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



Status:Recruiting
Conditions:Blood Cancer, Blood Cancer, Hematology
Therapuetic Areas:Hematology, Oncology
Healthy:No
Age Range:18 - Any
Updated:2/22/2019
Start Date:August 7, 2017
End Date:July 2023
Contact:Vanderbilt-Ingram Service for Timely Access
Email:cip@vanderbilt.edu
Phone:800-811-8480

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A Phase II Trial of Pevonedistat and Azacitidine in MDS or MDS/MPN Patients Who Fail Primary Therapy With DNA Methyl Transferase Inhibitors

This study will evaluate the treatment combination of pevonedistat and azacitidine in the
setting of DNA methyltransferase inhibitor(s) failure in patients with relapsed/refractory
myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative neoplasm.

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.
We found this trial at
5
sites
601 Elmwood Avenue
Rochester, New York 14642
(585) 275-2100
Principal Investigator: Jason Mendler, MD
Univ of Rochester Medical Center One of the nation's top academic medical centers, the University...
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1601 Northwest 12th Avenue
Miami, Florida 33136
(305) 243-6545
Principal Investigator: Justin Watts, MD
University of Miami Miller School of Medicine The University of Miami Leonard M. Miller School...
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Miami, FL
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2220 Pierce Ave
Nashville, Tennessee 37232
615-936-8422
Vanderbilt-Ingram Cancer Center The Vanderbilt-Ingram Cancer Center, located in Nashville, Tenn., brings together the clinical...
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New York, New York 10065
Principal Investigator: Virginia Klimek, MD
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New York, NY
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Westwood, Kansas 66205
Principal Investigator: Barry Skikne, MD
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Westwood, KS
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