Pevonedistat and Azacitidine as Maintenance Therapy After Allogeneic Stem Cell Transplantation for Non-Remission AML
Condition: Acute Myeloid Leukemia (AML)
MeSH terms: Leukemia; Leukemia, Myeloid, Acute
Intervention: Pevonedistat; transplant; Azacitidine
Intervention description: To assess the toxicity and efficacy of a combination of Pevonedistat and Azacitidine as post allogeneic hematopoietic stem cell transplant maintenance therapy for non-remission AML.; Although hematopoietic stem cell transplantation (HSCT) is curative for many patients with AML, AML in relapse at the time of transplant is still a major challenge with low rates of leukemia-free survival even with an intensive myeloablative conditioning.; To assess the toxicity and efficacy of a combination of Pevonedistat and Azacitidine as post allogeneic hematopoietic stem cell transplant maintenance therapy for non-remission AML.
Intervention MeSH terms: Azacitidine; Pevonedistat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This research is being done to find out the toxicity and efficacy of a combination of
      Pevonedistat and Azacitidine as post allogeneic hematopoietic stem cell transplant
      maintenance therapy for non-remission AML and to see the overall diseases free survival,
      relapse, and GVHD after treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥ 18 years (or age of majority at participating site, whichever is greater) and ≤
             70 years.

          2. Non-remission AML at the time of transplant proven via bone marrow aspiration and/or
             biopsy.

             o"Not in remission" is defined as "greater than 5.0% bone marrow blasts by aspirate
             morphology," as determined by a bone marrow aspirate obtained within 2 weeks of study
             registration.

               -  For primary induction failure patients: Patients must have failed at least 2
                  induction regimens.

               -  For patients with relapsed disease: Patients who relapse more than 6 months after
                  preceding remission must fail at least one reinduction regimen to be eligible.
                  For patients in whom the preceding remission is equal to or shorter than 6 months
                  duration, no re-induction regimen is required to qualify for this protocol.

               -  If the pre-transplant bone marrow aspirate and biopsy are hypo plastic (less than
                  10% cellularity), and blast percentages cannot be determined, the patient is
                  eligible if the preceding bone marrow met the above criteria.

               -  Patients with peripheral circulating blasts or patients with extramedullary
                  leukemia are eligible if bone marrow aspirate and biopsy meets the above
                  criteria.

          3. Karnofsky Performance Scale (KPS) above or equal to 70%

          4. Clinical laboratory values within the following parameters (repeat if more than 3 days
             before the first dose):

               1. Creatinine clearance ≥ 50 mL/min

               2. Hemoglobin > 8 g/dL. Patients may be transfused to achieve this value.

               3. White blood cell (WBC) count < 50,000/µL before administration of Pevonedistat on
                  Cycle 1 Day 1. Note: Hydroxyurea may be used to control the level of circulating
                  leukemic blast cell counts to not lower than 10,000/µL during the study.

               4. LFTs (ALT, AST) equal or less than 2.5 times upper limit of normal value.

               5. Bilirubin ≤ x 1.5 ULN limit

          5. Female patients who:

               -  Are postmenopausal (see Appendix for definition) 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 (see Appendix), at the same time, from the time of
                  signing the informed consent through 4 months after the last dose of study drug
                  (female and male condoms should not be used together), or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
                  symptothermal, post ovulation methods] withdrawal, spermicides only, and
                  lactational amenorrhea are not acceptable methods of contraception.)

             Male patients, even if surgically sterilized (i.e., status post vasectomy), who:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 4 months after the last dose of study drug (female
                  and male condoms should not be used together), or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
                  symptothermal, post ovulation methods for the female partner] withdrawal,
                  spermicides only, and lactational amenorrhea are not acceptable methods of
                  contraception.)

          6. 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 patient at any time without prejudice to future medical care.

        Exclusion Criteria:

          1. Treatment with any investigational products within 21 days of study registration.

          2. Known hypersensitivity to Azacitidine.

          3. Active uncontrolled infections or severe infectious disease, such as severe pneumonia,
             meningitis, or septicemia.

          4. Known central nervous system (CNS) involvement.

          5. Known human immunodeficiency virus (HIV) positivity.

          6. Known hepatitis B surface antigen-positive, or known active hepatitis C infection.

               -  Note: Patients who have isolated positive hepatitis B core antibody (ie, in the
                  setting of negative hepatitis B surface antigen and negative hepatitis B surface
                  antibody) must have an undetectable hepatitis B viral load. Patients who have
                  positive hepatitis C antibody may be included if they have an undetectable
                  hepatitis C viral load.

          7. Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of study procedures

          8. Major surgery within 14 days before the first dose of any study drug or a scheduled
             surgery during study period.

          9. Diagnosed or treated for another malignancy within 2 years before randomization or
             previously diagnosed with another malignancy and have any evidence of residual
             disease. Patients with non- melanoma skin cancer or carcinoma in situ of any type are
             not excluded if they have undergone resection.

         10. Life-threatening illness unrelated to cancer.

         11. Patients with uncontrolled coagulopathy or bleeding disorder.

         12. Known hepatic cirrhosis or severe pre-existing hepatic impairment

         13. Known cardiopulmonary disease defined as:

               -  Unstable angina;

               -  Congestive heart failure (New York Heart Association [NYHA] Class III or IV; see
                  appendix);

               -  Myocardial infarction (MI) within 6 months prior to first dose (patients who had
                  ischemic heart disease such as a (ACS), MI, and/or revascularization greater than
                  6 months before screening and who are without cardiac symptoms may enroll);

               -  Cardiomyopathy;

               -  Clinically significant arrhythmia:

                    1. History of polymorphic ventricular fibrillation or torsade de pointes,

                    2. Permanent atrial fibrillation [a fib], defined as continuous a fib for ≥ 6
                       months,

                    3. Persistent a fib, defined as sustained a fib lasting > 7 days and/or
                       requiring cardioversion in the 4 weeks before screening,

                    4. Grade 3 a fib defined as symptomatic and incompletely controlled medically,
                       or controlled with device (e.g. pacemaker), or ablation and

                    5. Patients with paroxysmal a fib or < Gr 3 a fib for period of at least 6
                       months are permitted to enroll provided that their rate is controlled on a
                       stable regimen.

               -  Implantable cardioverter defibrillator;

               -  Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing);

               -  Pulmonary hypertension

         14. Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic
             blood pressure > 95 mm Hg).

         15. Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to
             institutional guidelines.

         16. Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or
             radionuclide angiography.

         17. Known moderate to severe chronic obstructive pulmonary disease, interstitial lung
             disease, and pulmonary fibrosis.

         18. Systemic antineoplastic therapy or radiotherapy for other malignant conditions within
             14 days before the first dose of any study drug, except for hydroxyurea.

         19. Female patients who are both lactating and breastfeeding 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 patients 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 patients who intend to donate sperm during the course of this study or 4 months
             after receiving their last dose of study drug(s).

         22. Patients who need to use clinically significant CYP3A enzyme inducers (listed on
             Appendix A)