Nivolumab with or without Decitabine and Tetrahydrouridine in Treating Patients with Non-small Cell Lung Cancer

Inclusion Criteria

• Histologically or cytologically-proven non-small cell lung cancer (NSCLC)
• Subjects must have received 1 or more prior systemic therapies for this disease, (this can include neo-adjuvant or adjuvant chemotherapy if administered < 2 years prior to study enrollment), should not have had prior treatment with immunotherapy; (including immune checkpoint inhibitor drugs, or immunotherapy vaccines); patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations will need to have progressed on a tyrosine kinase inhibitor (TKI) treatment
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
• Disease that can be accessed by a bronchoscopic, surgical or percutaneous biopsy, eligible for biopsy from safety perspective, and agrees to biopsy prior to study; the pre-study biopsy can be waived if there is an archival biopsy specimen that was obtained after the most recent therapy or if the risks of biopsy are judged to be excessive by the study principal investigator (PI)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 – 2
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 8.5 g/dL or >= 5.6 mmol/L
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 30 mL/min for subject with creatinine levels > 1.5 x institutional ULN
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransaminase (ALT) glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases
• Albumin >= 2 mg/dL
• Patients with leptomeningeal disease are not eligible but patients with brain metastases are eligible – these patients should commence treatment on study > 1 week after completion of gamma knife or whole brain radiotherapy or > 4 weeks after surgical resection of brain metastasis; patients should ideally be off steroids at the start of study treatment, however patients on steroid taper and a dose of no more than 2 mg/day of dexamethasone can begin study treatment; and steroids should be tapered off as quickly as clinically feasible; repeat brain magnetic resonance imaging (MRI) after radiation is not required for eligibility but is strongly recommended, to establish the pre-treatment baseline status of any brain metastases, necessary to accurately assess for response or progression; patients with untreated, asymptomatic brain metastasis not requiring steroids are also eligible, however, these patients need to be discussed with the study PI prior to being registered
• Subjects must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Within 6 months prior to study drug administration, clinically significant cardiovascular/cerebrovascular disease defined as follows: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association classification class >= II), bleeding or pulmonary embolism or cardiac arrhythmias that was severe enough to cause hemodynamic compromise
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness (HIV-positive subjects on combination anti-retroviral therapy are ineligible
• Pregnancy or breastfeeding (pregnant or breastfeeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with oral THU-Dec
• Other severe acute or chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 2 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Has had prior chemotherapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 2 or at baseline) from adverse events due to a previously administered agent and meeting the criteria for organ function; patients who receive palliative radiation therapy within 1 week prior to day 1 are allowed; patients on treatment with targeted therapy (like EGFR or ALK TKIs) may start study treatment 5 days from last treatment; NOTE: subjects with =< grade 2 neuropathy or other clinically insignificant adverse events (AEs) as determined by the PI are an exception to this criterion and may qualify for the study following adequate pre-study documentation; NOTE: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Receiving other investigational agent concomitantly
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include superficial skin cancers that are surgically removed without need for systemic therapy, in situ cervical cancer, superficial bladder cancer or localized low grade prostate cancer not requiring active treatment
• Has active or documented history of autoimmune disease that has required systemic treatment in the preceding 2 years (i.e. required use of disease modifying agents such as corticosteroids or other immunosuppressive drugs); patients with psoriasis and rheumatoid arthritis with no evidence of disease flare off immunosuppression for > 1 year may be allowed after discussion with the study PI; replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has known history of, or any evidence of active, non-infectious pneumonitis
• Has an active infection requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 217 days after the last dose of trial treatment; women of childbearing potential (WOCBP) should agree to methods of contraception described in the protocol; WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; in addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level > 40 mIU/mL; women of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to contraception for a period of 23 weeks after the last dose of investigational product; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; these durations have been calculated using the upper limit of the half-life for nivolumab (25 days); and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days; *HIGHLY EFFECTIVE METHODS OF CONTRACEPTION: ** Male condoms with spermicide ** Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject’s WOCBP partner female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug ** Non-hormonal IUDs, such as ParaGard ** Tubal ligation ** Vasectomy ** Complete abstinence; complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs; subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests; acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence * LESS EFFECTIVE METHODS OF CONTRACEPTION: ** Diaphragm with spermicide ** Cervical cap with spermicide ** Vaginal sponge ** Male condom without spermicide ** Progestin only pills by WOCBP subject or male subject’s WOCBP partner ** Female condom; a male and female condom must not be used together
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days of planned start of study therapy; NOTE: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed