This is a Phase 2, open-label, multicenter study to assess the efficacy and safety of second/third-line treatment with nab-paclitaxel in combination with the epigenetic modifying therapy of CC-486 or immunotherapy of durvalumab, and nab-paclitaxel monotherapy in subjects with advanced non-small cell lung cancer (NSCLC).

This Phase 2 study will test the hypothesis that epigenetic modifying therapy of CC-486 or immunotherapy of durvalumab can improve the anti-tumor activity of nab-paclitaxel in subjects with advanced non-small cell lung cancer (NSCLC) who have received no more than one prior chemotherapy regimen for their advanced disease. It will further assess efficacy and safety of nab-paclitaxel monotherapy in this setting. Each subject will receive study therapy as second- or third-line of treatment. Approximately 240 male and female subjects with advanced NSCLC will be assigned to one of the following treatment arms (approximately 80 subjects per group): nab-paclitaxel /CC-486 combination therapy, nab-paclitaxel/durvalumab combination therapy or nab-paclitaxel monotherapy prior to receiving first dose of Investigational Product. A permuted-block randomization method will be employed to assign the subjects among the treatment arms that are enrolling simultaneously, when applicable, stratified by the following baseline factors: ECOG performance status (0 versus 1), gender (males versus females), and smoker (yes versus no). Treatment assignments of subjects to the nab-paclitaxel/CC-486 combination therapy and nab-paclitaxel monotherapy arms will be conducted completely in a randomized fashion.

Inclusion Criteria: 1.Age ≥ 18 years the time of signing the Informed Consent Form (ICF).

2. Understand and voluntarily provide written informed consent prior to the conduct of any study related assessments/procedures.

3. Able to adhere to the study visit schedule and other protocol requirements. 4. Histologically or cytologically confirmed advanced NSCLC who will receive study therapy as second- or third-line of treatment for advanced disease.

5. No other current active malignancy requiring anticancer therapy. 6. Radiographically documented measurable disease (defined by the presence of ≥ 1 radiographically documented measurable lesion).

7. One prior platinum-containing chemotherapy for metastatic or recurrent NSCLC unless patients are ineligible to receive it. Patients may have received no more than one line of chemotherapy; immunotherapy in prior line of treatment (first or second line) is allowed. Absolute neutrophil count (ANC) ≥ 1500 cells/mm3.

8. Platelets ≥ 100,000 cells/mm3. 9. Hemoglobin (Hgb) ≥ 9 g/dL. 10. Aspartate transaminase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine transaminase (ALT/serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 × upper limit of normal range (ULN) or ≤ 5.0 × ULN if liver metastases.

11. Total bilirubin ≤ 1.5 ULN (unless there is a known history of Gilberts Syndrome).

12. Serum creatinine ≤ 1.5 x ULN, or calculated creatinine clearance ≥ 60 mL/min (if renal impairment is suspected 24-hour urine collection for measurement is required).

13. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 14. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 15. Females of childbearing potential [defined as a sexually mature woman who (1) have not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months)] must:

1. Have a negative pregnancy test (ß-hCG) as verified by the study doctor within 72 hours prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact.
2. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting investigational product (IP), during the study therapy (including dose interruptions), and for 3 months after discontinuation of study therapy.

Male subjects must:

1. Practice true abstinence* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 6 months following IP discontinuation, even if he has undergone a successful vasectomy.

2. Refrain from semen or sperm donation while taking durvalumab and for at least 3 months after the last dose of durvalumab.

   16. Females must abstain from breastfeeding during study participation and 3 months after IP discontinuation.

   Exclusion Criteria:

   • The presence of any of the following will exclude a subject from enrollment:

     1. Refractory to prior taxane therapy for advanced disease. Prior taxane used in the adjuvant setting does not exclude eligibility, provided there is no disease recurrence within 12 months upon completion of chemotherapy in that setting.
     2. Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if asymptomatic and clinically stable for at least 8 weeks following completion of therapy). MRI of the brain (or CT scan w/contrast) is preferred.
     3. Only evidence of disease is non-measurable at study entry.
     4. Known activating EGFR mutations (such as exon 19 deletions or L858R).
     5. Known activating EML4-ALK mutations.
     6. Preexisting peripheral neuropathy of Grade > 2 (per NCI CTCAE v4.0).
     7. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
     8. Venous thromboembolism within 1 month prior to Cycle 1 Day 1.
     9. Current congestive heart failure (New York Heart Association Class II-IV).
     10. History of the following within 6 months prior to Cycle 1 Day 1: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant electrocardiogram (ECG) abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder.
     11. Known hepatitis B or C virus (HBV/HCV) infection, known history of human immunodeficiency virus (HIV) infection, or receiving immunosuppressive or myelosuppressive medications that would in the opinion of the investigator, increase the risk of serious neutropenic complications, history of active primary immunodeficiency, active tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice).
     12. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
     13. History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis or multiple allergies. Any lung disease that may interfere with the detection or management of suspected drug-related pulmonary toxicity.
     14. Subject has a clinically significant malabsorption syndrome, persistent diarrhea, or known sub-acute bowel obstruction > NCI CTCAE Grade 2, despite medical management.
     15. Treatment with any chemotherapy, investigational product, biologic or hormonal therapy for cancer treatment within 28 days prior to signing the ICF. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g. hormone replacement therapy) is acceptable.
     16. History of or suspected allergy to any IP or their excipients.
     17. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
     18. Currently enrolled in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices.
     19. Any other clinically significant medical condition, psychiatric illness, and/or organ dysfunction that will interfere with the administration of the therapy according to this protocol or which, in the views of investigator, preclude combination chemotherapy.
     20. Any other malignancy within 5 years prior to randomization/treatment assignement, or advanced malignant hepatic tumors, with the exception of adequately treated squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, uteri, non-melanomatous skin cancer, carcinoma in situ of the breast, or incidental histological finding of prostate cancer (TNM Classification of Malignant Tumours (TNM) stage of T1a or T1b). (All treatment of which should have been completed 6 months prior to signing ICF).
     21. Radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting IP, and/or from whom ≥ 30% of the bone marrow was irradiated. Prior radiation therapy to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed.
     22. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
     23. Any medical condition that confounds the ability to interpret data from the study.
     24. Female patients who are pregnant or breastfeeding or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab.
     25. Male patients of reproductive potential who are not willing to employ effective birth control from screenin to 90 days after the last dose of durvalumab and from screening to 6 months after the last dose of of nab-paclitaxel.
     26. History of allogenic organ transplantation.
     27. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

   • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection)

   • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent

   • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) 28. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP.

     29. Prior enrollment and treatment in a previous durvalumab clinical study. 30. Patients who have received prior anti-PD-1 or anti PD-L1:

   • Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.

   • All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.

   • Must not have experienced a ≥ Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Subjects with endocrine AE of ≤ Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.

   • Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.