Safety and Efficacy Study of CC-486 in Subjects With Myelodysplastic Syndromes

Inclusion Criteria:

1. Male or female, ≥ 18 years of age at the time of signing the informed consent document
2. Documented diagnosis of MYELODYSPLASTIC SYNDROMES (MDS), classified according to FRENCH-AMERICAN BRITISH (FAB) classification criteria

Adequate course of treatment with an injectable hypomethylating agent (azacitidine for injection or decitabine) as the last therapeutic intervention for MDS prior to beginning screening for this study. Adequate is defined as:

1. having received at least 6 consecutive 4-week treatment cycles with azacitidine for injection, or
2. having received at least 4 consecutive 6-week treatment cycles with decitabine (3-day regimen) or at least 6 consecutive 4-week treatment cycles with decitabine (5-day regimen), or
3. having demonstrated inability to tolerate treatment with an injectable hypomethylating agent because of unacceptable drug-related toxicity after at least 3 months of attempted treatment: Three 28-day cycles of azacitidine for injection or decitabine 5-day regimen; two 42-day cycles of decitabine 3-day regimen.

Documented disease progression or stable disease as best response to treatment (or attempted treatment) with azacitidine for injection or decitabine. Those achieving an objective response to treatment regimen with an injectable hypomethylating agent (HMA) are excluded from participation in this study.

Definitions of disease progression are modified from INTERNATIONAL WORKING GROUP (IWG) 2006 criteria and include:

- Pre-injectable hypomethylating agent baseline bone marrow myeloblasts:

Less than 5%: ≥ 100% increase to ≥ 8% blasts

≥ 5%: ≥ 50% increase to ≥ 10% blasts Note: ≥ 30% blasts is considered acute myeloid leukemia (AML )per FAB classification. Subjects known to have ≥ 30% blasts are not eligible for inclusion in this study.recognizing eastern cooperative oncology group) limitations of blast cell quantification, Protocol will allow subjects with pre-enrollment bone marrow blast counts up to 33% on the screening bone marrow examination to be considered for inclusion. Assessment may be made according to local bone marrow examination to facilitate enrollment of eligible subjects into the treatment phase of the study.

- Any clinical worsening from pre-injectable hypomethylating agents (HMA) baseline condition, including:

sustained clinically-significant worsening (investigator's assessment) from baseline granulocyte, platelet, or hemoglobin values (≥ 2 values, separated by ≥ 2 weeks) - worsening granulocytes should be ≥ 50% decrease from pre-injectable HMA baseline value - worsening platelets should be ≥ 50% decrease from pre-injectable HMA baseline value (untransfused)

worsening hemoglobin should be ≥ 1.5 g/dL decrease from preinjectable HMA baseline value in subjects not receiving RBC transfusions

meaningful worsening in RBC or platelet transfusion requirement

Definition of stable disease is based on modified IWG 2006 criteria:

1. Failure to achieve any objective response (CR - complete remission, PR - partial remissino, mCR - marrow complete remission, or HI - hematologic improvement), but no evidence of disease progression within the 8 weeks leading to the subject's first dose of investigational product (IP), Cycle 1, Day 1
2. Have the last dose of the prior treatment regimen injectable HMA - (azacitidine for injection or decitabine) not more than 16 weeks prior to screening for this study (date of informed consent signature).
3. No less than 3 weeks between the last dose of the prior treatment regimen injectable HMA - (azacitidine for injection or decitabine) and the planned date of first dose of IP (
4. Have an eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2

Females subjects of childbearing potential (FCBP)1 may participate, providing they meet the following conditions:

1. Have two negative pregnancy tests as verified by the investigator prior to starting any IP therapy: serum pregnancy test at screening and negative serum or urine pregnancy test (investigator's discretion) within 72 hours prior to starting treatment with IP (Cycle 1, Day 1). They must agree to ongoing pregnancy testing during the course of the study (before beginning each subsequent cycle of treatment), and after the last dose of any IP. This applies even if the subject practices complete abstinence2 from heterosexual contact.
2. Agree to practice true abstinence2 (which must be reviewed on a monthly basis and source documented) or agree to the use of highly effective methods of contraception from 28 days prior to starting azacitidine, and must agree to continue using such precautions while taking azacitidine (including dose interruptions) and for up to 90 days after the last dose of azacitidine. Cessation of contraception after this point should be discussed with a responsible physician
3. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of IP.

Note that the screening serum pregnancy test can also be used as the test prior to starting IP if it is performed within the 72-hour timeframe.

9. Male subjects must:

Male subjects must:

Either practice true abstinence2 from heterosexual contact (which must be reviewed on a monthly basis) or agree to avoid fathering a child, to use highly effective methods of contraception, male condom plus spermicide during sexual contact with a pregnant female or a female of child bearing potential (even if he has undergone a successful vasectomy) from starting dose of IP (Cycle 1 Day 1), including dose interruptions through 90 days after receipt of the last dose of azacitidine.

Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP.

10. Understand and voluntarily sign an informed consent document prior to any study-related assessments or procedures conducted.

11. Be able to adhere to the study visit schedule and other protocol requirements.

12. Understand and voluntarily sign a biomarker-specific component of the informed consent document prior to any study-related procedures conducted.

Extension Phase

At the Investigator's discretion and following confirmation of eligibility criteria below, subjects can enter the Extension Phase (EP):

1. Subjects who have signed the informed consent for the EP of the study;
2. Subjects receiving oral azacitidine and continuing in the treatment phase demonstrating clinical benefit as assessed by the Investigator are eligible to receive oral azacitidine in the EP;
3. Subjects who do not meet any of the criteria for study discontinuation

Exclusion Criteria:

Rapidly-progressing MDS defined as:

1. Known clinically-significant doubling in marrow or per IP peripheral blood blast percentage (to ≥ 20%) in the 8-week period leading to the first dose of IP (Cycle 1, Day 1)
2. ≥100% increase in WBC count (myeloid cell line and monocyte series) within the 8-week period leading to Cycle 1, Day 1
3. AML - FAB (FRENCH-AMERICAN-BRITISH) classification: ≥ 30% blasts in bone marrow). Subjects known to have ≥ 30% blasts are not eligible for inclusion in this study. Recognizing limitations of blast cell quantification, this protocol will allow subjects with pre-enrollment (screening/baseline) bone marrow blast counts up to 33% to be considered for inclusion.
4. Prior allogeneic stem cell transplant
5. Prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative at any time in the subject's prior history
6. Prior or ongoing response (IWG 2006: HI, PR, CR, or marrow CR) to treatment with azacitidine for injection or decitabine, at any time in the subject's prior history, which includes relapsed disease
7. Ongoing medically significant adverse events from previous treatment, regardless of the time period

Use of any of the following within 28 days prior to the first dose of IP:

1. thrombopoiesis-stimulating agents ([TSAs]; eg, Romiplostim, Eltrombopag, Interleukin-11)
2. ESAs (Erythropoiesis stimulating agent) and other RBC hematopoietic growth factors (eg, interleukin-3)
3. hydroxyurea
4. Concurrent use of corticosteroids unless the subject is on a stable or decreasing dose for ≥ 1 week prior to enrollment for medical conditions other than MDS
5. 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

Prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 3 years. However, subjects with the following history/concurrent conditions are allowed:

1. Basal or squamous cell carcinoma of the skin
2. Carcinoma in situ of the cervix
3. Carcinoma in situ of the breast
4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)

Significant active cardiac disease within the previous 6 months, including:

1. New York Heart Association (NYHA) class IV congestive heart failure;
2. Unstable angina or angina requiring surgical or medical intervention; and/or
3. Myocardial infarction
4. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
5. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection

Any of the following laboratory abnormalities:

1. Serum Aspartate transaminase / Serum glutamic oxaloacetic transaminase (AST/SGOT) Alanine aminotransaminase / Serum glutamic pyruvate transaminase (ALT/SGPT) > 2.5 x ULN (upper limit of normal)
2. Serum total bilirubin > 1.5 x upper limit of normal (ULN). Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis). Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs' test or over 50% of indirect bilirubin
3. Serum creatinine > 2.5 x ULN (upper limit of normal)
4. Absolute WBC (white blood cell) count ≥ 20 x 109/L
5. Known or suspected hypersensitivity to azacitidine, mannitol, its constituents, or to any other humanized monoclonal antibody
6. Pregnant, planning to become pregnant starting from 28 days prior to receiving CC-486 throughout your participation in the study, and for at least 90 days following your last dose of study treatment, or breast-feeding females
7. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
8. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
9. Any condition that confounds the ability to interpret data from the study, including known or suspected conditions other than MDS, associated with anemia
10. Having received any prior MAb (monoclonal antibodies) against CTLA-4 (cytotoxic T lymphocyte-associated antigen), PD-1, or PD-L1 or having received other investigational monoclonalantibodies (MAbs) within 6 months
11. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, or CNS leukemia

Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener's syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves' disease; rheumatoid arthritis; hypophysitis, uveitis; etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:

1. Subjects with vitiligo or alopecia;
2. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement for ≥ 3 months; or
3. Subjects with psoriasis not requiring systemic treatment
4. History of primary immunodeficiency
5. Active myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML)