Conditions: Leukemia, Myeloid, Acute Myelodysplastic Syndromes
Keywords: Drug Therapy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of pevonedistat administered as a single agent and in combination with azacitidine in adult east Asian participants with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).

Detailed description:
The drug being tested in this study is called Pevonedistat. Pevonedistat is being tested to treat people with myelodysplastic syndromes MDS (including nonproliferative chronic myelomonocytic leukemia \[CMML\]) and AML (acute myeloid leukaemia) as a single-agent and in combination treatment with azacitidine. This study will look at the safety and tolerability, the recommended phase 2/phase 3 dose of pevonedistat administered in combination with azacitidine, pharmacokinetics and response to treatment in participants who take single agent pevonedistat compared to participants who take pevonedistat and azacitidine.

The study will enroll approximately 37 participants. Participants will be assigned into one of the four treatment groups which will remain disclosed to the patient and study doctor during the study. Participants will be first enrolled at single-agent low dose level (25 mg/m\^2). If this dose is tolerable, participants will be enrolled in parallel at single-agent higher dose level (44 mg/m\^2) and in combination treatment cohorts.

* Pevonedistat 25 mg/m\^2
* Pevonedistat 44 mg/m\^2
* Pevonedistat 10 mg/m\^2 and azacitidine 75 mg/m\^2 combination
* Pevonedistat 20 mg/m\^2 and azacitidine 75 mg/m\^2 combination Participants will receive pevonedistat infusion intravenously and azacitidine via intravenous or subcutaneous route.

This multi-center trial will be conducted in Japan, Korea and Taiwan. The overall time to participate in this study is approximately 24 months. Participants will attend the End of Study (EOS) visit for safety, 30 days after receiving their last dose of study drug or before the start of subsequent antineoplastic therapy (other than hydroxyurea).

Arms:
arm 1: Pevonedistat, 25 milligram per square meter (mg/m\^2), 60-minute infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in 21-day treatment cycles. arm 2: Pevonedistat, 44 mg/m\^2, 60-minute infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in 21-day treatment cycles. arm 3: Pevonedistat 10 mg/m\^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m\^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles. arm 4: Pevonedistat 20 mg/m\^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m\^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles.

Interventions: intervention 1: Pevonedistat 25 mg/m^2 intervention 2: Pevonedistat 44 mg/m^2 intervention 3: Pevonedistat 10 mg/m^2 intervention 4: Pevonedistat 20 mg/m^2 intervention 5: Azacitidine 75 mg/m^2
Intervention descriptions: intervention 1: Pevonedistat 25 mg/m\^2 intravenous infusion. intervention 2: Pevonedistat 44 mg/m\^2 intravenous infusion. intervention 3: Pevonedistat 10 mg/m\^2 intravenous infusion. intervention 4: Pevonedistat 20 mg/m\^2 intravenous infusion. intervention 5: Azacitidine 75 mg/m\^2 intravenous or subcutaneous formulation.

Protocol document:
Prot_000.pdf: 


Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
Confidential
1
CLINICAL STUDY PROTOCOL PEVONEDISTAT-1012
AMENDMENT 03
Pevonedistat
A Phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as Single Agent and in 
Combination with Azacitidine in Adult East Asian Patients with Acute Myeloid Leukemia (AML) 
or Myelodysplastic Syndromes (MDS)
Protocol Number:
Pevonedistat-1012
Indication:
Acute myeloid leukemia and myelodysplastic syndromes
Phase:
1/1b
Sponsor:
Millennium Pharmaceuticals, Inc.
Therapeutic Area:
Oncology
Protocol History
Original
24 February 2015
Amendment 01
30 October 2015
Amendment 02 
04 February 2016
Amendment 03
23 June 2017
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000
Approved by:
Note: If this document was approved electronically, the electronic approval signatures may be found at the end 
of the document.
Global Clinical Lead
(or designee)
Signature
Date 
Study Clinical Science Lead 
(or designee)
Signature
Date
Program Statistician
(or designee)
Signature
Date
Clinical Pharmacologist
(or designee)
Signature
Date
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Millennium Pharmaceuticals 
and any unauthorized use or disclosure of such information without the prior written authorization of 
Millennium Pharmaceuticals is expressly prohibited.
Property of Tak
Program
Program
(or de
(or d
da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
dromes
rome
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Febru
30 Octo
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Non-C
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ty 


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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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3
15. Clarify that lymphoblasts and myelocytes are included in hematology test measures. 
16. Clarify the percentage increase of bone marrow and circulating blasts in the progressive 
disease definition.
17. Provide additional information on definition of relapse after clinical response.
18. Clarify that for acute myeloid leukemia patients, all complete remission includes both 
complete remission and complete remission with incomplete count recovery.
19. Update the investigator responsibilities for compliance with updated International 
Council for Harmonisation guidelines.
20. Allow the use of moderate and strong cytochrome P450 3A inhibitors during treatment
Cycle 2 and beyond for all study arms. 
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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PROTOCOL SUMMARY
Study Title: A Phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as Single 
Agent and in Combination with Azacitidine in Adult East Asian Patients with Acute Myeloid 
Leukemia (AML) or Myelodysplastic Syndromes (MDS)
Number of Patients: Approximately 37 patients will be enrolled in this study.
Study Objectives
Primary
!
To evaluate safety and tolerability of pevonedistat administered as a single agent in East 
Asian patients with relapsed/refractory (R/R) AML or R/R higher-risk (HR) MDS.
!
To evaluate safety and tolerability and determine the recommended phase 2/phase 3 dose of 
pevonedistat administered in combination with azacitidine in East Asian patients with AML 
or HR MDS.
!
To characterize the pharmacokinetics (PK) of pevonedistat administered as a single agent or 
in combination with azacitidine in East Asian patients.
Secondary
!
To evaluate disease response in both AML and MDS that may be observed with the 
single-agent pevonedistat or with a combination of pevonedistat and azacitidine.
Overview of Study Design:
This is a multicenter, open-label, phase 1/1b dose escalation and expansion study of pevonedistat 
administered intravenously (IV) as a single agent and in combination with azacitidine in 
approximately 37 adult East Asian patients with World Health Organization defined AML or HR 
MDS. Patients will be administered a 60-minute IV infusion of pevonedistat with or without 
azacitidine (administered IV or subcutaneously).
The Single-Agent Arm will include East Asian patients with R/R AML or R/R MDS (including 
nonproliferative chronic myelomonocytic leukemia [CMML]) that meets the Revised International 
Prognostic Scoring System (IPSS-R) criteria for the very high, high, or intermediate risk group 
(higher risk [HR] MDS). Each 21-day treatment cycle includes treatment with pevonedistat (starting 
Property of Takeda
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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6
Combination Arm:
Male and female East Asian patients with AML [1], including leukemia secondary to prior 
chemotherapy or resulting from an antecedent hematologic disorder, who have failed to 
achieve CR or who have relapsed after prior therapy (R/R) and are not candidates for 
potentially curative treatment. Patients are not to have been previously treated with 
azacitidine or decitabine.
Male and female East Asian patients aged 60 years or older with previously untreated AML 
who have bone marrow blasts <30% and who are not candidates for standard induction 
chemotherapy. Patients are not to have been previously treated with azacitidine or decitabine.
Male and female East Asian patients with MDS [2] that meets the IPSS-R criteria for the very 
high, high, or intermediate risk group [3], for whom standard curative, life-prolonging 
treatment does not exist or is no longer effective (R/R). Patients are not to have been 
previously treated with azacitidine or decitabine.
Male and female East Asian patients with previously untreated MDS [2] that meets the 
IPSS-R criteria for the very high, high, or intermediate risk group [3]. Patients are not to have 
been previously treated with azacitidine or decitabine.
Male and female East Asian patients with CMML-2 or CMML-1 that meets the IPSS-R 
criteria for the very high, high, or intermediate risk group [3]; patients with CMML-1 must 
have bone marrow blasts ≥5% [2]. Patients are not to have been previously treated with 
azacitidine or decitabine.
Duration of Study: The estimated total study duration includes 24 months of accrual plus the 
additional follow-up of 10 months after the last patient is enrolled.
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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STUDY OVERVIEW DIAGRAM
Abbreviations: AZA=azacitidine, C=combination, PD=progressive disease, Pev=pevonedistat, S=single-agent.
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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Serial Pharmacokinetic Sample Breakdown - Single-Agent Pevonedistat Arm, Cycle 1
Time
Pharmacokinetic Sampling Schedule
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Predose
Xa
Xb
End of infusionc
X
X
1 hour postinfusiond (±10 min)
X
X
2 hours postinfusiond (±20 min)
X
X
4 hours postinfusiond (±30 min)
X
X
6 hours postinfusiond (±30 min)
X
X
10 hours postinfusiond (±30 min)
X
X
24 hours postdose (±1 hour)e
X
X
48 hours postdose (±1 hour)e
Xb
X
Abbreviation: IV=intravenous.
a The sample is to be collected within 1 hour before the start of pevonedistat infusion.
b The sample is to be collected within 10 minutes before the start of pevonedistat infusion.
c The sample is to be collected at the end of pevonedistat infusion (immediately before stopping the IV infusion).
d The time of sample collection is to be based on the time of completion of pevonedistat infusion on Day 1 (or Day 5).
e The time of sample collection is to be based on the time of initiation of pevonedistat infusion on Day 1 (or Day 5).
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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the patient’s Baseline values, or to a level considered acceptable by the investigator after discussion with the medical monitor (Section 6.4.1).
b The EOS visit will occur 30 days (+10 days) after the last dose of study drugs or before the start of subsequent antineoplastic therapy (other than 
hydroxyurea), if that occurs sooner.
c If dosing falls on a Monday, the collection window may be extended to collect samples on a previous Friday.
d Vital sign measurements, including body temperature, diastolic and systolic blood pressure, and heart rate will be obtained during the following visits: 
Days 1, 3, and 5 (predose [before pevonedistat infusion] and 1 hour [±10 minutes]); Days 8 and 15; and EOS. A sitting position is preferred for collection 
of vital signs. If a supine position is used, it should be used consistently for the same patient throughout the study. When the timing of vital signs 
assessment coincides with the timing of a blood draw, vital signs will be measured before blood sample collection. Either oral or axial body temperature 
may be used, but the same method for measuring body temperature (oral or axial) should be used consistently for the same patient throughout the study.
e On Day 1 of Cycle 2 and all subsequent treatment cycles, the 12-lead ECGs will be performed before any study drug dosing.
f
Use of moderate and strong CYP3A inhibitors are excluded for 7 days prior to first dose of study drug(s) and during treatment Cycle 1 only for both the 
Single-Agent Arm and the Combination Arm. For treatment Cycle 2 and beyond, the use of moderate and strong CYP3A inhibitors is permitted for both 
the Single-Agent Arm and the Combination Arm. See Section 6.5 for additional details.
g Hematology samples will be collected predose on Days 1, 3, and 5; at the Day 8 (±1 day) and Day 15 (±1 day) visits; and at EOS. On Days 1, 3 and 5, 
samples may be drawn within 24 hours predose. Please note: The sample for WBC count must be drawn before each dose on Days 1, 3, and 5 of each 
cycle. WBC count must be <50,000/µL before administration of pevonedistat; hydroxyurea may be used to control the level of WBC counts to no 
lower than 10,000/µL while on pevonedistat.
h Samples for the full clinical chemistry panel will be collected on Day 1 (predose) of each cycle and at EOS.
i
The select chemistry panel will include the following: blood urea nitrogen, creatinine, lactate dehydrogenase, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase, and alanine aminotransferase. The select chemistry panel will be collected predose (when applicable) on Days 3, 5, and 15 of each cycle. 
In the event of a dose delay, creatinine measurements can be delayed up to 3 days.
j
Urinalysis with microscopic analysis will include assessments of turbidity and color, pH, specific gravity, protein, phosphate, ketones, occult blood, nitrite, 
and leukocytes. These samples will be analyzed locally. See Section 7.4.11 for additional details. 
k SAEs will be entered on the eCRF and also reported to BI Medical, Inc. Serious pretreatment events (occurring before the first dose of any study drug) will 
only be reported to BI Medical, Inc and will not be entered on the eCRF. SAEs should be monitored until they are resolved or are clearly determined to be due 
to a patient’s stable or chronic condition or intercurrent illness(es).
l
Bone marrow aspirates will be collected to assess disease response at Cycle 2 and Cycle 4, within 6 days before the Day 21 visit, provided that the disease 
assessment is available before Day 1 of the following cycle. After Cycle 4, bone marrow assessments will be performed after completion of every third 
cycle (eg, Cycle 7, Cycle 10). Additional bone marrow aspirates may be performed if warranted by changes in peripheral blood counts.
m Only for patients who withdraw from the study for reasons other than disease progression.
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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SCHEDULES OF EVENTS – COMBINATION ARM
Combination Arm (Pevonedistat on Days 1, 3, and 5 in Combination With Azacitidine on Days 1 to 5, 8, and 9 of a 28-day 
Cycle) – Cycle 1
Screen
-inga
Treatment Cycle (28 Days)
EOSb
Week 1
Week 2
Week 3
Week 4
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 6
Day 7
Day 8
Day 9
Day 15
(1 day)
Day 22
(1 day)
Study Drug Administration
Pevonedistat infusionc, d
X
X
X
Azacitidine 
administrationd, e
X (Days 1 through 5, inclusive)
X
X
Procedures
Informed consent
X
Inclusion/exclusion
X
Demographics
X
Complete medical 
history
X
Physical examination 
including neurological 
exam
X
Symptom-directed 
medical history and 
physical exam
Xf
X
X
X
X
Height
X
Weight
X
Xf
ECOG performance 
status
X
Xf
X
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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Combination Arm (Pevonedistat on Days 1, 3, and 5 in Combination With Azacitidine on Days 1 to 5, 8, and 9 of a 28-day 
Cycle) – Cycle 1
Screen
-inga
Treatment Cycle (28 Days)
EOSb
Week 1
Week 2
Week 3
Week 4
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 6
Day 7
Day 8
Day 9
Day 15
(1 day)
Day 22
(1 day)
Vital signsg
X
X
X
X
X
X
X
X
X
X
12-Lead ECGh
X
X
X
X
X
Concomitant 
medications/therapyi
Recorded from the time of the first dose of any study drug through 30 days (+10 days) after the last dose of study drug(s)
Hematologyj
X
Xf
X
X
X
X
X
X
X
X
Coagulationk
X
Full chemistry panell
X
Xf
X
X
X
X
X
X
X
Select chemistry panelm
X
Urinalysis with 
microscopic analysisn
X
Xf
X
X
X
Echocardiogramo
X
Serum pregnancyp
X
Xf
HBV and HCV 
screeningq
X
Serious pretreatment 
events and SAE collection
Serious pretreatment events and SAEs will be recorded from the time the informed consent is signed through 30 days (+10 days) after 
the last dose of study drugs. See Section 10.3 for additional information.
AE collection
Recorded from the first dose of any study drug through 30 days (+10 days) after the last dose of study drug(s)
Blood samples for PKs 
(see Serial 
Pharmacokinetic Sample 
Breakdown -
Pevonedistat+Azacitidine 
Combination Arm)
X
X
X
X
X
X
X
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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Combination Arm (Pevonedistat on Days 1, 3, and 5 in Combination With Azacitidine on Days 1 to 5, 8, and 9 of a 28-day 
Cycle) – Cycle 1
Screen
-inga
Treatment Cycle (28 Days)
EOSb
Week 1
Week 2
Week 3
Week 4
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 6
Day 7
Day 8
Day 9
Day 15
(∀1 day)
Day 22
(∀1 day)
Bone marrow collection:
For disease monitoring, 
cytogenetics, and 
karyotypeu,v
X
X
Xw
For molecular analysisx
X
Site-generated mutation 
report
X
Site-generated 
cytogenetics reportz
X
Abbreviations: AE=adverse event, CYP=cytochrome P450; DME=drug metabolizing enzymes, DNA=deoxyribonucleic acid, ECG=electrocardiogram, 
ECOG=Eastern Cooperative Oncology Group, eCRF=electronic case report form, EOS=End of Study (visit), HBcAb= hepatitis B core antibody, 
HBsAb=hepatitis B surface antibody, HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HCVAb=hepatitis C virus 
antibody, IV=intravenous(ly), miR=microRNA, mRNA=messenger ribonucleic acid, PK=pharmacokinetic, SAE=serious adverse event, WBC=white blood 
cell.
a Screening assessments will be performed within 28 days before the Cycle 1 Day 1 dose of study drugs.
b The EOS visit will occur 30 days (+10 days) after the last dose of study drugs or before the start of subsequent antineoplastic therapy (other than 
hydroxyurea), if that occurs sooner.
c Patients will receive IV pevonedistat at a dose specified in Section 6.3. On Days 1, 3, and 5, when both study drugs are administered, azacitidine will be 
administered first, followed by pevonedistat. The infusion may be slowed or stopped and restarted for any associated infusion-related reactions. See 
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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Combination Arm (Pevonedistat on Days 1, 3, and 5 in Combination With Azacitidine on Days 1 to 5, 8, and 9 of a 28-day 
Cycle) – Cycle 1
Screen
-inga
Treatment Cycle (28 Days)
EOSb
Week 1
Week 2
Week 3
Week 4
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 6
Day 7
Day 8
Day 9
Day 15
(1 day)
Day 22
(1 day)
Section 6.1 for details of study drug administration.
d If required by local regulations or local clinical guidelines or preferred by the investigator, study drugs and protocol assessments may be administered in an 
in-patient setting during Cycle 1. For patients in Japan only, the full chemistry, hematology, and coagulation laboratory evaluations will be performed on the 
day the patient is discharged from the hospital.
e During Cycle 1, azacitidine 75 mg/m2 will be administered IV on Days 1 through 5 (inclusive), 8, and 9. The dose of azacitidine may be reduced due to 
toxicities in accordance with Section 6.4.2.1 and Section 6.4.3.1. On Days 1, 3, and 5, when both drugs are administered, azacitidine will be administered first, 
followed by pevonedistat. Every effort should be made to administer study drug(s) around the same time of the day. See Section 6.1 for details of study drug
administration.
f
Except for measurement of WBC count, procedures conducted during the Screening period that are performed within 24 hours of Cycle 1 Day 1 can also be 
used as the Baseline evaluation and do not need to be repeated. If dosing falls on a Monday, the collection window may be extended to collect samples on a 
previous Friday.
g Vital sign measurements, including body temperature, diastolic and systolic blood pressure, and heart rate, will be obtained during Screening; on all dosing 
days (predose [before pevonedistat infusion] and 1 hour [±10 minutes] after the completion of pevonedistat infusion); Day 15; at EOS, and as clinically 
indicated. The Day 1 vital sign measurements will be taken before the azacitidine infusion, before the pevonedistat infusion, and 30 minutes, 1 hour, 4 hours, 
and 6 hours after the pevonedistat infusion. On dosing days when azacitidine is administered alone, an assessment of vital signs will be made predose and 
1 hour (10 minutes) postdose. On Days 3 and 5 (when both pevonedistat and azacitidine are administered), an assessment of vital signs will be made before 
the azacitidine dose, before the pevonedistat infusion, and 1 hour (5 minutes) after completion of the pevonedistat infusion. At predose and 1 hour after 
completion of pevonedistat administration on Day 1, orthostatic blood pressure and heart rate measurements will be taken with the patient in a supine 
position and then standing, after waiting approximately 3 to 4 minutes. At all other time points, a sitting position is preferred for collection of vital signs. If a 
supine position is used, it should be used consistently for the same patient throughout the study. When the timing of vital signs assessment coincides with the 
timing of a blood draw, vital signs will be measured before blood sample collection. Either oral or axial body temperature may be used, but the same method 
for measuring body temperature (oral or axial) should be used consistently for the same patient throughout the study.
h A 12-lead ECG will be performed during Screening and on Cycle 1 Day 1 predose (before azacitidine dosing), immediately after the infusion of pevonedistat 
is complete (up to10 minutes), and 6 hours (1 hour) after the infusion of pevonedistat is complete. On Days 3 and 5, 12-lead ECGs will be performed before 
pevonedistat dosing as well as 30 minutes (5 minutes) and 90 minutes (5 minutes) after the start of pevonedistat infusion.
i
Use of moderate and strong CYP3A inhibitors are excluded for 7 days prior to first dose of study drug(s) and during treatment Cycle 1 only for both the 
Single-Agent Arm and the Combination Arm. For treatment Cycle 2 and beyond, the use of moderate and strong CYP3A inhibitors is permitted for both 
the Single-Agent Arm and the Combination Arm. See Section 6.5 for additional details.
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
Confidential
20
Combination Arm (Pevonedistat on Days 1, 3, and 5 in Combination With Azacitidine on Days 1 to 5, 8, and 9 of a 28-day 
Cycle) – Cycle 1
Screen
-inga
Treatment Cycle (28 Days)
EOSb
Week 1
Week 2
Week 3
Week 4
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 6
Day 7
Day 8
Day 9
Day 15
(∀1 day)
Day 22
(∀1 day)
j
Hematology samples will be collected during Screening; before infusion with study drug(s) on Days 1, 2, 3, 5, and 8 (∀1 day); Day 15 (∀1 day); Day 22 
(∀1 day); and at the EOS visit. On Days 1, 3, and 5, samples can be drawn within 24 hours predose. Please note: The sample for WBC count must be 
drawn before each dose on Days 1, 3, and 5 of Cycle 1. WBC count must be #50,000/μL before administration of pevonedistat; hydroxyurea may be 
used to control the level of WBC counts to no lower than 10,000/μL while on pevonedistat. An additional sample will be taken on Cycle 1 Day 1 at 
4 hours after the completion of pevonedistat infusion.
k Coagulation panel at Screening includes prothrombin time (international normalized ratio) and activated partial thromboplastin time.
l
Samples for the full clinical chemistry panel will be collected during Screening; Cycle 1 Days 1, 3, 5, 8, (∀1 day), 15 (∀1 day), and 22 (∀1 day) predose where 
applicable; and EOS. In addition, samples will be taken on Day 1 at 4 hours after infusion with pevonedistat.
m The select chemistry panel will be collected on Day 2 and will include the following: blood urea nitrogen, creatinine, lactate dehydrogenase, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. In the event of a dose delay, creatinine measurements can be delayed up to 
3 days.
n Urinalysis with microscopic analysis will include assessments of turbidity and color, pH, specific gravity, protein, phosphate, ketones, occult blood, nitrite, 
and leukocytes. These samples will be analyzed locally. See Section 7.4.11 for additional details. 
o Echocardiogram or multiple-gated acquisition scan will be used to assess left ventricular ejection fraction.
p A serum pregnancy test will be performed for women of childbearing potential during Screening and predose Cycle 1. The results must be available and 
negative before the first dose of pevonedistat is administered.
q HBV and HCV screening may be conducted any time during the Screening period. HBV screening may include testing for HBsAg, HBsAb, HBcAb, or HBV 
viral load, as appropriate and per local institutional guidelines. HCV screening may include testing for anti-HCV antibody and viral load, as appropriate and 
per local institutional guidelines. Patients, who are HBsAg negative, and HBsAb and/or HBcAb positive, and/or HCVAb positive with negative viral load at 
screening will be monitored by assessment of viral load (HBV-DNA; HCV-RNA) as needed and based on local institutional guidelines.
r
SAEs will be entered on the eCRF and also reported to BI Medical, Inc. Serious pretreatment events (occurring before the first dose of any study drug) will 
only be reported to BI Medical, Inc and will not be entered on the eCRF. SAEs should be monitored until they are resolved or are clearly determined to be due 
to a patient’s stable or chronic condition or intercurrent illness(es).
s Blood samples (approximately 3 mL each) for determination of plasma concentrations of pevonedistat will be collected from all patients in the Combination 
Arm during Cycle 1 at prespecified time points. A total of ~54 mL of blood will be drawn for PK analyses.
t
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Serial Pharmacokinetic Sample Breakdown - Pevonedistat+Azacitidine Combination Arm, Cycle 1
Time
Pharmacokinetic Sampling Schedule
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Predose
X a
X b
End of infusionc
X
X
1 hour postinfusiond (±10 min)
X
X
2 hours postinfusiond (±20 min)
X
X
4 hours postinfusiond (±30 min)
X
X
6 hours postinfusiond (±30 min)
X
X
10 hours postinfusiond (±30 min)
X
X
24 hours postdose (±1 hour)e
Xb
X
48 hours postdose (±1 hour)e
Xb
X
Abbreviation: IV=intravenous.
a The sample is to be collected within 1 hour before the start of pevonedistat infusion and before azacitidine administration.
b The sample is to be collected within 10 minutes before the start of azacitidine administration.
c The sample is to be collected at the end of pevonedistat infusion (immediately before stopping the IV infusion).
d The time of sample collection is to be based on the time of completion of pevonedistat infusion on Day 1 (or Day 5).
e The time of sample collection is to be based on the time of initiation of pevonedistat infusion on Day 1 (or Day 5).
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Combination Arm (Pevonedistat on Days 1, 3, and 5 in Combination With Azacitidine on Days 1 to 5, 8 and 9 of a 28-day 
Cycle) – Cycle 2 and Beyond
Treatment Cycle (28 Days)a
Day 24
(4 days)
EOSb
Week 1
Week 2
Week 3 
Day 1
Predose
Day 1
Postdose
Day 3
Day 5
Day 8
(1 day)d
Day 9
(1 day)d
Day 15
(1 day)
Study Drug Administration
Pevonedistat infusionc
X
X
X
Azacitidine administrationd
X (Days 1 through 5, inclusive)
X
X
Procedures
Symptom-directed medical history 
and physical exam
Xf
Xe
X
X
Weight
Xf
ECOG performance status
Xf
X
Vital signsg
X
X
X
X
X
X
X
12-Lead ECGh
X
Concomitant medications/ therapyi
Recorded from the time of the first dose of any study drug through 30 days (+10 days) after the last dose of study 
drug(s)
Hematologyj
Xf
X
X
X
X
X
Full chemistry panelk
Xf
X
Select chemistry panell
X
X
X
Blood phosphate
X
Urinalysis with microscopic analysism
Xf
Bone marrow aspirate for disease 
monitoringn
X
Xo
Serious pretreatment events and SAE 
collectionp
Recorded from the time the informed consent is signed through 30 days (+10 days) after the last dose of study drugs. 
See Section 10.3 for additional information.
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Combination Arm (Pevonedistat on Days 1, 3, and 5 in Combination With Azacitidine on Days 1 to 5, 8 and 9 of a 28-day 
Cycle) – Cycle 2 and Beyond
Treatment Cycle (28 Days)a
Day 24
(4 days)
EOSb
Week 1
Week 2
Week 3 
Day 1
Predose
Day 1
Postdose
Day 3
Day 5
Day 8
(1 day)d
Day 9
(1 day)d
Day 15
(1 day)
AE collection
Recorded from the first dose of any study drug through 30 days (+10 days) after the last dose of study drug(s)
Abbreviations: AE=adverse event, CYP=cytochrome P450; ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, eCRF=electronic case 
report form, EOS=End of Study (visit), IV=intravenous(ly), SAE=serious adverse event; WBC=white blood cell.
a For a new cycle of treatment with study drugs to begin, toxicities considered to be related to treatment with study drugs must have resolved to ≤Grade 1, to 
the patient’s Baseline values, or to a level considered acceptable by the investigator after discussion with the medical monitor (Section 6.4.1).
b The EOS visit will occur 30 days (+10 days) after the last dose of study drug(s) or before the start of subsequent antineoplastic therapy (other than 
hydroxyurea), if that occurs sooner.
c Patients will receive IV pevonedistat at a dose specified in Section 6.3. On Days 1, 3, and 5, when both study drugs are administered, azacitidine will be 
administered first, followed by pevonedistat. The infusion may be slowed or stopped and restarted for any associated infusion-related reactions. See 
Section 6.1 for details of study drug administration.
d Azacitidine 75 mg/m2 may be administered IV or subcutaneously (per investigator’s choice) on Days 1 through 5 (inclusive), 8, and 9 of each cycle. The 
dose of azacitidine may be reduced due to toxicities in accordance with Section 6.4.2.1 and Section 6.4.3.1. On Days 1, 3, and 5, when both drugs are 
administered, azacitidine will be administered first, followed by pevonedistat. Every effort should be made to administer study drug(s) around the same time 
of the day. See Section 6.1 for details of study drug administration.
e For patients who achieve complete remission, Day 8 physical examination is not necessary.
f
If dosing falls on a Monday, the collection window may be extended to collect samples on a previous Friday.
g Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature, will be collected on all dosing days in all cycles, at EOS, and as 
clinically indicated. On dosing days when azacitidine is administered alone, an assessment of vital signs will be made predose and 1 hour (5 minutes) 
postdose. On dosing days when both pevonedistat and azacitidine are administered, an assessment of vital signs will be made before the azacitidine infusion, 
before the pevonedistat infusion, and 1 hour (5 minutes) after completion of the pevonedistat infusion. A sitting position is preferred for collection of vital 
signs. If a supine position is used, it should be used consistently for the same patient throughout the study. When the timing of vital signs assessment 
coincides with the timing of a blood draw, vital signs will be measured before blood sample collection. Either oral or axial body temperature may be used, 
but the same method for measuring body temperature (oral or axial) should be used consistently for the same patient throughout the study.
h On Day 1 of Cycle 2 and all subsequent treatment cycles, the 12-lead electrocardiograms will be performed before any study drug infusion.
i
Use of moderate and strong CYP3A inhibitors are excluded for 7 days prior to first dose of study drug(s) and during treatment Cycle 1 only for both the 
Single-Agent Arm and the Combination Arm. For treatment Cycle 2 and beyond, the use of moderate and strong CYP3A inhibitors is permitted for both 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
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25
Combination Arm (Pevonedistat on Days 1, 3, and 5 in Combination With Azacitidine on Days 1 to 5, 8 and 9 of a 28-day 
Cycle) – Cycle 2 and Beyond
Treatment Cycle (28 Days)a
Day 24
(4 days)
EOSb
Week 1
Week 2
Week 3 
Day 1
Predose
Day 1
Postdose
Day 3
Day 5
Day 8
(1 day)d
Day 9
(1 day)d
Day 15
(1 day)
the Single-Agent Arm and the Combination Arm. See Section 6.5 for additional details.
j
Hematology samples will be collected before infusion with study drug(s) during Cycle 2 on Days 1, 3, and 5; Day 8 (1 day); Day 15 (1 day); and at the 
EOS visit. On Days 1, 3, and 5, samples can be drawn within 24 hours predose. Please note: The sample for WBC count must be drawn before each 
dose on Days 1, 3, and 5 of each cycle. WBC count must be <50,000/µL before administration of pevonedistat; hydroxyurea may be used to control 
the level of WBC counts to no lower than 10,000/µL while on pevonedistat.
k Samples for the full clinical chemistry panel will be collected before infusion with study drugs on Day 1 and at the EOS visit. On Day 1, samples can be 
drawn within 24 hours predose. For Day 1 dosing only: if dosing falls on a Monday, the collection window may be extended to collect samples on the 
previous Friday.
l
The select chemistry panel will include the following: blood urea nitrogen, creatinine, lactate dehydrogenase, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase, and alanine aminotransferase. The select chemistry panel will be collected predose (when applicable) on Days 3, 5, and 15 of each cycle. 
On Days 3 and 5, samples can be drawn within 24 hours predose. In the event of a dose delay, creatinine measurements can be delayed up to 3 days.
m Urinalysis with microscopic analysis will include assessments of turbidity and color, pH, specific gravity, protein, phosphate, ketones, occult blood, nitrite, 
and leukocytes. These samples will be analyzed locally. See Section 7.4.11 for additional details. 
n Bone marrow aspirates will be collected to assess disease response at Cycle 2 and Cycle 4, any time between Days 20 and 28, provided that the disease 
assessment is available before Day 1 of the following cycle. After Cycle 4, bone marrow assessments will be performed after completion of every third 
cycle (eg, Cycle 7, Cycle 10). Additional bone marrow aspirates may be performed if warranted by changes in peripheral blood counts.
o Only for patients who withdraw from the study for reasons other than disease progression.
p SAEs will be entered on the eCRF and also reported to BI Medical, Inc. SAEs should be monitored until they are resolved or are clearly determined to be 
due to a patient’s stable or chronic condition or intercurrent illness(es). Serious pretreatment events (occurring before the first dose of any study drug) will 
only be reported to BI Medical, Inc and will not be entered on the eCRF.
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26
TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................29
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................30
1. BACKGROUND AND STUDY RATIONALE..............................................................33
1.1 Scientific Background ..............................................................................................33
1.1.1 Diseases Under Treatment .................................................................................33
1.1.2 Pevonedistat.......................................................................................................34
1.2 Nonclinical Experience.............................................................................................35
1.2.1 Single-Agent Pevonedistat .................................................................................35
1.2.2 Pevonedistat With Azacitidine ...........................................................................36
1.3 Clinical Experience ..................................................................................................37
1.4 Pharmacokinetics of Pevonedistat.............................................................................38
1.4.1 Nonclinical PK and Risk Assessment for Drug-Drug Interactions ......................38
1.4.2 Clinical PK ........................................................................................................39
1.5 Study Rationale ........................................................................................................40
1.5.1 Rationale for Dose and Schedule........................................................................40
1.5.2 Rationale for the Combination of Pevonedistat+Azacitidine...............................41
1.5.3
...............42
1.6 Potential Risks and Benefits .....................................................................................43
1.6.1 Single-Agent Pevonedistat .................................................................................43
1.6.2 Azacitidine.........................................................................................................45
1.6.3 Pevonedistat+Azacitidine...................................................................................47
1.6.4 Potential for DDIs..............................................................................................48
2. STUDY OBJECTIVES ..................................................................................................49
2.1 Primary Objectives...................................................................................................49
2.2 Secondary Objective.................................................................................................49
2.3 
.............................................................................................49
3. STUDY ENDPOINTS....................................................................................................50
3.1 Primary Endpoints....................................................................................................50
3.2 Secondary Endpoints................................................................................................50
3.3 
..............................................................................................50
4. STUDY DESIGN...........................................................................................................51
4.1 Overview of Study Design........................................................................................51
4.2 Number of Patients...................................................................................................53
4.3 Duration of Study.....................................................................................................53
5. STUDY POPULATION.................................................................................................54
5.1 Inclusion Criteria......................................................................................................54
5.2 Exclusion Criteria.....................................................................................................57
6. STUDY DRUG..............................................................................................................59
6.1 Study Drug Administration.......................................................................................59
6.1.1 Single-agent Pevonedistat Arm ..........................................................................60
6.1.2 Pevonedistat+Azacitidine Combination Arm – Azacitidine Dosing....................60
6.2 Definitions of Dose-Limiting Toxicity......................................................................60
6.3 Dose Escalation Rules ..............................................................................................62
6.4 Dose Modification Guidelines ..................................................................................63
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
Confidential
27
6.4.1 Criteria for Retreatment and Dose Delays ..........................................................63
6.4.2 Dose Modification for Hematologic Toxicities...................................................64
6.4.3 Dose Modification for Nonhematologic Toxicities.............................................66
6.5 Excluded Concomitant Medications and Procedures.................................................67
6.6 Permitted Concomitant Medications and Procedures.................................................69
6.7 Precautions and Restrictions.....................................................................................70
6.8 Management of Clinical Events................................................................................71
6.8.1 Leukostasis in Patients Receiving Pevonedistat..................................................71
6.8.2 Hemodynamic Compromise in Patients Receiving Pevonedistat.........................72
6.8.3 Hepatotoxicity in Patients Receiving Pevonedistat .............................................72
6.8.4 Hematologic Toxicity in Patients Receiving Pevonedistat ..................................73
6.8.5 Extravasation .....................................................................................................73
6.9 Blinding and Unblinding ..........................................................................................73
6.10 Description of Investigational Agents.....................................................................73
6.10.1 Pevonedistat.....................................................................................................73
6.10.2 Azacitidine.......................................................................................................74
6.11 Preparation, Reconstitution, and Dispensation ........................................................74
6.12 Packaging and Labeling..........................................................................................74
6.13 Storage, Handling, and Accountability....................................................................74
7. STUDY CONDUCT ......................................................................................................75
7.1 Study Personnel and Organizations...........................................................................75
7.2 Arrangements for Recruitment of Patients ................................................................75
7.3 Treatment Arm Assignments ....................................................................................75
7.4 Study Procedures......................................................................................................76
7.4.1 Informed Consent ..............................................................................................76
7.4.2 Patient Demographics ........................................................................................76
7.4.3 Medical History.................................................................................................76
7.4.4 Physical Examination.........................................................................................77
7.4.5 Patient Height ....................................................................................................77
7.4.6 Patient Weight ...................................................................................................77
7.4.7 ECOG Performance Status.................................................................................77
7.4.8 Vital Signs .........................................................................................................77
7.4.9 Electrocardiogram..............................................................................................77
7.4.10 Concomitant Medications and Procedures........................................................77
7.4.11 Clinical Laboratory Evaluations.......................................................................78
7.4.12 Echocardiogram...............................................................................................79
7.4.13 Pregnancy Test.................................................................................................79
7.4.14 Hepatitis Testing..............................................................................................80
7.4.15 Adverse Events................................................................................................80
7.4.16 Enrollment .......................................................................................................80
7.4.17 Pharmacokinetic Measurements.......................................................................81
7.4.18
....................................81
7.4.19 Disease Assessment .........................................................................................83
7.4.20 Bone Marrow Aspirate and Biopsy Collection for Disease Assessment and 
Molecular Analyses.....................................................................................87
7.5 Study Compliance ....................................................................................................88
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
Confidential
28
7.6 Completion of Treatment..........................................................................................88
7.7 Discontinuation of Treatment With Study Drug and Patient Replacement.................89
7.7.1 Patient Replacement: .........................................................................................89
7.8 Withdrawal of Patients From Study..........................................................................89
7.9 Completion of Study.................................................................................................90
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................90
8.1 Statistical Methods ...................................................................................................90
8.1.1 Determination of Sample Size............................................................................90
8.1.2 Randomization and Stratification .......................................................................91
8.1.3 Populations for Analysis ....................................................................................91
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................91
8.1.5 Demographic and Baseline Characteristics.........................................................91
8.1.6 Efficacy Analysis...............................................................................................92
8.1.7 Pharmacokinetics 
......................................................................92
8.1.8 Safety Analysis ..................................................................................................93
8.1.9 Interim Analysis.................................................................................................94
8.2 Pharmacokinetic Modeling .......................................................................................94
9. STUDY COMMITTEES................................................................................................95
9.1 Independent Data Monitoring Committee.................................................................95
10. ADVERSE EVENTS ...................................................................................................95
10.1 Definitions..............................................................................................................95
10.1.1 Pretreatment Event Definition..........................................................................95
10.1.2 Adverse Event Definition.................................................................................95
10.1.3 Serious Adverse Event Definition ....................................................................96
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................97
10.3 Monitoring of Adverse Events and Period of Observation.......................................98
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events........99
11. ADMINISTRATIVE REQUIREMENTS .....................................................................99
11.1 Good Clinical Practice............................................................................................99
11.2 Data Quality Assurance ........................................................................................100
11.3 Electronic Case Report Form Completion.............................................................100
11.4 Study Monitoring .................................................................................................100
11.5 Ethical Considerations..........................................................................................101
11.6 Patient Information and Informed Consent............................................................101
11.7 Patient Confidentiality..........................................................................................101
11.8 Investigator Compliance.......................................................................................101
11.9 On-site Audits ......................................................................................................102
11.10 Investigator and Site Responsibility for Drug Accountability..............................102
11.11 Product Complaints ............................................................................................102
11.12 Closure of the Study ...........................................................................................103
11.13 Record Retention................................................................................................103
12. USE OF INFORMATION..........................................................................................104
13. INVESTIGATOR AGREEMENT..............................................................................105
14. REFERENCES...........................................................................................................106
15. APPENDICES ...........................................................................................................110
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
Confidential
29
15.1 Revised International Prognostic Scoring System for MDS...................................110
15.2 Eastern Cooperative Oncology Group Scale for Performance Status.....................111
15.3 Cockcroft-Gault Equation.....................................................................................111
15.4 New York Heart Association Classification of Cardiac Disease............................112
15.5 Excluded CYP3A Inhibitors and Inducers.............................................................113
15.5.1 Classification of CYP3A Inhibitors................................................................113
15.5.2 Classification of CYP3A Inducers..................................................................114
15.6 Body Surface Area Calculation.............................................................................114
15.7 3+3 Dose Escalation and Expansion Flowchart.....................................................115
15.8 Absolute Neutrophil Count Calculation ................................................................117
15.9 Definition of Postmenopausal...............................................................................118
15.10 Methods of Contraception Considered to be Effective.........................................119
15.11 Amendment 01 Rationale and Purposes ..............................................................121
15.12 Amendment 02 Rationale and Purposes ..............................................................124
15.13 Amendment 03 Detailed Summary of Changes...................................................125
LIST OF TABLES
Table 6.a
Planned Dose Levels...................................................................................63
Table 6.b 
Azacitidine Dose Adjustment Based on Hematology Laboratory Value Nadir 
Counts.........................................................................................................65
Table 6.c 
Azacitidine Dose Adjustment Based on Bone Marrow Aspirate Cellularity.65
Table 6.d 
Concomitant Medications Excluded During the Study.................................68
Table 6.e 
Permitted Concomitant Medications and Procedures ...................................69
Table 7.a 
Modified IWG Response Criteria for Altering Natural History of MDS ......85
Table 7.b 
Response Criteria for Hematologic Improvement ........................................87
Table 15.a 
IPSS-R Prognostic Score Values ...............................................................110
Table 15.b 
110
Table 15.c 
IPSS-R Prognostic Risk Categories/Scores................................................111
Table 15.d 
In Vivo Inhibitors of CYP3A ....................................................................113
Table 15.e 
In Vivo Inducers of CYP3A......................................................................114
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Pevonedistat (MLN4924, TAK-924)
Clinical Study Protocol Pevonedistat-1012 Amendment 03
Confidential
30
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC24
area under the plasma concentration-time curve from the time 0 to 24 hours
AUC∞
area under the plasma concentration-time curve from 0 to infinity
AUClast
area under the plasma concentration-time curve from 0 to the last measurable 
concentration
AUCτ
area under the plasma concentration-time curve during a dosing interval, where tau (τ) 
is the length of the dosing interval.
BCRP
breast cancer resistance protein
BSA
body surface area
BUN
blood urea nitrogen
CDL
cullin-dependent ubiquitin E3 ligase
Cdt-1
chromatin-licensing and DNA-replication factor-1
CL
clearance
Cmax
single-dose maximum (peak) concentration
CMML
chronic myelomonocytic leukemia
CR
complete remission
CRi
complete remission with incomplete blood count recovery
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DDI
drug-drug interactions
DLT
dose-limiting toxicity
DME
drug metabolizing enzyme
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
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Abbreviation
Term
eCRF
electronic case report form
EDC
electronic data capture
EOS
End of Study (visit)
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
hERG
human ether-à-go-go related gene
HI
hematologic improvement
HIV
human immunodeficiency virus
HR
higher-risk
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IPSS-R
Revised International Prognostic Scoring System
IRB
institutional review board
IV
intravenous(ly)
IWG
International Working Group
LDH
lactate dehydrogenase
LFT
liver function test
LVEF
left ventricular ejection fraction
MDS
myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
miR
microRNA
MLN4924
research name of pevonedistat hydrochloride; TAK-924
mRNA
messenger ribonucleic acid
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Abbreviation
Term
MTD
maximum tolerated dose
NAE
NEDD8 activating enzyme
NCI
National Cancer Institute
NEDD8
neural precursor cell expressed developmentally down-regulated protein 8
NFE2
nuclear factor erythroid 2
Nrf2
NFE2-related factor 2
OATP
organic anion-transporting polypeptide
ORR
overall response rate
PD
progressive disease (disease progression)
P-gp
P-glycoprotein
PI
prescribing information
PK
pharmacokinetic(s)
PR
partial remission
RBC
red blood cell
R/R
relapsed/refractory
SAE
serious adverse event
SC
subcutaneous
t1/2
terminal disposition half-life
Tmax
single-dose first time of occurrence of maximum (peak) concentration
ULN
upper limit of the normal range
US
United States
USP
United States Pharmacopeia
Vss
volume of distribution at steady-state
WBC
white blood cell
WHO
World Health Organization
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1.
BACKGROUND AND STUDY RATIONALE
1.1
Scientific Background
1.1.1
Diseases Under Treatment
1.1.1.1
Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a type of cancer that affects myeloid cells. AML 
encompasses a family of hematologic malignancies that can be categorized according to 
their cytogenetic and associated genetic abnormalities, which have major prognostic 
importance. For both Western and Asian populations, the majority of patients with AML are 
older than 60 years of age [4-6]; approximately 35% of patients with newly diagnosed AML 
are 75 years of age or older [7].
Treatment of AML requires initial induction chemotherapy with the goal of achieving 
complete remission (CR) with resolution of morphologically detectable disease and 
restoration of normal blood counts. This is followed by post-remission therapy to eradicate 
minimal residual disease. Both chemotherapy and allogeneic stem cell transplantation have 
been used, and each approach plays a significant role. Intensive combination chemotherapy 
usually includes cytarabine (also referred to as Ara-C) and anthracyclines with a CR rate 
between 45% and 60% (60% to 70% among younger patients) [8]. Stem cell transplantation 
has a greater antileukemia effect but is associated with a higher risk of treatment-related 
morbidity and mortality.
Although patients diagnosed with AML may initially experience relatively high CR rates, 
fewer than 25% of elderly AML patients live for 5 years, because most relapse with resistant 
disease [6,9]; cure of AML occurs only in a minority of patients with the available forms of 
chemotherapy [10].
1.1.1.2
Myelodysplastic Syndromes
Myelodysplastic Syndromes (MDS) are biologically and clinically heterogeneous 
hematopoietic disorders derived from an abnormal multipotent progenitor cell. Like AML, 
MDS occurs more frequently among the elderly; among Japanese patients, the median age at 
diagnosis is 76 years [11]. MDS can be classified as lower-risk or higher-risk (HR) based on 
life expectancy and the likelihood of progression to AML. Median survival for patients with 
MDS varies from years to months and decreases with increasing risk classification.
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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, and decrease progression to AML. Treatment 
guidelines in Asia generally follow the National Comprehensive Cancer Network guidelines 
[12], and options vary based on an assessment of risk [3]. Although supportive care 
(eg, antibiotics as needed for infections, red blood cell [RBC] transfusions) may be the sole 
treatment for patients with lower-risk MDS, treatment for patients with higher-risk disease 
often includes hematopoietic growth factor therapy, immunosuppressive therapies, and 
deoxyribonucleic acid (DNA) hypomethylating agents (azacitidine and decitabine). Rarely, 
intensive chemotherapy is used in patients with HR MDS, but it generally results in 
significant toxicity and modest responses 
(uptodate.com/contents/treatment-of-high-or-very-high-risk-myelodysplastic-syndromes, 
Treatment of high or very high risk myelodysplastic syndromes, Accessed 08 December 
2014) [13,14].
Hypomethylating agents produce objective hematologic responses in approximately half of 
MDS patients, including Asian patients [15,16], delay leukemic progression, improve 
quality of life, and–for azacitidine only–prolong survival in MDS patients. Nevertheless, 
treatment with hypomethylating agents is not curative, and most patients relapse within 
2 years. Lenalidomide, an immunomodulatory thalidomide congener, significantly improves 
RBC transfusion-independence rates and increases hemoglobin, but it is approved only for 
use in patients with the 5q syndrome subtype of low-risk MDS [13,14].
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 [17]. 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-syndromes, 
Treatment of high or very high risk myelodysplastic syndromes, Accessed 08 December 
2014) [13,14].
1.1.2
Pevonedistat
Pevonedistat (MLN4924, TAK-924) is a first-in-class small molecule inhibitor of the 
NEDD8 (neural precursor cell expressed developmentally down-regulated protein 
8)-activating enzyme (NAE) that is being developed for the treatment of malignancies. 
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NEDD8-activating enzyme is an E1 activating enzyme and is an essential component of the 
NEDD8 conjugation pathway, which controls the activity of a subset of ubiquitin E3 ligases, 
multiprotein complexes that transfer ubiquitin molecules to protein substrates that are then 
targeted to the proteasome for degradation. Cullin-dependent ubiquitin E3 ligases (CDLs) 
require conjugation to NEDD8 to be activated. Cullin-dependent ubiquitin E3 ligases control 
the timely ubiquitination and consequent proteasomal degradation of proteins with important 
roles in cell cycle progression and signal transduction, cellular processes that are integral to 
tumor cell growth, proliferation, and survival. Inhibitors of NAE activity may be of 
therapeutic value in the treatment of various cancers by disrupting proteasomal degradation 
of a variety of critical regulatory proteins.
1.2
Nonclinical Experience
1.2.1
Single-Agent Pevonedistat
Pevonedistat treatment of cultured tumor cells resulted in growth inhibition of a wide variety 
of cell lines. Changes in protein levels observed in cultured cells treated with pevonedistat 
were consistent with the inhibition of NAE, in particular a decrease in NEDD8-cullin levels 
and a reciprocal increase in the levels of known CDL substrates, including nuclear factor 
erythroid 2 (NFE2)-related factor 2 (Nrf2) and chromatin-licensing and DNA-replication 
factor-1 (Cdt-1). In most cell lines evaluated, NAE inhibition by pevonedistat led to DNA 
re-replication and accumulation of cells in the S phase of the cell cycle; this resulted in DNA 
damage and subsequent cell death through apoptosis [18-20].
Pevonedistat demonstrated pharmacodynamic and antitumor activity in solid tumor, 
lymphoma, and AML xenograft models when administered to immunocompromised mice 
by the subcutaneous (SC) route. Results from testing a variety of AML nonclinical models 
in vitro and in vivo suggest that AML cells are particularly sensitive to pevonedistat (see the 
Investigator’s Brochure [IB] for more details).
In vitro assay results indicated a low risk for human ether-à-go-go related gene (hERG) 
channel inhibition by pevonedistat or its 3 major circulating metabolites. In a Good 
Laboratory Practice (GLP)-compliant cardiovascular safety pharmacology assessment in 
male beagle dogs dosed via intravenous (IV) infusion at 15, 30, or 40 mg/kg (300, 600, or 
800 mg/m2, respectively), pevonedistat was not well tolerated at doses 30 mg/kg. Mortality 
and/or moribundity were observed within 24 hours postdose as a result of gastrointestinal 
injury at 40 mg/kg. In a separate GLP-compliant, 2-cycle, repeat-dose toxicology study in 
dogs, no test article-related effects were noted in the electrocardiogram (ECG) data.
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The systemic toxicity of pevonedistat was assessed in GLP-compliant repeat-dose studies in 
rats and dogs. The dose-limiting toxicities (DLTs) in the 2-cycle studies for both species 
were gastrointestinal toxicity and bone marrow and lymphoid tissue depletion. Most adverse 
effects were resolving or had resolved after a 2-week recovery period. Pevonedistat did not 
result in lethality in either of the 5-cycle studies. The primary adverse test article-related 
effects in IV-dosed dogs included an acute phase response (increased body temperature, 
decreased albumin, increased globulin, increased monocytes and neutrophils, and increased 
fibrinogen levels); neutrophilic infiltrates in multiple tissues; and in males, vacuolation and 
degeneration of the seminiferous epithelium of the testes. Most adverse effects were 
reversing or had reversed after a 2-week recovery period in both rats and dogs. Given that 
there were prominent effects on testes and ovaries noted at all doses tested in the 
GLP-compliant repeat-dose toxicology studies in both dogs and rats, pevonedistat likely 
represents a substantial reproductive and developmental hazard.
Detailed information regarding the nonclinical pharmacology and toxicology of pevonedistat
may be found in the IB.
1.2.2
Pevonedistat With Azacitidine
The combination of pevonedistat with azacitidine demonstrated synergistic or additive 
effects on viability of AML cell lines treated in vitro. Combination index analysis 
demonstrated synergy of pevonedistat with azacitidine in 2 AML cell lines (OCI-M2 and 
NB-4) and additivity in 2 additional AML cell lines (THP-1 and HL-60). The combination 
of pevonedistat and azacitidine in HL-60 and OCI-M2 cell lines resulted in increased DNA 
damage (measured by phospho-H2AX) and apoptosis (measured by cleaved caspase-3) 
compared to the levels of these markers induced by single-agent pevonedistat or azacitidine.
The benefit of the combination of pevonedistat with azacitidine was confirmed in vivo with 
immunocompromised mice bearing HL-60, OCI-M2, and THP-1 subcutaneous tumor 
xenografts. Pevonedistat in combination with azacitidine demonstrated additive or 
synergistic antitumor activity and tumor regression in all 3 subcutaneous xenograft models, 
which represent both azacitidine-sensitive (OCI-M2) and azacitidine-insensitive (HL-60 and 
THP-1) models. In OCI-M2, azacitidine and pevonedistat as single agents inhibited tumor 
growth, but the combination of these agents resulted in tumor regressions with a statistical 
assessment of synergy. In THP-1, although pevonedistat as a single agent inhibited tumor 
growth without causing regressions and azacitidine as a single agent had only a marginal 
effect on tumor growth, the combination caused regressions and delayed tumor regrowth 
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following the treatment period. In HL-60, tumor regressions were seen with the combination 
of pevonedistat and azacitidine at dose levels that had minimal or moderate antitumor 
activity as single agents. Furthermore, in a disseminated xenograft model in which 
HL-60 cells were inoculated into immunocompromised mice by IV injection, pevonedistat 
and azacitidine as single agents both extended survival time compared to a control group, 
but the combination extended survival time longer than would be expected from an additive 
combination, thereby demonstrating a synergistic effect on survival.
Detailed information regarding the nonclinical pharmacology and toxicology of pevonedistat 
may be found in the IB.
1.3
Clinical Experience
As of 22 January 2015, approximately 350 patients diagnosed with advanced malignancies 
including solid tumors, AML, melanoma, lymphoma, multiple myeloma, HR MDS, and 
acute lymphoblastic leukemia (ALL) have been enrolled in the overall clinical development 
program. Among these indications, pevonedistat has reported single-agent clinical activity in 
a phase 1 study (Study C15003) in relapsed/refractory (R/R) AML patients. In 
Study C15003, responses (complete remissions and partial remissions) were observed in a 
variety of patient settings, including postallogeneic transplant, therapy-related AML, and 
primary refractory AML [21]. In addition, a combination with azacitidine is currently being 
investigated in elderly patients with treatment-naïve AML; combination treatments in 
patients with solid tumors are also being investigated with docetaxel, gemcitabine, and a 
combination of carboplatin and paclitaxel.
Study C15009 is currently evaluating the combination of escalating doses of pevonedistat on 
Days 1, 3, and 5 with 75 mg/m2 azacitidine administered (IV or SC) on a 5-on/2-off 
(weekend)/2-on schedule in 28-day cycles in treatment-naïve AML patients, aged ≥60 years, 
who are unlikely to benefit from standard induction therapy [22]. As of 22 January 2015, 
data are available for 42 patients enrolled in Study C15009 who received at least 1 dose of 
pevonedistat in combination with azacitidine; these patients had completed a total of 
approximately 170 cycles. In the dose escalation cohorts, 6 patients received 20 mg/m2
pevonedistat, and 3 patients received 30 mg/m2. The maximum tolerated dose (MTD) was 
determined to be 20 mg/m2 pevonedistat given on Days 1, 3, and 5 in combination with 
75 mg/m2 azacitidine given on Days 1 through 5, 8, and 9, in 28-day treatment cycles. The 
DLTs supporting this determination were elevations in LFTs (please refer to the IB for 
additional information regarding DLTs in Study C15009). The most common adverse events 
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(AEs), reported by ≥25% of patients, were constipation, febrile neutropenia, anemia, 
decreased appetite, thrombocytopenia, and fatigue. Additional preliminary safety 
information from Study C15009 is provided in Section 1.6.3. The nature and frequency of 
the reported toxicities (excluding DLTs) were similar to previous reports for azacitidine 
alone. Preliminary pharmacokinetic (PK) data showed that addition of azacitidine did not 
alter the known PK profile of single-agent pevonedistat.
In Study C15009, a total of 13 patients experienced partial remission or better; 5 patients 
had a best response of complete remission, and 8 patients had a best response of partial 
remission as of the data cutoff of 22 January 2015. Combination therapy with pevonedistat 
and azacitidine was generally well tolerated. The characteristics of the observed responses 
suggest an added benefit from the addition of pevonedistat compared with azacitidine alone.
1.4
Pharmacokinetics of Pevonedistat
1.4.1
Nonclinical PK and Risk Assessment for Drug-Drug Interactions
The absorption, distribution, metabolism, and excretion properties of pevonedistat have been 
studied in Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and chimpanzees. The 
whole blood clearance (CL) is low in all animal species, likely as a result of the extensive 
partitioning of pevonedistat into RBCs. The plasma terminal disposition half-life (t1/2) varied 
from short (less than 1 hour in rats) to relatively long (15 hours in monkeys). The major 
elimination pathway of pevonedistat in animals is through the hepatic route. Urinary 
excretion of unchanged pevonedistat was negligible (<5%) in rats and primates. After an IV 
dose of [14C] pevonedistat, radioactivity was primarily excreted in the feces in intact rats and 
in bile duct-cannulated rats; excretion was almost complete by 24 hours postdose. No 
plasma metabolite accounted for more than 10% of the total plasma radioactivity, suggesting 
potentially low systemic exposure to metabolites.
In vitro pevonedistat is metabolized via hydroxylation and oxidation, predominantly by 
cytochrome P450 (CYP) 3A4 with a small contribution from CYP2D6. Therefore, there is a 
potential for drug-drug interactions (DDIs) when pevonedistat is co-administered with drugs 
that are CYP3A inhibitors or inducers. A phase 1 DDI study (C15011) is currently 
evaluating the effects of CYP3A-mediated inhibition of pevonedistat in patients with solid 
tumors (see Section 1.6.4). Pevonedistat does not inhibit CYP1A2, 2C9, 2C19, 2D6, or 
3A4/5 and weakly and reversibly inhibits both CYP2B6 and 2C8; it does not induce 
CYP1A2, 2B6, and 3A4/5. On the basis of these in vitro data, pevonedistat is unlikely to 
affect the PK of drugs that are metabolized by these CYPs. In vitro, pevonedistat is a 
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substrate for the drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance 
protein (BCRP) and is also a weak inhibitor of BCRP-mediated transport (concentration 
producing 50% inhibition [IC50] of 6.3 M). Additional transport studies with organic 
anion-transporting polypeptides (OATPs) in sandwich-cultured human hepatocytes showed 
that pevonedistat can inhibit the hepatic uptake of estrone-3-sulfate, simvastatin, and 
lovastatin (IC50 of 29.1 M, 0.4-4.9 M, and 0.9 M, respectively). Inhibition of 
OATP-mediated uptake of simvastatin and lovastatin was observed in hepatocytes from 
some, but not all, donors. On the basis of these data, co-administration of pevonedistat with 
known P-gp or BCRP inhibitors is generally not permitted, whereas the potential exists, 
albeit low, for drug interactions with BCRP or OATP substrates.
Additional details on nonclinical PK information are provided in the IB.
1.4.2
Clinical PK
Clinical PK data are summarized in the IB. Single- and multiple-dose PK of pevonedistat 
have been evaluated in adult patients with solid tumors or hematologic malignancies. In 
these studies, pevonedistat was administered IV at dose levels of 25 to 278 mg/m2 and with 
various daily or intermittent dosing schedules within 21-day treatment cycles. Plasma 
concentrations of pevonedistat declined in a multi-exponential manner at the end of a 1-hour 
IV infusion, with little or no notable drug accumulation upon repeat dosing as frequently as 
once a day. This observation is consistent with a mean terminal elimination half-life of 
approximately 10 hours (range, 7.7-15.2 hours) estimated across doses and schedules. 
Pevonedistat PK was linear over the dose range studied based on the area under the plasma 
concentration-time curve (AUC) from the time 0 to 24 hours (AUC24) that increased 
proportionately with dose. Upon exploration of the effects of patient-specific covariates on 
pevonedistat population PK, body size and age influenced the clearance of pevonedistat, 
whereas only body size was important for all volume of distribution parameters. 
Additionally, data are available in 29 treatment-naïve, elderly AML patients who received 
IV pevonedistat at 20 mg/m2 (n=26) and 30 mg/m2 (n=3) on Days 1, 3, and 5 in combination 
with IV/SC azacitidine 75 mg/m2 on a 5-on/2-off (weekend)/2-on schedule (Study C15009) 
[22]. These data indicate that pevonedistat PK remains unaffected by 5 continuous days of 
azacitidine dosing when compared to single-agent pevonedistat PK data from the earlier 
study in AML patients.
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1.5
Study Rationale
This is an open-label, phase 1/1b dose escalation and expansion study of pevonedistat alone 
and in combination with 75 mg/m2 azacitidine to be conducted in adult East Asian patients 
(eg, patients from countries including but not limited to Japan, Taiwan, and South Korea) 
with AML or HR MDS. The pevonedistat clinical program is intended to be expanded 
globally, and all the safety and PK information generated to date have come from patients in 
the United States (US). This study is intended to assess the safety, tolerability, and PK of 
pevonedistat alone and in combination with 75 mg/m2 azacitidine, over a range of 
prespecified dose levels, in East Asian patients with hematologic malignancies, in order to 
support global clinical development.
1.5.1
Rationale for Dose and Schedule
Because this study will be the first clinical study of pevonedistat in East Asia, the safety, 
tolerability, and PK profiles of pevonedistat when given as a single agent will be evaluated 
first. Additionally, evaluation of the PK similarity of single-agent pevonedistat between 
Western and Asian populations can be used to support future evaluation of pevonedistat in 
combination with other standard-of-care agents in Asia. A total of 227 patients with solid 
tumors or hematologic malignancies from 4 phase 1 studies conducted in the US received 
pevonedistat via 1-hour IV infusion at doses ranging from 25 to 278 mg/m2 on multiple 
schedules for up to 19 cycles. The majority of patients in these studies were White; although 
only 6 patients were Asian in the existing clinical database, no obvious differences in the 
kinetic behavior were noted. In 1 of these studies (Study C15003), pevonedistat was 
evaluated in 72 patients previously diagnosed with AML, MDS, or ALL, for whom standard 
curative, life-prolonging treatment did not exist or was no longer effective. Of these, 
43 patients received pevonedistat on Days 1, 3, and 5 at the dose levels of 25 to 78 mg/m2. 
Because no study drug-related deaths were reported, all but 1 of the study drug-related 
serious adverse events (SAEs) were laboratory abnormalities, and all of these events 
resolved and the patients recovered, the dose and schedule of 50 mg/m2 pevonedistat on 
Days 1, 3, and 5 of a 21-day cycle was chosen as the recommended phase 2 dose for 
pevonedistat when given as a single agent.
In the ongoing Study C15009, which administers pevonedistat+azacitidine in patients 
60 years of age and older with AML, 23 patients (79%) were DLT-evaluable. Two of these 
patients experienced a DLT at a pevonedistat dose of 30 mg/m2: 1 patient developed Grade 2 
increased bilirubin, and 1 patient developed Grade 3/4 increased transaminases without 
clinical sequelae. No patients experienced DLTs at a pevonedistat dose of 20 mg/m2. Based 
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on these results, the MTD of the combination was determined to be 20 mg/m2 pevonedistat 
(Days 1, 3, and 5 of each 28-day cycle) and azacitidine 75 mg/m2 (Days 1-5, 8, and 9 of 
each 28-day cycle). One additional event of Grade 4 increased transaminases was observed 
in the expansion cohort. This patient was successfully rechallenged at a lower dose of 
pevonedistat [22].
Although the metabolic profiles and disposition pathways of pevonedistat remain to be fully 
characterized in humans, attributes such as IV administration and body surface area 
(BSA)-adjusted dosing minimize the likelihood for ethnic-related differences in pevonedistat 
exposures between populations in Western and Asian countries. 
The starting dose of 25 mg/m2 pevonedistat (single agent) 
on Days 1, 3, and 5 is 50% lower than the MTD determined in Western patient populations. 
The starting dose of 10 mg/m2 pevonedistat in combination with 75 mg/m2 azacitidine is 
50% lower than the MTD determined in Study C15009. The same azacitidine dose, 
administration route, and schedule is approved in East Asia (including Japan); based on 
available PK information, addition of azacitidine did not appear to alter the PK profile of 
single-agent pevonedistat in the Western patient population. The dose level(s) determined to 
be safe during the escalation phase of the study will then be expanded to further confirm 
safety and investigate PK.
1.5.2
Rationale for the Combination of Pevonedistat+Azacitidine
Azacitidine is a chemical analogue of cytidine that is widely used for the treatment of 
patients with AML. While azacitidine is not approved for AML in the US, it is nonetheless 
one of the most frequently prescribed agents used to treat elderly, unfit patients with AML. 
In Japan, azacitidine is used to treat MDS and AML with a low blast percentage (<30%) in 
the bone marrow. In Taiwan and South Korea, azacitidine is approved for the treatment of 
high-risk MDS and is used in the treatment of some unfit elderly patients with AML. 
According to oncologist/hematologist surveys conducted by the sponsor, it is estimated that 
azacitidine is administered in up to approximately 36% of unfit elderly patients with AML 
in the US and up to approximately 30% in Europe.
The rationale for combining pevonedistat with azacitidine in patients with AML and MDS is 
2-fold: the single-agent activity observed with azacitidine [23] and pevonedistat [24] in 
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patients with AML or related diseases such as MDS and the preclinical evidence supporting 
the improved benefit of pevonedistat administered in combination with azacitidine in AML 
xenograft models; see Section 1.2.2 and the IB for more information. The possible toxicity 
from each product will be mitigated with multiple risk-mitigation strategies.
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1.6
Potential Risks and Benefits
1.6.1
Single-Agent Pevonedistat
Safety information gained from clinical studies of pevonedistat and from toxicology studies 
in rats and dogs has been used to guide the safety evaluation of pevonedistat. Additional 
information on risks is provided in the IB.
Based on preliminary findings in single-agent clinical studies and the toxicities noted in the 
toxicology studies done in rats and dogs, the identified risks of pevonedistat treatment are as 
follows:
!
Increased heart rate.
!
Diarrhea.
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
Nausea.

Vomiting.

Pyrexia.

Liver function test abnormal.

Musculoskeletal pain.

Myalgia.
Please refer to the IB for a discussion of the potential risks associated with pevonedistat.
Hepatotoxicity has been noted following administration of pevonedistat in patients with 
advanced malignancy, including elevations of liver transaminases, alkaline phosphatase, and 
bilirubin. Grade 1 through 4 increases in alanine aminotransferase and aspartate 
aminotransferase have been observed in patients with hematological and solid tumor 
malignancies receiving pevonedistat as a single agent and in combination with 
standard-of-care therapies. The patients experiencing these changes in laboratory values 
have been asymptomatic. The elevations in laboratory values have been reversible with dose 
modification including dose delay and reduction. Patients with elevated transaminases have 
been successfully rechallenged at lower doses.
At doses equal to or below 100 mg/m2 on a Day 1, 3, and 5 or a Day 1, 4, 8, and 11 
schedule, there have been reports of changes in serum creatinine from baseline levels of 
Grade 0 to Grade 1, and from baseline levels of Grade 1 to Grade 2. 
Patients must be carefully evaluated at Screening and before each pevonedistat dose for 
early symptoms and signs of hemodynamic compromise and/or active infection. Particular 
attention should be paid to unexplained fever, tachycardia, hypotension, orthostasis, 
tachypnea, recent nausea and vomiting, and clinical evidence of dehydration. Guidance on 
rehydration is provided in Section 6.8.2.
One patient died of AML complicated by leukostasis within hours after receiving the first 
dose of pevonedistat (see the IB for additional information). Guidance on management of 
leukostasis is provided in Section 6.8.1.
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A comprehensive review of the clinical trial safety data has shown that toxicity involving 
multi-organ failure on Cycle 1 Day 1, including SAEs of renal, hepatic, and cardiac failure, 
some with a fatal outcome, has been observed in pevonedistat studies. Based on the 
observation that these events are associated with higher pevonedistat doses, the sponsor has 
determined that newly enrolling patients will receive pevonedistat at doses equal to or below 
100 mg/m2. Our current understanding of the renal toxicity observed with pevonedistat 
suggests that it is not a primary event but is likely secondary to hemodynamic changes 
occurring in the setting of a type of acute phase response. Patients will be monitored closely 
for events of multi-organ failure after pevonedistat dosing.
These potential toxicities will be managed by careful, frequent monitoring and intervention, 
as needed, with supportive care. It is possible that pevonedistat will have toxicities that were 
not observed in or predicted from the studies completed in rats and dogs, or have not yet 
been identified in patients.
Patients will be monitored closely for these anticipated and potential toxicities as well as for 
unanticipated toxicities when they are receiving this agent and for at least 30 days after their 
last dose. To limit the risks to patients, during dose escalation, a minimum of 3 patients will 
be enrolled at each new dose level of pevonedistat, as applicable, and observed through the 
completion of the first cycle before additional patients are treated. In this study, dosing with 
single-agent pevonedistat is not expected to exceed 44 mg/m2. Although therapeutic efficacy 
is a desired outcome of treatment with the study drugs, it is unknown whether patients will 
benefit from this study. Even if proven efficacious, it is still possible that some patients may 
receive suboptimal doses of pevonedistat.
See Section 6.8 for information on management of clinical events that may occur with study 
treatment.
1.6.2
Azacitidine
In worldwide clinical studies, adverse reactions to azacitidine were qualitatively similar 
between the IV and SC routes of administration [33]. In clinical studies with SC 
administration of azacitidine, adverse reactions of neutropenia, thrombocytopenia, anemia, 
nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to 
increase in incidence with higher doses of azacitidine. Adverse reactions that tended to be 
more pronounced during the first 1 or 2 cycles of SC treatment compared with later cycles 
included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site 
erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, 
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and insomnia. There did not appear to be any adverse reactions that increased in frequency 
over the course of treatment.
Adverse reactions that appeared to be specifically associated with the IV route of 
administration included infusion site reactions (eg, erythema or pain) and catheter site 
reactions (eg, infection, erythema, or hemorrhage) [33].
Adverse reactions identified during postmarketing use of azacitidine include interstitial lung 
disease, tumor lysis syndrome, injection site necrosis, and Sweet syndrome (acute febrile 
neutrophilic dermatosis) [33].
Refer to the Study Manual for azacitidine prescribing information (PI) or refer to the 
summary of product characteristics, as applicable, for additional information regarding the 
anticipated risks and benefits of azacitidine.
1.6.2.1
Anemia, Neutropenia, and Thrombocytopenia
Azacitidine causes anemia, neutropenia, and thrombocytopenia. Complete blood counts 
should be monitored frequently for response and/or toxicity, at least once prior to each 
dosing cycle. After administration of the recommended dosage for the first cycle, dosage for 
subsequent cycles should be adjusted based on nadir counts and hematologic response (see 
Section 6.4.2.1).
1.6.2.2
Severe Pre-existing Hepatic Impairment
Caution is needed when administering azacitidine in patients with liver disease. Patients 
with extensive tumor burden due to metastatic disease have been reported to experience 
progressive hepatic coma and death during azacitidine treatment, with such events occurring 
most frequently in patients with Baseline albumin levels <30 g/L. Azacitidine is 
contraindicated in patients with advanced malignant hepatic tumors.
1.6.2.3
Renal Abnormalities
Patients with renal impairment should be closely monitored for toxicity because azacitidine 
and its metabolites are primarily excreted by the kidneys. Renal abnormalities ranging from 
elevated serum creatinine to renal failure and death have been reported in patients treated 
with IV azacitidine in combination with other chemotherapeutic agents for non-MDS 
conditions. Renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in 
association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L), developed 
in 5 patients with chronic myeloid leukemia treated with azacitidine and etoposide.
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1.6.3
Pevonedistat+Azacitidine
In the ongoing Study C15009, which administers pevonedistat+azacitidine in patients aged 
60 years or older with AML, a total of 13 patients experienced partial remission or better as 
of 22 January 2015. Five patients had a best response of complete remission, and 8 patients 
had a best response of partial remission. None of the clinical data observed thus far suggest 
any lack of efficacy relative to established therapies that would constitute a significant risk 
to the patient populations in the clinical studies.
As of 22 January 2015, safety data from 42 patients in Study C15009 who received ≥1 dose 
of pevonedistat+azacitidine indicate that the most common AEs (occurring in ≥25% of 
patients) include constipation (40%), febrile neutropenia (33%), and anemia, decreased 
appetite, thrombocytopenia, and fatigue (29% each). 
Four patients experienced DLTs (increased LFTs). Because of these events, subsequent 
patients were dosed at 20 mg/m2; 2 patients experienced DLTs at this dose. 
A total of 27 (64%) patients experienced at least 1 SAE. SAEs that were reported for more 
than 1 patient were febrile neutropenia (12 patients), pneumonia (4 patients), sepsis 
(3 patients), and pyrexia and epistaxis (2 patients each).
Eight patients treated with pevonedistat (either 20 mg/m2 or 30 mg/m2), discontinued from 
Study C15009 participation because of a TEAE. Two patients discontinued because of 
febrile neutropenia; both events were considered related to treatment with pevonedistat. 
Other events leading to discontinuation that were assessed by study investigators as at least 
possibly related to study drug treatment were ALT increased, AST increased, blood ALP 
increased, and multi-organ failure. 
Ten on-study deaths (within 30 days of the last dose of study drug) had been reported in 
Study C15009; none of the deaths was assessed as related to study treatment.
Some of these common events, including myelosuppression with increased susceptibility to 
infection, bleeding, and anemia, are considered potential risks of pevonedistat because of the 
occurrence of these events in phase 1 clinical studies in which pevonedistat was 
administered at high doses. Other common events, such as decreased appetite and febrile 
neutropenia, are considered potential risks that are confounded by underlying disease or 
malignancy.
Based on the known individual safety profiles of pevonedistat and azacitidine, the following 
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potential risks of combination therapy may apply: myelosuppression, gastrointestinal events, 
electrolyte imbalances, hypophosphatemia, decreased renal function, hepatotoxicity, cardiac 
arrhythmias, cardiomyopathies, musculoskeletal pain, bleeding, and injection site reactions.
Please refer to the IB, which will be updated regularly throughout the duration of this study, 
for further details on the clinical development program for pevonedistat.
1.6.4
Potential for DDIs
The potential risk of DDIs between pevonedistat and concomitantly administered drugs is 
currently informed by available nonclinical and clinical data (see Section 1.4.1). 
Study C15011, a phase 1 DDI study, is currently ongoing and enrolling patients. The study 
assesses the effect of multiple doses of fluconazole (a moderate CYP3A inhibitor) as well as 
the effect of multiple doses of itraconazole (a strong CYP3A inhibitor) on the PK, safety, 
and tolerability of a single dose of IV pevonedistat. As a general precaution, patients 
receiving concomitant medications, particularly those with narrow therapeutic indices, 
should be carefully monitored because the DDI potential between pevonedistat and other 
drugs has not been formally studied in humans. Patients should also be instructed to consult 
with the investigator before taking any new medications, including over-the-counter 
products and herbal supplements.
No formal clinical assessments of DDIs between azacitidine and other agents have been 
conducted. Please consult the azacitidine PI in the Study Manual for additional information.
See Section 6.5 for information on concomitant medications that are prohibited during this 
study.
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2.
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objectives are as follows:
!
To evaluate safety and tolerability of pevonedistat administered as a single agent in 
East Asian patients with R/R AML or R/R HR MDS.
!
To evaluate safety and tolerability and determine the recommended phase 2/phase 3 
dose of pevonedistat administered in combination with azacitidine in East Asian 
patients with AML or HR MDS.
!
To characterize the PK of pevonedistat administered as a single agent or in 
combination with azacitidine in East Asian patients.
2.2
Secondary Objective
The secondary objective is to evaluate disease response in both AML and MDS that may be 
observed with the single-agent pevonedistat or with a combination of pevonedistat and 
azacitidine.
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3.
STUDY ENDPOINTS
3.1
Primary Endpoints
The primary endpoints are as follows:
!
Safety parameters: AEs, SAEs, DLTs during Cycle 1 (dose-escalation phase only), 
and abnormal laboratory values reported.
!
Summary statistics of PK parameters of pevonedistat, including single-dose 
maximum (peak) concentration (Cmax), area under the plasma concentration- time 
curve during a dosing interval (AUCτ), and CL, when administered alone and during 
concomitant administration of azacitidine during Cycle 1 (dose escalation and 
expansion phases).
3.2
Secondary Endpoints
The secondary endpoints are as follows:
!
ORR (CR+PR [for AML] or CR+PR+hematologic improvement [HI] [for MDS]).
!
CR.
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4.
STUDY DESIGN 
4.1
Overview of Study Design
This is a multicenter, open-label, phase 1/1b dose escalation and expansion study of 
pevonedistat administered IV as a single agent and in combination with azacitidine in adult 
East Asian patients with World Health Organization (WHO)-defined AML or HR MDS 
(Revised International Prognostic Scoring System [IPSS-R] very high/high/intermediate) 
(see Section 15.1).
It is expected that approximately 37 patients will be enrolled in this study. Once enrolled, 
patients will be administered pevonedistat (administered via 60-minute IV infusion) with or 
without azacitidine (administered IV or SC).
The Single-Agent Arm will include East Asian patients with R/R AML or R/R HR MDS 
(including nonproliferative chronic myelomonocytic leukemia [CMML]). In the 
Single-Agent Arm, each 21-day treatment cycle includes treatment with pevonedistat 
(starting dose of 25 mg/m2) on Days 1, 3, and 5, followed by a rest period of 16 days. 
Samples for PK will be collected during Cycle 1. Enrollment in the second dose level 
(44 mg/m2) will only begin after the data from the first group of 3 patients in the 
Single-Agent Arm has been reviewed and the dose has been found to be safe and tolerable. 
In parallel with the opening of enrollment for the second dose level in the Single-Agent 
Arm, enrollment will begin for the first dose level of the Combination Arm. The 
Combination Arm will include East Asian patients with R/R AML or R/R HR MDS 
(including R/R nonproliferative CMML) as well as previously untreated AML or HR MDS 
(including nonproliferative CMML). In the pevonedistat+azacitidine Combination Arm, 
each 28-day treatment cycle includes the following: treatment with pevonedistat (starting 
dose of 10 mg/m2) on Days 1, 3, and 5; treatment with azacitidine (75 mg/m2) on Days 1 
through 5, and 8 through 9; and a rest period of 19 days. Samples for PK will be collected 
during Cycle 1. Enrollment in the Combination Arm will not begin until 3 patients have 
successfully completed Cycle 1 of the 25 mg/m2 Single-Agent Arm.
Patients, including those who achieve a CR, may receive pevonedistat and/or azacitidine 
until they experience disease progression or symptomatic deterioration. Study drug may be 
discontinued if a patient experiences study drug-related toxicities or if, in the opinion of the 
investigator or sponsor, continuation on study may jeopardize the safety of the patient. 
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Patients may discontinue therapy at any time for any reason. Patients will attend the End of 
Study (EOS) visit for safety 30 days after receiving their last dose of study drug.
The 3+3 approach will be used during the dose-escalation phase, as detailed in Section 6.3.
The dose level(s) determined to be safe during the dose-escalation phase of the study may
then be expanded to as many as 12 patients in total to further confirm safety and investigate 
PK. Based on the geographic distribution of patients in the dose escalation/expansion phases 
(Single-agent and/or Combination Arms) and emerging PK and safety data, additional
patients may be added in the expansion phase, as needed, to further characterize the PK, 
safety, and tolerability in a particular East Asian geographic region.
In the Single-Agent Arm, at least 1 Japanese patient will be included in each group of 
3 patients in the dose-escalation phase. If a dose expansion group of up to 6 patients is added 
at the highest dose level, at least 1 additional Japanese patient will be included, unless at 
least 3 Japanese patients were enrolled at that dose level during dose escalation and 
emerging data support an adequate characterization of PK and safety; in this case, no 
additional Japanese patients are needed in the expansion phase.
In the Combination Arm, at least 1 Japanese patient will be included in each group of 
3 patients in the dose-escalation phase. Following dose escalation, an additional group of up 
to 6 patients will be added in the expansion phase, for a total of up to 12 patients at the 
highest dose level. The total number of Japanese patients at the highest dose level will be at 
least 6.
Toxicity will be evaluated according to National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010 [34]. 
DLTs are defined in Section 6.2.
Adverse events will be assessed, and laboratory values, vital signs, and ECGs will be 
obtained, to evaluate the safety and tolerability of pevonedistat administered as a single 
agent or in combination with azacitidine.
Serial blood samples for determination of the plasma concentration of pevonedistat will be 
obtained during Cycle 1 at prespecified time points as described in the Schedules of Events
and in Section 7.4.17.
 Treatment-emergent resistance will also be monitored. 
 
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Disease response assessments will be conducted using International Working Group (IWG) 
criteria [35] for AML and modified IWG criteria [36] for MDS (including CMML).
No formal interim analysis is planned, but safety and PK data will be reviewed on an 
ongoing basis during the dose escalation and expansion phases of the study.
4.2
Number of Patients
Approximately 37 patients will be enrolled in this study from 6 to 9 study centers in East 
Asian countries including but not limited to Japan, Taiwan, and South Korea. Enrollment is 
achieved when the first dose of any study drug has been administered.
4.3
Duration of Study
Patients, including those who achieve a clinical response, may receive study treatment until 
they experience disease progression, until their treatment is discontinued for any other 
reason outlined in Section 7.7, or until the study is stopped. Patients will be considered to 
have completed the study if they have completed study treatment and performed the EOS 
visit or until the sponsor terminates the study.
Patients will be followed for 30 days (+10 days) after the last dose of study drug to permit
further detection of any treatment-related AEs. Analyses for the clinical study report will be 
conducted after the study is complete.
It is anticipated that enrollment into this study will last for approximately 24 months. The 
estimated total study duration includes 24 months of accrual plus the additional follow-up of
10 months after the last patient is enrolled.
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5.
STUDY POPULATION
5.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. East Asian patients aged 18 years or older (if local regulation requires a minimum age 
for informed consent of more than 18 years, then patients must be the minimum age or 
older per the local regulation) when written study informed consent is obtained must
meet 1 of the following diagnosis criteria for either the Single-Agent Arm or the 
Combination Arm:

Single-Agent Arm:
o
Male and female patients with WHO-defined AML [1], including leukemia 
secondary to prior chemotherapy or resulting from an antecedent hematologic 
disorder, who have failed to achieve CR or who have relapsed after prior therapy 
(R/R) and are not candidates for potentially curative treatment, or
o
Male and female patients with WHO-defined MDS [2] that meets the 
International Prognostic Scoring System [IPSS-R] criteria for the very high, high, 
or intermediate risk group (Section 15.1) [3], for whom standard curative, 
life-prolonging treatment does not exist or is no longer effective (R/R), or
o
Male and female patients with WHO-defined CMML-2 or CMML-1 that meets 
the IPSS-R criteria for the very high, high, or intermediate risk group 
(Section 15.1), [3] for whom standard curative, life-prolonging treatment does 
not exist or is no longer effective (R/R); CMML-1 patients must have bone 
marrow blasts ≥5% [2].

Combination Arm:
o
Male and female patients with WHO-defined AML [1], including leukemia 
secondary to prior chemotherapy or resulting from an antecedent hematologic 
disorder, who have failed to achieve CR or who have relapsed after prior therapy 
(R/R) and are not candidates for potentially curative treatment, or
o
Male and female patients aged 60 years or older with previously untreated AML 
who have bone marrow blasts <30% and who are not candidates for standard 
induction chemotherapy, or
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o
Male and female patients with WHO-defined MDS [2] that meets the IPSS-R 
criteria for the very high, high, or intermediate risk group (Section 15.1) [3], for 
whom standard curative, life-prolonging treatment does not exist or is no longer 
effective (R/R), or
o
Male and female patients with previously untreated MDS [2] that meets the 
IPSS-R criteria for the very high, high, or intermediate risk group (Section 15.1) 
[3].
o
Male and female patients with WHO-defined CMML-2 or CMML-1 that meets 
the IPSS-R criteria for the very high, high, or intermediate risk group 
(Section 15.1) [3]; CMML-1 patients must have bone marrow blasts ≥5% [2].
2. For all AML patients: white blood cell (WBC) count <50,000/µL before administration 
of the first dose of pevonedistat on Cycle 1 Day 1. Note: hydroxyurea may be used to 
control the level of WBC counts to no lower than 10,000/µL during the study.
3. For the CMML patients: morphologically confirmed nonproliferative CMML, ie, WBC 
<20,000/µL before administration of the first dose of pevonedistat on Cycle 1 Day 1.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
(see Section 15.2).
5.
Clinical laboratory values within the following parameters within 3 days before the first 
dose of study drug:

Albumin ≥2.7 g/dL.

Total bilirubin ≤upper limit of normal (ULN).

Alanine aminotransferase and AST ≤2.5×ULN.

Calculated creatinine clearance ≥50 mL/min (see Section 15.3).

Hemoglobin >8 g/dL. Patients may be transfused to achieve this value. Elevated 
indirect bilirubin due to post-transfusion hemolysis is not exclusionary.
6. Able to undergo bone marrow aspiration and biopsy at Screening.
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7. Suitable venous access for the study-required blood sampling (ie, including PK and 
pharmacodynamic sampling).
8. Female patients who:

Are postmenopausal (not due to other medical reasons; see Section 15.9) for at least 
1 year before the Screening visit, or

Are surgically sterile, or

If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception (See Section 15.10), at the 
same time, from the time of signing the informed consent through 4 months after the 
last dose of pevonedistat (for patients in the Single-Agent Arm), or through 4 months 
after the last dose of azacitidine (for patients in the Combination Arm), or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
and postovulation methods], withdrawal, spermicides only, and lactational 
amenorrhea are not acceptable methods of contraception. Female and male condoms 
should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 4 months after the last dose of pevonedistat (for patients in the 
Single-Agent Arm), or through 4 months after the last dose of azacitidine (for 
patients in the Combination Arm), or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
9. Voluntary written consent must be given 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.
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5.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Acute promyelocytic leukemia (as diagnosed by morphologic examination of bone 
marrow, by fluorescent in situ hybridization or cytogenetics [t(15:17)] of peripheral 
blood or bone marrow, or by other accepted analysis) or AML associated with t(9;22) 
karyotypes or molecular evidence of such translocations.
2. (Combination Arm only) More than 3 prior lines of therapy.
3. (Combination Arm only) Prior therapy with hypomethylating agents (eg, azacitidine, 
decitabine).
4. Eligibility for a hematopoietic stem cell transplant.
5. Female patients who are in the lactation period, even if they discontinue breastfeeding, 
or who have a positive serum pregnancy test during the Screening period or a positive 
urine pregnancy test on Day 1 before first dose of study drug.
6. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of study procedures.
7. Treatment with any investigational products within 14 days before the first dose of any 
study drug.
8. (Combination Arm only) Known hypersensitivity to azacitidine or mannitol.
9. Active, uncontrolled infection or severe infectious disease, such as severe pneumonia, 
meningitis, septicemia, or methicillin-resistant Staphylococcus aureus infection.
10. Major surgery within 14 days before first dose or a scheduled surgery during the study 
period.
11. Life-threatening illness unrelated to cancer.
12. Known central nervous system involvement.
13. Prothrombin time (PT) or activated partial thromboplastin time (aPTT) >1.5ULN or 
active uncontrolled coagulopathy or bleeding disorder.
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14. Known human immunodeficiency virus (HIV) seropositive.
15. Known hepatitis B surface antigen (HBsAg) seropositive or known or suspected active 
hepatitis C infection. Note: patients who have isolated positive hepatitis B core antibody 
(HBcAb) and/or positive hepatitis B surface antibody (HBsAb) (ie, in the setting of 
negative HBsAg) may be included if they have an undetectable hepatitis B viral load. 
Patients who have positive hepatitis C antibody may be included if they have an 
undetectable hepatitis C viral load.
16. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
17. Known cardiopulmonary disease, defined as unstable angina, clinically significant 
arrhythmia, or congestive heart failure (New York Heart Association Class III or IV; see 
Section 15.4), myocardial infarction within 6 months of first dose of study drug, or 
severe pulmonary arterial hypertension.
18. Left ventricular ejection fraction (LVEF) <50% as assessed by echocardiogram or 
multiple-gated acquisition scan.
19. Treatment with moderate or strong CYP3A inhibitors or inducers within 7 days before 
the first dose of pevonedistat as described in Section 15.5. Patients must have no history 
of amiodarone use in the 6 months before the first dose of pevonedistat.
20. Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of 
any study drug, except for hydroxyurea.
21. Female patients who intend to donate eggs (ova) during the course of this study or 
4 months after receiving their last dose of pevonedistat (for patients in the Single-Agent 
Arm), or through 4 months after the last dose of azacitidine (for patients in the 
Combination Arm). 
22. Male patients who intend to donate sperm during the course of this study or 4 months 
after receiving their last dose of pevonedistat (for patients in the Single-Agent Arm), or 
through 4 months after the last dose of azacitidine (for patients in the Combination 
Arm).
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6.
STUDY DRUG
6.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
prior to drug administration. Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).
If required by local regulations or local clinical guidelines or preferred by the investigator, 
study drugs and protocol assessments may be administered in an in-patient setting during 
Cycle 1.
The amount of study drug to be administered will be based on BSA. BSA will be calculated 
using a standard formula (see example in Section 15.6) on Cycle 1 Day 1 and on Day 1 of 
subsequent cycles if the patient experiences a 5% change in body weight from the weight 
used for the most recent BSA calculation.
Patients will receive pevonedistat diluted with 5% dextrose in a 250-mL bag via a 60-minute 
IV infusion per the information provided in the Directions for Investigational Drug Use 
document located in the Pharmacy Manual. Pevonedistat should be administered through 
central or peripheral venous access. The entire content of the pevonedistat IV bag will be 
infused at a constant rate over 60 minutes, although the infusion may be slowed or stopped 
and restarted for any associated infusion-related reactions. To ensure that all the 
pevonedistat is administered, the infusion line will be flushed with saline or 5% dextrose 
immediately after administration. The volume used for line flushing is not considered a part 
of the volume of the pevonedistat IV bag to be documented. The total time from drug 
reconstitution to the end of infusion must not exceed 6 hours.
All doses must be taken as outlined in the Schedules of Events. For Cycle 1, every effort 
should be made to administer study drug(s) around the same time of the day. No doses 
should be missed or delayed during Cycle 1 due to patient scheduling. Dosing of 
pevonedistat should always be performed on schedule. However, occasional changes in 
azacitidine dosing are allowable after the first cycle: 1) a single dose can be administered 
within a window of ±2 clinic days of specified study day for holidays and other 
administrative reasons, and 2) a single dose can be missed for patient vacations. If 
extenuating circumstances prevent a patient from getting azacitidine treatment within this 
time, the patient may continue the study only with the written permission of the sponsor.
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Planned doses and dosing schedules will be as shown in Table 6.a; additional information is 
provided in Section 6.4. However, the date of Day 1 dosing may be modified by up to 2 days 
(for Cycle 2 and beyond) to accommodate inclement weather, holidays, vacations, or other 
administrative reasons. If extenuating circumstances prevent a patient from beginning 
treatment within this time, the patient may continue the study only with the written 
permission of the sponsor.
The start and end time of IV infusion should be recorded accurately, particularly when PK 
assessments are also performed.
6.1.1
Single-agent Pevonedistat Arm
Patients in the Single-Agent Arm will receive pevonedistat administered via 60-minute IV 
infusion on Days 1, 3, and 5 of each 21-day cycle; planned dose levels are described in 
Table 6.a. All doses must be taken as outlined in the Schedules of Events.
6.1.2
Pevonedistat+Azacitidine Combination Arm – Azacitidine Dosing
Patients in the Combination Arm will receive pevonedistat in combination with azacitidine, 
as outlined in the Schedules of Events. Planned dose levels are provided in Table 6.a.
Patients in the Combination Arm will receive azacitidine (75 mg/m2 [IV during Cycle 1; IV 
or SC in Cycles 2 and beyond, per the investigator’s choice]) on Days 1 through 5 and 
Days 8 through 9 of each 28-day treatment cycle (regardless of whether the patient is 
hospitalized during treatment). Please see the Vidaza (azacitidine) PI in the Study Manual 
for details on azacitidine administration.
In addition, patients will receive pevonedistat administered via 60-minute IV infusion on 
Days 1, 3, and 5 of each 28-day cycle. On Days 1, 3, and 5, when both study drugs are 
administered, azacitidine will be administered first, followed by pevonedistat. The infusion 
of pevonedistat will begin between 15 and 60 minutes after completion of administration of 
SC azacitidine or between 30 and 60 minutes after completion of administration of IV 
azacitidine. After Cycle 1, the investigator, without approval of the sponsor or designee, 
may choose to switch the route of azacitidine administration based on standard of care, 
clinical preference, or convenience.
6.2
Definitions of Dose-Limiting Toxicity
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 
14 June 2010 [34]. These criteria are provided in the Study Manual. DLTs will be defined as 
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any of the following events that are considered by the investigator to be at least possibly 
related to therapy with the study drug(s):

Grade 3 or greater nausea and/or emesis despite the use of optimal antiemetic 
prophylaxis. Optimal antiemetic prophylaxis is defined as an antiemetic regimen that 
employs both a 5-hydroxytryptamine 3 serotonin receptor antagonist and a 
corticosteroid given in standard doses and according to standard schedules.

Grade 3 or greater diarrhea that occurs despite maximal supportive therapy.

Grade 3 or greater arthralgia/myalgia despite the use of optimal analgesia.

Any other Grade 3 or greater nonhematologic toxicity with the following exceptions:
o
Brief (<1 week) fatigue.
o
Hypophosphatemia.

Persistent elevations of transaminases and bilirubin above Grade 2 beyond 2 days 
between doses will be considered dose limiting.

Other study drug-related nonhematologic toxicities Grade 2 or greater that, in the 
opinion of the investigator, require a dose reduction or discontinuation of therapy 
with pevonedistat.
Note that Grade 3 or greater hematologic toxicities, including Grade 3 or 4 febrile 
neutropenia, are not considered to be DLTs unless they meet the following criteria:
o
A delay in the initiation of Cycle 2 due to a lack of adequate recovery from 
treatment-related toxicity (recovery to ≤Grade 1 or to patient’s Baseline values):

Of more than 4 weeks due to hematologic toxicity believed not related to 
leukemic infiltration. Bone marrow evaluation may be required.

Of more than 2 weeks due to nonhematologic toxicities.
Although AEs meeting the protocol-specified definition of DLTs may occur at any point 
during treatment, only those AEs meeting the DLT definition occurring during Cycle 1 of
treatment will necessarily influence decisions regarding dose escalation, expansion of a dose 
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level, or evaluation of intermediate dose levels. Patients will be monitored through all cycles 
of therapy for treatment-related toxicities.
6.3
Dose Escalation Rules
This study will use a 3+3 design in the dose escalation phase for the pevonedistat 
Single-Agent Arm and pevonedistat+azacitidine Combination Arm. The escalation starts 
with single-agent pevonedistat (group of 3 patients) at 25 mg/m2 (Table 6.a). If this dose is 
safe and tolerable, the dose escalation will then be split into 2 independent arms: 1 for 
single-agent pevonedistat (1 additional planned dose level: 44 mg/m2) and the other for the 
pevonedistat+azacitidine combination (2 planned dose levels: 10 and 20 mg/m2), which will 
lead to confirmation of safety of single-agent pevonedistat and the RP2/3D for pevonedistat 
given in combination. Note that no intra-patient dose escalation is permitted. Specific rules 
for the 3+3 algorithm are as follows:
1. If 0 of 3 patients experiences DLT, dose escalation will proceed to the next higher 
dose level, at which 3 patients will be enrolled. 
2. If 1 of 3 patients experiences DLT, 3 more patients will be enrolled at that same dose 
level. Escalation will continue if 1 of 6 patients experiences DLT.
3. If 2 or more patients at any dose level experience DLT, dosing will stop, and 1 of the 
following options will be chosen by the sponsor:

Three additional patients will be added to the previous dose level, or declare the 
lower dose level as tolerable dose if 6 patients have already been dosed.

An intermediate dose between 25 and 44 mg/m2 may be tested for single-agent 
pevonedistat escalation; for the pevonedistat+azacitidine combination, an 
intermediate dose of 15 mg/m2 may be considered.
4. If 0 of 3 patients experiences DLT at the highest dose level, 3 additional patients will 
be enrolled at the same dose level (for a total of 6 patients in the dose-escalation 
phase at the highest dose level).
Escalation beyond 44 mg/m2 when given as single agent or 20 mg/m2 when combined with 
azacitidine is not expected to be necessary in this study. However, if pevonedistat exposures 
are unexpectedly lower than anticipated in the East Asian populations, and no DLTs have 
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occurred in the dose-escalation groups, the pevonedistat dose may be escalated further after 
discussion between the investigator and the sponsor based on available PK and safety data.
Table 6.a
Planned Dose Levels
Single-Agent Arm 
Dose Level
Dose (unit)
Dose-Escalation Phase 
(# of patients)
Expansion Phase
1
25 mg/m2
3~6
The highest tolerated
dose level may be 
expanded up to 
12 patients in total.
2
44 mg/m2
0~6
Combination Arm 
Dose Level
Dose (unit)
Dose-Escalation Phase 
(# of patients)
Expansion Phase
1
10 mg/m2 (in combination with 
azacitidine 75 mg/m2)
0~6
The highest tolerated
dose level may be 
expanded up to 
12 patients in total.
2
20 mg/m2 (in combination with 
azacitidine 75 mg/m2)
0~6
Evaluation of intermediate doses and/or expansion of any dose level studied during dose 
escalation are permissible, based on emerging data and following discussions between the 
sponsor and the investigators, if such measures are needed for patient safety or for a better 
understanding of the dose-related toxicity, PK, or pharmacodynamics of pevonedistat.
The dose escalation decision and expansion flowchart is provided in Section 15.7. 
Patients not receiving all doses of pevonedistat or azacitidine in Cycle 1 for reasons other 
than DLTs will be replaced within the dose group.
6.4
Dose Modification Guidelines
6.4.1
Criteria for Retreatment and Dose Delays
Retreatment Within a Cycle
If dosing of either drug is delayed for safety reasons, retreatment may be resumed upon 
resolution of the safety condition. For pevonedistat, a minimum of 1 full calendar day 
between any 2 doses should be maintained (eg, Day 1 [Monday] and Day 3 [Wednesday]). 
In each cycle, a maximum of 3 doses of pevonedistat and 7 doses azacitidine (as applicable) 
should not be exceeded.
If dosing is interrupted within a cycle because of toxicity, and if, in the opinion of the 
investigator and the sponsor or designee, it is in the patient’s interest to continue therapy 
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with the study drug(s), then after recovery of the toxicity or toxicities in question to 
Grade 1 or to the patient’s Baseline values, the dose of study drug may be reduced. For 
specific guidelines on azacitidine and pevonedistat dose reductions, see Sections 6.4.2 and 
6.4.3). 
Initiation of a New Cycle
Treatment with study drugs will be repeated every 21 days (Single-Agent Arm) or 28 days 
(Combination Arm). For therapy to resume, toxicity considered related to treatment with 
study drugs must have resolved to Grade 1, to the patient’s Baseline values, or to a level 
considered acceptable by the investigator after discussion with the sponsor or designee.
If a patient fails to meet the criteria for retreatment, initiation of the next cycle of treatment 
may be delayed for up to 2 weeks. At the end of that time, the patient should be reevaluated 
to determine whether the criteria for retreatment have been met. For a delay of >2 weeks, a 
discussion with the sponsor is required to determine whether the patient may continue 
treatment. A dose reduction (as detailed in Sections 6.4.2 and 6.4.3) would be triggered 
should treatment be delayed for >2 weeks because of incomplete recovery from 
treatment-related nonhematologic toxicity or >4 weeks because of incomplete recovery from 
treatment-related hematologic toxicity that is not related to leukemic infiltration.
6.4.2
Dose Modification for Hematologic Toxicities
A delay in the initiation of a cycle by >4 weeks because of lack of recovery from treatment-
related hematologic toxicity that is not related to leukemic infiltration will trigger a dose 
reduction, if treatment resumes. Recovery is defined as resolved to Grade 1, to the patient’s 
Baseline values, or to a level considered acceptable by the investigator after discussion with 
the medical monitor. If indicated, bone marrow evaluation will be performed to establish 
whether continued myelosuppression is related to persistent or progressing leukemic 
infiltration.
6.4.2.1
Azacitidine
For hematologic toxicities >Grade 1, azacitidine should be reduced in accordance with 
Table 6.b or Table 6.c and/or institutional guidelines, with prior agreement by the sponsor or 
designee.
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For patients with WBC count ≥3.0109/L, absolute neutrophil count (ANC) ≥1.5109/L, and 
platelets ≥75.0109/L, the azacitidine dose should be adjusted based on nadir counts for any 
given cycle as detailed in Table 6.b.
Table 6.b
Azacitidine Dose Adjustment Based on Hematology Laboratory Value 
Nadir Counts
Nadir Counts
% Dose in the Next Course
Absolute Neutrophil Count (109/L)
Platelets (109/L)
<0.5
<25.0
50%
0.5-1.5
25.0-50.0
67%
>1.5
>50.0
100%
Source: Vidaza PI [33].
Abbreviations: ANC=absolute neutrophil count, PI=prescribing information, WBC=white blood cell.
This table applies to patients with the following Baseline counts: WBC count ≥3.0109/L, ANC ≥1.5109/L, 
and platelets ≥75.0109/L.
For patients with Baseline counts of WBC <3.0109/L and/or ANC <1.5109/L and/or 
platelets 75.0109/L, dose adjustments should be based on nadir counts and bone marrow 
aspirate cellularity at the time of the nadir, as noted in Table 6.c, unless there is clear 
improvement in differentiation at the time of the next cycle (eg, the percentage of mature 
granulocytes is higher and ANC is higher than at the onset of that course); in this case, the 
dose of the current treatment should be continued.
Table 6.c
Azacitidine Dose Adjustment Based on Bone Marrow Aspirate 
Cellularity
Nadir Decrease in WBC or 
Platelet Counts from Baseline (%)
Bone Marrow Aspirate Cellularity at the Time of Nadir (%)
30-60
15-30
<15
% Dose in the Next Course
50-75
100
50
33
>75
75
50
33
Source: Vidaza PI [33].
Abbreviations: ANC=absolute neutrophil count, PI=Prescribing Information, WBC=white blood cell.
This table applies to patients with Baseline counts of WBC <3.0109/L and/or ANC <1.5109/L and/or 
platelets 75.0109/L.
If a nadir as defined in Table 6.c has occurred, the next course of treatment should be given 
28 days after the start of the preceding course, provided that both the WBC and the platelet 
counts are >25% above the nadir and rising. If a >25% increase above the nadir is not seen 
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by Day 28, counts should be reassessed every 7 days. If a 25% increase is not seen by 
Day 42, the patient should be treated with 50% of the scheduled azacitidine dose.
6.4.2.2
Pevonedistat
For patients who develop symptoms of leukostasis, pevonedistat should be held until 
leukostasis is treated. Treatment may include leukapheresis and hydroxyurea according to 
institutional guidelines. As soon as WBC count is <50,000/μL, pevonedistat may be 
restarted, following agreement with sponsor. 
For patients whose Baseline counts are WBC <3.0×109/L, ANC <1.5×109/L, or platelets 
<75.0×109/L, dose adjustments should be based on nadir counts and bone marrow biopsy 
cellularity at the time of the nadir (if available), unless there is clear improvement in 
differentiation (percentage of mature granulocytes and ANC are higher than at onset of that 
course) at the time of the next cycle, in which case the dose of the current treatment should 
be continued.
6.4.3
Dose Modification for Nonhematologic Toxicities
6.4.3.1
Azacitidine
Azacitidine Dose Adjustment Based on Renal Function and Serum Electrolytes
For renal toxicities, specifically elevated creatinine >Grade 1, azacitidine should be reduced 
in accordance with the PI [33] and/or institutional guidelines. Similarly, if unexplained 
elevations in serum creatinine (to >1.5× the ULN) or blood urea nitrogen (BUN) occur, the 
next cycle should be delayed until values return to normal or baseline, and the dose should 
be reduced by 50% on the next treatment course. See the Vidaza PI in the Study Manual for 
more details.
If unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, the azacitidine 
dose should be reduced by 50% on the next course. The azacitidine dose may be re-escalated 
back to 75 mg/m2 at the next cycle, if the toxicity has recovered to ≤Grade 1 or the patient’s 
Baseline value.
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6.4.3.2
Pevonedistat
Pevonedistat Dose Adjustment Based on Serum Transaminases and Total Bilirubin
Based on current data from Studies C15003 and C15009, it is anticipated that in some 
patients liver function tests ([LFTs] AST, ALT, and occasionally bilirubin) may be elevated 
for approximately 48 hours following the end of pevonedistat infusion on Cycle 1 Day 1. 
Dosing will continue only if there is no evidence of DLT before each dose, only if any 
elevations in the serum transaminases are Grade 1 or less, and only if any elevations in 
bilirubin are ≤1.5×ULN. Dosing may be delayed for 1 additional day, without reduction in 
dose, for resolution of effects on serum transaminases to Grade 1 and bilirubin to 
≤1.5×ULN. Persistent elevations of transaminases and bilirubin above Grade 2 beyond 
2 days between doses will be considered dose limiting.
For therapy to resume, toxicity considered related to treatment with the study drugs must 
have resolved to ≤Grade 1 or to the patient’s Baseline values. If dosing is interrupted within 
a cycle because of toxicity, and if, in the opinion of the investigator and the sponsor, it is in 
the patient’s interest to continue therapy with the study drugs, then after recovery of the 
toxicity or toxicities in question to ≤Grade 1 or to the patient’s Baseline values, the dose of 
pevonedistat may be reduced.
Pevonedistat Dose Adjustment Based on Hypophosphatemia
If hypophosphatemia is ≥Grade 3, study drug treatment should not be resumed until the 
hypophosphatemia is ≤Grade 2. Hypophosphatemia should be evaluated, monitored, and 
treated according to institutional guidelines.
Pevonedistat Dose Adjustment for Other Toxicities
For treatment-related nonhematologic toxicities >Grade 1, the dose of pevonedistat should 
be reduced by 1 dose level (if applicable) after discussion with sponsor.
6.5
Excluded Concomitant Medications and Procedures
Medications that are generally excluded but are allowed with certain exceptions listed in 
Table 6.d. 
The use of moderate and strong CYP3A inhibitors is prohibited for 7 days prior to the first 
dose of study drug(s) only during treatment Cycle 1 for both study arms. In treatment 
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Cycle 2 and beyond, the use of moderate and strong CYP3A inhibitors is permitted. See 
Section 15.5 for additional details of specific CYP3A inhibitors.
Table 6.d
Concomitant Medications Excluded During the Study
Therapy
Comment/Exceptions
Acetaminophen and 
acetaminophen-containing products
May be used judiciously but should not exceed a dose of 2 g in 
24 hours.
Systemic antineoplastic therapy, except 
for hydroxyurea
Hydroxyurea dosing may be adjusted to control the level of WBC 
counts to no lower than 10,000 while on study treatment. The dosing 
of hydroxyurea and changes to dosing of hydroxyurea must be 
recorded.
Moderate and strong CYP3A inhibitors
(see Section 15.5)
Excluded for 7 days prior to first dose of study drug(s) and during 
treatment Cycle 1 only for both the Single-Agent Arm and the 
Combination Arm. 
Limited use of the azole antifungal agents voriconazole and 
fluconazole, and ciprofloxacin during Cycle 1 is permitted only if 
clinically necessary and no suitable alternative exists. The patient 
may receive the azole antifungal or ciprofloxacin from 24 hours after 
the last pevonedistat dose until 72 hours before the next pevonedistat 
dose. For example, if a patient receives pevonedistat on a 
Monday (Day 1), Wednesday (Day 3), and Friday (Day 5) schedule, 
then the azole antifungal or ciprofloxacin may be administered from 
the Saturday after the Day 5 dose (Day 6) up to the Friday (Day 26) 
before the Monday dose of the next cycle.
For treatment Cycle 2 and beyond, the use of moderate and strong 
CYP3A inhibitors is permitted for both the Single-Agent Arm and 
the Combination Arm. See Section 15.5.
Moderate and strong CYP3A inducers 
[including St. John’s wort (Hypericum 
perforatum)]
(see Section 15.5)
Excluded from the study.
Known BCRP inhibitors 
(ie, cyclosporine and eltrombopag 
[Promacta])
Generally excluded but limited use is permitted only if clinically 
necessary and no suitable alternative exists. The patient may 
receive the BCRP inhibitor from 24 hours after the last pevonedistat 
dose until 72 hours before the next pevonedistat dose. For example, 
if a patient receives pevonedistat on a Monday (Day 1), Wednesday 
(Day 3), and Friday (Day 5) schedule, then the BCRP inhibitor may 
be administered from the Saturday after the Day 5 dose (Day 6) up 
to the Friday (Day 26) before the Monday dose of the next cycle.
Known P-gp inhibitors 
(ie, azithromycin
[Zithromax], captopril, carvedilol, 
felodipine, quercetin, quinidine, 
ranolazine, ticagrelor)
Generally excluded during the study but limited use is permitted 
only if clinically necessary and no suitable alternative exists. The 
patient may receive the P-gp inhibitor from 24 hours after the last 
pevonedistat dose until 72 hours before the next pevonedistat dose. 
For example, if a patient receives pevonedistat on a 
Monday (Day 1), Wednesday (Day 3), and Friday (Day 5) schedule, 
then the P-gp inhibitor may be administered from the Saturday after 
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Table 6.d
Concomitant Medications Excluded During the Study
Therapy
Comment/Exceptions
the Day 5 dose (Day 6) up to the Friday (Day 26) before the 
Monday dose of the next cycle.
Myeloid growth factors (eg, G-CSF, 
GM-CSF)
Generally excluded but allowed if deemed medically necessary, after 
discussion with sponsor.
Erythropoietin
Generally excluded but allowed if approved locally and deemed 
medically necessary, after discussion with sponsor.
Any investigational agent other than 
pevonedistat, including agents 
commercially available for indications 
other than AML or MDS 
(eg, eltrombopag, romiplostim)
Excluded during the study. 
Abbreviations: AML=acute myeloid leukemia, BCRP=breast cancer-resistance protein, CYP=cytochrome 
P450, G-CSF=granulocyte colony stimulating factor, GM-CSF=granulocyte macrophage colony-stimulating 
factor, P-gp=P-glycoprotein; WBC=white blood cell.
6.6
Permitted Concomitant Medications and Procedures
Medications and procedures that are specifically permitted during the study are listed in 
Table 6.e.
Table 6.e
Permitted Concomitant Medications and Procedures
Therapy
Comment
Antiemetics for azacitidine
May be administered according to institutional guidelines.
Hydroxyurea
Dosing of hydroxyurea may be adjusted to control the level of WBC counts to 
no lower than 10,000 while on treatment with study drugs. The dosing of 
hydroxyurea and changes to dosing of hydroxyurea should be recorded.
Patients may start or restart treatment with hydroxyurea during the study.
Moderate and strong CYP3A 
inhibitors
For treatment Cycle 2 and beyond, the use of moderate and strong CYP3A 
inhibitors is permitted for both the Single-Agent Arm and the Combination 
Arm. See Section 15.5.
Use of moderate and strong CYP3A inhibitors are excluded for 7 days prior to 
first dose of study drug(s) and during treatment Cycle 1 only for both the 
Single-Agent Arm and the Combination Arm.
RBC transfusion
To be considered for all patients with anemia, especially those with 
hemoglobin values <8 g/dL. RBC transfusion should occur at least 1 day 
prior to investigational product administration. 
Abbreviations: CYP=cytochrome P450; RBC=red blood cell; WBC=white blood cell.
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6.7
Precautions and Restrictions
Concomitant medications and procedures that are excluded or must be used with caution are 
described in Sections 6.5 and 6.6, respectively.
Certain situations may warrant further caution, such as modifying the dose of study drug(s). 
Dose modification guidelines are provided in Section 6.4.
It is not known what effects pevonedistat has on human pregnancy or development of the 
embryo or fetus. Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner. 
Nonsterilized female patients of reproductive age group and male patients should use highly 
effective methods of contraception (see list provided in Section 15.10) through defined 
periods during and after study treatment as specified below.
1) Use only contraceptive methods that are locally approved in each country
2) Female patients must meet 1 of the following:

Postmenopausal (not due to other medical reasons; see Section 15.10) for at least 
1 year before the Screening visit, or

Surgically sterile, or

If they are of childbearing potential (as defined in Section 7.4.13), agree to practice 
1 highly effective method and 1 additional effective (barrier) method of 
contraception, at the same time, from the time of signing the informed consent 
through 4 months after the last dose of pevonedistat (for patients in the Single-Agent 
Arm), or through 4 months after the last dose of azacitidine (for patients in the 
Combination Arm), or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea 
are not acceptable methods of contraception. Female and male condoms should not 
be used together.)

Female patients must agree not to donate eggs (ova) during the course of this study 
or 4 months after receiving their last dose of pevonedistat (for patients in the 
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Single-Agent Arm), or through 4 months after the last dose of azacitidine (for 
patients in the Combination Arm).
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and 
through 4 months after the last dose of study drug (if barrier methods are not locally 
approved to be used by males, then their female partners should use effective 
contraceptive methods as described in the above), or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)

Male patients must agree not to donate sperm during the course of this study or 
4 months after receiving their last dose of pevonedistat (for patients in the 
Single-Agent Arm), or through 4 months after the last dose of azacitidine (for 
patients in the Combination Arm).
6.8
Management of Clinical Events
Patients who experience an AE with pevonedistat should be followed closely for a 
recurrence of similar or other AEs upon subsequent dosing.
The most common adverse drug reactions for azacitidine are described in the Vidaza PI [33]. 
Please see the Vidaza PI in the Study Manual as applicable for details regarding the 
management of clinical events attributed to azacitidine.
Common AEs reported for patients receiving pevonedistat are listed in Section 1.6.1. Also 
refer to the most recent IB.
6.8.1
Leukostasis in Patients Receiving Pevonedistat
Pevonedistat treatment should be withheld for patients who develop symptoms of 
leukostasis (see Section 6.4.2.2). Treatment may include leukapheresis and hydroxyurea 
administration, per institutional guidelines. When the WBC of the patient is <50,000/L and 
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symptoms are improved, pevonedistat treatment may be restarted after consulting with the 
sponsor or designee.
6.8.2
Hemodynamic Compromise in Patients Receiving Pevonedistat
It is essential that the patients receiving pevonedistat are carefully evaluated at Screening 
and before each pevonedistat dose for early symptoms and signs of hemodynamic 
compromise and/or active infection. Particular attention should be paid to unexplained fever, 
tachycardia, hypotension, orthostasis, tachypnea, recent nausea and vomiting, and clinical 
evidence of dehydration. Patients who experience an untoward reaction with pevonedistat 
should be followed closely on subsequent dosing.
For patients for whom there is a concern of dehydration, the following guidance for 
rehydration before pevonedistat dosing may be considered: 500 mL/hour of 0.5 N saline 
given over 2 to 4 hours for a total of 1 to 2 L of fluid as clinically appropriate; each infusion 
of IV fluids should be recorded in the electronic case report forms (eCRFs).
For all patients with anemia, and especially for those with hemoglobin values <8 g/dL at 
Screening or during the conduct of the study, RBC transfusions should be considered before 
pevonedistat dosing based on the risk of inadequate oxygenation, underlying 
cardiopulmonary status, clinical judgment, and/or hospital guidelines; each RBC transfusion 
should be recorded in the eCRFs.
Patients who experience signs and symptoms of hemodynamic compromise after 
pevonedistat dosing (eg, tachycardia, hypotension, orthostasis, changes in mental status, 
syncope, and dizziness) should be followed closely and managed with supportive care, 
including hospitalization, as clinically indicated.
Patients who experience an untoward reaction with pevonedistat should be followed closely 
on subsequent dosing.
6.8.3
Hepatotoxicity in Patients Receiving Pevonedistat
Please refer to Section 6.4.3.2 for dose modifications or delay for LFT elevations in patients 
receiving pevonedistat. Frequent follow up of liver enzymes, bilirubin, and coagulation 
profile (INR) as well as supportive care are recommended according to institutional practice. 
Concomitant medications that may contribute to liver toxicity should be held if possible.
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6.8.4
Hematologic Toxicity in Patients Receiving Pevonedistat
Please refer to Section 6.4.2.2 for dose adjustments for hematologic toxicity in patients 
receiving pevonedistat. Supportive care and transfusion should be considered according to 
institutional practice at the medical discretion of the investigator.
6.8.5
Extravasation
Based on nonclinical findings as detailed in the IB, pevonedistat is considered a nonvesicant 
drug. Although no published guidelines are available for extravasation of nonvesicants, the 
investigator is encouraged to follow institutional guidelines. Some general advice in case of 
extravasation includes immediately stopping drug infusion and elevating the affected limb to 
minimize swelling.
6.9
Blinding and Unblinding
This is an open-label study; investigators and patients will know the individual treatment 
assignments. 
6.10
Description of Investigational Agents
Upon receipt of drug supply, contents must be verified promptly and the proper contacts 
notified of any discrepancies or damages as described in the Study/Pharmacy Manual.
6.10.1
Pevonedistat
The drug product is labeled pevonedistat (MLN4924 Injection).
Details are available in the IB.
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6.10.2
Azacitidine
Commercially available azacitidine is supplied as lyophilized powder in 100-mg, single-use 
vials. Refer to the Vidaza PI in the Study Manual for additional information regarding 
azacitidine [33].
6.11
Preparation, Reconstitution, and Dispensation
Pevonedistat and azacitidine are anticancer drugs; as with other potentially toxic 
compounds, caution should be exercised when handling pevonedistat and azacitidine.
Pevonedistat solution for injection vials should be removed and allowed to equilibrate to 
room temperature before dilution. Using aseptic technique, the specified amount of drug 
product solution should be removed and administered per the information provided in the 
Pharmacy Manual. For a detailed preparation of the infusion, refer to the Directions for 
Investigational Drug Use document located in the Pharmacy Manual. The pevonedistat 
prepared IV bag must be used within 6 hours. The vial must not be shaken at any time 
during dose preparation. The bag, needle, and syringe must be disposed of in a proper 
biohazard container.
Detailed reconstitution and dosage preparation instructions are provided in the Directions for 
Investigational Drug Use document located in the Pharmacy Manual.
Instructions for the preparation, reconstitution, and dispensation of azacitidine are provided 
in the Vidaza PI in the Study Manual.
6.12
Packaging and Labeling
Pevonedistat will be provided in 10-mL USP Type I glass vials. Each USP Type I glass vial 
nominally contains 5 mL of compounded sterile solution, sealed with a Teflon coated butyl 
rubber stopper and oversealed with an aluminum seal and a plastic cap.
Azacitidine is available as lyophilized powder in 100-mg, single-use vials from commercial 
supply with commercial packaging and labeling. Azacitidine may be sourced locally by the 
clinical sites when regulations allow for clinical site sourcing with appropriate labeling.
6.13
Storage, Handling, and Accountability
All investigational supplies are to be kept in a secure area with controlled access.
Vials of pevonedistat solution for injection are to be stored at 2°C to 8°C.
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Details of the storage and handling of azacitidine are provided in the Vidaza PI (available in 
the Study Manual).
A drug dispensing log, including records of drug received from the sponsor and drug 
administered to the patients, will be provided and kept at the study site. Disposal instructions 
are provided in the Pharmacy Manual.
7.
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Council for Harmonisation (ICH) 
guidelines.
If required by local regulations or local clinical guidelines or preferred by the investigator, 
study drugs and protocol assessments may be administered in an in-patient setting during 
Cycle 1.
7.1
Study Personnel and Organizations
The contact information for the medical monitor for this study, the central laboratories and 
any additional clinical laboratories, the contract research organization team, and the 
interactive voice/web response system may be found in the Study Manual. A full list of 
investigators is available in the sponsor’s investigator database.
7.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC). It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3
Treatment Arm Assignments
No randomization or stratification will be performed in this study. This study incorporates 
dose escalation and expansion phases of pevonedistat as single agent or combined with 
azacitidine. After the first single-agent dose level is deemed to be safe, single agent and 
combination dose escalation will be performed independently and simultaneously. 
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In the Single-Agent Arm, at least 1 Japanese patient will be included in each group of 
3 patients in the dose-escalation phase. If a dose expansion group of up to 6 patients is added 
at the highest dose level, at least 1 additional Japanese patient will be included, unless at 
least 3 Japanese patients were enrolled at that dose level during dose escalation and 
emerging data support an adequate characterization of PK and safety; in this case, no 
additional Japanese patients are needed in the expansion phase.
In the Combination Arm, at least 1 Japanese patient will be included in each group of 
3 patients in the dose-escalation phase. Following dose escalation, an additional group of up 
to 6 patients will be added in the expansion phase, for a total of up to 12 patients at the 
highest dose level. The total number of Japanese patients at the highest dose level will be at 
least 6.
7.4
Study Procedures
Refer to the Schedules of Events for timing of assessments. Separate subschedules for 
Cycle 1 and for Cycle 2 and beyond are provided for each treatment arm. Additional details 
are provided as necessary in the sections that follow and in the Study and Laboratory 
Manuals. When applicable, specific visit windows for assessments are provided in the 
footnotes to the study schedules. Day 1 of Cycle 2 and beyond may be modified by up to 
2 days to accommodate inclement weather, holidays, vacations, or other administrative 
reasons.
7.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard care.
7.4.2
Patient Demographics
As allowed by regulations, the date of birth, race, ethnicity, and sex of the patient will be 
recorded during Screening.
7.4.3
Medical History
During the Screening period, a complete medical history will be compiled for each patient. 
The history will emphasize the background and progress of the patient’s malignancy and 
include a description of prior therapies for it. In addition, concomitant medications will be 
recorded as specified in Section 7.4.10.
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7.4.4
Physical Examination
A physical examination will be completed per standard of care at Screening. A 
symptom-directed physical exam will be completed per standard of care at the times 
specified in the Schedules of Events and as clinically indicated.
7.4.5
Patient Height 
Height will be measured only during Screening.
7.4.6
Patient Weight
Weight will be measured at the time points listed in the Schedules of Events.
7.4.7
ECOG Performance Status
ECOG performance status (Section 15.2) will be assessed at the times specified in the 
Schedules of Events.
7.4.8
Vital Signs 
Vital sign measurements, including diastolic and systolic blood pressure, heart rate, and 
body temperature, will be taken according to the Schedules of Events and as clinically 
indicated. At the predose and 1 hour postdose time points on Cycle 1 Day 1, orthostatic 
blood pressure and heart rate measurements will be taken with the patient in a supine 
position and then standing, after waiting 3 to 4 minutes. At all other time points, a sitting 
position is preferred for the collection of vital signs. If a supine position is used, it should be 
used consistently for the same patient throughout the study.
Either oral or axial body temperature may be used, but the same method for measuring body 
temperature (oral or axial) should be used consistently for the same patient throughout the 
study.
7.4.9
Electrocardiogram
A 12-lead ECG will be administered at the time points specified in the Schedules of Events.
7.4.10
Concomitant Medications and Procedures
Concomitant medications and procedures (including transfusions) will be recorded from the 
time of the first dose of any study drug through 30 days (+10 days) after the last dose of 
study drug(s). See Section 6.5 and Section 6.6 for details regarding excluded and permitted 
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concomitant medications and procedures, respectively, including recording requirements for 
hydroxyurea and transfusions.
7.4.11
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally.
Hematology
Blood samples for analysis of the following hematologic parameters will be obtained as 
specified in the Schedules of Events and more frequently if clinically indicated.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential, including circulating blast 
count

Lymphoblasts

Myelocytes

Neutrophils (ANC) 
Note: ANC may be calculated from the leukocyte count 
with differential count; see Section 15.8.
Coagulation
Blood samples for a coagulation panel will be obtained as specified in the Schedules of 
Events. The coagulation panel will include prothrombin time (international normalized ratio) 
and activated partial thromboplastin time.
Clinical Chemistry
Blood samples for analysis of the following serum chemistry parameters will be obtained as 
specified in the Schedules of Events and more frequently if clinically indicated.
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Complete Serum Chemistry Panel

BUN

Creatinine

Bilirubin (direct)

Bilirubin (total)

Urate

Lactate 
dehydrogenase 
(LDH)

Phosphate

Albumin

Alkaline phosphatase 
(ALP)

AST

ALT

Glucose

Sodium

Potassium

Calcium

Chloride

Carbon dioxide (CO2 if 
available as part of 
chemistry panel from 
venous blood draw)

Magnesium
Select Serum Chemistry Panel

BUN

Creatinine

Bilirubin (total)

ALP

AST

ALT

LDH
Urinalysis
Urine samples for urinalysis will be obtained as specified in the Schedules of Events and 
more frequently if clinically indicated.
Urinalysis With Microscopic Analysis

Turbidity and color

pH

Specific gravity

Protein

Ketones

Occult blood

Nitrite

Phosphate

Leukocyte esterase

Microscopic assessment of 
leukocytes, erythrocytes, 
bacteria, casts, and crystals
7.4.12
Echocardiogram
LVEF should be assessed by echocardiography or multiple-gated acquisition scan at 
Screening.
7.4.13
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening 
and within 3 days prior to the first dose of study drug. The results from these tests must be 
available and negative before the first dose of study drug is administered. If the Cycle 1 
Day 1 serum pregnancy results are not available before dosing, a urine pregnancy test may 
be performed.
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Women of childbearing potential is defined as any sexually active female who meet the 
following criteria:
1. Those who have not undergone hysterectomy or bilateral oophorectomy, and
2. Those who have not had natural menopause for 12 consecutive months or longer 
(eg, FSH > 40 IU/L and no menopausal period for at least 12 consecutive months) 
(loss of menopausal periods following chemotherapy may not rule out childbearing 
potential).
7.4.14
Hepatitis Testing
Hepatitis testing will be performed at Screening. As appropriate, and according to local 
guidelines for the management of hepatitis B virus infection, hepatitis B virus (HBV) 
screening may include the following: HBsAg, HBsAb, HBcAb, and HBV viral load. 
Hepatitis C virus (HCV) screening is to include the anti-HCV antibody (HCVAb); if 
positive, this test should be followed by a reactive viral load test. Patients, who are HBsAg 
negative, and HBsAb and/or HBcAb positive, and/or HCVAb positive with negative viral 
load at screening, enrolled in this study will be monitored by assessment of viral load 
(HBV-DNA; HCV-RNA) as needed and based on local institutional guidelines. If a patient’s 
viral load becomes positive for HBV and/or HCV at any time during the study, and infection 
is confirmed, the patient will be withdrawn from the study and treated per local institutional 
guidelines.
7.4.15
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedules of Events. Refer to Section 10 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.
7.4.16
Enrollment
A patient is considered to be enrolled in the study when the first dose of any study drug has 
been administered.
Procedures for the completion of the enrollment information are described in the Pharmacy 
and Study Manual.
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7.4.17
Pharmacokinetic Measurements
Blood samples (approximately 3 mL) for the determination of plasma concentrations of 
pevonedistat will be collected from all patients during Cycle 1 of the study. The timing, but 
not the number, of PK blood samples may be changed if emerging data indicate that an 
alteration in the sampling scheme is needed to better characterize the PK of pevonedistat.
The exact date and time of each sample collection and the actual start and stop times of the 
infusion should be recorded accurately, with particular care given to the recording of blood 
sampling times that occur close to the infusion.
To ensure that the measurements are representative of plasma exposure, blood draws will be 
conducted in the arm opposite a patient’s IV infusion. In the case that only a single arm is 
available, blood may be drawn as distal to the site for IV infusion as feasible, and the site of 
blood draw should be documented.
Details regarding the preparation, handling, and shipping of samples are provided in the 
Study Manual.
If deemed appropriate, the blood samples collected in this study may be additionally 
analyzed to determine the plasma concentrations of pevonedistat major metabolites in 
humans.
7.4.17.1
Single-Agent Arm
In all patients in the Single-Agent Arm, blood samples for PK analysis will be collected 
during Cycle 1 at the times specified in the Serial Pharmacokinetic Sample Breakdown -
Single-Agent Pevonedistat Arm.
7.4.17.2
Combination Arm
In all patients in the Combination Arm, blood samples for PK analysis will be collected 
during Cycle 1 at the times specified in the Serial Pharmacokinetic Sample Breakdown -
Pevonedistat+Azacitidine Combination Arm.
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Details regarding the preparation, handling, and shipping of these samples are provided in 
the Study Manual.
7.4.19
Disease Assessment
Disease assessments will be performed in conjunction with bone marrow assessments (see 
the Schedules of Events).
7.4.19.1
Revised Recommendations of the IWG Response Criteria for AML
In patients with AML, assessment of disease response will follow the criteria outlined in the 
Revised Recommendations of the IWG for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia [35]. When possible, the same qualified physician will interpret results to reduce 
variability.
Investigators are encouraged to consult the reference for a more detailed explanation of the 
response criteria.
CR, CR with incomplete blood count recovery (CRi), and PR are defined using the 
following criteria:
Morphologic CR: A CR designation requires that the patient achieve the 
morphologic leukemia-free state and have an ANC of more than 1,000/μL and 
platelets of ≥100,000/μL. A morphologic leukemia-free state requires less than 
5% blasts in an aspirate sample with marrow spicules and with a count of at least 
200 nucleated cells. Hemoglobin concentration or hematocrit has no bearing on 
remission status, although the patient must be independent of transfusions. There 
should be no residual evidence of extramedullary leukemia.
Morphologic CRi: After chemotherapy, some patients fulfill all of the criteria for 
CR except for residual neutropenia (<1,000/μL) or thrombocytopenia 
(<100,000/μL).
PR: This designation requires all of the hematologic values for a CR but with a 
decrease of at least 50% in the percentage of blasts to between 5% and 25% in the 
bone marrow aspirate. Thus, if the pretreatment bone marrow blast percentage was 
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50% to 100%, the percentage of blasts must decrease to a value between 5% and 
25%; if the pretreatment blast percentage was 20% to less than 49%, then it must 
decrease by at least half to a value of more than 5%. A repeat bone marrow 
aspiration after several weeks may be required to distinguish between a PR and 
increased blasts caused by bone marrow regeneration. A value of ≤5% blasts may 
also be considered a PR if Auer rods are present.
Definition of Progressive Disease
Because the IWG criteria for AML do not provide a standardized definition for progressive 
disease (PD) [35], in this protocol, PD is defined as 1 of the following:

>50% increase in bone marrow blasts from Baseline value (to a maximum of 
100% blasts).

>50% increase in circulating blasts from Baseline value (to a maximum of 
100% blasts) in peripheral blood (in the exceptional case when bone marrow 
examination is not possible).

Development of biopsy-proven extramedullary disease or new sites of 
extramedullary leukemia.
Note: When deciding PD for patients with high blasts at Baseline (eg, >70% blasts), 
investigators are encouraged to use best medical judgement based on the patient’s overall 
clinical profile and in consideration of local institutional guidelines. 
Definition of Relapse After CR
Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral blood or 
>5% blasts in the bone marrow not attributable to any other cause (eg, bone marrow 
regeneration after consolidation therapy). In the setting of recent treatment, if there are no 
circulating blasts and the bone marrow contains 5% to 20% blasts, a repeat bone marrow 
performed at least a week later is necessary to distinguish relapse from bone marrow 
regeneration.
Investigators should note that some patients may benefit from continued treatment even 
though their bone marrow blast counts may fluctuate over the course of the first 4 cycles. 
For example, 2 of the 6 responders in the single-agent pevonedistat study in R/R AML had 
asymptomatic transient increases in bone marrow blasts after achieving a response. In these 
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2 cases, bone marrow blasts increased from less than 5% to more than 20% and then 
decreased. In addition, another responder in that study had an asymptomatic transient 
increase in bone marrow blasts before achieving a response. In that case, bone marrow blasts 
almost doubled before response. These 3 patients were allowed to remain on study because 
their investigators felt they were clinically benefiting from continued treatment despite 
changes in their bone marrow blast counts. 
Therefore, it might be in the best interest of the patient to continue study treatment in spite 
of transient elevation on bone marrow blast counts that could potentially qualify as PD. In 
those cases, a discussion between the investigator and the sponsor is required before the 
patient can continue study treatment.
7.4.19.2
IWG Response Criteria for MDS
The revised recommendations of the IWG for response criteria in myelodysplasia will be 
used for assessment of disease response in patients with MDS, including CMML [36]. 
Investigators are encouraged to consult the reference for a more detailed explanation of the 
response criteria.
Table 7.a
Modified IWG Response Criteria for Altering Natural History of MDS
Category
Response Criteria (responses must last at least 4 weeks)
Complete remission
Bone marrow: ≤5% myeloblasts with normal maturation of all cell linesa
Persistent dysplasia will be noteda
Peripheral bloodb
Hgb ≥11 g/dL
Platelets ≥100×109/L
Neutrophils ≥1.0×109/L
Blasts 0%
Partial remission
All CR criteria if abnormal before treatment except:
Bone marrow blasts decreased by ≥50% from pretreatment but still >5%
Cellularity and morphology not relevant
Marrow CR
Bone marrow: ≤5% myeloblasts and decrease by ≥50% from pretreatment
Peripheral blood: if HI responses, they will be noted in addition to marrow CR
Stable disease
Failure to achieve at least PR, but no evidence of progression for >8 weeks
Failure
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in the percentage of bone marrow blasts, or progression to a more 
advanced MDS or CMML FAB/WHO subtype than pretreatment
Relapse after CR or 
PR
At least 1 of the following:
Return to pretreatment bone marrow blast percentage
Decrement of ≥50% from maximum remission/response levels in granulocytes or 
platelets
Reduction in Hgb concentration by ≥1.5 g/dL or transfusion dependence
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Table 7.a
Modified IWG Response Criteria for Altering Natural History of MDS
Category
Response Criteria (responses must last at least 4 weeks)
Cytogenic response
Complete
Disappearance of the chromosomal abnormality without appearance of new ones
Partial
At least 50% reduction of the chromosomal abnormality
Disease progression
For patients with:
Less than 5% blasts: ≥50% increase in blasts to >5% blasts
5% to 10% blasts: ≥50% increase to >10% blasts
10% to 20% blasts: ≥50% increase to >20% blasts
20% to 30% blasts: ≥50% increase to >30% blasts
Any of the following:
At least a 50% decrement from maximum remission/response in granulocytes or 
platelets
Reduction in Hgb by ≥2 g/dL
Transfusion dependence
Source: Cheson et al 2006 [36].
Abbreviations: CMML=chronic myelomonocytic leukemia, CR=complete remission, 
FAB=French-American-British, Hgb=hemoglobin, HI=hematologic improvement, IWG=International 
Working Group, MDS=myelodysplastic syndromes, PR=partial remission, WHO=World Health 
Organization.
a Dysplastic changes should consider the normal range of dysplastic changes.
b In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, 
maintenance) before the 4-week period. Such patients can be included in the response category into which 
they fit at the time the therapy is started. Transient cytopenias during repeated chemotherapy courses should 
not be considered as interrupting durability of response, as long as they recover to the improved counts of 
the previous course.
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Table 7.b
Response Criteria for Hematologic Improvement
Hematologic Improvementa
Response criteria (responses must be at least 8 weeks)
Erythroid response 
(pretreatment, <11 g/dL)
Hgb increase by ≥1.5 g/dL
Relevant reduction of units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions per 8 weeks compared with the pretreatment 
transfusion number in the previous 8 weeks. Only RBC transfusions given 
for an Hgb of ≤9.0 g/dL pretreatment will count in the RBC transfusion 
response evaluation
Platelet response 
(pretreatment, <100×109/L)
Absolute increase of ≥30×109/L for patients starting with >20×109/L platelets
Increase from <20×109/L to >20×109/L and by at least 100% 
Neutrophil response 
(pretreatment, <1.0×109/L)
At least 100% increase and an absolute increase >0.5×109/L
Progression or relapse after 
HIb
At least 1 of the following:
At least 50% decrement from maximum response levels in granulocytes 
or platelets
Reduction in Hgb by ≥1.5 g/dL
Transfusion dependence
Abbreviations: Hgb=hemoglobin, HI=hematologic improvement, RBC=red blood cell.
a Pretreatment counts will be the average of Screening and Cycle 1 Day 1 predose samples.
b In the absence of another explanation, such as acute infection, repeated courses of chemotherapy, 
gastrointestinal bleeding, hemolysis, and so forth. It is recommended that the 2 kinds of erythroid and 
platelet responses be reported overall as well as by the individual response pattern.
If a patient has an increase of >50% marrow blasts but, in the opinion of the investigator is 
deriving clinical benefit, the patient may continue with treatment after discussion with the 
sponsor.
7.4.20
Bone Marrow Aspirate and Biopsy Collection for Disease Assessment and 
Molecular Analyses
A bone marrow biopsy (in addition to bone marrow aspirate) is required only at Screening to 
confirm diagnosis; for all other time points, only bone marrow aspirate will be collected 
unless major changes in the patient’s underlying hematological disease are suspected. 
However, a bone marrow biopsy may be collected with bone marrow aspirate in accordance 
with institutional guidelines. If a biopsy was done within 28 days prior to enrollment, this 
archival biopsy may be used and does not need to be repeated. Historical results from up to 
2 months prior to enrollment are acceptable for disease classification, but not disease status.
If historical results do not show either t(15;17) or t(9;22), then these results can be used to 
ensure eligibility, provided a formal confirmatory report is sent as soon as it becomes 
available. 
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Bone marrow aspirate collection at Screening is required for study entry to assess disease 
burden, cytogenetics, and karyotype. Bone marrow aspirates will also be collected at the end 
of Cycle 2 and Cycle 4 (Day 21 [-6 days] for the Single-Agent Arm and any time between 
Days 20 and 28 for the Combination Arm, provided that the disease assessment is available 
before Day 1 of the following cycle) to assess disease response. After Cycle 4, bone marrow 
aspirates will be performed after completion of every third cycle (eg, Cycle 7, Cycle 10, 
etc.), and at the EOS visit for patients who withdraw for reasons other than disease
progression. 
. 
7.5
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s). The appropriate study personnel will 
maintain records of study drug receipt and dispensing.
7.6
Completion of Treatment
Patients will be considered to have completed treatment if they discontinue treatment for any
of the reasons outlined in Section 7.7.
There are no subsequent protocol-specified assessments after the completion of study
treatment.
The EOS visit is to be completed 30 days (+10 days) after the last dose of study drug or 
before the start of subsequent antineoplastic therapy (other than hydroxyurea), if that occurs 
sooner. See the Schedules of Events for appropriate assessments during the EOS visit.
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7.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Patients will receive treatment until PD or discontinuation for any other reason, including 
those outlined below. Patients may be allowed to remain on study, after discussion 
between the investigator and the medical monitor, even if they meet the criteria for PD 
based only on bone marrow blast counts.
Treatment with study drug may be discontinued for any of the following reasons:

AE.

Protocol violation.

Progressive disease.

Symptomatic deterioration.

Initiation of hematopoietic stem cell transplant.

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for the EOS visit will 
be completed as specified in the Schedules of Events. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
7.7.1
Patient Replacement:
Patients in the escalation phase who are withdrawn from the treatment or experience dosing 
delay or dosing reduction in either pevonedistat or azacitidine during Cycle 1 for reasons 
other than DLT will be replaced.
7.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.
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
Study terminated by sponsor.

Withdrawal by subject.

Death.

Progressive disease.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
7.9
Completion of Study
Patients will be considered to have completed the study if they have completed study 
treatment and the EOS visit or until the sponsor terminates the study.
8.
STATISTICAL AND QUANTITATIVE ANALYSES
8.1
Statistical Methods
Analyses will be primarily descriptive in nature. No formal statistical hypothesis testing will 
be performed. A formal statistical analysis plan will be developed and finalized before 
database lock.
Summary tabulations will be presented to display the number of observations, mean, 
standard deviation, median, minimum, and maximum for continuous variables along with 
the number and percentage (calculated using non-missing values) per category for 
categorical data, unless specified otherwise.
8.1.1
Determination of Sample Size
This study will use a 3+3 design in the dose escalation phase for single-agent pevonedistat 
and the pevonedistat+azacitidine combination. The escalation starts with single-agent 
pevonedistat (group of 3 patients) at 25 mg/m2. If this dose is safe and tolerable, the 
escalation will then be split into 2 independent arms: 1 for single-agent pevonedistat and the 
other for the pevonedistat+azacitidine combination. At the highest tolerated dose level, an 
additional 3 patients will be added during the dose escalation phase to confirm safety and 
tolerability. Assuming this study schema and also assuming an additional 6 patients in the 
dose expansion phase, the estimated number of patients for the study via simulation is 30 to 
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33. To further allow for other considerations, such as the number of PK-evaluable patients 
and number of patients required per country or East Asian race group at the highest dose 
level, the estimated number of patients to be enrolled in this study is approximately 37.
8.1.2
Randomization and Stratification
No randomization or stratification will be performed in this study.
8.1.3
Populations for Analysis
The populations used for analysis will include the following:

Safety population: patients who receive at least 1 dose of study drug will be used 
for all safety analyses and efficacy analyses.

PK population: patients who have sufficient dosing in Cycle 1 and pevonedistat 
concentration-time data to reliably estimate PK parameters by noncompartmental 
analysis methods and who have not received any excluded concomitant medications 
per the protocol.

Response-Evaluable population: patients who receive at least 1 dose of study drug, 
have a Baseline disease assessment, and have at least 1 post-Baseline disease 
assessment will be used for analyses of response.

DLT-Evaluable population: patients who either experience DLT during Cycle 1 or 
receive all scheduled doses of study drug in Cycle 1 without DLT.
8.1.4
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations. No 
imputation of values for missing data will be performed unless specified otherwise. The 
relevance of missing sample data will be assessed.
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
8.1.5
Demographic and Baseline Characteristics
Demographic and Baseline characteristics, including gender, age, race, weight, height, 
Baseline disease characteristics, and other parameters as appropriate, will be summarized in 
a descriptive fashion.
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8.1.6
Efficacy Analysis
Efficacy measures will include disease response and duration of disease response. Analysis 
of all efficacy measures will be descriptive. Disease response in patients with AML will be 
based on the ORR (CR+PR [for AML] and CR+PR+HI [for MDS]) and CR as determined 
by the investigator using the Revised Recommendations of the IWG for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in Acute Myeloid Leukemia (Section 7.4.19.1).
For AML patients, all CR includes both CR and CRi.
Disease response in patients with MDS will be based on the best overall response as 
determined by the investigator using the revised IWG response criteria for MDS 
(Section 7.4.19.2) [36]. The duration of response will be defined in patients with disease 
response (CR or PR) as the time between the first documentation of response and disease 
progression. Responders without disease progression will be censored at the last clinical 
assessment of response.
8.1.7
Pharmacokinetics 
PK Analysis
Individual values and descriptive statistics of pevonedistat plasma concentration-time data 
and PK parameters will be listed and tabulated by treatment arm, dose level, and study day 
(Single-agent and Combination Arms). PK parameters of pevonedistat alone or combined 
with azacitidine in individual patients will be estimated using noncompartmental methods. 
PK parameters include, but are not limited to, Cmax, Tmax, the area under the plasma 
concentration-time curve from 0 to the last measurable concentration (AUClast), AUCτ, CL, 
volume of distribution at steady-state (Vss), t1/2, area under the plasma concentration-time 
curve from 0 to infinity (AUC∞), and accumulation ratio, as data permit.
For each of the treatment arms, individual and mean pevonedistat plasma concentration-time 
data will be listed by patient identification number and plotted over time (including nominal 
and actual times) by dose level and study day using linear and logarithmic scales. The 
relationships between dose and Cmax or AUC will also be explored graphically for dose 
proportionality, as deemed appropriate.
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8.1.8
Safety Analysis
The incidence of DLT will be tabulated for each dose group and treatment (single agent or 
combination). In addition, to assess the relationship between toxicities and pevonedistat 
dose, the preferred term of individual toxicities will be summarized by their frequency and 
intensity for each dose group and treatment. The DLT-Evaluable population will be used for 
the analysis of DLTs.
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and changes 
from Baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
Safety population. Exposure to study drug and reasons for discontinuation will be tabulated.
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days (+10 days) after the last dose of study drug will be tabulated.
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will include the following categories:
!
Treatment-emergent AEs.
!
Drug-related treatment-emergent AEs.
!
Treatment-emergent Grade 3, Grade 4, and Grade 5 AEs (presented by grade and 
overall).
!
Drug-related treatment-emergent Grade 3, Grade 4, and Grade 5 AEs (presented by 
grade and overall).
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
The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of all patients).

SAEs.
A listing of treatment-emergent AEs resulting in study drug discontinuation will be 
provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change 
from Baseline in clinical laboratory parameters) will be presented for all scheduled 
measurements over time. Mean laboratory values over time will be plotted for key 
laboratory parameters.
Descriptive statistics for the actual values (and/or the changes from Baseline) of vital signs 
and weight over time will be tabulated by scheduled time point.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE 
version 4.03 grade from Baseline to the worst post-Baseline value. Graphical displays of key 
safety parameters, such as scatter plots of Baseline versus worst post-Baseline values, may 
be used to understand the pevonedistat safety profile.
All concomitant medications collected from Screening through the study period will be 
classified to preferred terms according to the WHO drug dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of pevonedistat.
8.1.9
Interim Analysis
As this is a phase 1/1b study, no formal interim analysis is planned. Safety and PK data will 
be reviewed on an ongoing basis during the dose escalation and expansion phases of the 
study.
8.2
Pharmacokinetic Modeling 
Individual pevonedistat plasma concentration-time data may be combined with other study 
data (including dosing information and patient-specific covariates) from previous and future 
pevonedistat clinical trials to create an analysis dataset for population PK analysis. Details 
of the modeling approach will be provided in a separate analysis plan, and the results of 
these analyses will be reported separately.
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9.
STUDY COMMITTEES
9.1
Independent Data Monitoring Committee
An independent data monitoring committee (IDMC) has been formed to periodically 
monitor the overall conduct of studies within the pevonedistat program, including to review 
accumulating clinical study data and safety data (both clinical and nonclinical) and to make 
recommendations to Millennium to safeguard the interests of study participants. 
Additionally, the IDMC may make recommendations relating to the selection, recruitment, 
and retention of study participants, patient management, improving adherence to protocol-
specified regimens, and procedures for data management and quality control.
Further details regarding the IDMC will be provided in the IDMC charter.
10.
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study 
participation.
10.1.2
Adverse Event Definition
AE means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product whether or not it is related to the 
medicinal product. This includes any newly occurring event or a previous condition that has 
increased in severity or frequency since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from Baseline.
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10.1.3
Serious Adverse Event Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life threatening (refers to an AE in which the patient was at risk of death at the 
time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 4.03, effective date 14 June 2010 [34]. Clarification should be 
made between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), 
because the terms serious and severe are NOT synonymous. The general term severe is often 
used to describe the intensity (severity) of a specific event; the event itself, however, may be 
of relatively minor medical significance (such as a Grade 3 headache). This is NOT the 
same as serious, which is based on patient/event outcome or action criteria described above, 
and is usually associated with events that pose a threat to a patient’s life or ability to 
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function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For 
example, a WBC count of 1000/mm3 to less than 2000 is considered Grade 3 (severe) but 
may not be considered serious. Seriousness (not intensity) serves as a guide for defining 
regulatory reporting obligations.
10.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF (see Section 10.3 for the 
period of observation). Any clinically relevant deterioration in laboratory assessments or 
other clinical finding is considered an AE. When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) 
must be reported (see Section 10.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance or designee (contact information provided 
below). This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event. The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site. A sample of the SAE Form may be found in the Study Manual. 
Follow-up information on the SAE or serious pretreatment event may be requested by 
Millennium. SAE report information must be consistent with the data provided on the eCRF.
SAE Reporting Contact Information
BI Medical, Inc
Korea: 00798-8171773
Taiwan: 00801-814742
Japan: 0120-490-849
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, investigators, 
and ethics committees as applicable, in accordance with national regulations in the countries 
where the study is conducted. Specifically in the EU, the sponsor will ensure that all relevant 
information from SUSARs that are fatal or life-threatening is recorded and reported as soon 
as possible to the regulatory authorities in all the Member States concerned, and to the 
Ethics Committee, and in any case no later than 7 days after knowledge by the sponsor of 
such a case, and relevant follow-up information is subsequently communicated within an 
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additional 8 days. All other SUSARs shall be reported to the regulatory authorities 
concerned and to the Ethics Committee concerned as soon as possible within a maximum of
15 days of first knowledge by the sponsor. The sponsor will also inform all the investigators 
in the clinical trial.
Once a year throughout the conduct of the clinical trial, the sponsor will provide the 
regulatory authorities in whose territory the clinical trial is being conducted and the Ethics 
Committees with a listing of all SUSARs that have occurred over the past year and a report 
of the subjects’ safety.
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before study drug was given are not to be considered AEs unless the condition deteriorated 
in an unexpected manner during the trial (eg, surgery was performed earlier or later than 
planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of 
the event and the relationship of the event to study drug administration. For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [34]. The criteria are provided in 
the Study Manual.
Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question: Is there a reasonable possibility that the AE is associated with the 
study drug?
10.3
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from administration of the first dose of study drug through 
30 days (+10 days) after administration of the last dose of study drug and recorded in 
the eCRFs.

Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the informed consent 
form (ICF) up to first dose of study drug but will not be recorded in the eCRF.
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
Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from the first dose of study drug through 30 days 
(+10 days) after administration of the last dose of study drug and recorded in the 
eCRF. After this period, only related SAEs must be reported to the Millennium 
Department of Pharmacovigilance or designee. SAEs should be monitored until they 
are resolved or are clearly determined to be due to a patient’s stable or chronic 
condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug. The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 10.2). 
The pregnancy must be followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee (see Section 10.2). Every effort should be made to follow the pregnancy for the 
final pregnancy outcome.
11.
ADMINISTRATIVE REQUIREMENTS
11.1
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s). The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB. 
The investigator is responsible for supervising any individual or party to whom the 
investigator delegates trial-related duties and functions conducted at the trial site. If the 
investigator/institution retains the services of any individual or party to perform trial-related 
duties and functions, the investigator/institution should ensure this individual or party is 
qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
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11.2
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient. Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based electronic data capture (EDC) application. Millennium will have access to all 
data upon entry in the EDC application.
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution. Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
11.3
Electronic Case Report Form Completion 
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
eCRFs will be completed for each study patient. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible. The audit trail entry will show the user’s 
identification information and the date and time of the correction.
Millennium, or a designee, will retain the eCRF data and corresponding audit trails. A copy 
of the final archival eCRF in the form of a compact disk or other electronic media will be 
placed in the investigator’s study file.
11.4
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
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All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation. During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.
11.5
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards. The IRB/IEC will review all appropriate study documentation 
to safeguard the rights, safety, and well-being of the patients. The study will be conducted 
only at sites where IRB/IEC approval has been obtained. The protocol, IB, ICF, 
advertisements (if applicable), written information given to the patients (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the investigator or the sponsor, as allowed by local regulations.
11.6
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation. The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
11.7
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number. The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
11.8
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies). Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium. Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients. Millennium, 
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or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Millennium, or a designee, if 
circumstances permit, to discuss the planned course of action. Any departures from the 
protocol must be documented.
11.9
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection. Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
11.10
Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the trial site is the responsibility of the investigator. 
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site. Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with 
governing regulations.
11.11
Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals 
who identify a potential product complaint situation should immediately contact the Medical
Information Call Center/Dohmen Life Science Services and report the complaint. The 
contact information is as follows: 
Medical Information Call Center:
Dohmen Life Science Services
Phone:
1-866-835-2233
Fax:
1-800-881-6092
E-mail:
GlobalOncologyMedinfo@takeda.com
Hours:
Mon-Fri, 9 AM–7 PM, ET
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Whenever possible, the associated product should be maintained in accordance with the 
label instructions pending further guidance from a Millennium Quality representative.
Product complaints in and of themselves are not AEs. If a product complaint results in an 
SAE, an SAE form should be completed and sent to BI Medical, Inc. (refer to Section 10.2).
11.12
Closure of the Study
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause. Written 
notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients.

Failure to enroll patients at an acceptable rate.

Insufficient adherence to protocol requirements.

Insufficient, incomplete, and/or unevaluable data.

Determination of efficacy based on interim analysis.

Plans to modify, suspend, or discontinue the development of the study drug.
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded. In the event 
that any access devices for the EDC application have been provided, these will be returned 
to Millennium once the site’s participation in the study has concluded.
11.13
Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s). If the investigator withdraws from the responsibility of keeping the study 
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records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.
12.
USE OF INFORMATION
All information regarding study drug supplied by Millennium to the investigator is 
privileged and confidential information. The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from 
Millennium. It is understood that there is an obligation to provide Millennium with complete 
data obtained during the study. The information obtained from the clinical study will be used 
toward the development of study drug and may be disclosed to regulatory authority(ies), 
other investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.
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13.
INVESTIGATOR AGREEMENT
I have read Protocol Pevonedistat-1012 Amendment 03: A Phase 1/1b, Open-label Study of 
Pevonedistat (MLN4924, TAK-924) as Single Agent and in Combination with Azacitidine 
in Adult East Asian Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic 
Syndromes (MDS).
I agree to conduct the study as detailed herein and in compliance with International Council 
for Harmonisation Guidelines for Good Clinical Practice and applicable regulatory 
requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)
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14.
REFERENCES
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Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 
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2.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 
2008 revision of the World Health Organization (WHO) classification of myeloid 
neoplasms and acute leukemia: rationale and important changes. Blood 
2009;114(5):937-51.
3.
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. 
Revised international prognostic scoring system for myelodysplastic syndromes. 
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Kuendgen A, Germing U. Emerging treatment strategies for acute myeloid leukemia 
(AML) in the elderly. Cancer Treat Rev 2009;35(2):97-120.
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epidemiological investigation of leukemia incidence between 2003 and 2007 in 
Nanjing, China. Journal of hematology & oncology 2010;3:21.
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Matsunaga T, Yamashita K, Kubuki Y, Toyama T, Imataki O, Maeda K, et al. Acute 
myeloid leukemia in clinical practice: a retrospective population-based cohort study 
in Miyazaki Prefecture, Japan. Int J Hematol 2012;96(3):342-9.
7.
Laubach J, Rao AV. Current and emerging strategies for the management of acute 
myeloid leukemia in the elderly. Oncologist 2008;13(10):1097-108.
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NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia version 
1.2015. National Comprehensive Cancer Network. 2014.
9.
Coleman M, Alexe D-M, Albreht T, Mckee M. Responding to the challenge of 
cancer in Europe. Ljubljana: Institute of Public Health of the Republic of Slovenia; 
2008.
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DeVita V, Lawrence T, Rosenberg S, DePinho R, Weinberg R, editors. DeVita, 
Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology 8th ed. 
Philadelphia, PA: Lippincott Williams & Wilkins; 2008.
11.
Chihara D, Ito H, Katanoda K, Shibata A, Matsuda T, Sobue T, et al. Incidence of 
myelodysplastic syndrome in Japan. J Epidemiol 2014;24(6):469-73.
12.
NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes 
version 1.2015. National Comprehensive Cancer Network. 2014.
13.
Zeidan AM, Linhares Y, Gore SD. Current therapy of myelodysplastic syndromes. 
Blood Rev 2013;27(5):243-59.
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Klepin HD, Rao AV, Pardee TS. Acute myeloid leukemia and myelodysplastic 
syndromes in older adults. J Clin Oncol 2014;32(24):2541-52.
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Uchida T, Ogawa Y, Kobayashi Y, Ishikawa T, Ohashi H, Hata T, et al. Phase I and 
II study of azacitidine in Japanese patients with myelodysplastic syndromes. Cancer 
Sci 2011;102(9):1680-6.
16.
Lee YG, Kim I, Yoon SS, Park S, Cheong JW, Min YH, et al. Comparative analysis 
between azacitidine and decitabine for the treatment of myelodysplastic syndromes. 
Br J Haematol 2013;161(3):339-47.
17.
Mufti GJ, Potter V. Myelodysplastic syndromes: who and when in the course of 
disease to transplant. Hematology 2012;2012:49-55.
18.
Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, et al. An 
inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 
2009;458:732-6.
19.
Lin JJ, Milhollen MA, Smith PG, Narayanan U, Dutta A. NEDD8-targeting drug 
MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering 
checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res 
2010;70(24):10310-20.
20.
Milhollen MA, Narayanan U, Soucy TA, Veiby PO, Smith PG, Amidon B. 
Inhibition of NEDD8-activating enzyme induces rereplication and apoptosis in 
human tumor cells consistent with deregulating CDT1 turnover. Cancer Res 
2011;71(8):3042-51.
21.
Swords RT, Erba HP, DeAngelo DJ, Bixby DL, Altman JK, Maris M, et al. 
Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in 
patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 
study. Br J Haematol 2015;169(4):534-43.
22.
Swords RT, Savona MR, Maris MB, Erba HP, Berdeja JG, Foran JM, et al. 
Pevonedistat (MLN4924), an investigational, first-in-class NAE inhibitor, in 
combination with azacitidine in elderly patients with acute myeloid leukemia (AML) 
considered unfit for conventional chemotherapy: Updated results from the phase 1 
C15009 trial. 2014 Annual Meeting of the American Society of Hematology (ASH); 
06-09 December 2014; San Francisco, CA.
23.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et 
al. Efficacy of azacitidine compared with that of conventional care regimens in the 
treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, 
phase III study. Lancet Oncol 2009;10(3):223-32.
24.
Swords RT, Kelly KR, Smith PG, Garnsey JJ, Mahalingam D, Medina E, et al. 
Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute 
myeloid leukemia. Blood 2010;115(18):3796-800.
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25.
Bacher U, Kern W, Alpermann T, Schnittger S, Kohlmann A, Klein HU, et al. 
Prognosis in patients with MDS or AML and bone marrow blasts between 10% and 
30% is not associated with blast counts but depends on cytogenetic and molecular 
genetic characteristics. Leukemia 2011;25(8):1361-4.
26.
Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, 
et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic 
syndromes and low blast count acute myeloid leukemias. Leukemia 
2011;25(7):1147-52.
27.
Rhyasen GW, Starczynowski DT. Deregulation of microRNAs in myelodysplastic 
syndrome. Leukemia 2012;26(1):13-22.
28.
Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F, et al. 
MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid 
leukemia. Blood 2008;111(6):3183-9.
29.
Li Z, Lu J, Sun M, Mi S, Zhang H, Luo RT, et al. Distinct microRNA expression 
profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci 
U S A 2008;105(40):15535-40.
30.
Palma CA, Al Sheikha D, Lim TK, Bryant A, Vu TT, Jayaswal V, et al. MicroRNA-
155 as an inducer of apoptosis and cell differentiation in Acute Myeloid Leukaemia. 
Mol Cancer 2014;13:79.
31.
Gerloff D, Grundler R, Wurm AA, Brauer-Hartmann D, Katzerke C, Hartmann JU, 
et al. NF-kappaB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute 
myeloid leukemia. Leukemia 2014:1-13.
32.
Chen WL, Wang JH, Zhao AH, Xu X, Wang YH, Chen TL, et al. A distinct glucose 
metabolism signature of acute myeloid leukemia with prognostic value. Blood 
2014;124(10):1645-54.
33.
VIDAZA (azacitidine for injection) for SC or IV use [package insert]. Summit, NJ: 
Celgene Corporation, 2014.
34.
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.
35.
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH. Revised 
recommendations of the International Working Group for diagnosis, standardization 
of response criteria, treatment outcomes, and reporting standards for therapeutic 
trials in acute myeloid leukemia. J Clin Oncol 2003;21(24):4642-9.
36.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, 
et al. Clinical application and proposal for modification of the International Working 
Group (IWG) response criteria in myelodysplasia. Blood 2006;108(2):419-25.
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37.
Schanz J, Tuchler H, Sole F, Mallo M, Luno E, Cervera J, et al. New comprehensive 
cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and 
oligoblastic acute myeloid leukemia after MDS derived from an international 
database merge. J Clin Oncol 2012;30(8):820-9.
38.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J 
Clin Oncol 1982;5(6):649-55.
39.
The Criteria Committee of New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, 
Brown & Co; 1994.
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15.
APPENDICES
15.1
Revised International Prognostic Scoring System for MDS
Tables are adapted from mds-foundation.org/ipss-r-calculator/, Revised International
Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes Risk Assessment 
Calculator, Accessed 05 January 2015, based on Greenberg et al. [3].
Table 15.a
IPSS-R Prognostic Score Values
Prognostic Variable
0
0.5
1
1.5
2
3
4
Cytogenetics
Very Good
Good
Intermediate
Poor
Very Poor
BM Blast %
≤2
>2 to <5
5 to 10%
>10%
Hemoglobin
≥10
8 to <10
<8
Platelets
≥100
50 to 
<100
<50
ANC
≥0.8
<0.8
Source: Greenberg et al, Blood 120: 2454, 2012 [3].
Abbreviations: ANC=absolute neutrophil count, BM=bone marrow, IPSS-R=Revised International Prognostic 
Scoring System.
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b
Poo
P
lic
0%
e marrow
marro
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Table 15.c
IPSS-R Prognostic Risk Categories/Scores
Risk Category
Risk Score
Very low
≤1.5
Low
>1.5 to 3
Intermediate
>3 to 4.5
High
>4.5 to 6
Very high
>6
Source: Greenberg et al, Blood 120: 2454, 2012 [3].
Abbreviation: IPSS-R=Revised International Prognostic Scoring System.
15.2
Eastern Cooperative Oncology Group Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.
5
Dead.
Source: Oken MM, et al. 1982 [38].
15.3
Cockcroft-Gault Equation
For male subjects:
Creatinine clearance= (140age[years])weight [kg]
OR
(140age[years])weight [kg]
72(serum creatinine[mg/dL])
0.81(serum creatinine[mol/L])
For female subjects:
Creatinine clearance= 0.85(140age[years])weight [kg]
OR 0.85(140age[years])weight [kg]
72(serum creatinine[mg/dL])
0.81(serum creatinine[mol/L])
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15.4
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence 
of cardiovascular 
disease.
II
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, Brown & Co; 1994 [39].
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15.5
Excluded CYP3A Inhibitors and Inducers
Note that HIV medications that are strong or moderate CYP3A inhibitors or inducers are not 
included in this list because HIV-positive patients are excluded from study participation.
15.5.1
Classification of CYP3A Inhibitors
Use of moderate and strong CYP3A inhibitors listed in Table 15.d should be avoided for 
7 days prior to initiation of pevonedistat therapy and for the duration of Cycle 1 only. The 
use of moderate and strong CYP3A inhibitors is permitted in treatment Cycle 2 and beyond. 
The moderate CYP3A inhibitor amiodarone has a long half-life (mean of 58 days). 
Consequently, amiodarone must be discontinued 6 months before the first dose of 
pevonedistat.
Table 15.d
In Vivo Inhibitors of CYP3A 
Strong Inhibitors
5-fold increase in AUC
Moderate Inhibitors
2-fold, but <5-fold increase in AUC
Clarithromycin
Amiodarone
Itraconazole
Aprepitant
Ketoconazole
Diltiazem
Nefazodone
Erythromycin
Voriconazolea
Ciprofloxacina
Posaconazole
Cimetidine
Telithromycin
Fluconazolea
Conivaptan
Verapamil
Tofisopam
Dronedarone
Abbreviations: AUC=area under the plasma concentration-time curve, CYP=cytochrome P450.
This is not an exhaustive list; please refer to the following sources: 
medicine.iupui.edu/flockhart/table htm and 
fda.gov/CDER/drug/drugInteractions/tableSubstrates htm for additional information.
a Permitted only if the patient’s clinical condition requires the use of the azole antifungal agents, 
voriconazole and fluconazole, or ciprofloxacin. The patient may receive the azole antifungal or 
ciprofloxacin from 24 hours after the last pevonedistat dose to 72 hours before the next pevonedistat 
dose. For example, if a patient receives pevonedistat on a Monday (Day 1), Wednesday (Day 3), and 
Friday (Day 5) schedule, then the azole antifungal or ciprofloxacin may be administered (if clinically 
necessary and no suitable alternative) from the Saturday after the Day 5 dose (Day 6) up to the Friday 
(Day 26) before the Monday dose of the next cycle.
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15.5.2
Classification of CYP3A Inducers
Use of the moderate and strong CYP3A inducers listed in Table 15.e should be avoided 
during pevonedistat therapy.
Table 15.e
In Vivo Inducers of CYP3A
Strong Inducers
≥80% decrease in AUC
Moderate Inducers
50% to 80% decrease in AUC
Carbamazepine
Bosentan
Phenytoin
Modafinil
Phenobarbital
Nafcillin
Primidone
Rifabutin
Rifampin
Rifapentine
St. John’s wort
Abbreviations: AUC=area under the plasma concentration versus time curve, CYP=cytochrome P450.
This is not an exhaustive list; please refer to the following sources: 
medicine.iupui.edu/flockhart/table htm and 
fda.gov/CDER/drug/drugInteractions/tableSubstrates.htm for additional information.
15.6
Body Surface Area Calculation
BSA should be calculated using a standard formula. An example formula follows:
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15.7
3+3 Dose Escalation and Expansion Flowchart
Figure footnotes appear on next page.
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Section 15.7 Figure Footnotes
Abbreviations: A=azacitidine 75 mg/m2, DLT=dose-limiting toxicity, P10=pevonedistat 10 mg/m2, 
P20=pevonedistat 20 mg/m2, P25=pevonedistat 25 mg/m2, P44=pevonedistat 44 mg/m2.
* dosing stop.
**dosing stop, 1 of the following options will be chosen by the sponsor:

Three additional patients will be added to the previous dose level, or declare the lower dose level as 
tolerable dose if 6 patients have already been dosed.

An intermediate dose between 25 and 44 mg/m2 may be tested for single-agent arm; for the 
combination arm, an intermediate dose of 15 mg/m2 may be considered.
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15.8
Absolute Neutrophil Count Calculation 
ANC=total leukocyte count×total percentage of neutrophils (segmented neutrophils+band 
neutrophils)
Example:
If total leukocyte count=4.3; segmented neutrophils=48%; band neutrophils=2%,
Then: 4300×(0.48+0.02)=4300×0.5=ANC of 2150.
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15.9
Definition of Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. Please refer to the following source for additional information: European Heads 
of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_ CTFG_Contraception.pdf
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15.10 Methods of Contraception Considered to be Effective 
Acceptable Contraception Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered to be highly effective. Such methods include the 
following:

Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulationa:
–
Oral.
–
Intravaginal.
–
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulationa:
–
Oral.
–
Injectable.
–
Implantable.b

Intrauterine device.b

Intrauterine hormone-releasing system.b

Bilateral tubal occlusion.b

Vasectomised partner.b,c

Sexual abstinence.d
Contraception Methods Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include the following:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action.
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
Male or female condom with or without spermicide.e

Cap, diaphragm, or sponge with spermicide.e
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_ 
CTFG_Contraception.pdf
a
Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which 
may reduce the efficacy of the contraception method.
b
Contraception methods that in the context of this guidance are considered to have low user dependency.
c
Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the woman of childbearing potential participant of the study and that the vasectomised partner has 
received medical assessment of the surgical success.
d
In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
e
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier 
methods) are also considered acceptable, but not highly effective birth control methods.
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
Specify that a phase 1 drug-drug interactions (DDI) study is ongoing in the 
pharmacokinetics of pevonedistat/DDI risk assessment section.

Update the section on the rationale for the combination of pevonedistat and azacitidine. 

Change the observed increases in alanine aminotransferase and aspartate 
aminotransferase to Grade 1 through 4.

Update the risk language regarding increases in serum creatinine.

Clarify that pevonedistat escalation beyond 44 mg/m2 when given as single agent may 
be allowed.

Update the section on the risks and benefits from the ongoing study with pevonedistat 
plus azacitidine.

Clarify that the study population will include East Asian patients only. 

Clarify that the primary endpoints will include summary statistics of PK parameters.

Specify that the Combination Arm will include East Asian patients with 
relapsed/refractory (R/R) acute myeloid leukemia (AML) or R/R higher-risk (HR) 
myelodysplastic syndromes (MDS) (including R/R chronic myelomonocytic leukemia 
[CMML]) and previously untreated AML or HR MDS (including CMML).

Clarify that for inclusion into the study, patients must be aged 18 years or older and 
meet diagnostic criteria when written study informed consent is obtained.

Specify that hydroxyurea may be used to control WBC counts no lower than 10,000/µL
rather than circulating leukemic blast cell counts.

Revise the inclusion criteria to include the diagnosis of nonproliferative CMML.

Update exclusion criteria to exclude patients with prothrombin time or activated partial 
thromboplastin time >1.5 times the upper limit of the normal range.

Add persistent elevations of transaminases and bilirubin above Grade 2 beyond 2 days 
between doses as a dose-limiting toxicity.

Specify in the text that the delay period for initiation of a cycle will be >4 weeks.

Clarify the limited use of known P-glycoprotein inhibitors during the study.

Specify that the use of investigational agents for the treatment of MDS will be 
excluded during the study.

Modify the period of contraception use after the last dose of study drug for women of 
childbearing potential to 4 months.

Correct the description of the investigational product formulation.

Correct the drug product labeling. 

Delete coordinating investigators from study personnel. 

Remove gamma glutamyl transferase from the complete serum chemistry panel.

Remove urobilinogen from the urinalysis with microscopic analysis.

Add urine safety assessments to the Clinical Laboratory Evaluations section.

Change the sample collected at Screening for genotyping variations in genes encoding 
drug-metabolizing enzymes from peripheral blood samples to buccal swabs.
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15.13
Amendment 03 Detailed Summary of Changes
The primary section(s) of the protocol affected by the changes in Amendment 03 are 
indicated. The corresponding text has been revised throughout the protocol. 
Change 1: Adjust contraception requirements to be consistent with CTFG 
recommendations.
The primary change occurs in Section 6.7 Precautions and Restrictions:
Initial 
wording:
It is not known what effects pevonedistat has on human pregnancy or 
development of the embryo or fetus. Therefore, female patients 
participating in this study should avoid becoming pregnant, and male 
patients should avoid impregnating a female partner. Nonsterilized female 
patients of reproductive age group and male patients should use effective 
methods of contraception through defined periods during and after study 
treatment as specified below.
1) Some examples of effective contraceptive methods include 
intrauterine devices (IUD), hormonal contraceptives, condom and 
others
2) Use only contraceptive methods that are locally approved in each 
country
3) Female patients must meet 1 of the following:

Postmenopausal (not due to other medical reasons) for at least 
1 year before the Screening visit, or

Surgically sterile, or

If they are of childbearing potential (as defined in 
Section 7.4.13), agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the 
informed consent through 4 months after the last dose of 
pevonedistat (for patients in the Single-Agent Arm), or through 
4 months after the last dose of azacitidine (for patients in the 
Combination Arm), or

Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, postovulation 
methods] and withdrawal are not acceptable methods of 
contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), must 
agree to 1 of the following:

Practice effective barrier contraception during the entire study 
treatment period and through 4 months after the last dose of 
study drug (if barrier methods are not locally approved to be 
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used by males, then their female partners should use effective 
contraceptive methods as described in the above), or

Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, postovulation methods 
for the female partner] and withdrawal are not acceptable 
methods of contraception.)
Amended or 
new 
wording:
It is not known what effects pevonedistat has on human pregnancy or 
development of the embryo or fetus. Therefore, female patients 
participating in this study should avoid becoming pregnant, and male 
patients should avoid impregnating a female partner. Nonsterilized female 
patients of reproductive age group and male patients should use highly 
effective methods of contraception (see list provided in Section 15.10) 
through defined periods during and after study treatment as specified 
below.
1) Some examples of effective contraceptive methods include 
intrauterine devices (IUD), hormonal contraceptives, condom and 
others
2) Use only contraceptive methods that are locally approved in each 
country
3) Female patients must meet 1 of the following:

Postmenopausal (not due to other medical reasons; see 
Section 15.10) for at least 1 year before the Screening visit, or

Surgically sterile, or

If they are of childbearing potential (as defined in 
Section 7.4.13), agree to practice 21 highly effective methods
and 1 additional effective (barrier) method of contraception, 
at the same time, from the time of signing the informed consent 
through 4 months after the last dose of pevonedistat (for 
patients in the Single-Agent Arm), or through 4 months after 
the last dose of azacitidine (for patients in the Combination 
Arm), or

Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, postovulation 
methods] and], withdrawal, spermicides only, and lactational 
amenorrhea are not acceptable methods of contraception. 
Female and male condoms should not be used together.)

Female patients must agree not to donate eggs (ova) during 
the course of this study or 4 months after receiving their last 
dose of pevonedistat (for patients in the Single-Agent Arm), 
or through 4 months after the last dose of azacitidine (for 
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patients in the Combination Arm).
Male patients, even if surgically sterilized (ie, status postvasectomy), must 
agree to 1 of the following:

Practice effective barrier contraception during the entire study 
treatment period and through 4 months after the last dose of 
study drug (if barrier methods are not locally approved to be 
used by males, then their female partners should use effective 
contraceptive methods as described in the above), or

Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, postovulation methods 
for the female partner] and], withdrawal, spermicides only, 
and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used 
together.)

Male patients must agree not to donate sperm during the 
course of this study or 4 months after receiving their last 
dose of pevonedistat (for patients in the Single-Agent Arm), 
or through 4 months after the last dose of azacitidine (for 
patients in the Combination Arm).
Rationale for Change:
The update in contraception requirements was included for consistency with 
program-wide updates.
The following sections also contain this change:

Section 5.1 Inclusion Criteria.

Section 5.2 Exclusion Criteria.

Section 15.10 Methods of Contraception Considered to be Effective.
Change 2: Clarify that when additional electrocardiograms will be performed 
immediately following pevonedistat administration, there is up to a 10-minute window 
for measurement.
The primary change occurs in the Schedules of Events for the Single-Agent Arm, 
Cycle 1, footnote f:
Initial 
wording:
f
A 12-lead ECG will be performed during Screening; predose on Cycle 1 Day 1; and 
on Cycle 1 Days 1, 3, and 5, 6 hours (± 1 hour) after the completion of the 
pevonedistat infusion. An additional ECG will also be performed on Cycle 1 Day 1 
immediately following pevonedistat administration (within 5-10 minutes after the 
completion of pevonedistat infusion).
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Amended or 
new 
wording: 
f
A 12-lead ECG will be performed during Screening; predose on Cycle 1 Day 1; and 
on Cycle 1 Days 1, 3, and 5, 6 hours (± 1 hour) after the completion of the 
pevonedistat infusion. An additional ECG will also be performed on Cycle 1 Day 1 
immediately following pevonedistat administration (within 5 up to 10 minutes after 
the completion of pevonedistat infusion).
Rationale for Change:
Text describing the window of measurement was revised for clarity. 
The Schedules of Events for the Combination Arm, Cycle 1, footnote h, also contains this 
change.
Change 3: Clarify that vital signs assessment includes a ±10-minute window.
The primary change occurs in the Schedules of Events for the Single-Agent Arm, Cycle 
1, footnote e:
Initial 
wording:
e Vital sign measurements, including body temperature, diastolic and systolic blood 
pressure, and heart rate, will be obtained during Screening; on all dosing days 
(predose [20 minutes before pevonedistat infusion ±10 minutes] and 1 hour [±10 
minutes] after the completion of pevonedistat infusion); on Day 2, Day 8, and Day 15; 
at EOS; and as clinically indicated. The Day 1 vital sign measurements will be taken 
pre-infusion and 30 minutes, 1 hour, 4 hours, and 6 hours after the completion of 
pevonedistat infusion.
Amended or 
new 
wording:
e Vital sign measurements, including body temperature, diastolic and systolic blood 
pressure, and heart rate, will be obtained during Screening; on all dosing days 
(predose [20 minutes before pevonedistat infusion ±10 minutes] and 1 hour [±10 
minutes] after the completion of pevonedistat infusion); on Days 2, 8, and 15; at EOS; 
and as clinically indicated. The Day 1 vital sign measurements will be taken pre-
infusion and 30 minutes (±10 minutes), 1 hour (±10 minutes), 4 hours (±10 
minutes), and 6 hours (±10 minutes) after the completion of pevonedistat infusion.
Rationale for Change:
The addition of the ±10-minute window was made to allow flexibility in vital sign 
measurement.
The following sections also contain this change:

The Schedules of Events for the Single-Agent Arm, Cycle 2 and Beyond, 
footnote d.

The Schedules of Events for the Combination Arm, Cycle 1, footnote g.

The Schedules of Events for the Combination Arm, Cycle 2 and Beyond, footnote g.
Change 4: Allow multiple-gated acquisition scans to also be used to assess left 
ventricular ejection fraction.
The primary change occurs in Section 7.4.12 Echocardiogram:
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Added text: 
Echocardiogram
LVEF should be assessed by echocardiography or multiple-gated 
acquisition scan at Screening.
Rationale for Change:
Multiple-gated acquisition scans were included to allow flexibility in the assessment of 
left ventricular ejection fraction.
The following sections also contain this change:

The Schedules of Events for the Single-Agent Arm, Cycle 1, footnote m.

The Schedules of Events for the Combination Arm, Cycle 1, footnote n.

Section 5.2 Exclusion Criteria.
Change 5: Clarify that the period of observation and collection for serious adverse events 
(SAEs) includes a +10-day window 30 days following the last administration of study 
drug.
The primary change occurs in Section 10.3 Monitoring of Adverse Events and Period of 
Observation:
Added text: 
Related and unrelated SAEs will be reported to the Millennium 
Department of Pharmacovigilance or designee from the first dose of study 
drug through 30 days (+10 days) after administration of the last dose of 
study drug and recorded in the eCRF. After this period, only related SAEs 
must be reported to the Millennium Department of Pharmacovigilance or 
designee. SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).
Rationale for Change:
The addition of the + 10-day window to the Study Procedures section and the Schedules 
of Events was made for consistency throughout the protocol.
The following sections also contain this change:

The Schedules of Events for the Single-Agent Arm, Cycle 1.

The Schedules of Events for the Combination Arm, Cycle 1.

The Schedules of Events for the Single-Agent Arm, Cycle 2 and Beyond.

The Schedules of Events for the Combination Arm, Cycle 2 and Beyond. 
Change 6: Update the designation for the entity for SAE reporting.
The primary change occurs in Section 10.2 Procedures for Recording and Reporting 
Adverse Events and Serious Adverse Events:
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Change 9: Revise the test parameters for urinalysis with microscopic analysis for both 
study arms to include phosphate, and no longer include bilirubin and glucose.
The primary change occurs in Section 7.4.11 Clinical Laboratory Evaluations:
Initial 
wording: 
Urinalysis
Urine samples for urinalysis will be obtained as specified in the 
Schedules of Events and more frequently if clinically indicated.
Urinalysis With Microscopic Analysis

Turbidity and 
color

pH

Specific 
gravity

Protein

Ketones

Bilirubin

Occult 
blood

Nitrite

Glucose

Leukocyte esterase

Microscopic 
assessment of 
leukocytes, 
erythrocytes, bacteria, 
casts, and crystals
Amended or 
new wording:
Urinalysis
Urine samples for urinalysis will be obtained as specified in the 
Schedules of Events and more frequently if clinically indicated.
Urinalysis With Microscopic Analysis

Turbidity and 
color

pH

Specific 
gravity

Protein

Ketones

Bilirubin

Occult blood

Nitrite

Phosphate

Glucose 

Leukocyte esterase

Microscopic 
assessment of 
leukocytes, 
erythrocytes, bacteria, 
casts, and crystals
Rationale for Change:
The urine tests for bilirubin and glucose were no longer considered necessary and were 
therefore removed. The urine test for phosphate was initially included in the panel of 
urine safety tests, and when these were removed from the protocol (as of 
Amendment 03), phosphate was added to the urinalysis tests. 
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The following sections also contain this change:

The Schedules of Events for the Combination Arm, Cycle 2 and Beyond, footnote l.

The Schedules of Events for the Single-Agent Arm, Cycle 1, footnote k.

The Schedules of Events for the Single-Agent Arm, Cycle 2 and Beyond, footnote i.

The Schedules of Events for the Combination Arm, Cycle 1, footnote m.
Change 10: Remove urine safety assessments from the clinical laboratory evaluations for 
both study arms.
The primary change occurs in Section 7.4.11 Clinical Laboratory Evaluations: 
Deleted text:
Urine samples for safety assessment will be obtained as specified in 
the Schedules of Events and more frequently if clinically indicated.
Urine Safety Assessment

Albumin

Creatinine

Phosphate 
Rationale for Change:
Urine safety assessments were removed because these assessments were no longer 
considered necessary for patients in either treatment arm.
The following sections also contain this change:

The Schedules of Events for the Combination Arm, Cycle 2 and Beyond, 
footnote m.

The Schedules of Events for the Single-Agent Arm, Cycle 2 and Beyond, footnote i.
Change 11: Clarify that in the event of a dose delay, creatinine measurements can be 
delayed by up to 3 days.
The primary change occurs in the Schedules of Events Single-Agent Arm, Cycle 1, 
footnote k:
Added text:
k The select chemistry panel will include the following: blood urea nitrogen, 
creatinine, lactate dehydrogenase, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase, and alanine aminotransferase. The select chemistry panel will 
be collected on Day 2. In the event of a dose delay, creatinine measurements 
can be delayed up to 3 days.
Rationale for Change:
The addition of up to a 3-day window was made to allow flexibility in creatinine 
measurement.
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The following sections also contain this change:

The Schedules of Events for the Single-Agent Arm, Cycle 2 and Beyond, 
footnote h.

The Schedules of Events for the Combination Arm, Cycle 1, footnote l.

The Schedules of Events for the Combination Arm, Cycle 2 and Beyond, footnote k.
Change 12: Provide a definition of postmenopausal.
The primary change occurs in Section 15.9 Definition of Postmenopausal:
Added text: 
15.9 Definition of Postmenopausal
A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high FSH level in the 
postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal 
replacement therapy. However in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient. Please refer to 
the following source for additional information: European Heads of 
Medicines Agencies (HMA) Clinical Trial Facilitation Group 
(CTFG); see hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_ 
CTFG_Contraception.pdf
Rationale for Change:
The addition of the definition of postmenopausal was included for clarity and for 
consistency with program-wide updates.
Change 13: Clarify the minimum interval between doses of pevonedistat.
The primary change occurs in Section 6.4.1 Criteria for Retreatment and Dose Delays:
Initial 
wording:
Retreatment Within a Cycle
If dosing of either drug is delayed for safety reasons, retreatment may be 
resumed upon resolution of the safety condition. For pevonedistat, a 
minimum of 48 hours between any 2 doses should be maintained. In each 
cycle, a maximum of 3 doses of pevonedistat and 7 doses azacitidine (as 
applicable) should not be exceeded.
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Amended or 
new 
wording:
Retreatment Within a Cycle
If dosing of either drug is delayed for safety reasons, retreatment may be 
resumed upon resolution of the safety condition. For pevonedistat, a 
minimum of 48 hours 1 full calendar day between any 2 doses should be 
maintained (eg, Day 1 [Monday] and Day 3 [Wednesday]). In each 
cycle, a maximum of 3 doses of pevonedistat and 7 doses azacitidine (as 
applicable) should not be exceeded.
Rationale for Change:
Text describing the interval between doses of pevonedistat was revised for clarity.
Change 14: Remove the restriction on the timing of platelet transfusions and clarify the 
timing of transfusions for red blood cells, if necessary, to least 1 day prior to 
investigational product administration.
The primary change occurs in Section 6.6 Permitted Concomitant Medications and 
Procedures, Table 6.e:
Description 
of Change:
Text restricting the timing of platelet transfusions was removed, and text was added to 
clarify that RBC transfusion should occur at least 1 day prior to investigational 
product administration.
Amended or 
new 
wording:
Table 6.e
Permitted Concomitant Medications and Procedures
Therapy
Comment
Antiemetics for 
azacitidine
May be administered according to institutional guidelines.
Hydroxyurea
Dosing of hydroxyurea may be adjusted to control the level of 
WBC counts to no lower than 10,000 while on treatment 
with study drugs. The dosing of hydroxyurea and changes 
to dosing of hydroxyurea should be recorded.
Patients may start or restart treatment with hydroxyurea 
during the study.
Platelet transfusion
Can be administered at any time except during investigational 
product administration. Each transfusion episode, including 
the type of transfusion (platelet), should be recorded.
Red blood cell RBC
transfusion
To be considered for all patients with anemia, especially 
those with hemoglobin values <8 g/dL. RBC transfusion 
should occur at least 1 day prior to investigational 
product administration.
Rationale for Change:
The update in permitted transfusion procedures was made to provide clarity on the window 
for transfusion prior to investigational product administration and to eliminate a transfusion 
procedure for which there was no scientific basis to keep.
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Change 15: Clarify that lymphoblasts and myelocytes are included in hematology test 
measures.
The primary change occurs in Section 7.4.11 Clinical Laboratory Evaluations:
Added text:
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential, including 
circulating blast count

Lymphoblasts

Myelocytes

Neutrophils (ANC) 
Note: ANC may be calculated from the 
leukocyte count with differential count; see 
Section 15.8.
Rationale for Change:
The addition of lymphoblasts and myelocytes was made for clarity.
Change 16: Clarify the percentage increase of bone marrow and circulating blasts in the 
progressive disease definition.
The primary change occurs in Section 7.4.19.1 Revised Recommendations of the IWG 
Response Criteria for AML:
Initial 
wording:
Definition of Progressive Disease
Because the IWG criteria for AML do not provide a standardized 
definition for progressive disease (PD) [35], in this protocol, PD is 
defined as 1 of the following:

>50% increase in bone marrow blasts from Baseline value to 
>30% blasts.

>50% increase in circulating blasts from Baseline value to 
>30% blasts in peripheral blood (in the exceptional case when bone 
marrow examination is not possible).

Development of biopsy-proven extramedullary disease or new sites 
of extramedullary leukemia.
Amended or 
new 
wording:
Definition of Progressive Disease
Because the IWG criteria for AML do not provide a standardized 
definition for progressive disease (PD) [35], in this protocol, PD is 
defined as 1 of the following:

>50% increase in bone marrow blasts from Baseline value (to >30%
a maximum of 100% blasts).
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
>50% increase in circulating blasts from Baseline value (to >30% a 
maximum of 100% blasts) in peripheral blood (in the exceptional 
case when bone marrow examination is not possible).

Development of biopsy-proven extramedullary disease or new sites 
of extramedullary leukemia.
Note: When deciding PD for patients with high blasts at Baseline 
(eg, >70% blasts), investigators are encouraged to use best medical 
judgement based on the patient’s overall clinical profile and in 
consideration of local institutional guidelines. 
Rationale for Change:
The update in the definition of progressive disease was made to add flexibility for 
investigators when deciding if a patient has progressive disease.
Change 17: Provide additional information on definition of relapse after clinical 
response.
The primary change occurs in Section 7.4.19.1 Revised Recommendations of the IWG 
Response Criteria for AML:
Added text:
Definition of Relapse After CR
Relapse after CR is defined as a reappearance of leukemic blasts in 
the peripheral blood or >5% blasts in the bone marrow not 
attributable to any other cause (eg, bone marrow regeneration after 
consolidation therapy). In the setting of recent treatment, if there are 
no circulating blasts and the bone marrow contains 5% to 20% 
blasts, a repeat bone marrow performed at least a week later is 
necessary to distinguish relapse from bone marrow regeneration.
Rationale for Change:
This change was made to clarify the definition of relapse after complete response. 
Change 18: Clarify that for acute myeloid leukemia patients, all complete remission 
includes both complete remission and complete remission with incomplete count 
recovery.
The primary change occurs in Section 8.1.6 Efficacy Analysis:
Added text:
For AML patients, all CR includes both CR and CRi.
Rationale for Change:
This change was made to clarify the definition of clinical response for AML patients.
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Change 19: Update the investigator responsibilities for compliance with updated 
International Council for Harmonisation guidelines.
The primary change occurs in Section 11.1 Good Clinical Practice: 
Added text:
The investigator is responsible for supervising any individual or party 
to whom the investigator delegates trial-related duties and functions 
conducted at the trial site. If the investigator/institution retains the 
services of any individual or party to perform trial-related duties and 
functions, the investigator/institution should ensure this individual or 
party is qualified to perform those trial-related duties and functions 
and should implement procedures to ensure the integrity of the trial-
related duties and functions performed and any data generated.
Rationale for Change:
Investigator responsibilities were updated to comply with updated changes in ICH 
guidelines.
Change 20: Allow the use of moderate and strong cytochrome P450 3A inhibitors during 
treatment Cycle 2 and beyond for all study arms.
The primary change occurs in Section 6.5 Excluded Concomitant Medications and 
Procedures:
Initial 
wording:
Medications that are generally excluded but are allowed with certain 
exceptions listed in Table 6.d. 
Amended 
or new 
wording:
The use of moderate and strong CYP3A inhibitors is prohibited for 
7 days prior to the first dose of study drug(s) only during treatment 
Cycle 1 for both study arms. In treatment Cycle 2 and beyond, the use of 
moderate and strong CYP3A inhibitors is permitted. See Section 15.5 for 
additional details of specific CYP3A inhibitors.
Rationale for Change:
Preliminary data from 11 patients who completed protocol-specified dosing and PK 
evaluations to assess the effect of itraconazole, a strong CYP3A inhibitor, on 
pevonedistat PK indicated that systemic exposures of pevonedistat following IV 
administration at 20 mg/m2 in the presence of itraconazole were similar to systemic 
exposures in the absence of itraconazole. The data support removing moderate or strong 
CYP3A inhibitors from the list of prohibited concomitant medications in ongoing and 
planned pevonedistat clinical studies.
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The following sections also contain this change:

Section 5.2 Exclusion Criteria.

Table 6.d
Concomitant Medications Excluded During the Study.

Table 6.e
Permitted Concomitant Medications and Procedures.

The Schedules of Events for the Single-Agent Arm, Cycle 1, footnote g.

The Schedules of Events for the Single-Agent Arm, Cycle 2 and Beyond, footnote f.

The Schedules of Events for the Combination Arm, Cycle 1, footnote i.

The Schedules of Events for the Combination Arm, Cycle 2 and Beyond, footnote i.

Section 15.5 Excluded CYP3A Inhibitors and Inducers.
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Statistical Analysis Plan, Study P-1012
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.........................................4
1. INTRODUCTION............................................................................................................6
1.1 Study Design..............................................................................................................6
1.2 Study Objectives ........................................................................................................8
1.2.1 Primary Objectives ..............................................................................................8
1.2.2 Secondary Objectives...........................................................................................8
1.2.3
........................................................................................8
2. POPULATIONS FOR ANALYSIS..................................................................................9
2.1 Intent-to-Treat Population...........................................................................................9
2.2 Per-Protocol Population..............................................................................................9
2.3 Response-Evaluable Population..................................................................................9
2.4 Safety Population .......................................................................................................9
2.5 Pharmacokinetic-Evaluable Population.......................................................................9
2.6 Pharmacodynamics Population...................................................................................9
2.7 DLT Evaluable Population .........................................................................................9
3. HYPOTHESES AND DECISION RULES.....................................................................10
4. INTERIM ANALYSIS...................................................................................................10
5. STATISTICAL METHODOLOGY ...............................................................................10
5.1 Sample Size Justification..........................................................................................10
5.2 Randomization and Stratification..............................................................................11
5.3 Unblinding ...............................................................................................................11
5.4 Data Handling ..........................................................................................................11
5.4.1 Methods for Handling Missing Data...................................................................11
5.4.2 Definition of Baseline Values ............................................................................11
5.4.3 Windowing of Visits..........................................................................................12
5.4.4 Justification of Pooling ......................................................................................12
5.4.5 Withdrawals, Dropouts, Loss to Follow-up ........................................................12
5.5 Patient Disposition ...................................................................................................12
5.6 Demographics and Baseline Disease Characteristics.................................................12
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5.6.1 Demographics....................................................................................................12
5.6.2 Inclusion/Exclusion Criteria...............................................................................13
5.6.3 Medical History.................................................................................................13
5.6.4 Baseline Disease Status......................................................................................13
5.7 Treatments and Medications .....................................................................................15
5.7.1 Concomitant Medications ..................................................................................15
5.7.2 Study Treatments...............................................................................................15
5.8 Efficacy Analyses.....................................................................................................18
5.8.1 Primary Efficacy Endpoint.................................................................................20
5.8.2 Secondary Efficacy Endpoints ...........................................................................20
5.8.3 Other Efficacy Endpoints...................................................................................20
5.9 Pharmacokinetic 
.................................................................20
5.9.1 Pharmacokinetic Analyses .................................................................................20
5.9.2
...........................................................................................25
5.10 Safety Analyses ......................................................................................................26
5.10.1 Adverse Events................................................................................................26
5.10.2 Laboratory Data...............................................................................................33
5.10.3 Electrocardiograms ..........................................................................................36
5.10.4 Vital Signs .......................................................................................................37
5.10.5 Disseminated Intravascular Coagulation (DIC) and PT/PTT.............................38
5.10.6 Echocardiograms .............................................................................................38
5.10.7 Urine Safety Assessment..................................................................................38
5.10.8 Pregnancy Test.................................................................................................39
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................39
7. PROGRAMMING CONSIDERATIONS .......................................................................39
7.1 Statistical Software...................................................................................................39
7.2 Rules and Definitions ...............................................................................................39
8. REFERENCES...............................................................................................................39
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE(s)
Adverse event (or events)
ALT
Alanine aminotransferase (SGPT)
ANC
absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the plasma concentration-time curve
AUMC
Area under the first moment curve
BNP
B-type natriuretic peptide
BSA
body surface area
Cmax
CL
Maximum plasma concentration
Total clearance (after IV administration)
CMML
chronic myelomonocytic leukemia
CPK
Creatine phosphokinase
Cr
Creatinine
CR
complete remission
CRi
complete remission with incomplete recovery 
CRF
Case Report Form
CRM
Continual Reassessment Method
CRP
C-reactive protein
CV
coefficient of variation
DBP
diastolic blood pressure
DIC
disseminated intravascular coagulation
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ELN
European Leukemia Net
EOS
End of study
FAB
French-American-British
HLT
high level term
IDMC
Independent Data Monitor Committee
IPSS-R
International Prognostic Scoring System
IV
intravenous
IWG
International Working Group
LLQ
limit of quantification
LPO
last patient out
LVEF
left ventricular ejection fraction
MDS
Myelodysplastic syndromes 
MedDRA
Medical Dictionary for Regulatory Activities
miR
microRNA
MDS
Myelodysplastic Syndromes
Abbreviation
Term
MRT
mean residence time
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MTD
Maximum Tolerated Dose
NAE
Nedd8-Activating Enzyme
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PD
Progressive Disease
PK
Pharmacokinetic
PR
Partial Remission
PT
preferred term
PT
ORR
prothrombin time
Overall Response Rate
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
Red blood cell
SAE
serious adverse event
SBP
SC
systolic blood pressure
Subcutaneously
SD
stable disease
SOC 
system organ class
t1/2z
tmax
Terminal elimination half-life
Time to reach Cmax    
TAD
time after dosing
Vss
volume of distribution at steady state (after IV administration)  
WBC
White blood cell   
WHO
World Health Organization
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1.   
INTRODUCTION
In general, the purpose of the Statistical Analysis Plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies.  Specifically, this plan has the following purpose:
To prospectively (a priori) outline the types of analyses and data presentations that will 
address the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1   
Study Design
This is a multicenter, open-label, phase 1/1b dose escalation and expansion study of
pevonedistat administered IV as a single agent and in combination with azacitidine in adult
East Asian patients with World Health Organization (WHO)-defined AML or High Risk 
(HR) MDS (Revised International Prognostic Scoring System [IPSS-R] very 
high/high/intermediate)
It is expected that approximately 37 patients will be enrolled in this study. Once enrolled,
patients will be administered pevonedistat (administered via 60-minute IV infusion) with or
without azacitidine (administered IV or SC).
The Single-Agent Arm will include East Asian patients with R/R AML or R/R HR MDS
(including nonproliferative chronic myelomonocytic leukemia [CMML]). In the Single-
Agent Arm, each 21-day treatment cycle includes treatment with pevonedistat (starting dose
of 25 mg/m2) on Days 1, 3, and 5, followed by a rest period of 16 days. Samples for PK will
be collected at prespecified time points during Cycle 1. Enrollment in the second dose level 
(44 mg/m2) will only begin after the data from the first group of 3 patients in the Single-
Agent Arm has been reviewed and the dose has been found to be safe and tolerable.
In parallel with the opening of enrollment for the second dose level in the Single-Agent
Arm, enrollment will begin for the first dose level of the Combination Arm. The
Combination Arm will include East Asian patients with R/R AML or R/R HR MDS
(including R/R nonproliferative CMML) as well as previously untreated AML or HR MDS
(including nonproliferative CMML). In the pevonedistat+azacitidine Combination Arm,
each 28-day treatment cycle includes the following: treatment with pevonedistat (starting
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dose of 10 mg/m2) on Days 1, 3, and 5; treatment with azacitidine (75 mg/m2 [IV during 
Cycle 1; IV or SC in Cycles 2 and beyond, per the investigator’s choice]) on Days 1 through 
5, and 8 through 9; and a rest period of 19 days. Samples for PK will be collected at 
prespecified time points during Cycle 1. Enrollment in the Combination Arm will not begin 
until 3 patients have successfully completed Cycle 1 of the 25 mg/m2 Single-Agent Arm.
The 3+3 approach will be used during the dose escalation phase. The dose level(s) 
determined to be safe during the dose escalation phase of the study may then be expanded to 
as many as 12 patients in total to further confirm safety and investigate PK. Based on the 
geographic distribution of patients in the dose escalation/expansion phases (Single-agent 
and/or Combination Arms) and emerging PK and safety data, additional patients may be 
added in the expansion phase, as needed, to further characterize the PK, safety, and 
tolerability in a particular East Asian geographic region.
In the Single-Agent Arm, at least 1 Japanese patient will be included in each group of
3 patients in the dose escalation phase. If a dose expansion group of up to 6 patients is added
at the highest dose level, at least 1 additional Japanese patient will be included, unless at
least 3 Japanese patients were enrolled at that dose level during dose escalation and
emerging data support an adequate characterization of PK and safety; in this case, no
additional Japanese patients are needed in the expansion phase.
In the Combination Arm, at least 1 Japanese patient will be included in each group of
3 patients in the dose escalation phase. Following dose escalation, an additional group of up
to 6 patients will be added in the expansion phase, for a total of up to 12 patients at the
highest dose level. The total number of Japanese patients at the highest dose level will be at
least 6.
No formal interim analysis is planned, but safety and PK data will be reviewed on an 
ongoing basis during the dose escalation and expansion phases of the study.
Toxicity will be evaluated according to National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.
Adverse events will be assessed, and laboratory values, vital signs, and ECGs will be
obtained, to evaluate the safety and tolerability of pevonedistat administered as a single
agent or in combination with azacitidine.
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Disease response assessments will be conducted using International Working Group (IWG)
criteria for AML and modified IWG criteria for MDS (including CMML). Patients, 
including those who achieve a Complete Remission (CR), may receive pevonedistat and/or 
azacitidine until they experience disease progression or symptomatic deterioration. Study
drug may be discontinued if a patient experiences study drug-related toxicity or if, in the 
opinion of the investigator or sponsor, continuation on study may jeopardize the safety of
the patient. Patients may discontinue therapy at any time for any reason. Patients will attend 
the End of Study (EOS) visit for safety 30 days (+10 days) after receiving their last dose of 
study drug.
1.2   
Study Objectives
1.2.1   Primary Objectives
!
To evaluate safety and tolerability of pevonedistat administered as a single agent in 
East Asian patients with R/R AML or R/R HR MDS.
!
To evaluate safety and tolerability and determine the recommended phase 2/phase 3 
dose of pevonedistat administered in combination with azacitidine in East Asian 
patients with AML or HR MDS.
!
To characterize the PK of pevonedistat administered as a single agent or in 
combination with azacitidine in East Asian patients.
1.2.2   Secondary Objectives
The secondary objective is to evaluate disease response in both AML and MDS that may be
observed with the single-agent pevonedistat or with a combination of pevonedistat and
azacitidine.
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2.   
POPULATIONS FOR ANALYSIS
2.1   
Intent-to-Treat Population
Not applicable for a phase 1/1b study.
2.2   
Per-Protocol Population
Not applicable for a phase 1/1b study.
2.3   
Response-Evaluable Population
The response-evaluable population is defined as all patients who receive at least 1 dose of 
study drug, have a baseline disease assessment, and have at least 1 post-Baseline disease 
assessment.
Response analyses will be performed using the response-evaluable population.
2.4   
Safety Population
The safety population is defined as all enrolled patients who receive at least 1 dose of study 
drug.
All safety and efficacy analyses will be performed using the safety population.
2.5   
Pharmacokinetic-Evaluable Population
The PK-evaluable population is defined as all enrolled patients who have sufficient dosing 
in Cycle 1 and pevonedistat concentration-time data to reliably estimate PK parameters by 
noncompartmental analysis methods and who have not received any excluded concomitant 
medications per the protocol
PK analyses will be performed using the PK-evaluable population.
2.6   
Pharmacodynamics Population
Not applicable for this study.
2.7   
DLT Evaluable Population
The DLT-evaluable population is defined as patients who either experience DLT during 
Cycle 1 or receive all scheduled doses of study drug in Cycle 1 without DLT. 
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3.   
HYPOTHESES AND DECISION RULES
Not applicable for a phase I study.
4.   
INTERIM ANALYSIS
As this is a phase I study there is no formal interim analysis.  There will be an ongoing 
review of safety data with the medical monitor and study investigators, as well as within an 
internal Safety Working Group and the Independent Data Monitor Committee (IDMC).   
5.   
STATISTICAL METHODOLOGY
Analyses will be primarily descriptive in nature. No formal statistical tests will be 
performed. Summary tabulations will be presented that display the number of observations, 
mean, standard deviation, median, minimum, and maximum for continuous variables, and 
the number and percent (calculated using non-missing values) per category for categorical 
data, unless specified otherwise.
Due to the use of the 3+3 methodology for dose escalation, at a minimum, three patients will 
be dosed at any given dose level.  Data may be pooled across dose levels and treatments for 
summary purposes.   When appropriate, data will be summarized for the pooled dose levels 
below the highest tolerable dose, at highest tolerable dose, and for all patients.   Data from 
each schedule may be summarized separately. Patients will be analyzed at the dose level to 
which they were originally assigned, including those who receive subsequent treatment at a 
lower dose level.
5.1   
Sample Size Justification
It is anticipated that approximately 37 patients will be enrolled to the dose-escalation and 
expansion cohorts for the determination of the highest tolerable dose of single-agent arm and 
combination arm and further evaluation of this dose.
This study uses a 3+3 design to identify the tolerated dose in the dose escalation phase for 
single-agent pevonedistat and the pevonedistat+azacitidine combination. The tolerated dose 
is defined as the highest dose that generates a DLT rate of ≤25% during Cycle 1. The 
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escalation starts with single-agent pevonedistat (group of 3 patients) at 25 mg/m2. If this 
dose is safe and tolerable, the escalation will then be split into 2 independent arms: single-
agent pevonedistat and pevonedistat+azacitidine combination. At the highest tolerated dose 
level, an additional 3 patients will be added during the dose escalation phase to confirm 
safety and tolerability. Assuming this study schema and also assuming an additional 6 
patients in the dose expansion phase, the estimated number of patients for the study via 
simulation is 30 to 33. To further allow for other considerations, such as the number of PK-
evaluable patients and number of patients required per country or East Asian race group at 
the highest dose level, the estimated number of patients to be enrolled in this study is 
approximately 37.
5.2   
Randomization and Stratification
No randomization or stratification will be performed in this study. 
5.3   
Unblinding
As this is an open-label study, no unblinding methodology is required.
5.4   
Data Handling
5.4.1   
Methods for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations.  No 
imputation of values for missing efficacy and safety data will be performed unless specified 
otherwise. The relevance of missing sample data will be assessed. Data that are potentially 
spurious or erroneous will be examined according to standard data management operating 
procedures.
5.4.2   
Definition of Baseline Values
Unless otherwise specified, for each safety parameter, the baseline value is defined as the 
value collected at the time closest to, but prior to, the start of study drug administration.  For 
analysis of ECG data, the baseline value is the average of the screening and Cycle 1 Day 1 
predose value.
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5.4.3   
Windowing of Visits
All data will be categorized based on the scheduled visit at which they were collected. The 
analysis of PK data and determination of PK parameters will be based on the actual elapsed 
time post dose.
5.4.4   
Justification of Pooling
All data from all sites will be pooled.  Study center or treatment-by-center interaction will 
not be included in any statistical analysis.
5.4.5   
Withdrawals, Dropouts, Loss to Follow-up
Patients in the escalation phase who are withdrawn from treatment during Cycle 1 for 
reasons other than DLT will be replaced. Generally, no additional patients will be enrolled 
due to withdrawals, dropouts, or loss to follow-up.    
5.5   
Patient Disposition
A tabulation of patient disposition data will include the number of patients for the following 
categories: patients treated (safety population), patients in the DLT-evaluable population, 
patients in the PK-evaluable population, patients in the response-evaluable population, and
patients discontinued from the study. The primary reason for study discontinuation will also 
be summarized in this table.
All data will be summarized by each dose level and treatment, and also by Japanese and 
non-Japanese patients.  Percentages will be based on the number of patients in the safety 
population, and they will be calculated for highest tolerable dose, and the study total.
Data concerning patient disposition (e.g. reason for study termination, patient population) 
will be presented in by-patient listings.
5.6   
Demographics and Baseline Disease Characteristics
5.6.1   
Demographics
Baseline demographics will be summarized by each dose level and treatment, and also by 
Japanese and non-Japanese ethnicities for all patients in the safety population.  Baseline 
demographic data to be evaluated will include age at date of informed consent, sex, 
ethnicity, race, height, weight, baseline disease characteristics and body surface area (BSA).   
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BSA is calculated using the following formula based on the patient’s height and weight 
collected at screening.  If a weight at screening is not available, the Cycle 1 Day 1 pre-dose 
weight can be used.
       BSA = 
No inferential statistics will be generated.
Demographic data will also be presented in a by-patient listing.
5.6.2   
Inclusion/Exclusion Criteria
All inclusion/exclusion information on enrolled patients will be included in a by-patient 
listing.  The listing will include whether all criteria were satisfied.  For patients who did not 
satisfy the criteria, the criteria number will be listed with the deviation, along with whether 
an exception was obtained.  
5.6.3   
Medical History
5.6.3.1   General Medical History
Patients with a medical (and/or surgical) history will be presented in a by-patient listing, 
including the medical and surgical history, date of onset and the outcome status (whether it 
is resolved or ongoing). 
5.6.3.2   Disease-Specific History
Not applicable for this study.
5.6.4   
Baseline Disease Status
Baseline disease characteristics (MDS: disease type such as de novo MDS or secondary 
MDS, disease subtype will be summarized for secondary MDS, months from initial
diagnosis, French-American-British (FAB) category, WHO classification, revised WHO 
classification and IPSS-R category; AML: disease type such as de novo AML or secondary 
AML, disease subtype will be summarized for secondary AML, months from initial 
diagnosis, revised WHO classification and evidence of extramedullary disease) will be 
3600
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(
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summarized for all patients in the safety population.  ECOG performance status will be 
summarized similarly in the same table. Both Baseline disease characteristics and ECOG 
status will also be summarized by Japanese and non-Japanese patients. Separate by-patient
listings will also be presented for baseline disease characteristics and ECOG performance 
status.  
Separate tables for MDS and AML will summarize the numbers and percentages of patients 
who had prior therapy (including months from last dose of chemotherapy to first dose of 
pevonedistat), prior radiation (including the total lifetime dose of radiation received and 
months from last prior radiation to first dose of pevonedistat), prior surgery (including 
months from last prior surgery to first dose of pevonedistat) and prior transplant (including 
type of procedure and months from last procedure to first dose of pevonedistat) for all 
patients in the safety population. These tables will also be summarized by Japanese and non-
Japanese patients. Separate by-patient listings will also be presented for prior therapies, prior 
radiation, prior surgery, and prior transplants.
A separate table will summarize the results of the bone marrow biopsy samples taken at 
screening.  This will include myeloblast percentage. This table will also be performed by 
Japanese and non-Japanese patients. Bone marrow biopsy data and sample collection will 
also be presented in by-patient listings.
AML patients will be classified into 3 categories: Adverse, Intermediate and Favorable
based on the 2017 European LeukemiaNet (ELN) risk stratification by genetics algorithm.
Property of Takeda: For Non-Co
will
will su
his 
is will
wi
and 
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Subject to the Applicable Terms of Use
pati
atients
en
rst 
st dose
do
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recei
surgery
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trans
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Statistical Analysis Plan, Study P-1012
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The ELN risk classification results will be summarized by dose group and treatment and all 
patients, and also by Japanese and non-Japanese patients, and will also be included in a by-
patient listing. The ELN risk classification criteria use the version published by Döhner, et 
al., 2017.
A listing will be generated for patients who receive hydroxycarbamide (hydroxyurea) at 
enrollment, which includes screening WBC and screening bone marrow aspirate 
myeloblasts.
5.7   
Treatments and Medications
5.7.1   
Concomitant Medications
All concomitant medications will be mapped to preferred terms according to the World 
Health Organization (WHO) drug dictionary.  The number and percentage of patients in the 
safety population taking concomitant medications will be tabulated by WHO drug generic
term. Tabulations will be performed for all patients in the safety population by dose and 
treatment.  Hydroxyurea use will also be captured in this table. Concomitant procedures will 
not be coded.
Concomitant medications and procedures will be presented in separate by-patient listings.
5.7.2   
Study Treatments
Patients will be administered pevonedistat (administered via 60-minute IV infusion) with or 
without azacitidine (administered IV or SC).
In the Single-Agent Arm, each 21-day treatment cycle includes treatment with pevonedistat 
on Days 1, 3, and 5, followed by a rest period of 16 days. 
In the pevonedistat+azacitidine Combination Arm, each 28-day treatment cycle includes the 
following: treatment with pevonedistat (starting dose of 10 mg/m2) on Days 1, 3, and 5; 
treatment with azacitidine (75 mg/m2) on Days 1 through 5, and 8 through 9; and a rest 
period of 19 days. 
All dosing information for each visit will be presented in a by-patient listing.
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5.7.2.1   Duration of Follow-up
The duration of follow-up is defined as time from the date of first dose of study treatment to 
the date of death or last known visit.  If a subject dies, the duration will equal the date of 
death minus the date of first dose + 1, with a censor variable = 1 (censored for follow-up).  If 
a subject is alive, the duration will equal the date when the subject was last known to be 
alive minus the date of first dose + 1, with a censor variable = 0 (event for follow-up).
5.7.2.2   Extent of Exposure
The extent of exposure to pevonedistat will be based on the number of cycles and the mean 
number of doses administered per cycle. The distribution of the number of cycles received 
will be presented by dose level or treatment to which patients were initially assigned, as well 
as for all patients. Patients will be considered to have been treated for a cycle if they receive 
at least one dose of pevonedistat during that cycle. Percentages will be calculated by dose 
level and treatment and for all the patients.  
The mean number of doses per cycle will be calculated for each patient and summarized for 
each dose levels and treatments and the study total.
Percent Dosing Intensity will be calculated using the following equations for Daily Expected 
Dose (mg), Daily Prepared Dose (mg), and Daily Dose Received (mg):  
)
Volume
Prepared
(mL)
infused
actually 
bag
IV
of
Volume
(
*
Dose
Prepared
Daily 
Received
Dose
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Level
Dose
Scheduled
Dose
Prepared
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Entry 
Study 
at 
Assigned
Level
Dose
=
Dose
Expected
Daily 
2
2
2
2


Daily Expected Dose and Daily Prepared Dose may differ if there are dose decreases.  The 
scheduled dose level will be collected on the electronic case report form (eCRF) for each 
dosing day.  Body surface area (BSA) will be calculated at baseline, and at subsequent visits 
if the patient experiences a >5% change in body weight from the weight used for the most 
recent BSA calculation.  
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Total Dose Received, Total Dose Expected, and Dosing Intensity for pevonedistat will be 
based on the following formulas: 
100
*
Expected
Dose
Total
Received
Dose
Total
Intensity 
Dosing
Percent 
cycles
 treated
of
number 
*
cycle
per 
doses
  
3
*
Dose
Expected
Daily 
Expected
Dose
Total
ed
administer
at  was
pevonedist
 that 
days
all
across
Received
Dose
Daily 
of
Sum
Received
Dose
Total



Total Dose Expected will be calculated based on the BSA measured at baseline.  If there are 
dose increases the Dosing Intensity may exceed 100%.  The number of patients with ≥100% 
intensity, 80% - <100%, 50 - <80, and <50% intensity will be summarized by dose level and 
treatment, as well as for all patients.
For azacitidine dosing, the percentage of all doses that were administered IV or SC will be 
calculated for the combination arms. The extent of exposure will be summarized separately 
for IV and SC in a similar manner as pevonedistat.  A separate column will be generated for 
each dose level of pevonedistat, and the number of cycles of azacitidine administered will be 
summarized. 
The mean number of doses per cycle will be calculated for each patient and summarized by
pevonedistat dose level and the study total.
Daily Expected Dose, Total Dose Received, Total Dose Expected, and Dosing Intensity for 
azacitidine will be based on the following formulas:  
100
*
Expected
Dose
Total
Received
Dose
Total
Intensity 
Dosing
Percent 
cycles
 treated
all
across
cycle"
per 
doses
7
*
Dose
Expected
Daily 
"
of
Sum
  
Expected
Dose
Total
dosing
of
days
all
across
Dose
Actual
of
Sum
Received
Dose
Total
BSA
*
mg/m
75
Dose
Expected
Daily 
2




Dosing intensity for azacitidine will be summarized by pevonedistat dose level in a similar 
manner to pevonedistat dosing intensity.
5.7.2.3   Treatment Compliance and Modifications
The actions on study drugs (Dose Held, Dose Missed, Dose Reduced, Dose Interrupted, 
Dose Delayed, Dose Incomplete, or Discontinued) will be summarized by dose level for 
pevonedistat, azacitidine IV, and azacitidine SC respectively.  Data will be summarized for 
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Cycle 1 only as well as all cycles combined.  A patient will count only once for each type of
action.  
5.8   
Efficacy Analyses
Since this is a phase I study, efficacy is not a primary endpoint.  A summary of the best 
overall response as determined by the investigator using the Revised IWG guidelines will be 
presented as a measure of antitumor activity of pevonedistat.
For AML patients, response will be based on the best overall response as determined by the 
investigator using the Revised Recommendations of IWG response criteria for AML.  The 
number and percentage of patients in each disease response category (e.g. complete 
remission [CR], CR with incomplete recovery [CRi], partial remission [PR], stable disease 
[SD], clinical benefit despite PD, progressive disease [PD] and relapse after CR) and ORR 
(CR+PR) will be presented for each dose level and treatment and all patients, and also 
summarized by Japanese and non-Japanese patients.
For MDS patients, response will be based on the best overall response as determined by the 
investigator using the revised IWG response criteria for MDS. The number and percentage 
of patients in each disease response category (e.g. complete remission [CR], partial 
remission [PR], marrow CR, stable disease [SD], relapse after CP/PR, 
and progressive disease [PD]) and ORR (CR+ PR+Hematologic Improvement [HI]) will be 
presented for each dose level and treatment and all patients, and also summarized by 
Japanese and non-Japanese patients.
For the disease response CR and ORR, AML patients and MDS patients will be combined 
and the number of patients and percentage will be presented for each dose level and 
treatment and all patients, and also summarized by Japanese and non-Japanese patients.
For each AML patient in the response-evaluable population, the best percent change (i.e., 
largest reduction) from baseline in the myeloblast count from bone marrow aspirates will be 
calculated and displayed in separate waterfall plots to show the distribution of response 
across all patients.  The waterfall plots will be generated by dose level of pevonedistat and 
the study total, and also by Japanese and non-Japanese patients.  A separate set of plots will 
be generated for MDS patients.  Unscheduled visits will also be included in such displays. 
Bone marrow aspirate myeloblast counts and percent change from baseline in myeloblast 
count will be summarized over time separately for AML and MDS patients, and by Japanese 
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Statistical Analysis Plan, Study P-1012
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and non-Japanese patients. A separate set of waterfall plots for the combined AML and 
MDS patients will also be generated.
If bone marrow aspirate myeloblast counts is <1%, a conservative value of 1% will be 
assigned. If bone marrow aspirate myeloblast count is UNABLE TO DETECT, 0% will be
assigned.
Differential counts taken from bone marrow aspirate samples will be displayed in lines over 
time for patients by dose level of pevonedistat. The average line and the median line will 
also be drawn in different colors from the lines for individual patients.  Cell types examined 
will include myeloblasts, promyelocytes, myelocytes, metamyelocytes, neutrophil bands, 
and segmented neutrophils. For myeloblasts (bone marrow aspirate samples), separate line 
graphs will be generated for each patient by dose level. Bone marrow differential counts will 
also be presented in by-patient listings.
The duration of response will be summarized for each dose and treatment for all patients, 
and by Japanese and non-Japanese patients, and will also be presented in a by-patient listing 
for all response-evaluable patients with disease response (CR or PR in AML and MDS 
patients).  For AML and MDS patients, duration of response is the time (in both days and 
months) from the date of first documented response per the investigator response assessment 
to the date of first documentation of progressive disease (PD, including clinical benefit 
despite PD responses) after the first documented response or, if the patient discontinues 
treatment, the date of last disease assessment. The duration of response (in months), time to 
first response (in months) and the number of cycles of response will also be included. In 
addition, the date of first response, the date of progressive disease, and the number of cycles 
of response will be shown in the by-patient listing.  
The duration of SD or better will be presented in a by-patient listing for all response-
evaluable patients. Duration of SD or better is the time from the date of first dose to the date 
of first documentation of PD (including clinical benefit despite PD responses), or the date of 
last disease assessment if the patient discontinues treatment before PD. In addition, the date 
of first dose, the date of first SD or better, the date of first documentation of PD, and the 
number of cycles with SD or better will be shown. The duration of SD or better (in months) 
and the number of cycles with SD or better will also be summarized descriptively for each 
dose level and treatment and by Japanese and non-Japanese for all response-evaluable 
patients. 
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Pre-treatment disease status assessment and disease response category will be presented in 
by-patient listings.
5.8.1   
Primary Efficacy Endpoint
Not applicable for this study.
5.8.2   
Secondary Efficacy Endpoints
!
ORR (CR+PR [for AML] or CR+PR+hematologic improvement [HI] [for MDS]).
!
CR.
5.8.3   
Other Efficacy Endpoints 
Not applicable for this study.
5.9   
Pharmacokinetic
5.9.1   
Pharmacokinetic Analyses
Serial blood samples (~ 3 mL) for the determination of plasma concentrations of 
pevonedistat will be collected only during Cycle 1 of the study for Schedules A (single –
agent pevonedistat arm) and B (pevonedistat + azacitidine combination arms)
Single-Agent Pevonedistat Arm, Cycle 1
!
Day 1:
o
Within 1 hour before the start of pevonedistat infusion
o
At the end of the pevonedistat infusion (immediately before stopping the IV
infusion)
o
At 1 hour (∃10 minutes), 2 hours (∃20 minutes), 4 hours (∃30 minutes), 6
hours (∃30 minutes), and 10 hours (∃30 minutes) after completion of the 
pevonedistat infusion
!
Day 2:  
o
24 hours (∃1 hour) after initiation of pevonedistat Cycle 1, Day 1 infusion.
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yses
yses
mL)
mL) fo
for
ollected 
llected
arm) an
rm) a
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Only and Subject to the Applicable Terms of Use
ovement
eme
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
Day 3:  
o
48 hours (1 hour) after initiation of pevonedistat Cycle 1, Day 1 infusion.
The sample is to be collected Within 10 minutes before the start of the 
pevonedistat infusion

Day 5:  
o
Within 10 minutes before the start of pevonedistat infusion
o
At the end of the pevonedistat infusion (immediately before stopping the IV 
infusion)
o
At 1 hour (10 minutes), 2 hours (20 minutes), 4 hours (30 minutes), 6
hours (30 minutes), and 10 hours (30 minutes) after completion of the 
pevonedistat infusion

Day 6:  24 hours (1 hour) after initiation of pevonedistat Cycle 1, Day 5 infusion

Day 7:  48 hours (1 hour) after initiation of pevonedistat Cycle 1, Day 5 infusion
Pevonedistat +Azacitidine Combination Arm, Cycle 1

Day 1:
o
Within 1 hour before the start of pevonedistat infusion and before azacitidine 
administration
o
At the end of the pevonedistat infusion (immediately before stopping the IV 
infusion)
o
At 1 hour (10 minutes), 2 hours (20 minutes), 4 hours (30 minutes), 6
hours (30 minutes), and 10 hours (30 minutes) after completion of the 
pevonedistat infusion

Day 2:  
o
24 hours (1 hour) after initiation of pevonedistat Cycle 1, Day 1 infusion.
The sample is to be collected within 10 minutes before the start of azacitidine 
administration

Day 3:  
o
48 hours (1 hour) after initiation of pevonedistat Cycle 1, Day 1 infusion.
The sample is to be collected within 10 minutes before the start of azacitidine 
administration

Day 5:  
o
The sample is to be collected within 10 minutes before the start of azacitidine 
administration
o
At the end of the pevonedistat infusion (immediately before stopping the IV 
infusion)
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Parameters
Definition
Method of Determination
Rac (AUC)
Observed accumulation ratio (based on 
AUC)
AUC(Day 5) / AUC(Day 1)
CL
Total clearance (after IV administration)
Dose / AUC∞after single dosing or dose / 
AUClast after multiple dosing
Vss
Volume of distribution at steady-state
(after IV administration)
CL*MRT where the mean residence time 
(MRT) is derived as AUMC∞/ AUC∞-
TI/2 with TI the infusion duration and 
AUMC∞ the area under the first moment 
curve from time zero to infinity calculated 
by trapezoidal method.
To report lambdaz, t1/2z, AUC, CL, and Vss, the terminal disposition phase data time span 
must be greater than or equal to 2, the number of data points included in the calculation must 
be at least 3, and R2 must be greater than or equal to 0.8.
Individual pevonedistat plasma concentration-time data (including nominal and actual times; 
TAD derived as shown in table below) and individual plasma PK parameters will be listed 
by patient ID and summarized descriptively by treatment arm (Single-agent and 
Combination arms), dose level and study day (Cycle1, Day 1 or Day 5 up to 48 hours) for 
overall, Japanese and other Asian population respectively as deemed appropriate (or as data 
permit.
Nominal TAD*
Treatment 
arm
Day
Protocol Specified Time Point
0 hour
A (single 
agent arm)
1
Within 1 hour before the start of 
pevonedistat infusion
B
(combination 
arm)
1
Within 1 hour before the start of 
pevonedistat infusion and before 
azacitidine administration
0 hour
A
5
Within 10 minutes before the start of 
pevonedistat infusion
B
5
Within 10 minutes before the start of 
azacitidine administration
1 hour
A, B
1, 5
At the end of the pevonedistat infusion 
(immediately before stopping the IV 
infusion)
2 hours
A, B
1, 5
1 hour after completion of the 
pevonedistat infusion
3 hours
A, B
1, 5
2 hours after completion of the 
pevonedistat infusion 
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Nominal TAD*
Treatment 
arm
Day
Protocol Specified Time Point
5 hours
A, B
1, 5
4 hours after completion of the 
pevonedistat infusion
7 hours
A, B
1, 5
6 hours after completion of the 
pevonedistat infusion
11 hours
A, B
1, 5
10 hours after completion of the 
pevonedistat infusion
24 hours
A
2
24 hours after initiation of pevonedistat
Cycle 1, Day 1 infusion
6
24 hours after initiation of pevonedistat
Cycle 1, Day 5 infusion
24 hours
B
2
24 hours after initiation of pevonedistat
Cycle 1, Day 1 infusion. Within 10 
minutes before the start of azacitidine 
administration
6
24 hours (1 hour) after initiation of 
pevonedistat Cycle 1, Day 5 infusion
48 hours
A
3
48 hours after initiation of pevonedistat
Cycle 1, Day 1 infusion. Within 10 
minutes before the start of the 
pevonedistat infusion
7
48 hours after initiation of pevonedistat
Cycle 1, Day 5 infusion
48 hours
B
3
48 hours after initiation of pevonedistat
Cycle 1, Day 1 infusion. Within 10 
minutes before the start of azacitidine 
administration
7
48 hours after initiation of pevonedistat
Cycle 1, Day 5 infusion
*For concentration measurements concurrent with bone marrow aspirates, nominal TAD 
will not be assigned and will be summarized separately.
Summary statistics (N, arithmetic mean, standard deviation, geometric mean [where 
appropriate], coefficient of variation [CV], median, minimum, and maximum) will be 
calculated if there is less than 50% of the values missing as described previously. The 
arithmetic mean and geometric mean will be reported on at least 2 non-missing values; and 
the median, standard deviation and CV will be reported on at least 3 non-missing values.
The summary statistics will be calculated for overall, Japanese and other Asian population 
respectively as deemed appropriate (or as data permit).
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For each of the treatment arms, individual and mean pevonedistat plasma concentration-time 
data will be plotted over time (using nominal time for mean and actual TAD for individual 
data) by treatment arm, dose level and study day using linear and semi-logarithmic scales for 
overall, Japanese and other Asian population respectively as deemed appropriate (or as data 
permit). Box plots of pevonedistat dose-normalized AUC and Cmax on Day 1 and Day 5, 
Cycle 1 will be provided for overall, Japanese and other Asian population respectively as 
permitted by data.
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5.10   Safety Analyses
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and changes
from Baseline in the patient’s vital signs, weight, and clinical laboratory results using the
Safety population.
5.10.1   Adverse Events
5.10.1.1   Adverse Events
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent is defined as any AE that occurs after administration of the 
first dose of study treatment and up through 30 days (+10 days) after the last dose of study
drug, any event that is considered drug-related regardless of the start date of the event, or 
any event that is present at baseline but worsens in severity after baseline.
AEs will be tabulated by system organ class (SOC), high level term (HLT), and preferred 
term (PT) for all patients and also by Japanese and non-Japanese patients. Summary 
tabulations include the following categories:
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inciden
ncide
t’s vital
s vita
e Event
e Even
Advers
Adver
will be 
will be
MedDR
MedD
fifirst 
ri
e
d
Only and Subject to the Applicable Terms of Use


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
Treatment-emergent AEs

Drug-related treatment-emergent AEs  

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

Grade 4 or higher treatment-emergent AEs

Grade 4 or higher drug-related treatment-emergent AEs

Grade 3 drug-related treatment-emergent AEs

Grade 4 drug-related treatment-emergent AEs

Grade 5 drug-related treatment-emergent AEs

Treatment-emergent AEs resulting in study drug discontinuation

SAEs

Drug-related SAEs

The most commonly reported treatment-emergent AEs (i.e., those events reported 
by 10% of all patients).
Treatment-emergent AEs that occur after administration of the first dose of study drug and
through 30 days after the last dose of study drug will be tabulated by SOC, HLT, PT.  The 
most commonly reported (at least 10% of all patients) treatment-emergent AEs will be 
presented by preferred term.  The most commonly reported (at least 10% of all patients) 
treatment-emergent AEs by preferred term will also be summarized by treatment cycles
(Cycle 1, Cycle 2-3, Cycle 4-5, Cycle 6-7, Cycle 8+). All adverse events will also be 
reported in by-patient listings.
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:   

If the start date has month and year but day is missing, the event will be considered 
treatment emergent if both the month and year of the start date of the event are on or 
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after the month and year of the date of the first dose of pevonedistat and on or before 
the month and year of the date of the last dose of pevonedistat plus 30 days.

If the start date has year, but day and month are missing, the event will be considered 
treatment emergent if the year of the start date of the event is on or after the year of 
the date of the first dose of pevonedistat and on or before the year of the date of the 
last dose of pevonedistat plus 30 days.

If the start date of an event is completely missing, then the event is assumed to be 
treatment emergent.
5.10.1.2   Serious Adverse Events
The number and percentage of patients experiencing at least one treatment emergent serious 
AE (SAE) will be summarized by MedDRA SOC, HLT, and PT for all patients and also by 
Japanese and non-Japanese patients. Similar summary will be generated for treatment 
emergent drug-related SAEs.
A by-patient listing of the SAEs will be presented (the patient listing will contain all SAEs 
regardless of treatment emergent AE status).
An additional listing of treatment emergent C1D1 grade 2 or higher SAEs will also be 
generated.
5.10.1.3   Deaths
A by-subject listing of the deaths will be presented for all patients and also by Japanese and 
non-Japanese patients.  All deaths occurring on-study and during follow-up will be 
displayed (regardless of treatment emergent AE status). On-study death is defined as the 
death that occurs between the first dose of study drug and 30 days after the last dose of study 
drug.
5.10.1.4   Treatment-Emergent Adverse Events Resulting in Discontinuation of Study 
Drug
The number and percentage of patients experiencing at least one treatment-emergent adverse 
event resulting in discontinuation of study drug will be summarized by MedDRA SOC, 
HLT, and PT for all patients and also by Japanese and non-Japanese patients.
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A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug 
will be presented.  All treatment-emergent AEs resulting in discontinuation of study drug 
occurring on-study and during follow-up will be displayed.
5.10.1.5   Dose Limiting Toxicities (DLTs)
DLT in Cycle 1 will be tabulated for each dose group and treatment (single agent or
combination). The number and percentage of DLT will be summarized by preferred term of
individual toxicities for each dose group and treatment for all patients and also by Japanese 
and non-Japanese patients. 
A by-patient listing of DLTs in Cycle 1 will be presented by dose group and treatment for all 
patients and also by Japanese and non-Japanese in the DLT-evaluable population. Patients 
will be grouped by the dose group and treatment to which they were originally assigned at 
enrollment.
The DLT-Evaluable population will be used for the analysis of DLTs.
5.10.1.6   Hemorrhages
Patients of with hemorrhagic events (SMQ Hemorrhages) will be summarized respectively 
for occurrences of thrombocytopenia, platelet count decreased, and lab platelet toxicity 
grade of at least 2.
5.10.1.7   Myalgia and Musculoskeletal Pain Events
A listing of patients who experience treatment emergent myalgia, arthralgia, and 
musculoskeletal pain events will be presented.
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5.10.1.8   Acute Renal Failure Events
A listing of treatment-emergent acute renal failure events will be generated. The 
corresponding preferred terms are listed as below:

Acute kidney injury

Acute phosphate nephropathy

Acute prerenal failure

Anuria

Azotemia

Continuous hemodiafiltration

Dialysis

Hemodialysis

Neonatal anuria

Nephropathy toxic

Oliguria

Peritoneal dialysis

Prerenal failure

Renal failure

Renal failure acute

Renal failure neonatal

Renal impairment

Renal impairment neonatal

Albuminuria

Blood creatinine abnormal

Blood creatinine increased

Blood urea abnormal

Blood urea increased

Blood urea nitrogen/creatinine ratio increased

Creatinine renal clearance abnormal

Creatinine renal clearance decreased

Creatinine urine abnormal

Creatinine urine decreased

Crystal nephropathy

Glomerular filtration rate abnormal

Glomerular filtration rate decreased

Hypercreatininaemia

Nephritis

Oedema due to renal disease

Protein urine present

Proteinuria

Renal function test abnormal

Renal transplant

Renal tubular disorder

Renal tubular necrosis

Tubulointerstitial nephritis

Urea renal clearance decreased

Urine output decreased
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5.10.1.9   Liver Function Test (LFT) Elevations
A listing of treatment-emergent LFT elevations will be generated. The corresponding 
preferred terms are listed as below:

Acute hepatic failure

Hyperbilirubinemia

Liver function test

Liver function test abnormal

Alanine aminotransferase

Alanine aminotransferase abnormal

Alanine aminotransferase increased

Aspartate aminotransferase

Aspartate aminotransferase increased

Mitochondrial aspartate 
aminotransferase increased

Aspartate aminotransferase abnormal

Blood alkaline phosphatase

Blood alkaline phosphatase abnormal

Blood alkaline phosphatase increased

Blood bilirubin

Bilirubin urine

Bilirubin conjugated

Blood bilirubin abnormal

Blood bilirubin increased

Urine bilirubin increased

Bilirubin conjugated increased

Blood bilirubin unconjugated 
increased

Gamma-glutamyl transferase

Gamma-glutamyl transferase 
abnormal

Gamma-glutamyl transferase 
increased

Hepatic enzyme increased

Hepatic function abnormal
5.10.1.10    Tachycardia Events
A listing of treatment-emergent tachycardia events will be generated. The corresponding 
preferred terms are listed as below:

Heart rate increased

Heart rate irregular

Rebound tachycardia

Sinus tachycardia

Supraventricular tachyarrhythmia

Tachyarrhythmia

Tachycardia

Tachycardia paroxysmal

Palpitations
5.10.1.11   
Hypotension
A listing of treatment-emergent hypotension will be generated. The corresponding preferred 
terms are listed as below:

Blood pressure ambulatory decreased

Blood pressure decreased

Blood pressure orthostatic decreased

Blood pressure systolic decreased
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
Blood pressure diastolic decreased

Blood pressure orthostatic abnormal

Hypotension

Orthostatic hypotension
5.10.1.12   
Anemia
A separate table will display a cross-tabulation of patients who report a PT of anemia at the 
highest intensity and those who receive a concomitant medication of red blood cells at any 
point during the study.
A listing of treatment-emergent anemia will also be generated. The corresponding preferred 
terms are listed as below:

Anemia of chronic disease

Anemia of malignant disease

Anemia

Red blood cell count decreased

Hemoglobin decreased

Mean cell hemoglobin decreased

Hematocrit decreased
5.10.1.13   
Neutropenia
A listing of treatment-emergent neutropenia will also be generated. The corresponding 
preferred terms are listed as below:

Agranulocytosis

Granulocyte count decreased

Band neutrophil count decreased

Band neutrophil percentage decreased

Febrile neutropenia

Idiopathic neutropenia

Leukopenia

Febrile neutropenia

Neutropenia

Neutropenic infection

Neutropenic sepsis

Neutrophil count abnormal

Neutrophil count decreased

Neutrophil percentage abnormal

Neutrophil percentage decreased
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5.10.1.14    Overall Summary
The number and percentage of patients who experience any of the following groups will be 
summarized by dose group and treatment:

Any adverse event (including separate summaries of maximum toxicity grade 
experienced (Grade 1 to Grade 5))

Drug-related adverse event (including separate summaries of maximum toxicity 
grade experienced (Grade 1 to Grade 5))

Serious adverse event

Drug related serious adverse event

Treatment-emergent adverse events resulting in study drug discontinuation

On-study deaths
Percentages will be calculated for all the patients and all the highest tolerable dose patients.
5.10.2   Laboratory Data
For the purposes of summarization, all laboratory values will be converted to standardized 
units.  If a lab value is reported using a non-numeric qualifier (eg, less than (<) a certain 
value, or greater than (>) a certain value), the given numeric value will be used in the 
summarization, ignoring the non-numeric qualifier.  
If a subject has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE
grade from Baseline to the worst post-Baseline value. Summary tables will be generated to 
display the actual values and percent changes from baselines for selected labs. Graphical
displays will be used to show changes in laboratory measures over time for patients:
1) Box graphs of mean laboratory values over time for key laboratory parameters by
dose group and treatment.  
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For patients with neutrophil lab results reported as segmented neutrophils and neutrophil 
bands, ANC will be calculated as:
ANC=total leukocyte count × total percentage of neutrophils (segmented neutrophils + band 
neutrophils)
Creatinine clearance will be derived using one of the Cockcroft-Gault and CKD-EPI
formulas as follows:
Cockcroft-Gault equation:
For males:
)
mol/L]
[
creatinine
serum
(
81
.0
[kg]
 weight 
)
age[years]
-
(140
(mL/min)
Clearance
Creatinine




OR 
)
[mg/dL]
creatinine
serum
(
72
[kg]
 weight 
)
age[years]
-
(140
(mL/min)
Clearance
Creatinine



For females:
)
mol/L]
[
creatinine
serum
(
81
.0
[kg]
 weight 
)
age[years]
-
(140
0.85
(mL/min)
Clearance
Creatinine





OR
)
[mg/dL]
creatinine
serum
(
72
[kg]
 weight 
)
age[years]
-
(140
0.85
(mL/min)
Clearance
Creatinine




A cap value of 125 will be set to creatinine clearance (calculated from Cockcroft-Gault 
equation) higher than 125.
CKD-EPI equation (http://nephron.com/epi_equation): 
For males:
  
0.993
 x 
1)
  
9,
max(Scr/0.
 x 
1)
  
9,
min(Scr/0.
 x 
141
)
m
73
(mL/min/1.
GFR
Age
-1 209
-0 411
2 
, 
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where Scr = serum creatinine (mg/dL).
For black males:
1.159
 x 
0.993
 x 
1)
  
9,
max(Scr/0.
 x 
1)
  
9,
min(Scr/0.
 x 
141
)
m
/1.73
GFR(mL/min
Age
-1 209
-0 411
2 
,
where Scr = serum creatinine (mg/dL).
For females:
1.018
 x 
0.993
 x 
1)
  
7,
max(Scr/0.
 x 
1)
  
7,
min(Scr/0.
 x 
141
)
m
73
(mL/min/1.
GFR
Age
-1 209
-0 329
2 
,
where Scr = serum creatinine (mg/dL).
For black females:
1.159
x 
1.018
 x 
0.993
 x 
1)
  
7,
max(Scr/0.
 x 
1)
  
7,
min(Scr/0.
 x 
141
)
m
73
(mL/min/1.
GFR
Age
-1 209
-0 329
2 
,
where Scr = serum creatinine (mg/dL).
All chemistry and hematology lab data will also be presented in by-patient listings.
In addition, the urinalysis parameters will be presented in by-patient listings.  These include
turbidity and color, pH, specific gravity, protein, ketones, occult blood, nitrite, phosphate
and leukocyte esterase.
A separate listing of selected urinalysis parameters will be generated, including protein, 
occult blood, and leukocytes.
A by-patients listing of urine microscopic analysis parameters will be generated, which
include the patient ID, visit, and erythrocytes, leukocytes, bacteria, casts, and crystals.
5.10.3
Electrocardiograms
The number and percent of patients experiencing abnormal ECG results will be summarized 
for each scheduled time point by dose group and treatment.  
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QTcF and QTcB will be derived using the following formulas.
3
/
1
d
uncorrecte
Rate
r 
Ventricula
60
QT
QTcF







                
Rate
r 
Ventricula
60
QT
QTcB
d
uncorrecte

ECG findings will also be presented in by-patient listings.  
5.10.4   Vital Signs
Boxplots over time for temperature, DBP, SBP, and heart rate during Cycle 1 will be 
generated at the highest tolerable dose for each arm (single-agent arm and combination 
arm).  These will be summarized for measurements taken in the sitting position.
In addition, orthostatic hypotension will be defined as a decrease in systolic blood pressure 
of at least 20 mm Hg or in diastolic blood pressure of at least 10 mm Hg after the patient 
changes from a supine position to a standing position.  Orthostatic heart rate will be defined 
as increase in heart rate of at least 20 beats/min after the patient changes from a supine
position to a standing position.
A table will be generated to summarize the following at baseline and post dose for each dose 
group and treatment:

Percentage of patients who experienced orthostatic hypotension at baseline

Percentage of patients who had orthostatic heart rate at baseline

Percentage of patients who had both orthostatic hypotension and orthostatic heart 
rate at baseline

Percentage of patients who experienced orthostatic hypotension post dose

Percentage of patients who had orthostatic heart rate post dose

Percentage of patients who had both orthostatic hypotension and orthostatic heart 
rate post dose
Moreover, the summary table should also include the following:

Percentage of patients who had orthostatic hypotension post dose and did not have 
orthostatic hypotension at baseline

Percentage of patients who had orthostatic heart rate post dose and did not have 
orthostatic heart rate at baseline

Percentage of patients who had both orthostatic hypotension and orthostatic heart 
rate post dose and had neither orthostatic hypotension nor orthostatic heart rate at 
baseline

Percentage of patients who had orthostatic hypotension at baseline and did not have 
orthostatic hypotension post dose
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
Percentage of patients who had orthostatic heart rate at baseline and did not have 
orthostatic heart rate post dose

Percentage of patients who had both orthostatic hypotension and orthostatic heart 
rate at baseline and had neither orthostatic hypotension nor orthostatic heart rate post 
dose
An additional listing of patients who had orthostatic hypotension or orthostatic heart rate 
post dose will be presented.  The listing will include the baseline and post dose heart rate, 
SBP, and DBP in both the supine and standing positions.  The listing will also include the 
patient’s age and whether they were taking a beta blocking agent as a concomitant 
medication.  Patients should be considered to be taking a beta blocking agent if they are 
taking any of the following at C1D1:
Acebutolol, Atenolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol, Celiprolol, 
Esmolol, 
Labetalol, 
Levobunolol, 
Metipranolol, 
Metoprolol, 
Nadolol, 
Nebivolol, 
Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol, Timolol
Vital sign data will also be presented in a by-patient listing.
5.10.5   Disseminated Intravascular Coagulation (DIC) and PT/PTT
Data from the DIC panel at screening and prothrombin/partial thromboplastin times will be 
presented in separate by-patient listings.
5.10.6   Echocardiograms
Echocardiogram results (e.g. LVEF) will be presented in by-patient listing.
5.10.7   Urine Safety Assessment
The urine safety lab data will be presented in by-patient listings, where directly measured 
urine safety lab tests, the corresponding serum lab tests (serum creatinine, serum albumin, 
and serum phosphate), and the derived lab quantities mentioned below will be included:
1. Ratio of Urine Albumin/ Urine Creatinine 
100
[mg/dL]
creatinine
urine
/ml]
albumin[µg
urine
(mg/g)
Cr 
-
ine
Albumin/Ur
Urine


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2. Fractional Excretion of Phosphate (FRAC-PO4) 
5.10.8    Pregnancy Test 
Pregnancy test result will also be presented in a by-patient listing. 
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
There is no change made to the planned analysis from the protocol.
Reference materials for this statistical plan include Clinical Study Protocol P1012
Amendment 3 (Mar 2017)
7.   
PROGRAMMING CONSIDERATIONS
7.1   
Statistical Software 
SAS version 9.1 (or higher) will be used for all analyses.  
7.2   
Rules and Definitions
Patient populations are defined in Section 2.
Baseline values are defined as in Section 5.4.2.
Treatment emergent AEs are defined as in Section 5.10.1.1.
8.   
REFERENCES
1. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) 
classification of the myeloid neoplasms. Blood 2002;100(7):2292-302.
2. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The
2008 revision of the World Health Organization (WHO) classification of myeloid
neoplasms and acute leukemia: rationale and important changes. Blood
2009;114(5):937-51.
100
3229)]
.0
/
mmol/L]
phosphate[
(serum
[mg/dL])
creatinine
[(urine
88.4)]
 / 
[µmol/L]
creatinine
(serum
mg/dL])
phosphate[
[(urine
PO4
-
FRAC




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3. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S.
Department of Health and Human Services National Cancer Institute. 14 June 2010.
4. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in 
adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 
129(4):424-447.
5. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH. Revised 
recommendations of the International Working Group for diagnosis, standardization 
of response criteria, treatment outcomes, and reporting standards for therapeutic 
trials in acute myeloid leukemia. Journal of Clinical Oncology 2003;21(24):4642-9.
6. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, 
et al. Clinical application and proposal for modification of the International Working 
Group (IWG) response criteria in myelodysplasia. Blood 2006;108(2):419-25.
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