Pevonedistat and Azacitidine in MDS or MDS/MPN Patients Who Fail Primary Therapy With DNA Methyl Transferase Inhibitors

Inclusion criteria

Inclusion: * Signed and dated voluntary written informed consent 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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. * Male or female ≥ 18 years of age. * Morphologically confirmed diagnosis of MDS or MDS/MPN in accordance with WHO diagnostic criteria. * ECOG performance status of 0, 1 or 2. * Expected survival ≥ 3 months after consenting. * Refractory/relapsed disease following DNMTi failure. Refractory disease defined as either: * failure to achieve an objective response after at least 4 cycles of DNMTi therapy, or * failure to achieve an objective response with clear progressive disease on bone marrow biopsy after at least 2 cycles of DNMTi therapy. Relapsed disease is defined as having progressive disease after achieving an objective response after at least 2 cycles of DNMTi therapy. Previous DNMTi therapy may include 5'azacitidine, decitabine, or DNMTi therapy currently in clinical trials (e.g. SGI-110 (guadecitabine), ASTX727 or CC-486).To be considered DNMTi treatment failure, during each prior treatment cycle, patients must have received equivalent to minimum dosing of: decitabine 15mg/m2 daily x 5 days, or 5'azacitidine 50mg/m2 IV/SC daily x 5 days, SGI-110 (guadecitabine) 60mg/m2 SC daily x 5 days, or oral DNMTi therapy with ASTX727 20/100mg daily x 5 days, or oral DNMTi therapy with CC-486 200mg daily x 14 days * Recovery to ≤ Grade 1 or baseline of any toxicity due to prior systemic treatments, excluding alopecia. * Patient consent to collection of fresh bone marrow biopsy and aspirate for exploratory research obtained from a procedure performed no more than 28 days prior to initiating treatment on Cycle 1, Day 1. Requirement for bone marrow biopsy may be waived with approval of the study chair in the event that a bone marrow biopsy cannot be obtained. * Clinical laboratory values as specified below: * Serum albumin \> 2.7 g/dL * Total bilirubin ≤ 1.5 x ULN * ALT and AST ≤ 2 x ULN * Calculated creatinine clearance ≥ 50 mL/min (per the Cockcroft-Gault formula) * WBC ≤ 50,000/µL (use of hyroxyurea is permitted) * Hgb \<8g/dL should be transfused to provide adequate tissue perfusion as per the discretion of the investigators and local practice. Rechecking Hgb level prior to start on Cycle 1 Day 1 is not necessary as long as patients do not have inadequate oxygenation, underlying cardiopulmonary compromise, and/or any other reason deemed clinically significant to delay therapy per the investigator. * Women of childbearing potential must have a negative serum pregnancy test; and additionally agree to simultaneously use at least 2 methods of effective contraception or abstain from heterosexual intercourse from the time of signing consent, and until 4 months after patient's last dose of protocol-indicated treatment. Periodic abstinence (e.g. calendar,ovulation, symptothermal, postovulation methods for the female partner) and withdrawal are not acceptable methods of contraception. Women of child bearing potential are defined as those not surgically sterile or not post-menopausal. If a female patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for at least 1 year in the absence of an alternative medical cause, then patient will be considered a female of childbearing potential. Postmenopausal status in females under 55 years of age should be confirmed with a serum FSH level within laboratory reference range for postmenopausal women. \- Men, even if surgically sterilized (i.e. status post-vasectomy), who are sexually active with women of childbearing potential must agree to follow instructions for effective barrier contraception from the time of signing consent and until 4 months after last dose of protocol-indicated treatment. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods for the female partner) and withdrawal are not acceptable methods of contraception. Exclusion: * Diagnosis of acute myeloid leukemia (i.e. ≥ 20% peripheral or marrow blasts). * Any HSCT within 6 months prior to signing informed consent. * Any patient who is eligible for HSCT at the time of study screening. * Clinically significant graft versus host disease (GVHD) or GVHD requiring initiation of treatment or treatment escalation within 21 days, and/or \> Grade 1 persistent or clinically significant non-hematologic toxicity related to HSCT * Any previous treatment with pevonedistat or other NEDD8 inhibitor. * Treatment with any investigational products within 14 days before the first dose of protocol-indicated treatment. * Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of any study drug. * Major surgery requiring general anesthesia within 14 days before the first dose of any study drug or a scheduled surgery during study period. (Placement of a central line or port-a-catheter is acceptable within this time frame and does not exclude the patient.) * Treatment with clinically significant metabolic CYP3A inducers within 14 days before the first dose of study drug. Clinically significant CYP3A inducers are not permitted during the study. * Prolonged QTc interval \> 500 msec, calculated according to Fredericia's formula * Known cardiopulmonary disease defined as having one or more of the following: * Uncontrolled high blood pressure (i.e. systolic \> 180 mmHg or diastolic \> 95 mmHg); * Symptomatic cardiomyopathy; * Ischemic heart disease; Patients with acute coronary syndrome, myocardial infarction, and/or revascularization (e.g. coronary artery bypass graft, stent) within 6 months of first dose of study drug are excluded; Patients with a history of ischemic heart disease who have had revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll; * Arrhythmia (e.g. history of polymorphic ventricular fibrillation or torsade de pointes). Patients with symptomatic atrial fibrillation (Afib) incompletely controlled medically, or controlled by device (e.g. pacemaker) or by ablation in the past 6 months are excluded. However, patients with stable, AFib for a period of at least 6 months, whose Afib is controlled with medication, or who have a history of paroxysmal AFib are permitted to enroll; * Implantable cardioverter defibrillator; * Congestive heart failure (New York Heart Association \[NYHA\] Class III or IV; or Class II with a recent decompensation requiring hospitalization or referral to a heart failure clinic within 4 weeks before screening), * Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing). Mild regurgitation is not excluded; * Pulmonary hypertension. * Female patients who are both lactating and breastfeeding, who have a positive serum pregnancy test during screening, or who plan to become pregnant while in the trial or within 90 days after receiving protocol-directed treatment. * Active uncontrolled infection. Patients with infection under active treatment and controlled with antibiotics are not excluded. * Known Childs class B or C hepatic cirrhosis or severe pre-existing hepatic impairment. * Known hepatitis B surface antigen seropositivity or known or suspected active hepatitis C infection. Note: Patients who have isolated positive hepatitis B core antibody (i.e. in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. * Known human immunodeficiency virus (HIV) seropositivity. * Any serious concurrent condition that could, in the investigator's opinion, significantly interfere with completion of study procedures or protocol compliance. * 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). * 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).