Pevonedistat and Azacitidine as Maintenance Therapy After Allogeneic Stem Cell Transplantation for Non-Remission AML

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.

In preclinical studies Pevonedistat has shown significant single agent activity against mouse xenograft models of AML cell Line HL-60. Also this effect seemed to be synergistically enhanced by combining it with Azacitidine. In clinical arena, Pevonedistat has shown single agent activity in heavily pretreated patients with AML. In Study C15003, responses (complete responses \[CRs\] and partial responses \[PRs\]) were observed in a variety of patient settings, including post allogeneic transplant, therapy-related AML, and primary refractory AML, although some of the responses were of relatively short duration. Study C15009 is an ongoing phase 1b study evaluating the MTD of Pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2 Azacitidine (administered on a 5-on/2-off \[weekend\]/2-on schedule) in a 28-day treatment cycle in patients 60 years of age or older with treatment naïve AML who are unlikely to benefit from standard induction therapy. As of 22 June 2017, enrollment had completed and 15 patients remained on study. As of 22 January 2017, preliminary data are available for 64 patients enrolled in the study who received at least 1 dose of Pevonedistat in combination with Azacitidine; these patients had completed a total of approximately 360 cycles, with a median of 4 cycles of treatment In the dose escalation cohorts, 6 patients received 20 mg/m2 Pevonedistat, and 3 patients received 30 mg/m2. The most common events (reported by ≥ 25% of patients) were constipation (45%), nausea (42%), fatigue (39%), anemia (34%), febrile neutropenia (30%), decreased appetite (28%), and thrombocytopenia (27%). The MTD in this study was determined to be 20 mg/m2 Pevonedistat given on Days 1, 3, and 5, in combination with 75 mg/m2 Azacitidine given on Days 1 through 5, 8, and 9, in 28 day treatment cycles. A total of 45 (70%) patients experienced at least 1 SAE A total of 14 SAEs were reported for more than 1 patient, including: febrile neutropenia (16 patients); pneumonia (8 patients); pyrexia (4 patients); AML and sepsis (3 patients); and acute myocardial infarction, cellulitis, diverticulitis, dyspnea, embolism, hypoxia, mental status changes, multi-organ failure, and transaminase increased (2 patients each). A total of 19 patients treated with Pevonedistat (either 20 mg/m2 or 30 mg/m2), discontinued from Study participation because of a TEAE. No other events leading to discontinuation were assessed by study investigators as at least possibly related to study drug treatment. 11 on-study deaths had been reported; none assessed as related to study treatment. A total of 31 patients experienced PR or better. Eighteen patients had a best response of CR, 4 patients had a best response of CRi, and 9 patients had a best response of PR. One patient in the 30 mg/m2 dose level group achieved a CR; all other responses occurred in patients treated with 20 mg/m2.

The following studies are currently enrolling.

* Study 2001: A Phase 2, randomized, controlled Open-Label Clinical study of the efficacy and safety of Pevonedistat plus Azacitidine versus single-agent Azacitidine in patients with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia and low-blast acute myelogenous leukemia.
* Study 1012: A phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as Single Agent and in Combination with Azacitidine in adult East Asian patients with acute myeloid leukemia or myelodysplastic syndromes

Hence owing to the current knowledge of clinical and preclinical experience with Azacitidine and Pevonedistat alone and in combination, this combination appears feasible for testing in patients post-transplant with at very high risk of relapse.

The Investigator proposes a study using a combination of Pevonedistat and Azacitidine for maintenance therapy after allogeneic HSCT for non-remission. Patients will receive up to five 28 day cycles of the investigational maintenance therapy. Maintenance therapy will begin between days +30 to +45 post-transplant.

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)