A randomized, run-in, phase II study of nivolumab combined with ipilimumab and oral decitabine/cedazuridine (ASTX727) or nivolumab combined with ipilimumab in melanoma and NSCLC patients resistant to anti-PD-1/PD-L1

Prior treatment

• Sex and Reproductive Status a) Women who are pregnant or breastfeeding; b) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 6 months after the study; c) Women with a positive pregnancy test on enrollment or prior to investigational product administration; d) Sexually active fertile men not using effective birth control if their partners are WOCBP.
• Medical History and Concurrent Diseases a) Symptomatic brain metastases requiring immediate local intervention (radiotherapy (RT) and/or surgery); b) Leptominingeal involvement by disease; c) 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; d) 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.
• Prohibited Treatments and/or Therapies a) 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); b) Previous treatment with other investigational products, including cancer immunotherapy, within 30 days; c) Prior treatment with anti-CTLA-4, except in adjuvant setting

Other illness

• Target Disease Exceptions a) 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; b) Primary ocular melanoma.
• Other Exclusion Criteria a) Prisoners or subjects who are involuntarily incarcerated; b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

• Willing and able to give written informed consent.
• 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 oral decitabine/cedazuridine (ASTX727) and/or ipilimumab plus nivolumab, and for 7 months following completion of treatment. Men with female partners of childbearing potential should use effective contraception during this time. Age and Sex - Men and women of and over 18 years old. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 6 months (ie, 30 days [duration of ovulatory cycle] plus the time required for the investigational drugs to undergo approximately five half-lives) after the last dose of investigational drug. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as: 1) Amenorrhea >/= 12 consecutive months without another cause or 2) For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL. Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year Men receiving study drugs and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months (i.e. 90 days [duration of sperm turnover] plus the time required for the investigational drug to undergo approximately five half-lives))after the last dose of investigational product Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception).
• Target Population Melanoma cohort A: a) Histologic diagnosis of malignant melanoma; b) 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; c) Only one line of immunotherapy for advanced (unresectable Stage III or Stage IV) disease with anti-PD-1/PDL1 and its combinations; if BRAF mutant one line of targeted therapy is allowed prior to anti-PD-1/PDL1therapy.
• Target Population NSCLC cohort B: a) Histologic or cytologic diagnosis of NSCLC lacking EGFR-sensitizing mutation and/or ALK/ROS1 translocation; b) 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; c) Only one line of immunotherapy for advanced (unresectable Stage III or Stage IV) disease with anti-PD-1/PDL1 or its combinations; one line of chemotherapy is allowed prior to anti-PD-1/PDL-1 therapy.
• confirmed PD
• 4 weeks or greater since last treatment and
• Must have recovered from any acute toxicity associated with prior therapy
• Life expectancy greater than 16 weeks
• Subjects with adequate organ function defined as: a) WBC ≥3500/uL; b) ANC ≥2000/uL; c) Platelets ≥ 100 x 103/uL; d) Hemoglobin ≥ 9 g/dL; e) Creatinine < or <= 2.5 x ULN AND creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft- Gault formula below): Female: CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL. Male: CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL; f) AST: < or <= 2.5 x ULN for patients without liver metastasis; < or <= 5 x ULN for patients with liver metastasis; g) 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
• 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.