An Efficacy and Safety Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML) and Low-Blast Acute Myelogenous Leukemia (AML)
Condition: Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukemia, Myeloid, Acute
MeSH terms: Leukemia; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Syndrome
Intervention: Azacitidine; Pevonedistat
Intervention description: Azacitidine intravenous or subcutaneous formulation.; Pevonedistat intravenous infusion.
Intervention MeSH terms: Azacitidine; Pevonedistat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 120.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug Therapy

Summary:

      The purpose of this study is to evaluate the efficacy and safety of pevonedistat plus
      azacitidine versus single-agent azacitidine in participants with HR-MDS or CMML, or low-blast
      AML.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female participants 18 years or older.

          2. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with
             white blood cells [WBC] <20,000 per microliter [/mcL]) or low blast AML based on 1 of
             the following:

             French American British (FAB) Classifications:

               -  Refractory anemia with excess blasts (RAEB) - defined as having 5% to 20%
                  myeloblasts in the bone marrow.

               -  CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in
                  the blood.

             OR

             WHO Classifications:

               -  RAEB 1 - defined as having 5% to 9% myeloblasts in the bone marrow.

               -  RAEB 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to
                  19% blasts in the blood.

               -  CMML 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to
                  19% blasts in the blood.

               -  CMML 1 (Although CMML 1 is defined as having <10% myeloblasts in the bone marrow
                  and/or <5% blasts in the blood, these participants may enroll only if bone marrow
                  blasts >=5%.

               -  WHO defined AML with 20% to 30% myeloblasts in the bone marrow and <30%
                  myeloblasts in peripheral blood who are deemed by the investigator to be
                  appropriate for azacitidine based therapy.

          3. For MDS and CMML participants, prognostic risk category, based on the Revised
             International Prognostic Scoring System (IPSS R), of:

               -  Very high (>6 points),

               -  High (>4.5 to 6 points), or

               -  Intermediate (>3 to 4.5 points): a participant determined to be in the
                  Intermediate Prognostic Risk Category is only allowable in the setting of >=5%
                  bone marrow myeloblasts.

          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

          5. Clinical laboratory values within the following parameters (repeat within 3 days
             before the first dose of study drug if laboratory values used for randomization were
             obtained more than 3 days before the first dose of study drug):

               -  Albumin >2.7 g/dL.

               -  Total bilirubin <upper limit of normal (ULN) except in participants with
                  Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct
                  bilirubin <=1.5*ULN of the direct bilirubin.

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5*ULN.

               -  Creatinine clearance >=50 milliliter per minutes (mL/min).

               -  Hb >8 g/dL. Participants may be transfused to achieve this value. Elevated
                  indirect bilirubin due to post transfusion hemolysis is allowed.

          6. For CMML participants: WBC count <20,000/mcL before administration of the first dose
             of study drug on Cycle 1 Day 1; participants must have been off hydroxyurea for at
             least 1 week prior to WBC count assessment.

          7. Ability to undergo the study required bone marrow sample collection procedures.

          8. Suitable venous access for the study required blood sampling (that is, including
             pharmacokinetic (PK) and biomarker sampling).

          9. Female participants who:

               -  Are postmenopausal for at least 1 year before the Screening visit , or

               -  Are surgically sterile, or

               -  If they are of childbearing potential, agree to practice 1 highly effective
                  method and 1 additional effective (barrier) method of contraception at the same
                  time, from the time of signing the informed consent through 4 months after the
                  last dose of study drug, or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence [example, calendar,
                  ovulation, symptothermal, postovulation methods] withdrawal, spermicides only,
                  and lactational amenorrhea are not acceptable methods of contraception. Female
                  and male condoms should not be used together).

             Male participants, even if surgically sterilized (that is, status postvasectomy), who:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 4 months after the last dose of study drug, or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence [example, calendar,
                  ovulation, symptothermal, postovulation methods for the female partner]
                  withdrawal, spermicides only, and lactational amenorrhea are not acceptable
                  methods of contraception. Female and male condoms should not be used together).

         10. Voluntary written consent must be given before performance of any study related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the participant at any time without prejudice to future medical care.

        Exclusion Criteria:

          1. Previous treatment with decitabine or azacitidine or other hypomethylating agent.

          2. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow,
             by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone
             marrow, or by other accepted analysis.

          3. Eligible for allogenic stem cell transplantation.

          4. Participants with MDS, CMML, or low blast AML, whose only site of disease is
             extramedullary, example, the skin.

          5. Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of study procedures or could limit
             participant expected survival to less than 6 months.

          6. Treatment with any anti leukemic/anti MDS therapies (example, lenalidomide,
             cytarabine, anthracyclines, purine analogs) or with any investigational products
             within 14 days before the first dose of any study drug.

          7. Known hypersensitivity to mannitol.

          8. Active uncontrolled infection or severe infectious disease, such as severe pneumonia,
             meningitis, or septicemia.

          9. Major surgery within 14 days before first dose or a scheduled surgery during study
             period; insertion of a venous access device (example, catheter, port) is not
             considered major surgery.

         10. Diagnosed or treated for another malignancy within 2 years before randomization or
             previously diagnosed with another malignancy and have any evidence of residual
             disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type
             are not excluded if they have undergone resection.

         11. Life threatening illness unrelated to cancer.

         12. Prothrombin time (PT) or prolongation of the activated thromboplastin time (aPTT) >1.5
             ULN or active uncontrolled coagulopathy or bleeding disorder.

         13. Known human immunodeficiency virus (HIV) seropositive.

         14. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis
             C infection. Note: Participants who have isolated positive hepatitis B core antibody
             (that is, in the setting of negative hepatitis B surface antigen and negative
             hepatitis B surface antibody) must have an undetectable hepatitis B viral load.

         15. Known hepatic cirrhosis or severe pre-existing hepatic impairment.

         16. Known cardiopulmonary disease defined as unstable angina, clinically significant
             arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or
             IV) and/or myocardial infarction within 6 months prior to first dose, or severe
             pulmonary hypertension. As an example, well controlled atrial fibrillation would not
             be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.

         17. Treatment with strong cytochrome P450 (CYP) 3A inhibitors or inducers within 14 days
             before the first dose of study drug.

         18. Systemic antineoplastic therapy or radiotherapy for other malignant conditions within
             12 months before the first dose of any study drug, except for hydroxyurea.

         19. Female participants who are lactating and breast feeding or have a positive serum
             pregnancy test during the Screening period or a positive urine pregnancy test on Day 1
             before first dose of study drug.

         20. Female participants who intend to donate eggs (ova) during the course of this study or
             4 months after receiving their last dose of study drug(s).

         21. Male participants who intend to donate sperm during the course of this study or 4
             months after receiving their last dose of study drug(s).