Safety and Efficacy Study of CC-486 in Subjects With Myelodysplastic Syndromes
Condition: Myelodysplastic Syndromes
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: Oral Azacitidine; Durvalumab
Intervention description: Oral azacitidine (AZA) 100 mg, 150 mg, or 200 mg tablets twice daily (BID) on days 1 to 21 of each 28-day treatment cycle. Participants continued to receive their assigned study treatment unless disease progression, unacceptable toxicity, lost to follow-up or withdrawal by participant occurred.; Durvalumab 1500 mg by IV infusion on Day 1 of each 28 day treatment cycle.
Intervention MeSH terms: Azacitidine; Durvalumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 65.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Keywords provided by Celgene:; myelodysplastic syndromes; MDS; azacitidine; oral azacitidine (CC-486); decitabine; intermediate-1; intermediate-2 and high risk myelodysplastic syndromes (MDS); proliferative chronic myelomonocytic leukemia (CMML); Chronic; iHMA (injectable hypomethylating agents); PD-L1

Summary:

      Evaluate the safety and efficacy of oral azacitidne (CC-486) twice daily (BID) in subjects
      with myelodysplastic syndromes who failed to achieve an objective response post injectable
      hypomethylating agent (iHMA) treatment

      Reason for removing the combination arm: Due to difficulties with dose-finding, the
      durvalumab plus CC-486 combination arm was closed to enrollment.

      Extension:

      An Extension Phase (EP) has been added to allow subjects who are currently receiving oral
      azacitidine BID and who are demonstrating clinical benefit as assessed by the Investigator,
      to continue receiving oral azacitidine until the subject meets the criteria for study
      discontinuation.
    

Eligibility criteria:

        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

          3. 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:

               -  having received at least 6 consecutive 4-week treatment cycles with azacitidine
                  for injection, or

               -  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

               -  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.

          4. 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:

               1. Less than 5%: ≥ 100% increase to ≥ 8% blasts

               2. ≥ 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:

               1. 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

               2. meaningful worsening in RBC or platelet transfusion requirement

                  Definition of stable disease is based on modified IWG 2006 criteria:

                    -  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

          5. 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).

          6. 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 (

          7. Have an eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2

          8. 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:

          1. Male subjects must:

               1. 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.

          2. 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):

          -  Subjects who have signed the informed consent for the EP of the study;

          -  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;

          -  Subjects who do not meet any of the criteria for study discontinuation

        Exclusion Criteria:

          1. 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

          2. 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.

          3. Prior allogeneic stem cell transplant

          4. Prior exposure to the investigational oral formulation of decitabine, or other oral
             azacitidine derivative at any time in the subject's prior history

          5. 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

          6. Ongoing medically significant adverse events from previous treatment, regardless of
             the time period

          7. 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

          8. 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

          9. 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

         10. 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)

         11. 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

         12. 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)

         13. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence
             of active Hepatitis B Virus (HBV) infection

         14. 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

         15. Known or suspected hypersensitivity to azacitidine, mannitol, its constituents, or to
             any other humanized monoclonal antibody

         16. 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

         17. Any significant medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from participating in the study

         18. Any condition including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she were to participate in the study

         19. Any condition that confounds the ability to interpret data from the study, including
             known or suspected conditions other than MDS, associated with anemia

         20. 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

         21. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, or CNS
             leukemia

         22. 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

         23. History of primary immunodeficiency

         24. Active myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML)