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

Primary Objective:

To compare survival of patients treated with a combination of pevonedistat and azacitidine
after failure of DNA methyltransferase inhibitors (DNMTi) to historical survival for patients
with relapsed/refractory myelodysplastic syndrome (MDS) or myelodysplastic/
myeloproliferative overlap syndromes (MDS/MPN) who are ineligible for hematopoietic stem cell
transplant (HSCT)

Secondary Objectives:

- To determine the rate of hematologic improvement (HI) in patients with
relapsed/refractory MDS or MDS/MPN treated with pevonedistat and azacitidine after DNMTi
failure

- To determine the complete remission (CR) and marrow CR rates in patients with
relapsed/refractory MDS or MDS/MPN treated with pevonedistat and azacitidine after DNMTi
failure

- To determine the reduction of bone marrow blasts in patients with relapsed/refractory
MDS or MDS/MPN treated with pevonedistat and azacitidine after DNMTi failure

Exploratory Objectives:

- To correlate the mutation burden in patients with relapsed/refractory MDS or MDS/MPN
with response to treatment with pevonedistat and azacitidine

- To correlate genomic aberrations with rate of response and survival in
relapsed/refractory MDS or MDS/MPN patients treated with pevonedistat and azacitidine

- To measure the effect of pevonedistat treatment in combination with azacitidine on
quality of life in patients with relapsed/refractory MDS or MDS/MPN

- To define epigenetic biomarkers for pevonedistat use in relapsed/refractory MDS or
MDS/MPN

Inclusion:

- Subjects must be ≥18 years of age at the time of signing the Informed Consent Form
(ICF); must voluntarily sign an ICF; and must be able to meet all study requirements.-

- Morphologically confirmed diagnosis of MDS or MDS/MPN in accordance with WHO
diagnostic criteria,

- Relapsed or refractory disease. Relapse is defined as having progressive disease after
achieving an objective response after at least 2 cycles of DNMTi therapy. Refractory
disease is defined as having either not achieved an objective response after at least
4 cycles of DNMTi therapy or having no response with clear progressive disease after
at least 2 cycles of DNMTi therapy. Progressive disease and response criteria are
defined by the 2006 revised IWG response criteria for MDS or MDS/MPN.

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
failure, patients must have received minimum dosing of decitabine 15mg/m2 daily x 5 days,
or 5'azacitidine 50mg/m2 IV/SC daily x 5 days, or SGI-110 (guadecitabine) 60mg/m2 SC daily
x 5 days or ASTX727 20/100mg daily x 5 days, or CC-486 200mg daily x 14 days in each prior
cycle.

- Patient consent to provide fresh bone marrow biopsy and aspirate for exploratory
research collected from a procedure performed no more than 28 days prior to initiating
treatment on Cycle 1, Day 1

- Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of
0, 1 or 2

- Life expectancy of at least 3 months

- Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments,
excluding alopecia;

- Adequate organ function as demonstrated by the following:

- ALT (SGPT) and/or AST (SGOT) ≤ 2x upper limit of normal (ULN);

- Total bilirubin ≤ ULN;

- Calculated creatinine clearance ≥ 50 mL/min.

Exclusion:

- Any previous treatment with pevonedistat or other NEDD8 inhibitor

- Acute myelogenous leukemia (≥ 20% peripheral or bone marrow blasts)

- Concomitant chemotherapy, radiation therapy

- Active, uncontrolled infection. Patients with infection under active treatment and
controlled with antibiotics are eligible

- Any HSCT within 6 months prior to signing informed consent

- 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

- Concurrent condition that in the investigator's opinion would jeopardize compliance
with the protocol.