1. Subject is 18 years of age at the time of signing the informed consent form.
2. Subject has histologically or cytologically confirmed squamous or non-squamous
non-small cell lung cancer (NSCLC).
3. Subject has stage IIIB or IV NSCLC (American Joint Committee on Cancer [AJCC] Staging
Manual, 7th edition) and was pretreated with 1 prior systemic platinum based
4. Subject has provided a formalin fixed tumor tissue sample from a biopsy of a tumor
lesion either at the time of or after the diagnosis of metastatic disease has been
made AND from a site not previously irradiated to assess for programmed death-ligand
1 (PD-L1) status. Fine needle aspirates, endobronchial ultrasound (EBUS) or cell
blocks are not acceptable. Needle or excisional biopsies, or resected tissue is
required. Archival tissue may be acceptable. Submission of formalin-fixed paraffin
embedded tumor tissue sample blocks are preferred; if submitting unstained slides,
the slides should be freshly cut and submitted to the testing laboratory within 14
days from site slide sectioning date otherwise a new specimen will be requested.
5. Subject has radiographically-documented measurable disease, as per Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1.
6. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
7. Subject has adequate organ functions, evidenced by the following:
- Aspartame aminotransferase (AST) or serum glutamic oxaloacetic transaminase
(SGOT), alanine aminotransferase (ALT) or serum glutamic pyruvic transaminase
(SGPT) 2.5 x upper limit of normal range (ULN), or 5 x ULN range if liver
- Total bilirubin 1.5 x ULN
- Serum creatinine 1.5 x ULN
- Potassium within normal range, or correctable with supplements
8. Subject has adequate bone marrow function, evidenced by the following:
- Absolute neutrophil count 1.5 x 109 cells/L
- Platelets 100 x 10^9 cells/L
- Hemoglobin 9 g/dL
- International normalized ratio (INR) or prothrombin time (PT) 1.5 x ULN unless
subject is receiving anticoagulant therapy as long as PT or partial
thromboplastin time (PTT) is within therapeutic range of intended use of
- Activated partial thromboplastin time (aPTT) 1.5 x ULN unless subject is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
of intended use of anticoagulants
9. Female of childbearing potential (FCBP) (defined as a sexually mature woman who 1)
has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral
oophorectomy (the surgical removal of both ovaries) or, 2) if 45 years old has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had
menses at any time during the preceding 24 consecutive months)) must:
- Have two negative pregnancy tests as verified by the Investigator prior to starting
study therapy. She must agree to ongoing pregnancy testing during the course of the
study, and after end of study treatment. This applies even if the subject practices
true abstinence* from heterosexual contact.
- 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 two
effective methods of contraception without interruption, 28 days prior to
starting investigational product, during the study therapy (including dose
interruptions), and for 120 days after discontinuation (or longer if required by
local requirements) of study therapy. The two methods of contraception can
either be two barrier methods or a barrier method plus a hormonal method to
10. Male subjects must practice true abstinence* (which must be reviewed on a monthly
basis) or agree to the 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 3 months following investigational product
discontinuation (or longer if required by local requirements), even if he has
undergone a successful vasectomy.
- True abstinence is acceptable when this is in line with the preferred and usual
lifestyle of the subject. Note: Periodic abstinence (eg, calendar, ovulation,
symptothermal, postovulation methods) and withdrawal are not acceptable methods of
11. Subject is willing to adhere to the study visit schedule and other protocol
12. Subject understands and voluntarily signs an informed consent document prior to any
study related assessments/procedures are conducted.
1. Subject has known sensitizing endothelial growth factor receptor (EGFR) and/or
positive anaplastic lymphoma kinase (ALK) mutation.
2. Subject has been previously treated with azacitidine (any formulation), decitabine,
or any other hypomethylating agent.
3. Subject has received prior therapy with any other anti-programmed death-1
(anti-PD-1), or programmed death-ligand 1 (PD-L1) or programmed death-ligand 2
(PD-L2) agent or an antibody targeting other immuno-regulatory receptors or
mechanism, including participation in any other pembrolizumab trial and treatment
- Examples of such antibodies include (but are not limited to) antibodies against
indoleamine 2,3-dioxygenase (IDO), PD-L1, interleukin-2 receptor (IL-2R),
glucocorticoid-induced tumor necrosis factor receptor (GITR).
4. Subject has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or
who has not recovered (i.e. Grade 1 or at baseline) from adverse events due to
agents administered more than 4 weeks earlier.
5. Subject is currently participating and receiving study therapy or has participated in
a study of an investigational agent and received study therapy or used an
investigational device within 4 weeks prior to administration of pembrolizumab and
6. Subject has previous severe hypersensitivity reaction to another monoclonal antibody
7. Subject has a known or suspected hypersensitivity to azacitidine, mannitol, or any
other ingredient used in the manufacture of CC-486.
8. Subject has had 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.
9. Subject has received radiation therapy to the lung that is > 30 Gy within 6 months of
the first dose of trial treatment
10. Subject has received a live-virus vaccination within 30 days of planned treatment
start. Seasonal flu vaccines that do not contain live virus are permitted.
11. Subject has not recovered from the acute toxic effects of prior anticancer therapy,
radiation, or major surgery/significant trauma.
12. Subject has an active infection requiring therapy.
13. Subject has had an allogenetic tissue/solid organ transplant.
14. Subject has active autoimmune disease that has required systemic treatment within the
past 2 years (eg, with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment.
15. Subject has known active Hepatitis B, Hepatitis C or tuberculosis. Active Hepatitis B
is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known
positive Hep C antibody (Ab) result and known quantitative Hepatitis C virus (HCV)
ribonucleic acid (RNA) results greater than the lower limits of detection of the
16. Subject has had any other malignancy within 5 years prior to randomization, with the
exception of adequately treated in situ carcinoma of the cervix, uterus, or
nonmelanomatous skin cancer (all treatment of which should have been completed 6
months prior to enrollment).
17. Subject has a history of inflammatory bowel disease (eg, Crohn's disease, ulcerative
colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or
any other gastrointestinal disorder or defect that would interfere with the
absorption, distribution, metabolism, or excretion of the IP and/or predispose the
subject to an increased risk of gastrointestinal toxicity.
18. Subject has persistent diarrhea or clinically significant malabsorption syndrome or
known sub-acute bowel obstruction Grade 2, despite medical management.
19. Subject has significant active cardiac disease within the previous 6 months including
unstable angina or angina requiring surgical or medical intervention, significant
cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive
20. Subject has history of interstitial lung disease (ILD) OR a history of pneumonitis
that has required oral or IV steroids. Subjects whose pneumonitis was solely as a
result of radiation therapy for their NSCLC would not be excluded from the study
unless they received oral/IV steroids to manage the pneumonitis.
21. Subject has a known history or current diagnosis of human immunodeficiency virus
(HIV) infection, regardless of treatment status.
22. Subject has any other concurrent severe and/or uncontrolled medical condition that
would, in the Investigator's judgment, contraindicate subject participation in the
clinical study (eg, chronic pancreatitis, etc.).
23. Subject with uncontrolled or symptomatic central nervous system (CNS) metastases
and/or carcinomatous meningitis - Subjects with controlled and asymptomatic CNS
metastases may participate in this trial. The subject must have completed any prior
treatment for CNS metastases (must include radiotherapy and/or surgery) 28 days (
14 days for stereotactic radiosurgery) and, if on corticosteroid therapy, should be
receiving a stable dose of no greater than 4 mg/d dexamethasone (or equivalent
anti-inflammatory potency of another corticosteroid) for at least 14 days before
start of study treatment
24. Subject has not recovered from the acute toxic effects (Common Terminology Criteria
for Adverse Events [CTCAE] grade 1) of prior anticancer therapy, radiation, or
major surgery/significant trauma (except alopecia or other toxicities not considered
a safety risk for the subject at the Investigator's discretion).
25. Subject has an impaired ability to swallow oral medication.
26. Subject is pregnant or breast feeding.
27. Subject has any condition that confounds the ability to interpret data from the
28. Subject is or has an immediate family member (spouse or children) who is
investigational site or sponsor staff directly involved with this trial, unless
prospective Institutional Review Board (IRB) approval (by chair or designee) is given
allowing exception to this criterion for a specific subject.
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both