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

MDS are commonly divided into lower- or higher-risk categories based on the
Revised International Prognostic Scoring System (IPSS-R) for MDS, which is a
scoring system useful for estimating overall survival and the risk of
transformation to AML [1]. Overall, approximately 25% of patients with very
high, high, or intermediate IPSS-R scores will transform to AML within 0.7
years, 1.4 years, and 3.2 years, respectively [1]. Median survival for patients
with MDS varies from years to months and decreases with increasing IPSS-R score.
Because MDS are heterogeneous diseases, varied treatment options exist. Most
patients with MDS are managed with non-curative treatment strategies to control
symptoms, improve quality of life, improve overall survival (OS), and decrease
progression to AML. Treatment of patients with lower-risk MDS (often defined as
patients with <5% myeloblasts and/or normal or good risk cytogenetics and few
cytopenias) focuses on minimizing blood product transfusions and maximizing
quality of life through use of supportive care (eg, antibiotics as needed for
infections, red blood cell transfusions), growth factors such as erythropoiesis
stimulating factors or immunosuppressive drugs. Treatment for patients with
higher-risk disease often includes DNA hypomethylating agents (azacitidine and
decitabine) [6]. Rarely, intensive chemotherapy is used in patients with
higher-risk MDS (HR MDS), but it generally results in significant toxicity and
modest responses
(uptodate.com/contents/treatment-of-high-or-very-high-risk-myelodysplastic-syndr
omes, Treatment of high or very high risk myelodysplastic syndromes, Accessed
08 December 2014) [7-9].
Hypomethylating agents produce objective hematologic responses in approximately
half of MDS patients, delay leukemic progression, improve quality of life, and,
for azacitidine only, prolong survival in HR MDS patients. Nevertheless,
treatment with hypomethylating agents is not curative, and most patients
relapse within 2 years. Lenalidomide, an immunomodulatory thalidomide congener,
significantly improves red blood cell transfusion-independence rates and
increases hemoglobin, but it is approved only for use in patients with the 5q
syndrome subtype of low-risk MDS [7,8,10-12].
The only known curative therapy for MDS is allogenic stem cell transplantation.
However, only a minority of patients (typically with HR MDS) undergo this
procedure due to contraindications and the limited availability of appropriate
stem cell donors [13]. Even in these patients, treatment-related mortality and
morbidity and high relapse rates compromise long-term disease-free survival
(uptodate.com/contents/treatment-of-high-or-very-high-risk-myelodysplastic-syndr
omes, Treatment of high or very high risk myelodysplastic syndromes, Accessed
08 December 2014) [8,14,15]. More recent therapeutic approaches to MDS patients
with higher-risk disease have involved combining drugs with hypomethylating
agents, either to take advantage of synergistic properties of, for example,
histone deacetylase inhibition combined with epigenetic modification, or to
capitalize on non-overlapping mechanisms of action [16,17].
Please consult for more information Section 1 in de protocol

Primary
• To determine in patients with higher-risk myelodysplastic syndrome (HR MDS),
chronic myelomonocytic leukemia (CMML), and low-blast acute myelogenous
leukemia (AML) whether the combination of pevonedistat and azacitidine improves
event-free survival (EFS), when compared to single-agent azacitidine; for
patients with HR MDS or CMML, an event is defined as death or transformation to
AML; for patients with low-blast AML, an event is defined as death or disease
progression or relapse after CR.


Secondary
• To determine in patients with HR MDS, CMML, and low-blast AML, whether the
combination of pevonedistat and azacitidine improves overall survival (OS) when
compared to single-agent azacitidine.
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine improves 6-month and 1-year
survival rates when compared to single-agent azacitidine.
• To determine in patients with HR MDS and CMML whether the combination of
pevonedistat and azacitidine delays time to AML transformation when compared to
single-agent azacitidine.
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine, when compared to single agent
azacitidine, improves the rate of complete remission (CR), CR plus partial
remission (CR+PR), and/or overall response. Overall response in HR MDS and CMML
is defined as CR+PR+hematologic improvement (HI); overall response in low-blast
AML is defined as CR+PR.
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine, when compared to single agent
azacitidine, improves the rate of CR, CR+PR, as well as the overall response
rate (ORR) by Cycle 4.
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine, when compared to single-agent
azacitidine, improves duration of CR, CR+PR, and/or overall response.
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine improves time to first CR or PR
when compared to single-agent azacitidine.
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine delays time to subsequent therapy
when compared to single-agent azacitidine. Subsequent therapy is defined as
agent(s) with antileukemic/anti-myelodysplastic syndrome (MDS) activity (eg,
cytarabine, anthracyclines, purine analogues, and hypomethylating agents other
than azacitidine). Patients who discontinue study treatment to receive
single-agent azacitidine off study would not be counted as receiving subsequent
therapy.
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine improves rate of transfusion
independence when compared to single-agent azacitidine. Red blood cell (RBC) or
platelet transfusion independence requires that the patient receive no RBC or
platelet transfusions, respectively, for a period of at least 8 weeks.
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine reduces the percent of patients who
have at least one inpatient hospital admission(s) related to HR MDS, CMML, or
low-blast AML when compared to single-agent azacitidine.
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine delays time to disease progression
(progressive disease; PD), relapse or death when compared to single-agent
azacitidine.
• To evaluate in patients with HR MDS, CMML, and low-blast AML, the safety of
the combination of pevonedistat and azacitidine when compared to single-agent
azacitidine.
• To collect in patients with HR MDS, CMML, and low-blast AML, plasma
concentration-time data for pevonedistat to contribute to future population
pharmacokinetic (PK) analyses of pevonedistat.


Exploratory
• To determine in patients with HR MDS, CMML, and low-blast AML whether the
combination of pevonedistat and azacitidine improves bone marrow blast
reduction by Cycle 2 and Cycle 4 when compared to single-agent azacitidine.
• To evaluate in patients with HR MDS, CMML, and low-blast AML, the potential
relationship between baseline molecular characteristics of the tumor (such as
cytogenetic abnormalities and somatic mutations), circulating serum biomarkers
(including micro RNAs, proteins, and metabolites), and changes in gene
expression and epigenetic modifications (between Screening and specified
postdose time points) with the efficacy and/or safety of the combination of
pevonedistat and azacitidine.
• To determine in patients with low-blast AML, the percentage of CR and CRi
that are cytogenetic remissions.
• To determine minimal residual disease status in patients who achieve CR in
Cycle 4 or Cycle 7 and determine its relationship to EFS.
• To evaluate in patients with HR MDS, CMML, and low-blast AML, the potential
relationship between germline polymorphisms (such as in proteasome pathway
genes) and the efficacy and/or safety of the combination of pevonedistat and
azacitidine.
• To evaluate in patients with HR MDS, CMML, and low-blast AML, potential
mechanisms of treatment-emergent resistance, such as somatic mutations in
NEDD8-activating enzyme subunits and key signaling pathways, or change in
pathway activity, in tumors from patients who initially respond to therapy and
then exhibit progressive disease.
• To assess in patients with HR MDS, CMML, and low-blast AML, the effect on
health-related quality of life (HRQOL) of the the combination of pevonedistat
and azacitidine compared with single-agent azacitidine.
• To explore in patients with HR MDS, CMML, and low-blast AML, potential
relationships between polymorphic variations in genes encoding drug
metabolizing enzymes (DMEs) or transporters that may be implicated in
pevonedistat disposition and exposure to pevonedistat.

This study is a multicenter, global, randomized, controlled, open-label, phase
2 clinical study of the combination of pevonedistat and azacitidine versus
single-agent azacitidine administered in patients with HR MDS, CMML, or
low-blast AML who have not previously received a hypomethylating agent.
Once enrolled, patients will be randomized at a 1:1 ratio to receive study drug
(either single-agent azacitidine or the combination of pevonedistat and
azacitidine) in 28-day treatment cycles. All patients will be stratified into 4
categories: low-blast AML, Revised International Prognostic Scoring System
(IPSS-R) risk group of very high, high, or intermediate for MDS/CMML [2]. All
patients will receive azacitidine (75 mg/m2 [subcutaneous]) on Days 1 through
5, Day 8, and Day 9. Patients randomized to the combination arm will also
receive pevonedistat (20 mg/m2 via 60 minute infusion) on Days 1, 3, and 5 of
each cycle. Dose modifications may be allowed.
Patients, including those who achieve a CR, may receive study treatment until
they experience unacceptable toxicity, relapse, transformation to AML, or
progressive disease as defined in this study.
Patients with HR MDS or CMML may be allowed to continue study treatment (either
treatment arm) if they meet the criteria for progressive disease based only on
bone marrow blast count (without AML transformation) if , in the clinical
judgment of the investigator , the patient is still receiving clinical benefit
from this treatment and the continuation is endorsed by the sponsor*s project
clinician (or designee).Patients with low-blast AML in this study may also be
allowed to continue study treatment (either treatment arm), even if they meet
the criteria for progressive disease based only on bone marrow blast counts,
if, in the clinical judgment of the investigator, the patient is still
receiving clinical benefit from this treatment, and the continuation is
endorsed by the sponsor*s project clinician (or designee). Patients who meet
the criteria for PD and continue on study under these conditions must be
reconsented before continuing study treatment. Patients may choose to
discontinue at any time.
Patients will attend the End-of-Treatment (EOT) visit 30 days (+10 days) after
the last dose of study drug or before the start of subsequent antineoplastic
therapy if that occurs sooner. Patients will enter EFS follow-up (study visits
every 3 months, to include physical exam, clinical blood tests, HRQOL
assessments, hospitalization assessment, bone marrow aspirate sampling, and
disease assessment) if their disease has not transformed from HR MDS or CMML to
AML (for patients with HR MDS or CMML) or progressed (patients with low-blast
AML), and they have not started subsequent therapy. Patients will enter OS
follow-up (contacted every 3 months to document subsequent therapies and
survival status) when they have confirmed transformation to AML (for patient
with HR MDS or CMML) or experienced progressive disease (patients with
low-blast AML) or have started subsequent therapy.
Disease response assessments for all HR MDS and CMML patients will be based on
the Modified International Working Group (IWG) response criteria for MDS [3].
Disease response assessments for low-blast AML patients will be based on the
Revised Recommendations of the IWG for Diagnosis, Standardization of Response
Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in
Acute Myeloid Leukemia [4]. Formal disease assessments for study endpoints will
be determined based on local bone marrow aspirate blast counts and
transfusions, and central lab data (local lab data may be used for
time-sensitive clinical decisions).
Bone marrow samples (biopsy and/or aspirate) will be collected at Screening,
during treatment, and during follow-up for blast count evaluation (to inform
disease burden assessment). Bone marrow aspirate will also be used to analyze
tumor cytogenetics, to analyze baseline somatic mutations and other molecular
characteristics, to evaluate changes in epigenetic patterns, and to identify
treatment emergent mutations (including biomarkers of response and resistance
to the combination of pevonedistat and azacitidine, as well as biomarkers
related to potential toxicity). Samples will be collected and analyzed from
patients in both treatment arms.
Inpatient hospital admissions related to HR MDS, CMML, or low-blast AML, as
well as RBC- and platelet-transfusion independence, will be monitored as
secondary efficacy endpoints. Treatment emergent resistance will also be
monitored.
Sparse sampling for the determination of pevonedistat plasma concentrations
and, if appropriate, its metabolites will be collected from each patient in the
Combination Pevonedistat Plus Azacitidine Arm to contribute to a population PK
analysis of pevonedistat co-administered with azacitidine.
Adverse events and Eastern Cooperative Oncology Group (ECOG) performance status
will be assessed, and ECGs, clinical laboratory values, and vital signs will be
obtained, to evaluate the safety and tolerability of the study drug treatments.
Patient-reported HRQOL will be evaluated using the EORTC-QLQ-C30 and EQ 5D-5L
(all patients) and the QOL-E (American English-speaking US patients only)
questionnaires.

The patient will receive azacitidine by injection under your skin on Days 1, 2,
3, 4, 5, 8 and 9. If the patient is assigned to the combination arm, the
patient will also receive pevonedistat by infusion into your vein on days 1, 3
and 5 (for example, the first Monday, Wednesday and Friday of a 28-day cycle).
Pevonedistat is provided as a solution for IV infusion. The infusion of
pevonedistat is expected to last approximately one hour but may take longer,
depending on how you tolerate it. For patients taking the combination, on Days
1, 3, and 5, when both pevonedistat and azacitidine are administered,
azacitidine will be administered first, followed by pevonedistat. Safety
monitoring will be done to establish the effects of pevonedistat in combination
with azacitidine in your body.

All the assessments as stated in the protocol schedule of events are all
additional in comparison with the regular treatment.

Potential Risks From Phase 1 Studies (at Doses and Schedules Substantially
Higher than Currently Used in Clinical Studies)
• Single- or multi-organ failure (severe problems with the liver, kidneys,
and/or heart) that could cause death. This occurred at doses and schedules
that are no longer being used in current studies with pevonedistat.
• Severe problems with how your kidneys work. Many of these events occurred at
doses that are no longer being used in current studies with pevonedistat.
• Abnormal heart rhythms.
• Problems with the bone marrow that could lead to increased risk of infection,
bleeding and low blood counts (with or without fever).
• A reaction called an acute phase response where you may have a fever, high
white blood cell levels, and a change in certain protein levels in the body.
You will be checked by your study doctor for this during the study.
• Interference with normal function of your stomach and intestine which could
result in dehydration (lack of adequate water in the body), electrolyte or
chemical imbalance,
• Low phosphate level in your blood. Decreased phosphate level can lead to
muscle weakness and cramps, irritability, and confusion. If your phosphate
levels are low, you may be given phosphate supplements either by mouth or
intravenously (through the vein).
Potential Risks Possibly Due to Underlying Disease or Malignancy
• Decrease in appetite, chills (feeling cold), and/or feeling tired.
• Decreased number of white blood cells which could lead to infections
• Decreased number of white blood cells which could lead to infections, along
with a fever
• Bleeding in the stomach or intestines.
• Multi-organ failure in the context of infection

Potential Risks Based on Findings From Animal Studies
• Breakdown of the heart muscle and blood clots in the heart have been seen
when high doses of pevonedistat were administered
• Increased blood pressure in the artery that carries blood from the heart to
the lungs.
• Changes in the heart and blood vessels that could cause a high heart rate,
and high or low blood pressure.
• Degeneration of the intestines, including a reduction of body fluids and
electrolytes, accompanied by a severe infection.
• Damage to your testes or ovaries which could be a risk if de patient were to
have a baby and which could also result in sterility (unable to have a baby).
• If the patient or his partner were to become pregnant, there may be a risk
that the fetus would not grow normally.
• Decreased bone has been seen when high doses of pevonedistat were given to
animals. This may increase the risk of fractures in patients treated with
pevonedistat. However, no fractures were seen in animals.
• Prolongation of one of your blood clotting measurements that may result in
increased bleeding.

Your blood creatinine level is measured to check your kidney function. A small
number of patients have had mild increases in creatinine, which may mean there
is mild decrease in kidney function.

Benefit
It can increases the amount of time the patients live without worsening of the
patients disease