disease Exceptions

   1. Any malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix
   2. Primary ocular melanoma.
3. Medical History and Concurrent Diseases

   1. Symptomatic brain metastases requiring immediate local intervention (radiotherapy (RT) and/or surgery);
   2. Leptominingeal involvement by disease;
   3. Autoimmune disease: Patients with a documented history of Inflammatory Bowel Disease, including ulcerative colitis and Crohn's disease are excluded from this study as are patients with a documented history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], Systemic Lupus Erythematosus, autoimmune vasculitis \[e.g., Wegener's Granulomatosis\] and autoimmune hepatitis. Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome) are also excluded from this study;
   4. Any underlying medical condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.
4. Prohibited Treatments and/or Therapies

   1. Concomitant therapy with any anti-cancer agent; immunosuppressive agents; any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month prior to or after any dose of study drug); surgery or radiotherapy (except palliative surgery and/or radiotherapy to treat a non-target symptomatic lesion or to the brain after Sponsor approval); other investigational anti-cancer therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses);
   2. Previous treatment with other investigational products, including cancer immunotherapy, within 30 days;
   3. Prior treatment with anti-CTLA-4, except in adjuvant setting Other Exclusion Criteria

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   1. Prisoners or subjects who are involuntarily incarcerated;
   2. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.