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

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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.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 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,