Clinical trial NCT02610777
Conditions: Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic Leukemia, Myeloid, Acute
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2016-04-14; Completion date: 2021-07-23
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of pevonedistat plus azacitidine versus single-agent azacitidine in participants with HR-MDS or CMML, or low-blast AML.

Detailed description:
The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to treat people with MDS or CMML, or low-blast AML as a combination treatment with azacitidine. This study will look at the overall survival, event free survival and response to treatment in people who take pevonedistat and azacitidine when compared to people who take single-agent azacitidine.

The study will enroll 120 participants. Once enrolled, participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in 28-day treatment cycles:

* Pevonedistat 20 mg/m\^2 and azacitidine 75 mg/m\^2 combination
* Single-agent azacitidine 75 mg/m\^2

All participants will receive azacitidine via intravenous or subcutaneous route. Participants randomized to the combination arm will also receive pevonedistat intravenous infusion.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 44 months. Participants will attend the end-of-treatment visit 30 days after the last dose of study drug or before the start of subsequent anti-neoplastic therapy if that occurs sooner. Participants will enter event-free survival follow-up or response follow-up (study visits every 3 months) if their disease has not transformed to AML (for participants with HR MDS or CMML) or progressed (for participants with low-blast AML), and they have not started subsequent therapy. Participants will also enter overall survival follow-up (contacted every 3 months to document subsequent therapies and survival status).

Arms: arm 1: Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). arm 2: Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).
Interventions: intervention 1: Azacitidine intervention 2: Pevonedistat
Intervention descriptions: intervention 1: Azacitidine intravenous or subcutaneous formulation. intervention 2: Pevonedistat intravenous infusion.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety 
of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients with Higher-Risk 
Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute 
Myelogenous Leukemia
NCT Number: NCT02610777
Protocol Approve Date: 27 July 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
1
CLINICAL STUDY PROTOCOL PEVONEDISTAT-2001 AMENDMENT 04
A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of 
Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-Risk 
Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute 
Myelogenous Leukemia
Protocol Number:
Pevonedistat-2001
Indication:
Higher-Risk Myelodysplastic Syndromes, Chronic 
Myelomonocytic Leukemia, Low-Blast Acute Myelogenous 
Leukemia
Phase:
2
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2015-000221-37
Therapeutic Area:
Oncology
Protocol History
Original
25 February 2015
Amendment 01
21 October 2015
Amendment 02
13 September 2016
Amendment 03
17 November 2017
Amendment 04
27 July 2018
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, Massachusetts 02139 United States
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.
PPD
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
2
Rationale for Amendment 04
This document describes changes in reference to the protocol incorporating Amendment 04. 
The primary reason for this amendment is to employ overall survival (OS) as the primary 
endpoint of the study. OS is a clearly defined endpoint that is commonly used in studies with 
patients with higher-risk myelodysplastic syndrome (HR MDS) or chronic myelomonocytic 
leukemia (CMML) and low-blast acute myelogenous leukemia (AML). Event-free survival 
(EFS), the previous primary endpoint of the study, is now a secondary endpoint. These
changes affect the objectives and endpoints of the study. The protocol was also amended to 
clarify definitions of response, duration of the study, and concomitant medication therapy, 
and to update the metabolism profile of pevonedistat and the statistical analysis plan for the 
study.
Throughout the protocol where text previously read “HR MDS or CMML patients” and 
“low-blast AML patients,” text now reads “patients with HR MDS or CMML” and “patients 
with low-blast AML.”
Minor grammatical, editorial, formatting, and administrative changes not affecting the 
conduct of the study are included for clarification and administrative purposes only. 
For specific descriptions of text changes, the rationale for each change, and where the 
changes are located, see Section 15.13.
Changes in Amendment 04
 Update the pharmacokineticprofile of pevonedistatand risk assessment for drug-drug
interactions.
 Update the primary objective and endpoint of the study to OS.
 Update secondary objectives and endpoints of the study, including addition of EFS,and
clarify definitions of response tothe study treatment in the secondary endpoints.
 Update exploratory objectives and endpoints. 


 Update the percentage ofpatients withOS events initiating the timing of the OS analysis
and duration of the study.
 Update table for concomitant medications that are excluded while receiving single-agent
azacitidine study treatment.
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
3
7. Update table for concomitant medications that are excluded while receiving combination
treatment pevonedistat + azacitidine.
8. Add section for posttrial access to study medication.
9. Specify changes for determination of sample size to align with new primary endpoint.
10. Clarify definition of safety population for purposes of analysis.
11. Specify changes in general methodology for analysis of efficacy.
12. Specify analyses of primary efficacy endpoint OS.
13. Clarify methodology for analysis of secondary efficacy endpoints, including those that
are response-related.
14. Clarify populations for analyses of health-related quality of life.
15. Specify 
 will be provided 
16. Delete the exclusion of CYP3A inhibitors from the concomitant medicines table during
administration of pevonedistat therapy.
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
4
PROTOCOL SUMMARY
Study Title: A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and 
Safety of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-
Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute 
Myelogenous Leukemia
Number of Patients: It is expected that approximately 117 patients will be enrolled in this study.
Study Objectives
Primary
To determine in patients with higher-risk myelodysplastic syndrome (HR MDS) or chronic 
myelomonocytic leukemia (CMML) and low-blast acute myelogenous leukemia (AML)
whether the combination of pevonedistat and azacitidine improves overall survival (OS) when 
compared with single-agent azacitidine.
Secondary
To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine improves event-free survival (EFS) when 
compared with single-agent azacitidine; for patients with HR MDS or CMML, an event is 
defined as death or transformation to AML; for patients with low-blast AML, an event is 
defined as death.
To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine improves 6-month and 1-year survival rates 
when compared with single-agent azacitidine.
To determine in patients with HR MDS or CMML whether the combination of pevonedistat 
and azacitidine delays time to AML transformation when compared with single-agent 
azacitidine.
To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine, when compared with single-agent azacitidine, 
improves the rate of complete remission (CR) (composite CR [CR + CRi] in patients with 
low-blast AML), CR plus partial remission (composite CR + PR for patients with low-blast 
AML), overall response, and/or CR (not including CRi) in low-blast AML. Overall response 
in HR MDS or CMML is defined as CR + PR + hematologic improvement (HI); overall 
response in low-blast AML is defined as CR + CRi + PR.
To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine, when compared with single-agent azacitidine, 
improves the rate of CR (composite CR [CR + CRi] in patients with low-blast AML), CR + 
PR (composite CR + PR in patients with low-blast AML), the overall response rate (ORR), as 
well as CR (not including CRi) in low-blast AML by Cycle 4.
To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine, when compared with single-agent azacitidine, 
improves duration of CR (composite CR [CR + CRi] in patients with low-blast AML), CR + 
PR (composite CR + PR in patients with low-blast AML), overall response, and/or CR (not 
including CRi) in patients with low-blast AML.
To determine in patients with HR MDS or CMML and low-blast AML whether the 
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
5
combination of pevonedistat and azacitidine improves time to first CR (CR for HR 
MDS/CMML and low-blast AML; CR + CRi [composite CR] for low-blast AML), or PR 
when compared with single-agent azacitidine.
! To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine delays time to subsequent therapy when 
compared with single-agent azacitidine. Subsequent therapy is defined as agent(s) with 
antileukemic/anti–myelodysplastic syndrome (MDS) activity (eg, cytarabine, anthracyclines, 
purine analogues, and hypomethylating agents other than azacitidine). Patients who 
discontinue study treatment to receive single-agent azacitidine off study would not be counted 
as receiving subsequent therapy.
! To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine improves rate of transfusion independence when 
compared with single-agent azacitidine. Red blood cell (RBC) or platelet transfusion 
independence requires that the patient receive no RBC or platelet transfusions, respectively, 
for a period of at least 8 weeks.
! To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine reduces the percent of patients who have at least 
one inpatient hospital admission(s) related to HR MDS, CMML, or low-blast AML when 
compared with single-agent azacitidine.
! To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine delays time to disease progression (progressive 
disease; PD), relapse, or death when compared with single-agent azacitidine. 
! To evaluate in patients with HR MDS or CMML and low-blast AML, the safety of the 
combination of pevonedistat and azacitidine when compared with single-agent azacitidine.
! To collect in patients with HR MDS or CMML and low-blast AML plasma 
concentration-time data for pevonedistat to contribute to future population pharmacokinetic 
(PK) analyses of pevonedistat.
Exploratory
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
6
Overview of Study Design: This study is a multicenter, global, randomized, controlled, open-label, 
phase 2 clinical study of the combination of pevonedistat and azacitidine versus single-agent 
azacitidine administered in patients with HR MDS or CMML or low-blast AML who have not 
previously received a hypomethylating agent.
Once enrolled, patients will be randomized at a 1:1 ratio to receive study drug (either single-agent 
azacitidine or the combination of pevonedistat and azacitidine) in 28-day treatment cycles. All 
patients will be stratified into 4 categories: low-blast AML, Revised International Prognostic Scoring 
System (IPSS-R) risk group of very high, high, or intermediate for MDS/CMML [2]. All patients 
will receive azacitidine (75 mg/m2 [intravenous or subcutaneous]) on Days 1 through 5, Day 8, and 
Day 9. Patients randomized to the combination arm will also receive pevonedistat (20 mg/m2 via 
60-minute infusion) on Days 1, 3, and 5 of each cycle. Dose modifications may be allowed.
Patients, including those who achieve a CR, may receive study treatment until they experience 
unacceptable toxicity, relapse, transformation to AML, or progressive disease as defined in this 
study.
Patients with HR MDS or CMML may be allowed to continue study treatment (either treatment arm) 
if they meet the criteria for progressive disease based only on bone marrow blast count (without 
AML transformation) if, in the clinical judgment of the investigator, the patient is still receiving 
clinical benefit from this treatment and the continuation is endorsed by the sponsor’s project 
clinician (or designee). Patients with low-blast AML in this study may also be allowed to continue 
study treatment (either treatment arm), even if they meet the criteria for progressive disease based 
only on bone marrow blast counts, if, in the clinical judgment of the investigator, the patient is still 
receiving clinical benefit from this treatment, and the continuation is endorsed by the sponsor’s 
project clinician (or designee). Patients who meet the criteria for PD and continue on study under 
these conditions must be reconsented before continuing study treatment. Patients may choose to 
discontinue at any time. 
Patients will attend the End-of-Treatment (EOT) visit 30 days (+10 days) after the last dose of study 
drug or before the start of subsequent antineoplastic therapy if that occurs sooner. Patients will enter 
EFS follow-up (for patients with HR MDS/CMML) or response follow-up (for patients with 
low-blast AML), with study visits every 3 months, to include physical exam, clinical blood tests, 
HRQOL assessments, hospitalization assessment, bone marrow aspirate sampling, and disease 
assessment, if their disease has not transformed from HR MDS or CMML to AML (for patients with 
HR MDS or CMML) or progressed (for patients with low-blast AML), and they have not started 
subsequent therapy. Patients will enter OS follow-up (contacted every 3 months to document 
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
7
subsequent therapies and survival status) when they have confirmed transformation to AML (for 
patient with HR MDS or CMML) or experienced progressive disease (patients with low-blast AML) 
or have started subsequent therapy.
Disease response assessments for all HR MDS/CMML patients will be based on the Modified 
International Working Group (IWG) response criteria for MDS [3]. Disease response assessments for 
patients with low-blast AML will be based on the Revised Recommendations of the IWG for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in Acute Myeloid Leukemia [4]. Formal disease assessments for study endpoints 
will be determined based on local bone marrow aspirate blast counts and transfusions, and central lab 
data (local lab data may be used for time-sensitive clinical decisions). 
Bone marrow samples (biopsy and/or aspirate) will be collected at Screening, during treatment, and 
during follow-up for blast count evaluation (to inform disease burden assessment). Bone marrow 
aspirate will also be used to analyze tumor cytogenetics,
 
 
Samples will be 
collected and analyzed from patients in both treatment arms. 
Inpatient hospital admissions related to HR MDS or CMML or low-blast AML, as well as RBC- and 
platelet-transfusion independence, will be monitored as secondary efficacy endpoints. 
Treatment-emergent resistance will also be monitored. 
Sparse sampling for the determination of pevonedistat plasma concentrations and, if appropriate, its 
metabolites will be collected from each patient in the Combination Pevonedistat Plus Azacitidine 
Arm to contribute to a population PK analysis of pevonedistat co-administered with azacitidine. 
Adverse events and Eastern Cooperative Oncology Group (ECOG) performance status will be 
assessed, and ECGs, clinical laboratory values, and vital signs will be obtained, to evaluate the safety 
and tolerability of the study drug treatments. Patient-reported HRQOL will be evaluated using the 
EORTC-QLQ-C30 and EQ-5D-5L (all patients) and the QOL-E (American English-speaking US 
patients only) questionnaires.
Study Population:
Patients may be male or female, and must be 18 years or older.
All patients must have morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, 
with WBC <20,000/μL) or low-blast AML based on 1 of the following:
French-American-British (FAB) Classifications [5]:
! Refractory anemia with excess blasts (RAEB – defined as having 5%-20% myeloblasts in the 
bone marrow) 
! CMML with 10%- 19% myeloblasts in the bone marrow and/or 5%- 19% blasts in the blood
OR
World Health Organization (WHO) Classifications [6]: 
! Refractory anemia with excess blasts-1 (RAEB-1 – defined as having 5%-9% myeloblasts in 
the bone marrow)
! Refractory anemia with excess blasts-2 (RAEB-2 – defined as having 10%-19% myeloblasts 
in the bone marrow and/or 5%-19% blasts in the blood)
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
8
Chronic Myelomonocytic Leukemia-2 (CMML-2 – defined as having 10%-19% myeloblasts 
in the bone marrow and/or 5%-19% blasts in the blood 
Chronic Myelomonocytic Leukemia-1 (Although CMML-1 is defined as having <10% 
myeloblasts in the bone marrow and/or <5% blasts in the blood, these patients may enroll 
only if bone marrow blasts ≥5%)
WHO-defined AML with 20%-30% myeloblasts in the bone marrow (defined in this protocol 
as “Low-Blast AML”) and <30% myeloblasts in peripheral blood who are deemed by the 
investigator to be appropriate for azacitidine-based therapy
All patients with MDS or CMML must also have a Prognostic Risk Category, based on the Revised 
International Prognostic Scoring System (IPSS-R)[2], of:
Very high (>6 points), 
High (>4.5 – 6 points), or
Intermediate (>3 – 4.5 points): a patient determined to be in the Intermediate Prognostic Risk 
Category is only allowable in the setting of ≥5% bone marrow myeloblasts.
Complete eligibility details, including additional inclusion and exclusion criteria, are provided in the 
full protocol.
Duration of Study: Patients will be followed until approximately 60% of patients with HR 
MDS/CMML have experienced OS events, or termination of the study by the sponsor.
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
9
STUDY OVERVIEW DIAGRAM 1: 
PATIENTS WITH HIGHER-RISK MYELODYSPLASTIC SYNDROMES OR CHRONIC
MYELOMONOCYTIC LEUKEMIA
AE=adverse event, AML=acute myelogenous leukemia, CR=complete remission, D/C=discontinuation (of study 
treatment), EFS=event-free survival, MDS= myelodysplastic syndromes, OS=overall survival, PD=progressive disease, 
PR=partial remission.
Refer to Section 7.4.21 for response definitions (eg, CR, PR, transformation to AML, PD)
a
Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity (eg, lenalidomide, cytarabine, 
anthracyclines, purine analogues, and hypomethylating agents other than azacitidine). Patients who discontinue study 
treatment to receive single-agent azacitidine off study would not be counted as receiving subsequent therapy.
Screening
Azacitidine
Azacitidine + Pevonedistat
Treatment until discontinuation criterion met
D/C without evidence of  
transformation to AML
D/C due to 
transformation to AML
End of Study – death, or the sponsor terminates the study
End of Treatment visit
Transformation to AML OR 
initiation of subsequent therapya
D/C while in CR or PR
Death
Randomization
D/C due to 
PD (but not AML) OR
without Evidence of PD 
(eg, AE, Other)
End of Treatment visit
Bone marrow aspirate every 3 months until 1 of the 
following: transformation to AML, initiation of 
subsequent therapya, or death
Death while on 
treatment
Bone marrow aspirate 
upon relapse
Follow-Up every 3 months, for collection of subsequent therapiesa
(all lines) and survival status until death
Study Procedures
enrollment and study treatment
EFS
Follow-Up
monitor for transformation to AML
OS
Follow-Up
monitor for OS
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
10
STUDY OVERVIEW DIAGRAM 2: 
PATIENTS WITH LOW-BLAST ACUTE MYELOGENOUS LEUKEMIA
AE=adverse event, CR=complete remission, D/C=discontinuation (of study treatment), EFS=event-free survival, MDS= 
myelodysplastic syndromes, OS=overall survival, PD=progressive disease, PR=partial remission.
Refer to Section 7.4.21 for response definitions (eg, CR, PR, PD)
a
Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity (eg, lenalidomide, cytarabine, 
anthracyclines, purine analogues, and hypomethylating agents other than azacitidine). Patients who discontinue study 
treatment to receive single-agent azacitidine off study would not be counted as receiving subsequent therapy.
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
11
SCHEDULE OF EVENTS
Screening
(a,b)
Treatment Cycle (28 Days) (c,d,e)
EOT
(f)
Follow-up
Cycle 1
Cycle 2 and beyond
EFS
(HR MDS/
CMML)
Response
(AML)
OS
Days
1
2
3
5
8
15
21
1
3
5
Every
3 
months
Every
3
months
Every
3 
months
Procedures
Window
±1 
day
±1 
day
+10 
days
±2 
weeks
±2
weeks
±2 
weeks
Informed consent
X
Inclusion/Exclusion (g)
X
Demographics
X
Complete medical history and 
IPSS-R risk categorization 
(patients with HR MDS, CMML)
X
Modified Charlson comorbidity 
index assessment (h)
X
Complete physical examination 
X
X
Symptom-directed physical 
examination
X
X
X
X
Height
X
Weight
X
X(i)
X(i)
X
ECOG performance status
X
X
X
Vital signs (j)
X
X
X
X
X
X
X 
X
12-lead ECG (k)
X
X
Chest X-ray (l)
X
Pregnancy test (m)
X
X
X
X
Hematology (n)
X
X
X
X
X
X
X
X
X
X
X
Coagulation (o)
X
Complete chemistry panel (n,p)
X
X
X
X
X
Select chemistry panel (n,q)
X
X
X
X
X
X
X
X
Blood phosphate (r)
X
X
Reticulocyte count and ferritin (s)
X
X
X
X
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
12
Screening
(a,b)
Treatment Cycle (28 Days) (c,d,e)
EOT
(f)
Follow-up
Cycle 1
Cycle 2 and beyond
EFS
(HR MDS/
CMML)
Response
(AML)
OS
Days
1
2
3
5
8
15
21
1
3
5
Every
3 
months
Every
3
months
Every
3 
months
Procedures
Window
±1 
day
±1 
day
+10 
days
±2 
weeks
±2
weeks
±2 
weeks
Urinalysis with microscopic 
analysis (t)
X
X
EORTC-QLQ-C30 (u)
X
X
X
X
X
X
QOL-E (u)
X
X
X
X
X
X
EQ-5D-5L (u)
X
X
X
X
X
X
Hospitalization assessment (u)
X
X
X
X
X
Blood samples for PK
X (v)
X (v)
X (v)
X (w)
Bone marrow aspiration/biopsy and 
investigator disease assessment
See the Bone Marrow Collection and Assessment Schedule
Buccal swab for germline DNA 
analysis/DME genotyping
X (x)
SAE collection (y)
SAEs including serious pretreatment events will be reported from the time informed consent is signed 
through 30 days after the last dose of any study drug
AE collection
Recorded from the first dose of any study drug through 30 days after the last dose of any 
study drug
Concomitant medications/therapy
Recorded from the first dose of any study drug through 30 days after the last dose of any 
study drug
RBC and platelet transfusion 
documentation
Recorded from 8 weeks before randomization through 30 days after the last dose of any study drug
Subsequent therapies (z)
X
X
X
X
Survival follow-up contact
X
Study Drug Administration: Single-Agent Azacitidine or Combination Pevonedistat Plus Azacitidine (e,zz,zzz)
Pevonedistat infusion
Days 1, 3, and 5 of each cycle
Azacitidine administration
Days 1-5 and 8 and 9 of each cycle
AE=adverse event, ALP=alkaline phosphatase, ALT=alanine aminotransferase, AML=acute myelogenous leukemia, aPTT=activated partial thromboplastin time, AST=aspartate 
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
13
Screening
(a,b)
Treatment Cycle (28 Days) (c,d,e)
EOT
(f)
Follow-up
Cycle 1
Cycle 2 and beyond
EFS
(HR MDS/
CMML)
Response
(AML)
OS
Days
1
2
3
5
8
15
21
1
3
5
Every
3 
months
Every
3
months
Every
3 
months
Procedures
Window
±1 
day
±1 
day
+10 
days
±2 
weeks
±2
weeks
±2 
weeks
aminotransferase, BSA=body surface area, BUN=blood urea nitrogen, CMML=chronic myelomonocytic leukemia, DME=drug metabolizing enzymes, DNA=deoxyribonucleic 
acid, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, eCRF=electronic case report form, EFS=event-free survival, EOT=end of treatment, 
HRQOL=health-related quality of life, IPSS-R=Revised International Prognostic Scoring System, IV=intravenous(ly), LDH=lactate dehydrogenase, MDS=myelodysplastic 
syndromes, OS=overall survival, PK=pharmacokinetic, PT=prothrombin time, RBC=red blood cell, SAE=serious adverse event, SC=subcutaneous(ly), WBC=white blood cell.
(a) Screening assessments will be performed within 28 days before randomization. Baseline assessments are defined as those performed at the closest time before the start of study 
drug administration.
(b) Except for hematology, 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 the previous Friday.
(c) On dosing days, all procedures are to be performed prior to pevonedistat or azacitidine dosing unless specified otherwise. 
(d) For a new cycle of treatment with study drug(s) to begin, toxicities considered to be related to treatment with study drug(s) must have resolved to the level or grade defined in 
Section 6.3.1.
(e) The first dose of study drug must be administered within 5 days of randomization on study. It is strongly recommended that dosing for both treatment arms occur on the days 
specified. However, dosing of either drug may be delayed for safety reasons or other unavoidable circumstances (eg, weather conditions affecting clinic accessibility). If 
pevonedistat dosing is delayed, a minimum of 1 full calendar day 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. For the combination arm, pevonedistat and azacitidine should always be administered on the same day (eg, instead of 
pevonedistat dosing on Days 1, 3, and 5, it would be acceptable to dose on Days 1, 5, and 8). If dosing is adjusted, study procedures should be performed on the actual day of 
dosing.
(f) The EOT visit will occur 30 days (+10 days) after the last dose of study drug(s) or before the start of subsequent antineoplastic therapy if that occurs sooner. After the EOT visit, 
patients will enter EFS follow-up if their disease has not transformed to AML (for patients with HR MDS or CMML) or enter response follow-up if their disease has not 
progressed (for patients with low-blast AML) (as defined in Section 7.4.21), and they have not started subsequent therapy. Patients will enter OS follow-up when they have 
confirmed transformation to AML (for patients with HR MDS or CMML at study entry), experienced progressive disease (for patients with low-blast AML at study entry), or 
have started subsequent therapy.
(g) Confirmation of patient eligibility by the sponsor’s project clinician (or designee) is required prior to randomization. A Patient Eligibility Checklist must be completed and 
submitted by the investigator for review and approval by the sponsor or designee prior to patient randomization.
(h) See Section 15.7 for the modified Charlson comorbidity index. 
(i) Weight will be measured within 3 days before Day 1 dosing in each cycle, for calculating BSA. BSA will be calculated using a standard formula (see example in Section 15.8) 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.
(j) Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will be collected at Screening, predose on Days 1, 3, and 5 on each treatment arm of 
each treatment cycle, at EOT, and as clinically indicated. Vital sign measurements will be taken with the patient in the supine or sitting position.
(k) Additional ECGs may be performed as clinically indicated.
(l) If a chest X-ray or chest CT scan was performed within 2 months prior to randomization, the chest X-ray does not need to be performed during Screening.
(m) A serum pregnancy test will be performed for women of childbearing potential at Screening. A pregnancy test must also be performed for women of childbearing potential at 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
14
Screening
(a,b)
Treatment Cycle (28 Days) (c,d,e)
EOT
(f)
Follow-up
Cycle 1
Cycle 2 and beyond
EFS
(HR MDS/
CMML)
Response
(AML)
OS
Days
1
2
3
5
8
15
21
1
3
5
Every
3 
months
Every
3
months
Every
3 
months
Procedures
Window
±1 
day
±1 
day
+10 
days
±2 
weeks
±2
weeks
±2 
weeks
every cycle (typically performed on Day 1 of the cycle; however, if a serum pregnancy test is used, this may be performed up to 3 days before Day 1) with negative results 
available before the first dose is administered in that cycle. A pregnancy test will also be performed for women of childbearing potential at the EOT visit. Pregnancy tests may also 
be repeated during the study if requested by an IEC/IRB or if required by local regulations.
(n) Clinical laboratory evaluations will be performed by a central laboratory. The central laboratory results also should be used for determination of eligibility by the sponsor’s project 
clinician (or designee) prior to randomization. For dosing decisions and/or safety concerns, local hematology and chemistry results should be used; however, samples must still be 
sent to the central lab as well. Hematology and chemistry samples may be collected up to 3 days before Day 1 dosing and 24 hours before Days 3 and 5 dosing, when required. 
Local laboratory evaluations may be done more frequently at the investigator’s discretion.
(o) Coagulation panel includes PT and aPTT (to be performed by the central laboratory).
(p) The complete chemistry panel will include the following: BUN, creatinine, sodium, potassium, chloride, carbon dioxide, glucose, urate, total bilirubin, direct bilirubin, ALP, 
LDH, AST, ALT, albumin, magnesium, phosphate, and calcium.
(q) The select chemistry panel will include the following: BUN, creatinine, total bilirubin, ALP, AST, and ALT.
(r) Blood phosphate test to be performed on Day 5 of each treatment cycle or the day on which the third dose of pevonedistat is given if it is not Day 5 (to be performed by the central 
laboratory).
(s) Reticulocyte counts and ferritin level testing will be performed by the central laboratory only. Reticulocyte count and ferritin samples may be collected up to 3 days before Day 1 
dosing. 
(t) Urinalysis will include assessments of turbidity and color, pH, specific gravity, protein, ketones, bilirubin, occult blood, nitrite, glucose, and leukocyte esterase. Urine microscopic 
analysis will include erythrocytes, leukocytes, bacteria, casts, and crystals. These samples will be analyzed by a central laboratory.
(u) Patient-reported outcomes (HRQOL) and hospitalization assessment (ie, details regarding any hospitalizations since the last assessment) should be completed before any other 
study procedures are performed or study drug regimen is administered. The EORTC-QLQ-C30 and EQ-5D-5L will be completed for all patients, and the QOL-E will be 
completed for American English-speaking US patients only.
(v) Combination Pevonedistat Plus Azacitidine Arm only: blood samples (approximately 3 mL each) for the determination of pevonedistat plasma concentrations will be collected 
during Cycle 1 at the following time points: Day 1 at the end of the pevonedistat infusion (immediately before stopping the infusion), at 1.5 hours (#30 minutes) and at 4 hours 
(# 45 minutes) after completion of the pevonedistat infusion; Day 3 predose (within 10 minutes before azacitidine dosing); and Day 5 predose (within 10 minutes before 
azacitidine dosing), at the end of the pevonedistat infusion (immediately before stopping the infusion), and prior to the patient’s discharge from the clinic visit. The exact date and 
time of each sample collection and the actual start and stop times of the infusion should be recorded accurately, and particular care should be given to the recording of blood 
sampling times that occur close to the infusion. Details regarding the preparation, handling, and shipping of samples are provided in the Study Manual.
(w) Combination Pevonedistat Plus Azacitidine Arm only: blood samples (approximately 3 mL each) for the determination of pevonedistat plasma concentrations will be collected at 
Cycle 2 and Cycle 4 Day 1 (at the end of the pevonedistat infusion [immediately before stopping the infusion] and 3 hours [# 45 minutes] after completion of the pevonedistat 
infusion); an additional sample will be collected predose (within 10 minutes before azacitidine dosing) on Cycle 4 Day 3. The exact date and time of each sample collection and 
the actual start and stop times of the infusion should be recorded accurately, and particular care should be given to the recording of blood sampling times that occur close to the 
infusion. Details regarding the preparation, handling, and shipping of samples are provided in the Study Manual.
(x) 
.
CCI
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
15
Screening
(a,b)
Treatment Cycle (28 Days) (c,d,e)
EOT
(f)
Follow-up
Cycle 1
Cycle 2 and beyond
EFS
(HR MDS/
CMML)
Response
(AML)
OS
Days
1
2
3
5
8
15
21
1
3
5
Every
3 
months
Every
3
months
Every
3 
months
Procedures
Window
±1 
day
±1 
day
+10 
days
±2 
weeks
±2
weeks
±2 
weeks
(y) SAEs will be entered on the eCRF and also reported to 
 (see Section 10.2). Serious pretreatment events (occurring before the first dose of any study drug) will only be 
reported to 
 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). 
(z) Subsequent therapy is defined as an agent(s) with antileukemic/anti-MDS activity (eg, cytarabine, anthracyclines, purine analogues, and hypomethylating agents other than 
azacitidine). Patients who discontinue study treatment to receive single-agent azacitidine off study would not be counted as receiving subsequent therapy.
(zz) Combination Pevonedistat Plus Azacitidine Arm only: See Section 6.1.2 for pevonedistat dosing instructions. On Days 1, 3, and 5 when both study drugs are administered, 
azacitidine will be administered first followed by pevonedistat. Subsequent pevonedistat doses may be reduced due to toxicity in accordance with Section 6.3. 
(zzz) All patients will receive azacitidine 75 mg/m2 IV or SC on Days 1 through 5 (inclusive), Day 8, and Day 9 of each cycle in accordance with Section 6.1.1. The azacitidine dose 
may be reduced due to toxicity in accordance with Section 6.3. 
CCI
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
16
Bone Marrow Collection and Assessment Schedule
Assessment
Screening 
Cycle 2 Day 22
(+6 Days)
Cycle 4 Day 22 
(+6 days)
Cycle 7 Day 22 
(+6 days)
Cycle 10 Day 22 
(+6 days), and 
Then Every 3 
Cycles Thereafter
Relapse 
EFS/Response 
Follow-up
(Every 3 Months)
Bone marrow blast count
(Local and central analyses)
X (a)
X (b)
X (b,c)
X (b,c)
X (b,c)
X
X (c)
Cytogenetics (d) 
(Local analysis only)
X
X
X (c)
X (c)
X (c)
X
Mutation analysis (e)
(Local analysis only)
X
Molecular analysis (Central 
analysis only)
X(f)
X(f)
X(g)
X(g)
X (h)
CR=complete remission, EFS=event-free survival, FISH=fluorescence in situ hybridization, PCR=polymerase chain reaction, PD=progressive disease.
(a) A bone marrow biopsy (in addition to bone marrow aspirate) is required only at Screening to confirm the diagnosis; bone marrow aspirates will be collected at all other time 
points, at relapse or PD, and as clinically indicated (see Section 7.4.20 for detailed examples). However, a bone marrow biopsy may be collected with bone marrow aspirate in 
accordance with institutional guidelines. If a bone marrow aspirate and biopsy were performed within 28 days prior to randomization, these archival samples may be used to 
confirm diagnosis and do not need to be repeated. However, a bone marrow aspirate for molecular analysis is still required at Screening (see footnote (f) below). The bone 
marrow pathology report(s) will be submitted to the central laboratory. If a bone marrow biopsy is not collected routinely per country institutional guidelines, it is not required.
(b) A bone marrow aspirate for blast count (to inform disease burden assessment) will be performed on Day 22 (+6 days) of Cycle 2, Cycle 4, and every 3 cycles thereafter (Cycle 
7, Cycle 10, etc.). Results must be available before dosing starts in the next cycle. 
(c) Following Cycle 4, bone marrow aspirates will be performed only as clinically indicated in patients who achieve CR. In all other patients who do not achieve CR, bone marrow 
assessments will be performed after completion of every third treatment cycle. Additional bone marrow aspirates may be performed if warranted by changes in peripheral blood 
counts.
(d) Cytogenetics analysis will be done locally at the clinical site: a bone marrow aspirate sample will be tested according to institutional guidelines in a cytogenetics laboratory 
routinely used by the site. Analyses should be done by karyotype, and by FISH if possible. Results will be collected in the eCRF and the cytogenetics report(s) will be submitted 
to the central laboratory. 
(e) Mutation analysis to be performed locally at the clinical site according to institutional guidelines/standard practice (eg, genomic analysis or PCR analysis) and this information
will be collected from sites. If mutation analysis is not performed routinely per country/institutional guidelines, it is not required. Results will be collected in the eCRF and the 
mutation analysis report(s) will be submitted to the central laboratory.
(f) A fresh bone marrow aspirate obtained at screening, any time prior to the first administration of study drug, will be used for baseline molecular characterization. A bone marrow 
aspirate sample for molecular analysis will also be obtained on Day 22 (+6 days) of Cycle 2. Bone marrow aspirate samples will be sent to a central laboratory for molecular 
analysis.
(g) A bone marrow aspirate sample for molecular analysis will be obtained on Day 22 (+6 days) of Cycle 4. A bone marrow aspirate sample for molecular analysis will also be 
obtained Day 22 (+6 days) of Cycle 7 for patients who do not have a confirmed CR at Cycle 4. Bone marrow aspirate samples will be sent to a central laboratory for molecular 
analysis.
(h) If relapse is suspected, the sample for molecular analysis will be collected at the time the bone marrow sample for disease assessment is collected and sent to the central 
laboratory (per instructions in the Laboratory Manual). 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
17
TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................20
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................21
1. BACKGROUND AND STUDY RATIONALE..............................................................25
1.1 Scientific Background ..............................................................................................25
1.1.1 Diseases Under Treatment .................................................................................25
1.1.2 Study Drug: Pevonedistat...................................................................................28
1.2 Nonclinical Experience.............................................................................................28
1.2.1 Single-Agent Pevonedistat .................................................................................28
1.2.2 Pevonedistat With Azacitidine ...........................................................................29
1.3 Clinical Experience ..................................................................................................30
1.4 Pharmacokinetics of Pevonedistat.............................................................................32
1.4.1 Nonclinical Pharmacokinetics and Risk Assessment for Drug-Drug 
Interactions .................................................................................................32
1.4.2 Clinical Pharmacokinetics..................................................................................33
1.5 Study Rationale ........................................................................................................34
1.5.1 Rationale for Study Population...........................................................................34
1.5.2 Rationale for the Combination of Pevonedistat Plus Azacitidine ........................35
1.5.3 Rationale for Dose and Schedule of Study Drugs ...............................................35
1.5.4 Rationale for Molecular Analyses ......................................................................36
1.5.5 Rationale for Health-Related Quality of Life Assessments .................................40
1.6 Potential Risks and Benefits .....................................................................................41
1.6.1 Azacitidine.........................................................................................................41
1.6.2 Pevonedistat Plus Azacitidine ............................................................................42
1.6.3 Potential for Drug-Drug Interactions..................................................................44
2. STUDY OBJECTIVES ..................................................................................................45
2.1 Primary Objective.....................................................................................................45
2.2 Secondary Objectives ...............................................................................................45
2.3 Exploratory Objectives .............................................................................................47
3. STUDY ENDPOINTS....................................................................................................48
3.1 Primary Endpoint .....................................................................................................48
3.2 Secondary Endpoints................................................................................................48
3.3 Exploratory Endpoints..............................................................................................49
4. STUDY DESIGN...........................................................................................................50
4.1 Overview of Study Design........................................................................................50
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 All Patients – Azacitidine Dosing.......................................................................59
6.1.2 Additional Instructions for the Combination Arm – Pevonedistat Plus 
Azacitidine Dosing......................................................................................59
6.2 Reference/Control Therapy: Azacitidine...................................................................60
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
18
6.3 Dose Modification Guidelines ..................................................................................61
6.3.1 Criteria for Retreatment and Dose Delays ..........................................................61
6.3.2 Dose Modification for Hematologic Toxicities...................................................62
6.3.3 Dose Modification for Nonhematologic Toxicities.............................................64
6.4 Excluded Concomitant Medications and Procedures.................................................65
6.5 Permitted Concomitant Medications and Procedures.................................................66
6.6 Precautions and Restrictions.....................................................................................67
6.7 Management of Clinical Events................................................................................68
6.7.1 Azacitidine.........................................................................................................68
6.7.2 Combination Pevonedistat Plus Azacitidine .......................................................69
6.8 Blinding and Unblinding ..........................................................................................70
6.9 Description of Investigational Agents.......................................................................70
6.9.1 Azacitidine.........................................................................................................70
6.9.2 Pevonedistat.......................................................................................................70
6.10 Preparation, Reconstitution, and Dispensation ........................................................71
6.11 Packaging and Labeling..........................................................................................71
6.12 Storage, Handling, and Accountability....................................................................72
7. STUDY CONDUCT ......................................................................................................72
7.1 Study Personnel and Organizations...........................................................................72
7.2 Arrangements for Recruitment of Patients ................................................................72
7.3 Treatment Group Assignments .................................................................................73
7.4 Study Procedures......................................................................................................73
7.4.1 Informed Consent ..............................................................................................73
7.4.2 Inclusion/Exclusion Confirmation......................................................................74
7.4.3 Patient Demographics ........................................................................................74
7.4.4 Medical History and IPSS-R Risk Categorization...............................................74
7.4.5 Modified Charlson Comorbidity Index Assessment............................................76
7.4.6 Physical Examination.........................................................................................76
7.4.7 Patient Height ....................................................................................................76
7.4.8 Patient Weight ...................................................................................................76
7.4.9 Eastern Cooperative Oncology Group Performance Status.................................76
7.4.10 Vital Signs .......................................................................................................77
7.4.11 Electrocardiogram............................................................................................77
7.4.12 Chest X-ray......................................................................................................77
7.4.13 Enrollment .......................................................................................................77
7.4.14 Clinical Laboratory Evaluations.......................................................................77
7.4.15 Pregnancy Test.................................................................................................79
7.4.16 Health-Related Quality of Life Questionnaires.................................................79
7.4.17 Hospitalization Assessment..............................................................................81
7.4.18 Pharmacokinetic Measurements.......................................................................81
7.4.19
7.4.20 Bone Marrow Aspirate and Biopsy Collection and Analysis.............................82
7.4.21 Disease Assessment .........................................................................................85
7.4.22 Adverse Events................................................................................................90
7.4.23 Concomitant Medications and Procedures........................................................90
7.5 Completion of Treatment..........................................................................................91
CCI
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
19
7.6 Completion of Study.................................................................................................92
7.7 Discontinuation of Treatment With Study Drug, and Patient Replacement................92
7.8 Withdrawal of Patients From Study..........................................................................93
7.9 Study Compliance ....................................................................................................93
7.10 Posttreatment Follow-up Assessments (Event-Free Survival, Response 
Follow-up, and Overall Survival) ......................................................................94
7.11 Posttrial Access ......................................................................................................94
7.11.1 Posttrial Access................................................................................................94
7.11.2 Duration of PTA ..............................................................................................94
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................95
8.1 Statistical Methods ...................................................................................................95
8.1.1 Determination of Sample Size............................................................................95
8.1.2 Randomization and Stratification .......................................................................95
8.1.3 Populations for Analysis ....................................................................................95
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................96
8.1.5 Demographic and Baseline Characteristics.........................................................96
8.1.6 Efficacy Analysis...............................................................................................96
8.1.7 Analyses of Health-related Quality of Life .......................................................101
8.1.8 Pharmacokinetics/Pharmacodynamics/
...........................................101
8.1.9 Safety Analysis ................................................................................................102
8.1.10 Interim Analysis.............................................................................................104
9. STUDY COMMITTEES..............................................................................................104
9.1 Millennium Safety Monitoring ...............................................................................104
9.2 Independent Data Monitoring Committee...............................................................105
10. ADVERSE EVENTS .................................................................................................105
10.1 Definitions............................................................................................................105
10.1.1 Pretreatment Event Definition........................................................................105
10.1.2 Adverse Event Definition...............................................................................105
10.1.3 Serious Adverse Event Definition ..................................................................105
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events...............................................................................................107
10.3 Monitoring of Adverse Events and Period of Observation.....................................108
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events......108
10.5 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities........109
11. ADMINISTRATIVE REQUIREMENTS ...................................................................109
11.1 Good Clinical Practice..........................................................................................109
11.2 Data Quality Assurance ........................................................................................109
11.3 Electronic Case Report Form Completion.............................................................110
11.4 Study Monitoring .................................................................................................110
11.5 Ethical Considerations..........................................................................................111
11.6 Patient Information and Informed Consent............................................................111
11.7 Patient Confidentiality..........................................................................................111
11.8 Investigator Compliance.......................................................................................111
11.9 On-site Audits ......................................................................................................112
11.10 Investigator and Site Responsibility for Drug Accountability..............................112
11.11 Product Complaints ............................................................................................112
CCI
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11.12 Closure of the Study ...........................................................................................113
11.13 Record Retention................................................................................................114
12. USE OF INFORMATION..........................................................................................114
13. INVESTIGATOR AGREEMENT..............................................................................115
14. REFERENCES...........................................................................................................116
15. APPENDICES ...........................................................................................................122
15.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.......122
15.2 Cockcroft-Gault Equation.....................................................................................122
15.3 Definition of Postmenopausal...............................................................................122
15.4 Methods of Contraception Considered to be Effective ..........................................123
15.5 New York Heart Association Classification of Cardiac Disease ............................125
15.6 Excluded CYP3A Inducers...................................................................................125
15.7 Modified Charlson Comorbidity Index .................................................................126
15.8 Body Surface Area Calculation.............................................................................126
15.9 Formula for Absolute Neutrophil Count Calculation.............................................126
15.10 Amendment 01 Rationale and Purposes..............................................................128
15.11 Amendment 02 Rationale and Purposes..............................................................132
15.12 Amendment 03 Rationale and Purposes..............................................................136
15.13 Amendment 04 Detailed Description of Amendments to Text.............................137
LIST OF TABLES
Table 6.a
Concomitant Medications Excluded While Receiving Study Treatment: 
Single-Agent Azacitidine Arm ....................................................................65
Table 6.b
Concomitant Medications Excluded While Receiving Study Treatment: 
Combination Pevonedistat Plus Azacitidine Arm ........................................66
Table 6.c
Concomitant Medications and Procedures Permitted During the Study........66
Table 7.a
IPSS-R Prognostic Score Values .................................................................75
Table 7.b
IPSS-R Cytogenetic Risk Groups................................................................75
Table 7.c
IPSS-R Prognostic Risk Categories/Scores..................................................76
Table 7.d
Response Criteria for Altering Natural History of MDS and CMML ...........87
Table 7.e
Response Criteria for Hematologic Improvement for MDS and CMML ......89
Table 7.f
Response Criteria for AML.........................................................................89
Table 15.a
In Vivo Inducers of CYP3A......................................................................125
Table 15.b
Modified Charlson Comorbidity Index......................................................126
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BCRP
breast cancer resistance protein
BSA
body surface area
BUN
blood urea nitrogen
CCR
conventional care regimen
CDL
cullin-dependent ubiquitin E3 ligase 
Cdt-1
chromatin-licensing and DNA-replication factor-1
CI
confidence interval
Cmax
maximum (peak) concentration
CMH
Cochran-Mantel-Haenszel
CMML
chronic myelomonocytic leukemia
CO2
carbon dioxide
CR
complete remission 
CRi
complete remission with incomplete blood count recovery
CT
computed tomography
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DME
drug metabolizing enzyme
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EFS
event-free survival
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Abbreviation
Term
EQ-5D-5L
EuroQoL 5 dimensions 5 levels (a quality of life questionnaire of the “EuroQoL 
Group Association” that was expanded to a 5-level instrument)
EORTC-QLQ-C30  
European Organisation for the Research and Treatment of Cancer Core Quality 
of Life Questionnaire
EOT
end of treatment 
FAB
French-American-British
FISH
fluorescence in situ hybridization
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage colony-stimulating factor
hERG
human ether-à-go-go related gene 
HI
hematologic improvement
HIV
human immunodeficiency virus
HLT
high-level term
HR MDS
higher-risk MDS
HRQOL
health-related quality of life
IB
Investigator’s Brochure
IC50
concentrations producing 50% inhibition 
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IPSS-R
Revised International Prognostic Scoring System
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous; intravenously
IWG
International Working Group
IWRS
interactive web response system 
LDH
lactate dehydrogenase
LFT
liver function test
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, and its affiliates
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Abbreviation
Term
miRNAs
micro-RNAs
MLN4924
research name of pevonedistat hydrochloride; TAK-924
MRD
measurable residual disease
MTD
maximum tolerated dose
NAE
NEDD8-activating enzyme 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NEDD8
neural precursor cell expressed developmentally down-regulated protein 8
NGS
next-generation sequencing
Nrf2
NFE2-related factor 2
NYHA
New York Heart Association
OATP
organic anion-transporting polypeptides 
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease, disease progression
P-gp
P-glycoprotein 
PK
pharmacokinetic(s)
PR
partial remission 
PRO
patient-reported outcome
PT
preferred term
PT
prothrombin time
PTA
posttrial access
QALYs
quality-adjusted life years
QOL-E
Quality of Life in Hematological patients (myelodysplastic syndromes) 
(questionnaire from the Associazione QOL-ONE)
RAEB
refractory anemia with excess blasts
RAEB-t
refractory anemia with excess blasts in transformation
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SmPC
Summary of Product Characteristics
SOC
system organ class
SUSAR
suspected unexpected adverse reaction
t1/2
terminal disposition half-life
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Abbreviation
Term
TEAE
treatment-emergent adverse event
ULN
upper limit of the normal range
US
United States
USP
United States Pharmacopeia
USPI
United States prescribing information
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
Myelodysplastic syndromes (MDS) are a group of biologically and clinically heterogeneous 
hematopoietic disorders derived from an abnormal multipotent progenitor cell. The 
diagnosis of MDS is made based upon findings in the peripheral blood and bone marrow as 
interpreted within the clinical context. Most cases of MDS are diagnosed based upon the 
presence of 3 main features:

Otherwise unexplained quantitative changes in 1 or more of the blood and bone 
marrow elements (ie, red cells, granulocytes, platelets). 

Morphologic evidence of significant dysplasia (ie, ≥10 percent of erythroid 
precursors, granulocytes, or megakaryocytes) upon visual inspection of the 
peripheral blood smear, bone marrow aspirate, and bone marrow biopsy in the 
absence of other causes of dysplasia. 

Blast forms account for less than 20 percent of the total cells of the bone marrow 
aspirate and peripheral blood. Cases with higher blast percentages are considered to 
have acute myelogenous leukemia (AML). In addition, the presence of myeloid 
sarcoma or certain genetic abnormalities, such as those with t(8;21), inv(16), or 
t(15;17), are considered diagnostic of AML, irrespective of the blast cell count.
MDS are classified using the World Health Organization (WHO) classification system [6,7]
based upon a combination of morphology, immunophenotype, genetics, and clinical 
features. The WHO classification system was built upon the French-American-British 
(FAB) Cooperative Group classification [5].
MDS are commonly divided into lower- or higher-risk categories based on the Revised 
International Prognostic Scoring System (IPSS-R) for MDS, which is a scoring system 
useful for estimating overall survival and the risk of transformation to AML [2]. Overall, 
approximately 25% of patients with very high, high, or intermediate IPSS-R scores will 
transform to AML within 0.7 years, 1.4 years, and 3.2 years, respectively [2]. Median 
survival for patients with MDS varies from years to months and decreases with increasing 
IPSS-R score.
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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 (OS), and decrease progression to AML. Treatment 
of patients with lower-risk MDS (often defined as patients with <5% myeloblasts and/or 
normal or good risk cytogenetics and few cytopenias) focuses on minimizing blood product 
transfusions and maximizing quality of life through use of supportive care (eg, antibiotics as 
needed for infections, red blood cell transfusions), growth factors such as erythropoiesis 
stimulating factors or immunosuppressive drugs. Treatment for patients with higher-risk 
disease often includes DNA hypomethylating agents (azacitidine and decitabine) [8]. Rarely, 
intensive chemotherapy is used in patients with higher-risk MDS (HR MDS), but it 
generally results in significant toxicity and modest responses 
(uptodate.com/contents/treatment-of-high-or-very-high-risk-myelodysplastic-syndromes, 
Treatment of high or very high risk myelodysplastic syndromes, Accessed 08 December 
2014) [9-11]. 
Hypomethylating agents produce objective hematologic responses in approximately half of 
patients with MDS, delay leukemic progression, improve quality of life, and, for azacitidine 
only, prolong survival in patients with HR MDS. Nevertheless, treatment with 
hypomethylating agents is not curative, and most patients relapse within 2 years. 
Lenalidomide, an immunomodulatory thalidomide congener, significantly improves red 
blood cell transfusion-independence rates and increases hemoglobin, but it is approved only 
for use in patients with the 5q syndrome subtype of low-risk MDS [9,10,12-14].
The only known curative therapy for MDS is allogeneic 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 [15]. 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) [10,16,17]. More recent therapeutic approaches to 
patients with MDS with higher-risk disease have involved combining drugs with 
hypomethylating agents, either to take advantage of synergistic properties of, for example, 
histone deacetylase inhibition combined with epigenetic modification, or to capitalize on 
non-overlapping mechanisms of action [18,19].
As detailed by Zandberg et al, 2013 [20], chronic myelomonocytic leukemia (CMML) is a 
clonal stem cell disorder that displays features of both MDS and a myeloproliferative 
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neoplasm. Diagnostic criteria for CMML include persistent peripheral blood monocytosis 
(>10x109/L), absence of the Philadelphia chromosome and/or BCR-ABL1 fusion gene, 
absence of platelet-derived growth factor receptor or gene rearrangement, fewer than 20% 
blasts in the blood and the bone marrow, and dysplasia of 1 or more myeloid lineages [21]. 
CMML was classified as an MDS in the FAB classification system in 1982 [5], but was 
subsequently reclassified as a mixed myelodysplastic/myeloproliferative disorder by the 
WHO classification system in 2001 [22]. CMML shares clinical and biological features with 
MDS, including development of cytopenias and bone marrow failure, risk of progression to 
AML, and overlapping recurring cytogenetic abnormalities. Like MDS, it has a variable 
clinical course, with reported rates of transformation to AML of 15% to 52% and a median 
OS of 12 to 18 months [23-25]. Treatment modalities for the 2 diseases are also similar, 
including hematopoietic growth factors (erythropoiesis-stimulating agents and granulocyte 
colony-stimulating factor), transfusion support, hypomethylating agents, and allogeneic 
hematopoietic stem cell transplantation. 
Prognostic scoring systems for MDS, including the IPSS-R scoring system used in this 
study, have been routinely applied to patients with CMML and have been shown to be 
predictive of both transformation to AML and overall survival [26]. 
Low marrow blast count (20%-30%) WHO-defined AML was previously classified as 
refractory anemia with excess blasts in transformation (RAEB-t). WHO criteria now define 
AML as > 20% bone marrow blasts. In a phase 3 randomized trial, azacitidine significantly 
prolonged overall survival compared with conventional care regimens (CCRs) in patients 
with higher risk MDS [13]. A subgroup analysis of 113 elderly patients (median age, 
70 years) compared the effects of azacitidine versus CCRs on overall survival of these 
FAB-defined RAEB-t and WHO-defined AML [13]. Median overall survival for 
azacitidine-treated patients was 24.5 months compared with 16.0 months for CCR-treated 
patients (hazard ratio=0.47). Furthermore, azacitidine was associated with fewer total days 
in the hospital than CCR. In another phase 3 study, 191 patients with higher-risk MDS by 
FAB criteria were randomly assigned to azacitidine or best supportive care [27]. Of these, 
45 patients had WHO-defined AML. Response rates to azacitidine were similar in MDS and 
these low marrow blast AML patients. Azacitidine was associated with improvements in 
physical function, symptoms, and psychological state. Patients assigned to supportive care 
were permitted to cross over to azacitidine at the time of progression; this design limited 
survival analysis. Based on these studies, azacitidine-based therapy is a standard of care in 
low marrow blast count WHO-defined AML.
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1.1.2
Study Drug: 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 that is being developed for the treatment of malignancies. 
NEDD8-activating enzyme (NAE) 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. As detailed in Section 1.5, the 
nonclinical and preliminary clinical experience in AML with pevonedistat alone or in 
combination supports further evaluation in the subset of patients who are classified as HR 
MDS or CMML or low-blast AML.
1.2
Nonclinical Experience
1.2.1
Single-Agent Pevonedistat
Pevonedistat is a potent and selective inhibitor of NAE activity.
Pevonedistat treatment of cultured tumor cells resulted in growth inhibition of a wide variety 
of cell lines derived from acute leukemias, lymphomas, multiple myeloma, and a range of 
solid tumor types. 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 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 [28-30].
Pevonedistat demonstrated pharmacodynamic and antitumor activity in solid tumor, 
lymphoma, and AML xenograft models when administered to immunocompromised mice 
by the subcutaneous (SC) route. Very few preclinical models of HR MDS are available, and 
pevonedistat has not been tested specifically in HR MDS.
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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 Practices (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 
(≥600 mg/m2). Mortality and/or moribundity were observed within 24 hours postdose as a 
result of gastrointestinal injury (mucoid/soft feces, diarrhea with some macroscopic 
correlations [reddened mucosa]) 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.
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 Investigator’s Brochure (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 HL60). The combination of 
pevonedistat and azacitidine in HL60 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.
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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 (HL60 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 
following the treatment period. In HL60, 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 HL60 
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, pevonedistat has been administered to 351 patients in clinical 
studies. These include 227 patients diagnosed with advanced malignancies including solid 
tumors, AML, melanoma, lymphoma, multiple myeloma, HR MDS, and acute 
lymphoblastic leukemia who participated in studies of single-agent pevonedistat. In ongoing 
combination studies: 42 elderly patients with treatment-naïve AML (Study C15009) have 
been treated with pevonedistat plus azacitidine; 58 patients with solid tumors have received 
combination treatments with docetaxel, gemcitabine, or a combination of carboplatin and 
paclitaxel (Study C15010); and 24 patients with advanced solid tumors have received a 
single IV dose of pevonedistat alone and in combination with the cytochrome P450 (CYP) 
3A inhibitor probes, itraconazole or fluconazole, with the option to then continue receiving 
pevonedistat plus standard of care, either docetaxel, or carboplatin plus paclitaxel (Study 
C15011).
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Pevonedistat has reported single-agent clinical activity in a phase 1 study (Study C15003) in 
relapsed/refractory AML patients [31]. In Study C15003, responses (complete responses and 
partial responses) were observed in a variety of patient settings, including postallogeneic 
transplant, therapy-related AML, and primary refractory AML. 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 Study C15003 had asymptomatic, transient increases in bone marrow blasts 
after achieving a response. In these 2 cases, bone marrow blasts increased from less than 5% 
to more than 20%, and then went down. 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. 
In addition, Study C15009 is currently evaluating the combination of escalating doses of 
pevonedistat on Days 1, 3, and 5 plus 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, age 
≥60 years, who are unlikely to benefit from standard induction therapy [32]. Enrollment in 
Study C15009 is complete; however, final data are not yet available. Data available as of 
26 September 2014 showed that 29 patients (median age 78.0 years; 17 [59%] men) had 
received pevonedistat 20 mg/m2 (n=26) or 30 mg/m2 (n=3). Primary diagnoses were 
19 (66%) de novo AML and 10 (34%) secondary AML. Seventeen (59%) patients had 
intermediate-risk cytogenetics and 7 (24%) had adverse-risk cytogenetics (5 [17%] 
undetermined). The maximum tolerated dose (MTD) was determined to be 20 mg/m2
pevonedistat in combination with 75 mg/m2 azacitidine. During dose escalation, DLTs at the 
30 mg/m2 pevonedistat dose level included reversible Grade 2 increased bilirubin (n=1) and 
Grade 3/ Grade 4 increased transaminases (n=1) without clinical sequelae. In 1 of the 
22 patients treated at the MTD, 1 additional DLT (Grade 4 aspartate aminotransferase 
[AST]/alanine aminotransferase [ALT] elevation) was seen in the expansion cohort; this 
patient was successfully re-challenged with a reduced pevonedistat dose. The most common 
adverse events (AEs; reported by ≥25% of patients) were constipation, febrile neutropenia, 
anaemia, decreased appetite, nausea, thrombocytopenia, and fatigue. Thirteen patients (45%) 
experienced drug-related AEs that were ≥Grade 3, including febrile neutropenia, anaemia, 
thrombocytopenia, and leukopenia. Additional preliminary safety information from Study 
C15009 is provided in Section 1.6.2. The nature and frequency of the reported toxicities 
(excluding DLTs) were similar to previous reports for azacitidine alone. Preliminary 
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pharmacokinetics (PK) data showed that the addition of azacitidine did not alter the known 
PK profile of single-agent pevonedistat.
In the 25 response-evaluable patients, there were 5 (20%) complete remissions (CRs), 
2 (8%) complete remissions with incomplete blood count recovery (CRis), and 6 (24%) 
partial remissions (PRs), for an overall response rate of 52%. Eleven of the 13 responses 
occurred within the first 2 cycles of therapy and included 2 patients with bone marrow blasts 
>80%. Combination therapy with pevonedistat plus azacitidine was generally well tolerated. 
The characteristics of the observed responses suggest added benefit from the addition of 
pevonedistat compared with azacitidine alone in treatment-naïve AML patients, age 
≥60 years, who are unlikely to benefit from standard induction therapy. Furthermore, the 
overall response rate is not appreciably different from that of the subset of low-blast AML 
patients (blast count <30%), further supporting the use of this combination in this study’s 
patient population.
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.
1.4
Pharmacokinetics of Pevonedistat
1.4.1
Nonclinical Pharmacokinetics 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 is low in all animal species, likely as a result of the extensive 
partitioning of pevonedistat into red blood cells. 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 
CYP3A4 with a small contribution from CYP2D6. Results from the completed drug-drug 
interaction (DDI) Study C15011 indicated that multiple-dose administration of fluconazole, 
a moderate CYP3A inhibitor, had no clinically relevant effects on the PK of pevonedistat. 
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Pevonedistat systemic exposure in the presence of itraconazole, a strong CYP3A inhibitor, 
was only minimally increased compared with that in the absence of itraconazole (geometric 
mean dose-normalized AUC∞ratio of 1.14 [90% CI, 1.07 to 1.23]). The 14% increase in the 
pevonedistat geometric mean dose-normalized AUC was not considered clinically 
meaningful when viewed in the context of pevonedistat overall PK variability (coefficient of 
variation in AUC∞, 16%-34%), supporting inference of the lack of a clinically relevant 
effect of itraconazole, a strong CYP3A inhibitor on total systemic exposure (AUC) of 
pevonedistat (see Section 1.6.3). Pevonedistat does not inhibit CYP1A2, 2C9, 2C19, 2D6, 
and 3A4/5, and weakly and reversibly inhibits both CYP2B6 and 2C8; it does not induce 
CYP1A2, 2B6, and 3A4/5. When viewed in the context of clinically relevant concentrations 
at 20 mg/m2 (mean single-dose maximum [peak] concentration [Cmax] of ~0.5 µM), 
pevonedistat is unlikely to affect the PK of drugs that are metabolized by these CYP 
enzymes.
In vitro, pevonedistat is a 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 (concentrations producing 50% inhibition [IC50] of 6.3 M). Additional transport 
studies with organic anion-transporting polypeptides (OATP) in sandwich-cultured human 
hepatocytes showed that pevonedistat can inhibit the hepatic uptake of estrone-3-sulfate 
(IC50 of 29.1 µM) while inhibition of OATP-mediated uptake of simvastatin and lovastatin 
(IC50 of 0.4-4.9 µM and 0.9 µM, respectively) was observed in some, but not all, donors. On 
the basis of these data, pevonedistat at clinically relevant concentrations is unlikely to affect 
the PK of other drugs that are known BCRP or OATP substrates (IC50 >10-fold the unbound 
Cmax even with the lowest estimated value), whereas the potential exists, albeit low, for drug 
interactions with BCRP inhibitors. Refer to Section 1.6.3 for a summary of potential clinical 
DDIs, and Sections 6.4 and 6.5 for excluded and permitted concomitant medications in this 
study.
Additional details on nonclinical PK information are provided in the IB.
1.4.2
Clinical Pharmacokinetics
Clinical pharmacokinetic data are summarized in Section 5.2 of 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 
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manner at the end of a 1-hour IV infusion, with little or no notable drug accumulation upon 
repeat dosing. 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 a daily area under the 
plasma concentration-time curve (AUC0-24hr) that increased proportionately with dose. 
Consistent with in vitro data, pevonedistat was also found to extensively partition in human 
blood (mean blood-to-plasma concentration ratio of ~65) with observed concentrations of 
pevonedistat in whole blood and plasma declining in parallel over 24 hours. Upon 
exploration of the effects of patient-specific covariates on pevonedistat population PK, body 
size and age influenced clearance of pevonedistat, while only body size was important for all 
volume of distribution parameters. Additionally, data are available in 29 treatment-naïve, 
elderly patients with AML 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) [32]. These data indicate that pevonedistat PK 
remains unaffected by 5 continuous days of azacitidine dosing when compared to 
single-agent pevonedistat data from the earlier study in patients with AML (Study C15003).
1.5
Study Rationale
MDS include a heterogeneous group of myeloid disorders characterized by ineffective 
hematopoiesis and transformation to AML. Treatment with azacitidine increases OS in 
patients with HR MDS relative to conventional care [13]. Consequently, azacitidine is 
approved in many countries as a single agent in HR MDS.
Pevonedistat is an investigational, first-in-class inhibitor of the NEDD8-activating enzyme 
that has reported single-agent clinical activity in a phase 1 study in patients with 
relapsed/refractory AML [31]. Based on nonclinical studies in AML models that 
demonstrated a synergistic lethality in cell lines and tumor regression in murine xenografts 
when pevonedistat was combined with azacitidine, pevonedistat is being studied in 
combination with azacitidine in treatment-naïve elderly patients with AML who are unlikely 
to benefit from standard induction therapy (Study C15009). Preliminary results suggest that 
20 mg/m2 pevonedistat plus azacitidine is generally well tolerated and demonstrates early 
signs of clinical activity [32]. 
1.5.1
Rationale for Study Population
Given the overlapping treatments and pathophysiology between HR MDS and AML, this 
phase 2 study will evaluate OS and EFS (in HR MDS or CMML, an event is defined as 
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transformation to AML or death; in low-blast AML, an event is defined as death) of the 
combination of pevonedistat and azacitidine compared with single-agent azacitidine as a 
treatment for HR MDS or CMML or low-blast AML. Patients with CMML are included 
because CMML shares clinical and biological features with MDS, has a similar variable 
clinical course, and treatment modalities for the 2 diseases are also similar (see 
Section 1.1.1). Patients with CMML were also included in randomized studies of azacitidine 
conducted in the United States (US) and the European Union with similar response rates to 
patients with MDS [13,27]. The rationale for including low marrow blast count (20%-30%) 
WHO-defined AML is because low marrow blast count AML had been previously classified 
as refractory anemia with excess blasts in transformation (RAEB-t), which was part of the 
MDS spectrum, and it is a population of patients with AML who have been shown to benefit 
from azacitidine-based therapy (see Section 1.1.1).
1.5.2
Rationale for the Combination of Pevonedistat Plus Azacitidine
The rationale for combining pevonedistat with azacitidine in patients with AML and MDS is 
2-fold; namely, the single-agent activity observed with azacitidine [13] and pevonedistat 
[33] in 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. 
1.5.3
Rationale for Dose and Schedule of Study Drugs
The choice of doses and schedules for this study was based on Study C15009, which 
established the MTD of pevonedistat as 20 mg/m2 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 liver function tests (LFTs; see 
Section 1.3 and the IB for more information). 
The commonly used schedule of azacitidine administration in the United States is a 
5-on/2-off (weekend)/2-on schedule to avoid the logistical limitations associated with 
administering drugs to patients during the weekend. According to oncologist/hematologist 
surveys conducted by the sponsor, of the patients treated with azacitidine for AML in the 
United States, approximately 70% follow this schedule. Garcia et al conducted a 
retrospective evaluation of 3 schedules of azacitidine administration in 181 patients with 
MDS. Evaluated patients received 75 mg/m2 azacitidine on one of the following schedules: 
5 days, 5-on/2-off/2-on, or daily for 7 days. The overall response rates (38%, 71%, and 52%, 
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respectively) favored 5-on/2-off/2-on administration of azacitidine over a 7-day 
administration, with p = 0.0418. All schedules were well tolerated [34].
In this study, azacitidine may be administered using either the SC or the IV route of 
administration, given that comparable systemic exposures (AUC0-48hr) to azacitidine were 
achieved following either route in Study C15009. Furthermore, it has been reported that 
azacitidine is generally well tolerated regardless of the route of administration [35], which is 
also supported by preliminary data from Study C15009.
As detailed in Section 1.3, some patients in Study C15003 (single-agent pevonedistat in 
patients with relapsed/refractory AML) derived clinical benefit from continuing study 
treatment despite changes in their bone marrow blast counts. Standard MDS guidelines [36]
also recommend treatment for 6 cycles without altering dose or frequency of azacitidine 
regardless of cytopenias. Patients with HR MDS or CMML may be allowed to continue 
study treatment (either treatment arm) if they meet the criteria for progressive disease based 
only on bone marrow blast count (without AML transformation) if, in the clinical judgment 
of the investigator, the patient is still receiving clinical benefit from this treatment and the 
continuation is endorsed by the sponsor’s project clinician (or designee). Patients with low-
blast AML, in this study, may also be allowed to continue study treatment (either treatment 
arm), even if they meet the criteria for progressive disease based only on bone marrow blast 
counts, if, in the clinical judgment of the investigator, the patient is still receiving clinical 
benefit from this treatment, and the continuation is endorsed by the sponsor’s project 
clinician (or designee). Patients who meet the criteria for PD and continue on study under 
these conditions must be reconsented before continuing study treatment. If a patient has 
<50% increase in blast count from pretreatment, then this is stable disease and the patient 
should remain on study. 
1.5.4
Rationale for Molecular Analyses
Both AML and MDS are heterogeneous diseases with respect to both tumor biology and 
clinical outcome. Various studies confirm that survival for individual patients in both 
diseases is heavily influenced by the specific molecular pathology of their tumors. Along 
with age and performance status, cytogenetics are a key clinical predictor, and cytogenetic 
findings are incorporated into risk categorization schemes to guide treatment. 
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The European LeukemiaNet integrates cytogenetics and molecular features of 3 key AML 
genes (FLT3 ITD, CEBP, and NPM1) to classify patients into 4 prognostic risk groups [37].
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Leukemic cells that remain in the bone marrow following treatment are a major cause of 
disease relapse. Measurable residual disease (MRD) testing provides the sensitivity and 
specificity to identify the presence of these residual cells. Studies have shown that the 
sensitive detection of a leukemia-specific marker (eg, a mutation in the gene encoding 
nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic 
disease during remission [51]. Assessment of MRD is receiving recognition as a potential 
tool to assess the quality of response after chemotherapy and to plan post-remission 
strategies. PCR and multiparametric flow cytometry have become the most popular methods 
to investigate MRD in AML [52]. Methods to assess MRD by next-generation sequencing
(NGS) are also being explored [53].
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1.5.5
Rationale for Health-Related Quality of Life Assessments
When caring for patients with advanced and life-threatening diseases such as cancer, 
preserving their health-related quality of life (HRQOL) and reducing symptom burden are 
among the most important therapeutic goals. However, there are limited data on patient 
reported outcomes (PROs) among patients with HR MDS. In previous randomized clinical 
trials among patients with MDS, patients on the azacitidine arm experienced improvement in 
HRQOL as assessed by the EORTC-QLQ-C30 PRO instrument [62].
To compare the impact of treatment between the 2 patient groups in this study, HRQOL will 
be assessed by 3 instruments: EORTC-QLQ-C30 and EQ-5D-5L (all patients) and the 
QOL-E (US patients only). Data from these 3 instruments will facilitate assessment of 
important general, cancer-specific, and MDS-specific HRQOL domains and items, and 
ascertainment of how these may be correlated with certain clinical outcomes.
The EORTC-QLQ-C30 [63], designed to assess health-related quality of life in a wide range 
of cancer patient populations, has been administered in multiple randomized clinical trials of 
patients with MDS [62,64]. 
While the EORTC-QLQ-C30 assesses important HRQOL domains including global health 
status/quality of life, functioning, and symptoms over the past week, the QOL-E was
developed specifically for patients with MDS, with evidence for reliability and validity in 
this patient population [65]. As such, it is used to assess the specific impact of MDS on 
HRQOL that is not measured in general non–MDS-specific instruments.
Because oncology therapies may positively or negatively affect a patient’s quality of life, a 
common methodological approach used to quantify this effect is to “quality-adjust” survival 
rates in comparative treatment arms. The resulting data, referred to as quality-adjusted life 
years (QALYs), provide a measure of both the length and quality of life and are used for 
economic evaluation of new therapies. The data required for the assessment for QALY is 
captured by EQ-5D-5L.
Refer to Section 7.4.16 for additional details on the components and administration of these 
questionnaires. 
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1.6
Potential Risks and Benefits
1.6.1
Azacitidine
In clinical studies, adverse reactions to azacitidine were qualitatively similar between the IV 
and SC routes of administration [35]. 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 to 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, 
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).
Adverse reactions identified during postmarketing use of azacitidine include interstitial lung 
disease, tumor lysis syndrome, injection site necrosis, and Sweet’s syndrome (acute febrile 
neutrophilic dermatosis).
Refer to the VIDAZA (azacitidine) US Prescribing Information (USPI) [35],or the European 
Union (EU) Summary of Product Characteristics (SmPC) [66], as applicable, for the most 
recent information regarding the anticipated risks and benefits of azacitidine.
1.6.1.1
Anemia, Neutropenia, and Thrombocytopenia
Azacitidine causes anemia, neutropenia, and thrombocytopenia. Monitor complete blood 
counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. 
After administration of the recommended dosage for the first cycle, adjust dosage for 
subsequent cycles based on nadir counts and hematologic response (see Section 6.3.2.1).
1.6.1.2
Severe Pre-existing Hepatic Impairment
Caution is needed in patients with liver disease when administering azacitidine. Patients 
with extensive tumor burden due to metastatic disease have been reported to experience 
progressive hepatic coma and death during azacitidine treatment, especially in such patients 
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with baseline albumin <30 g/L [67]. Azacitidine is contraindicated in patients with advanced 
malignant hepatic tumors. 
1.6.1.3
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 myelogenous leukemia treated with azacitidine and etoposide.
1.6.2
Pevonedistat Plus Azacitidine
In the ongoing clinical study of the combination of pevonedistat and azacitidine in 
treatment-naïve patients with AML, age ≥60 years (Study C15009), among 
25 response-evaluable patients, 28% had a best response of CR or CRi (26 September 2014 
data cut) [32]. A majority of the responses have occurred within the first 2 cycles. Responses 
have been seen in patients with hyperproliferative phenotypes and adverse cytogenetics. 
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.
Preliminary safety data (as of 28 August 2015) from 56 patients in Study C15009 who 
received ≥1 dose of the combination of pevonedistat and azacitidine indicate that the very 
common AEs (≥10% of patients) have included constipation (43%), anemia (30%), 
fatigue (30%), febrile neutropenia (29%), decreased appetite (29%), thrombocytopenia 
(27%), dyspnea (25%), nausea (25%), neutropenia (20%), cough (16%), vomiting (16%), 
pyrexia (14%), pneumonia (14%), chills (13%), leukopenia (13%), pain in extremity (13%), 
insomnia (13%), sleep disturbances (13%), diarrhea (11%), edema peripheral (11%), 
hypoalbuminemia (11%), hypokalemia (11%), upper respiratory tract infections (11%), 
urinary tract infections (11%), oropharyngeal pain (11%), and anxiety (11%). 
Drug-related > Grade 3 adverse events include thrombocytopenia 8 (14%), febrile 
neutropenia 7 (13%), anemia 7 (13%), leukopenia 4 (7%), neutropenia 3 (5%), AST 
increased 4 (7%), ALT increased 3 (5%), transaminases increased 2 (4%), neutrophil count 
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decreased 1 (2%), blood pressure increased 1 (2%), pharyngitis 1 (2%), upper respiratory 
tract infections 1 (2%), constipation 1 (2%), cardiac failure 1 (2%), and heart failure 1 (2%).
The most detailed information on risks is provided in the Investigator’s Brochure and the 
Developmental Core Safety Information (DCSI) located within the Investigator’s Brochure.
Overall identified risks of pevonedistat include increased heart rate, diarrhea, nausea, 
vomiting, abnormal LFTs, pyrexia, myalgia, and musculoskeletal pain. 
Hepatotoxicity: Hepatotoxicity has been noted following administration of pevonedistat in 
patients with advanced malignancy, including elevations of liver transaminases (up to 
Grade 4), alkaline phosphatase (up to Grade 3), and bilirubin (up to Grade 3). Grade 1
through 4 increases in alanine aminotransferase and aspartate aminotransferase have been 
observed in patients receiving single-agent pevonedistat for relapsed and/or refractory AML. 
The patients experiencing these changes in laboratory values have been asymptomatic. This 
type of elevation in transaminases had been observed previously in patients treated with 
pevonedistat. 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. 
Some events are considered potential risks of pevonedistat because of the occurrence of 
these events in phase 1 clinical studies in which single-agent pevonedistat was administered 
at doses substantially higher than those being used in current clinical trials. Those events 
included multi-organ failure that could result in death, renal failure, cardiac arrhythmias 
(all supraventricular and all except 1 unrelated, the case of atrial fibrillation assessed by the 
investigator as related occurred in a patient with cardiovascular risk factors), 
myelosuppression with increased susceptibility to infection, bleeding, anemia, acute phase 
response, gastrointestinal toxicity including or resulting in dehydration, electrolyte 
imbalance, and hypophosphatemia.
Other events, such as fatigue, chills, decreased appetite, febrile neutropenia, and GI bleeding 
(all events assessed by an investigator as unrelated, the majority occurred in the setting of 
thrombocytopenia), are considered potential risks that are confounded by underlying disease 
or malignancy. 
Potential risks that are derived from findings in animal studies in rats and dogs include 
myocardial degeneration and thrombosis, cardiovascular changes that could result in 
tachycardia, decreased or increased systolic blood pressure, increased diastolic blood 
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pressure, pulmonary hypertension, enteropathy (including dehydration and electrolyte loss) 
with secondary sepsis, effects on testes and ovaries that represent a reproductive hazard 
including sterility, increased developmental risk to fetus or embryo, decreased trabecular 
bone (graded minimal to moderate) was noted in the femur and in the sternum in rats at all 
dose groups (low, medium, high) (this finding was considered adverse in the high-dose 
group; however, no bone fractures were noted at any of the doses), prolongation of the 
activated thromboplastin time (aPTT), and local tissue injury when administered 
subcutaneously (SC). Additional details may be found in the current IB.
Based on the known individual safety profiles of pevonedistat and azacitidine, the following 
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.
In Study C15009, patients receive azacitidine as either an IV infusion or subcutaneous 
injection. Preliminary data indicate that the route of azacitidine administration has no 
apparent effect on the safety profile of pevonedistat plus azacitidine. 
1.6.3
Potential for Drug-Drug Interactions
No formal clinical assessments of DDIs between azacitidine and other agents have been 
conducted. Please consult the VIDAZA USPI (Clinical Pharmacology [Section 12.3], 
Drug-Drug Interactions) for additional information [35].
The potential risk of DDIs between pevonedistat and concomitantly administered drugs is 
currently informed by available nonclinical and clinical data (see IB and Section 1.4). Study 
C15011, a phase 1 study to assess 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 (see 
Section 1.4.1) was completed. Based on results from C15011, administration of pevonedistat 
with moderate and strong CYP3A inhibitors is permitted in this study, while use of strong 
CYP3A inducers should be avoided. As a general precaution, patients receiving concomitant 
medications, particularly those with narrow therapeutic indices, should be carefully 
monitored as 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.
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See Section 6.4 for information on concomitant medications that are prohibited and 
Section 6.5 for information on medications that are permitted during this study.
2.
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective is:

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine improves overall survival (OS) when
compared with single-agent azacitidine.
2.2
Secondary Objectives 
The secondary objectives are:

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine improves event-free survival (EFS)
when compared with single-agent azacitidine; for patients with HR MDS or CMML,
an event is defined as death or transformation to AML; for patients with low-blast
AML, an event is defined as death (see Section 7.4.21).

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine improves 6-month and 1-year survival
rates when compared with single-agent azacitidine.

To determine in patients with HR MDS or CMML whether the combination of
pevonedistat and azacitidine delays time to AML transformation when compared
with single-agent azacitidine.

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine, when compared with single-agent
azacitidine, improves the rate of complete remission (CR) (composite CR [CR+ CRi]
in patients with low-blast AML), CR plus partial remission (composite CR + PR for
patients with low-blast AML), overall response, and/or CR (not including CRi) in
low-blast AML. Overall response in HR MDS or CMML is defined as CR + PR +
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hematologic improvement (HI); overall response in low-blast AML is defined as 
CR + CRi + PR.

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine, when compared with single-agent
azacitidine, improves the rate of CR (composite CR [CR + CRi] in patients with
low-blast AML), CR + PR (composite CR + PR in patients with low-blast AML), the
overall response rate (ORR), as well as CR (not including CRi) in low-blast AML by
Cycle 4.

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine, when compared with single-agent
azacitidine, improves duration of CR (composite CR [CR + CRi] in patients with
low-blast AML), CR + PR (composite CR + PR in patients with low-blast AML),
overall response, and/or CR (not including CRi) in patients with low-blast AML.

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine improves time to first CR (CR for HR
MDS/CMML and low-blast AML; CR + CRi [composite CR] for low-blast AML),
or PR when compared with single-agent azacitidine.

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine delays time to subsequent therapy when
compared with single-agent azacitidine. Subsequent therapy is defined as agent(s)
with antileukemic/anti-MDS activity (eg, cytarabine, anthracyclines, purine
analogues, and hypomethylating agents other than azacitidine). Patients who
discontinue study treatment to receive single-agent azacitidine off study would not
be counted as receiving subsequent therapy.

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine improves rate of transfusion
independence when compared with single-agent azacitidine. RBC or platelet
transfusion independence requires that the patient receive no RBC or platelet
transfusions, respectively, for a period of at least 8 weeks.

To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine reduces the percent of patients who have
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at least one inpatient hospital admission(s) related to HR MDS or CMML, or 
low-blast AML when compared with single-agent azacitidine. 
!
To determine in patients with HR MDS or CMML and low-blast AML whether the
combination of pevonedistat and azacitidine delays time to PD, relapse, or death
when compared to single-agent azacitidine.
!
To evaluate in patients with HR MDS or CMML and low-blast AML the safety of
the combination of pevonedistat and azacitidine when compared with single-agent
azacitidine.
!
To collect in patients with HR MDS or CMML and low-blast AML plasma
concentration-time data for pevonedistat to contribute to future population PK
analyses of pevonedistat.
2.3Exploratory Objectives
The exploratory objectives include:
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3.
STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoint is:
!
OS
3.2
Secondary Endpoints
The secondary endpoints are:
!
EFS; for patients with HR MDS or CMML, an event is defined as death or
transformation to AML; for patients with low-blast AML, an event is defined as
death (see Section 7.4.21).
!
Six-month and 1-year survival rates.
!
Time to AML transformation in patients with HR MDS or CMML.
!
CR (CR for HR MDS and CMML; CR + CRi [composite CR] for low-blast AML),
CR (CR for HR MDS and CMML; CR + CRi for low-blast AML) + PR, overall
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response (CR + PR + HI for HR MDS and CMML; CR + CRi + PR for low-blast 
AML), CR (not including CRi) in low-blast AML.
!
CR (CR for HR MDS and CMML; CR + CRi [composite CR] for low-blast AML),
CR (CR for HR MDS and CMML; CR + CRi for low-blast AML) + PR, overall
response (CR + PR + HI for HR MDS and CMML; CR + CRi + PR for low-blast
AML) by Cycle 4, CR (not including CRi) in low-blast AML by Cycle 4.
!
Duration of CR (CR for HR MDS and CMML, CR + CRi [composite CR] for low-
blast AML), CR (CR for HR MDS and CMML; CR + CRi for low-blast AML) + PR,
overall response (CR + PR + HI for HR MDS and CMML; CR + CRi + PR for
low-blast AML), and duration of CR (not including CRi) in low-blast AML.
!
Time to first CR (CR for HR MDS/CMML and low-blast AML; CR + CRi
[composite CR] for low-blast AML) or PR for HR MDS/CMML and low-blast
AML.
!
Time to subsequent therapy.
!
RBCs and platelet-transfusion independence.
!
Percentage of patients with at least 1 inpatient hospital admission related to HR MDS
or CMML (collected through transformation to AML or until initiation of subsequent
therapy, whichever occurs first) or low-blast AML (collected through AML
progression or until initiation of subsequent therapy, whichever occurs first).
!
Time to PD, relapse, or death.
!
AEs and serious adverse events (SAEs), abnormal clinical laboratory values, Eastern
Cooperative Oncology Group (ECOG) performance status, ECGs, and vital sign
measurements.
3.3
Exploratory Endpoints
The exploratory endpoints include:
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4.
STUDY DESIGN
4.1
Overview of Study Design
This study is a multicenter, global, randomized, controlled, open-label, phase 2 clinical 
study of the combination of pevonedistat and azacitidine versus single-agent azacitidine 
administered in patients with HR MDS or CMML and low-blast AML (see inclusion criteria 
2 and 3 for definitions) who have not previously received a hypomethylating agent. Patients 
with nonproliferative CMML (ie, white blood cell [WBC] <20,000/μL) are included because 
these patients were also included in both randomized studies of azacitidine conducted in the 
US and the European Union with similar response rates to patients with MDS.
General eligibility may be assessed prior to the formal Screening period if it is part of 
standard clinical practice. However, per the Schedule of Events, formal screening will occur 
during the Screening period, which may last up to 28 days prior to randomization. The 
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sponsor’s project clinician (or designee) will confirm patient eligibility prior to 
randomization by the investigator.
It is expected that approximately 117 patients will be enrolled in this study. Once enrolled, 
patients (MDS, CMML, and low-blast AML) will be randomized at a 1:1 ratio to receive 
study drug (either single-agent azacitidine or the combination of pevonedistat and 
azacitidine) in 28-day treatment cycles. All patients will be stratified into 4 categories: 
low-blast AML, IPSS-R risk groups of very high, high, or intermediate for MDS/CMML 
[2]. Note that patients with HR MDS/CMML with indeterminate cytogenetics findings at 
Screening should be assigned a cytogenetics prognostic variable of 2 points, ie, intermediate, 
for determining overall Prognostic Risk Category/Score; see Section 7.4.4. All patients will 
receive azacitidine (75 mg/m2 [IV or SC]) on Days 1 through 5, Day 8, and Day 9. Patients 
randomized to the combination arm will also receive pevonedistat (20 mg/m2 via 
60 ([±10]-minute infusion) on Days 1, 3, and 5. Modifications to the dose and schedule may 
be allowed as detailed in the Schedule of Events and Section 6.1.
Patients, including those who achieve a CR, may receive study treatment until they 
experience unacceptable toxicity, relapse, transformation to AML, or PD as defined in 
Section 7.4.21. Patients with HR MDS or CMML may be allowed to continue study 
treatment (either treatment arm) if they meet the criteria for progressive disease based 
only on bone marrow blast count (without AML transformation) if, in the clinical 
judgment of the investigator, the patient is still receiving clinical benefit from this 
treatment and the continuation is endorsed by the sponsor’s project clinician (or 
designee). Patients with low-blast AML in this study may also be allowed to continue 
study treatment (either treatment arm), even if they meet the criteria for progressive 
disease based only on bone marrow blast counts, if, in the clinical judgment of the 
investigator, the patient is still receiving clinical benefit from this treatment and the 
continuation is endorsed by the sponsor’s project clinician (or designee). Patients who 
meet the criteria for PD and continue on study under these conditions must be 
reconsented before continuing study treatment. Patients may choose to discontinue 
therapy at any time. 
Patients will attend the End-of-Treatment (EOT) visit 30 days (+10 days) after the last dose 
of study drug or before the start of subsequent antineoplastic therapy if that occurs sooner. 
After the EOT visit, patients will enter EFS follow-up (for patients with HR MDS or 
CMML) or response follow-up (for patients with low-blast AML), with study visits every 
3 months, to include physical exam, clinical blood tests, HRQOL assessments, 
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hospitalization assessment, bone marrow aspirate sampling, and disease assessment, if their 
disease has not transformed to AML (for patients with HR MDS or CMML) or progressed 
(for patients with low-blast AML), and they have not started subsequent therapy. Patients 
will enter OS follow-up (contacted every 3 months to document subsequent therapies and 
survival status) when they have confirmed transformation to AML (for patients with HR 
MDS or CMML) or experienced progressive disease (for patients with low-blast AML) or 
have started subsequent therapy.
Disease response assessments for all patients with HR MDS or CMML will be based on the 
Modified International Working Group (IWG) response criteria for MDS [3] as detailed in 
Section 7.4.21. Disease response assessments for patients with low-blast AML will be based 
on the Revised Recommendations of the IWG for Diagnosis, Standardization of Response 
Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute 
Myeloid Leukemia as detailed in Section 7.4.21 [4]. Formal disease assessments for study 
endpoints will be determined based on local bone marrow aspirate blast counts and 
transfusions, and central lab data (local lab data may be used for time-sensitive clinical 
decisions).
Inpatient hospital admissions related to HR MDS or CMML or low-blast AML, as well as 
transfusion independence, will be monitored as secondary efficacy endpoints. RBC- and 
platelet-transfusion independence requires that the patient receive no RBC or platelet 
transfusions, respectively, for a period of at least 8 weeks. Treatment-emergent resistance 
will also be monitored.
A bone marrow aspirate and biopsy will be collected at Screening, and bone marrow 
aspirates will be collected during treatment and follow-up for blast count evaluation (to 
inform disease burden assessment). 
 
 
 
 
 
 
 
 
 
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Sparse sampling for the determination of pevonedistat plasma concentrations and, if 
appropriate, its metabolites will be collected from each patient in the Combination 
Pevonedistat Plus Azacitidine Arm as described in the Schedule of Events to contribute to a 
population PK analysis of pevonedistat co-administered with azacitidine. 
Adverse events and ECOG performance status will be assessed, and ECGs, clinical 
laboratory values, and vital signs will be obtained, to evaluate the safety and tolerability of 
the study drug treatments. 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 [68]. Dose modification guidelines are presented in Section 6.3. 
4.2
Number of Patients
Approximately 117 patients (randomized in a 1:1 ratio) will be enrolled in this study from 
approximately 80 study centers globally. Enrollment is defined as when the patient is 
randomized onto study treatment.
4.3
Duration of Study
Patients, including those who achieve a CR, may receive study treatment until they 
experience PD or discontinuation for any other reason outlined in Section 7.5. Patients will 
be followed until approximately 60% of patients with HR MDS/CMML have experienced 
OS events, or termination of the study by the sponsor. Patients who are still receiving study 
treatment and continuing to derive clinical benefit may continue to receive pevonedistat at 
the discretion of the sponsor; the continuation of treatment may occur in a manner other than 
under the study protocol, in accordance with local regulations.
After discontinuing study treatment (including the EOT visit), patients will be followed for 
survival, subsequent therapy, and transformation to AML (for patients with HR MDS or 
CMML), or progression and relapse from CR (patients with low-blast AML).
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5.
STUDY POPULATION
5.1
Inclusion Criteria
Each patient must meet all of the following numbered inclusion criteria to be enrolled in the 
study: 
1. Male or female patients 18 years or older.
2. Morphologically confirmed diagnosis of MDS, nonproliferative CMML (ie, with 
WBC <20,000/µL), or low-blast AML based on 1 of the following:
French-American-British (FAB) Classifications [5]:

Refractory anemia with excess blasts (RAEB – defined as having 5% to 20% 
myeloblasts in the bone marrow).

CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% 
blasts in the blood.
OR
World Health Organization (WHO) Classifications [6,7]: 

Refractory anemia with excess blasts-1 (RAEB-1 – defined as having 5% to 9% 
myeloblasts in the bone marrow).

Refractory anemia with excess blasts-2 (RAEB-2 – defined as having 10% to 
19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood).

Chronic Myelomonocytic Leukemia-2 (CMML-2 – defined as having 10% to 
19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood). 

Chronic Myelomonocytic Leukemia-1 (Although CMML-1 is defined as having 
<10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these 
patients may enroll only if bone marrow blasts ≥5%).

WHO-defined AML with 20% to 30% myeloblasts in the bone marrow (defined 
in this protocol as “Low-Blast AML”) and < 30% myeloblasts in peripheral 
blood who are considered by investigator to be appropriate for azacitidine-based 
therapy.
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3. For patients with MDS and CMML, prognostic Risk Category, based on the Revised 
International Prognostic Scoring System (IPSS-R) [2], of:

Very high (>6 points), 

High (>4.5 - 6 points), or

Intermediate (>3 – 4.5 points): a patient determined to be in the Intermediate 
Prognostic Risk Category is only allowable in the setting of ≥5% bone marrow 
myeloblasts. 
Patients with indeterminate cytogenetics findings at Screening should be assigned a 
cytogenetics prognostic variable of 2 points (ie, intermediate) for determining overall 
Prognostic Risk Category/Score (see Section 7.4.4). 
4. ECOG performance status of 0 to 2 (see Section 15.1).
5. Clinical laboratory values within the following parameters (repeat within 3 days 
before the first dose of study drug if laboratory values used for randomization were 
obtained more than 3 days before the first dose of study drug):

Albumin >2.7 g/dL.

Total bilirubin <upper limit of normal (ULN) except in patients with Gilbert’s 
syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin ≤1.5 x 
ULN of the direct bilirubin.

ALT and AST <2.5 × ULN.

Creatinine clearance >50 mL/min (see Section 15.2).

Hemoglobin >8 g/dL. Patients may be transfused to achieve this value. Elevated 
indirect bilirubin due to post-transfusion hemolysis is allowed.
6. For patients with CMML: WBC count <20,000/µL before administration of the first 
dose of study drug on Cycle 1 Day 1; patients must have been off hydroxyurea for at 
least 1 week prior to WBC count assessment.
7. Ability to undergo the study-required bone marrow sample collection procedures. 
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8. Suitable venous access for the study-required blood sampling (ie, including PK 
 
).
9. Female patients who:
!
Are postmenopausal (see Section 15.3) 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 15.4), at 
the same time, from the time of signing the informed consent through 4 months 
after the last dose of study drug, 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.)
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 study drug, 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.)
10. 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. Previous treatment with decitabine or azacitidine or other hypomethylating agent.
2. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone 
marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or 
bone marrow, or by other accepted analysis.
3. Eligible for allogenic stem cell transplantation.
4. Patients with MDS, CMML, or low-blast AML, whose only site of disease is 
extramedullary, eg, the skin. 
5. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of study procedures or could limit patient 
expected survival to less than 6 months.
6. Treatment with any anti-leukemic/anti-MDS therapies (eg, lenalidomide, cytarabine, 
anthracyclines, purine analogs) or with any investigational products within 14 days 
before the first dose of any study drug.
7. Known hypersensitivity to mannitol.
8. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, 
meningitis, or septicemia.
9. Major surgery within 14 days before first dose or a scheduled surgery during study 
period; insertion of a venous access device (eg, catheter, port) is not considered 
major surgery.
10. Diagnosed or treated for another malignancy within 2 years before randomization or 
previously diagnosed with another malignancy and have any evidence of residual 
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are 
not excluded if they have undergone resection.
11. Life-threatening illness unrelated to cancer.
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12. Prothrombin time (PT) or aPTT > 1.5 ULN or active uncontrolled coagulopathy or 
bleeding disorder.
13. Known human immunodeficiency virus (HIV) seropositive.
14. Known hepatitis B surface antigen seropositive, or known or suspected active 
hepatitis C infection. Note: Patients who have isolated positive hepatitis B core 
antibody (ie, in the setting of negative hepatitis B surface antigen and negative 
hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
15. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
16. Known cardiopulmonary disease defined as unstable angina, clinically significant 
arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III 
or IV; see Section 15.5), and/or myocardial infarction within 6 months prior to first 
dose, or severe pulmonary hypertension. As an example, well-controlled atrial 
fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would 
be an exclusion.
17. Treatment with strong CYP3A inhibitors or inducers (see Section 15.6) within 
14 days before the first dose of pevonedistat.
18. Systemic antineoplastic therapy or radiotherapy for other malignant conditions 
within 12 months before the first dose of any study drug, except for hydroxyurea.
19. Female patients who are lactating and breastfeeding or 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.
20. Female patients who intend to donate eggs (ova) during the course of this study or 4 
months after receiving their last dose of study drug(s).
21. Male patients who intend to donate sperm during the course of this study or 4 months 
after receiving their last dose of study drug(s). 
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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).
The first dose of study drug must be administered within 5 days of randomization on study. 
It is strongly recommended that dosing for both treatment arms occur on the days specified 
(ie, azacitidine dosing on Days 1-5, 8, and 9; pevonedistat dosing on Days 1, 3, and 5). 
However, dosing of either drug may be delayed for safety reasons or other unavoidable 
circumstances (eg, weather affecting clinic accessibility). If pevonedistat dosing is delayed, 
a minimum of 1 full calendar day 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. For the combination arm, pevonedistat and azacitidine should always be 
administered on the same day (eg, instead of pevonedistat dosing on Days 1, 3, and 5, it 
would be acceptable to dose on Days 1, 5, and 8). If dosing is adjusted, study procedures 
should be performed on the actual day of dosing.
The amount of study drug (pevonedistat and/or azacitidine, as applicable) to be administered 
will be based on body surface area (BSA). BSA will be calculated using a standard formula 
(see example in Section 15.8) 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.
6.1.1
All Patients – Azacitidine Dosing
All patients will receive azacitidine (75 mg/m2 [IV or SC, per investigator’s choice]) on 
Days 1 through 5, Day 8, and Day 9 of each treatment cycle. The investigator, without 
approval of the sponsor’s project clinician, may choose to switch the route of azacitidine 
administration at any time based on standard of care, clinical preference, or convenience. 
Please see the most recent VIDAZA (azacitidine) USPI [35] or EU SmPC [66], for details 
on azacitidine administration.
6.1.2
Additional Instructions for the Combination Arm – Pevonedistat Plus 
Azacitidine Dosing
Patients assigned to the Combination Pevonedistat Plus Azacitidine Arm will receive 
azacitidine as described in Section 6.1.1 and will also receive pevonedistat (20 mg/m2) via 
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60 (±10) minute infusion on Days 1, 3, and 5. All doses must be taken as outlined in the
Schedule of Events.
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 infusion may be slowed or stopped and restarted for 
any associated infusion-related reactions. All infusion times must be recorded. The total 
time from drug reconstitution to end of infusion must not exceed 6 hours.
The entire content of the pevonedistat IV bag will be infused at a constant rate over 60 (±10) 
minutes. The start and end time of IV infusion should be recorded accurately, particularly in 
Cycle 1, when PK assessments are performed. 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.
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, and 
between 30 and 60 minutes after completion of administration of IV azacitidine. 
6.2
Reference/Control Therapy: Azacitidine
Azacitidine is a chemical analogue of cytidine that is widely used for the treatment of 
patients with AML. A phase 3, randomized, open-label, international study compared 
azacitidine (75 mg/m2 SC daily for 7 days, every 28 days) with investigator selected, 
conventional care regimens (CCRs) (eg, best supportive care, low dose cytarabine, or 
intensive chemotherapy) in 358 patients with HR MDS as defined at that time [13].
Approximately one third (n=113) of the patients in this study had refractory anemia with 
excess blasts in transformation (RAEB-t; 20%-30% bone marrow blasts); under the 2008 
WHO revised criteria, RAEB-t is now defined as AML [6]. A subanalysis of the study 
compared the relative efficacy and safety of azacitidine versus CCR in this patient subgroup 
(median age, 70 years) [69]. Of these 113 patients with WHO-defined AML, 86% were 
considered unfit for intensive chemotherapy. Two-year OS rates were higher with 
azacitidine versus CCR in the patients considered unfit for intensive chemotherapy (51% vs 
13%, respectively, p=0.0003). In addition, azacitidine was associated with fewer total days 
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in the hospital (26.0 vs 50.9 days per patient-year; relative risk=0.48; 95% confidence 
interval [CI] 0.44-0.52; p<0.0001) than CCR. In patients with unfavorable cytogenetics, 
median OS in the azacitidine (n=14) and CCR (n=13) groups was 12.3 and 5.3 months, 
respectively (hazard ratio=0.66; 95% CI 0.26-1.68; p=0.38), whereas the 2-year OS rate was 
38% for azacitidine, with no patients surviving more than 20 months in the CCR group 
(p=0.01) [69].
In a randomized phase 3 trial of azacitidine versus CCR in older patients with newly 
diagnosed AML, the median OS with azacitidine was 10.4 months, a 3.8 month (58%) 
increase over CCR. One-year survival with azacitidine was 47%, a 36% increase over CCR. 
Although the study did not reach statistical significance for its primary endpoint of OS 
(p=0.08), azacitidine demonstrated a clinically meaningful improvement. A sensitivity 
analysis of OS censoring at subsequent AML therapy demonstrated a statistically significant 
benefit for azacitidine versus CCR (12.1 vs 6.9 months, respectively; p=0.0147) [70].
6.3
Dose Modification Guidelines
6.3.1
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 to ≤Grade 1. For pevonedistat, a minimum of 1 full 
calendar day 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. If 
azacitidine is held for whatever reason, it may be resumed to complete a full treatment 
course as long as the full 7 doses are completed within the first 14 days of the cycle.
If dosing is interrupted within a cycle because of drug-related toxicity, and if the investigator 
and the sponsor’s project clinician (or designee) agree that it is in the patient’s interest to 
continue therapy 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 toxicity not related to drug (eg, disease-related toxicity), although a similar 
dose reduction is permitted, in general it is discouraged. If the reduced dose is well tolerated 
and the toxicity leading to dose reduction was ≤Grade 3, has resolved, and does not reoccur, 
the dose may resume at the original dose level in the next cycle after endorsement by the 
sponsor’s project clinician (or designee). For specific guidelines on azacitidine and 
pevonedistat dose reductions, see Sections 6.3.2 and 6.3.3). 
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Initiation of a New Cycle
Treatment with study drugs will be repeated every 28 days. It is strongly recommended that 
dosing for both treatment arms occur on the days specified. However, the initiation of a new 
cycle may be delayed for safety reasons or other unavoidable circumstances (eg, weather 
affecting clinic accessibility). For therapy to resume, nonhematologic 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 
sponsor’s project clinician (or designee). Criteria for dosing in a new cycle related to 
hematologic toxicities are detailed for azacitidine in Section 6.3.2.1 and for pevonedistat in 
Section 6.3.2.2.
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 re-evaluated 
to determine whether the criteria for retreatment have been met. A dose reduction (as 
detailed in Sections 6.3.2 and 6.3.3) would be triggered if treatment is delayed for >2 weeks 
because of incomplete recovery from treatment-related toxicity. If the reduced dose is well 
tolerated and the toxicity leading to dose reduction was ≤Grade 3, has resolved, and does not 
reoccur, the dose may resume at the original dose level in the next cycle after endorsement 
by the sponsor’s project clinician (or designee).
6.3.2
Dose Modification for Hematologic Toxicities
6.3.2.1
Azacitidine
Dose reduction or delays of azacitidine for hematologic toxicities (including fever and 
neutropenia) during the first 6 cycles of therapy are strongly discouraged, as it may impact 
patient outcome. Any potential dose reduction should be discussed and agreed first with the 
sponsor’s project clinician (or designee).
For hematologic AEs, the start of a new treatment cycle should be delayed and/or dose 
modifications should be considered if:

Absolute neutrophil count (ANC) is <500/µL. For patients with disease-related 
neutropenia, physician discretion may be used to initiate therapy with ANC ≥50% of 
baseline (baseline from the start of the previous cycle). In general, the use of growth 
factors should be restricted. However, to avoid dose delay, patients who experience 
Grade 4 neutropenia (ANC <500/µL) with or without fever may receive granulocyte 
colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating 
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factor (GM-CSF) between days 28 to 42 days of azacitidine monotherapy or 
combination after discussion and agreement with the sponsor’s project clinician (or 
designee). Any use of growth factors will be documented in the electronic case 
report form (eCRF). Patients who receive myeloid growth factors will not be 
included in assessment of neutrophil response.

Platelet count is <20,000/µL. For patients with disease-related thrombocytopenia, 
physician discretion may be used to initiate therapy with platelet count ≥50% of 
baseline (baseline from the start of the previous cycle). If the above criteria are not 
met, the start of the new cycle will be delayed until the above criteria are met. If a 
low ANC or platelet count causes the delay of the start of the new cycle of more than 
2 weeks, then the azacitidine dose will be decreased to 50 mg/m2 when treatment is 
resumed. Treatment may be held up to 6 weeks (42 days) due to toxicity before 
patient must be removed from protocol therapy. 
If the reduced dose is well tolerated and the toxicity leading to dose reduction was ≤Grade 3, 
has resolved, and does not reoccur, the dose may resume at the original dose level in the 
next cycle after endorsement by the sponsor’s project clinician (or designee).
If indicated, bone marrow evaluation will be performed to establish whether continued 
myelosuppression is related to persistent or progressing leukemic infiltration. 
6.3.2.2
Pevonedistat
It is not anticipated that pevonedistat dose modifications would be necessary due to 
myelosuppression. However, if clinically indicated in the opinion of the investigator, the 
pevonedistat dose may be reduced from 20 mg/m2 to 10 mg/m2. The pevonedistat dose may 
be re-escalated to 15 mg/m2 or 20 mg/m2 at the next cycle, if the toxicity has recovered to 
≤Grade 1 or the patient’s baseline. 
Although leukostasis is not anticipated in this study, pevonedistat should be held for 
symptoms of leukostasis until the leukostasis is treated per institutional guidelines. 
Pevonedistat may be restarted when WBC count is <50,000/µL and following agreement by 
the sponsor’s project clinician (or designee). 
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6.3.3
Dose Modification for Nonhematologic Toxicities
6.3.3.1
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 prescribing information [35] and/or institutional guidelines. 
Similarly, if unexplained elevations in serum creatinine or blood urea nitrogen (BUN) occur, 
the next cycle should be delayed until values return to normal or baseline values, and the 
dose should be reduced by 50% on the next treatment course. 
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 status. 
6.3.3.2
Pevonedistat
Pevonedistat Dose Adjustment Based on Serum Transaminases and Total Bilirubin
It is anticipated that LFTs (AST, ALT, and occasionally bilirubin) may be elevated for 
approximately 48 hours following the end of pevonedistat infusion on Cycle 1 Day 1. 
For elevated LFTs of Grade 2 or 3 that occur on or after Cycle 1 Day 3, pevonedistat should 
be held; once the elevated AST or ALT returns to ≤Grade 1, and/or elevated bilirubin 
returns to 1.5ULN or the patient’s baseline level, pevonedistat dose may be resumed at 
20 mg/m2. For pevonedistat, a minimum of 1 full calendar day between any 2 doses should 
be maintained, and a maximum of 3 doses of pevonedistat within the cycle must not be 
exceeded. 
For elevated LFTs of Grade 4 that occur on or after Cycle 1 Day 3, the pevonedistat dose 
should be held for the remainder of the cycle; if the elevated AST or ALT returns to ≤Grade 
1, and/or elevated bilirubin returns to 1.5ULN or the patient’s baseline level, then 
pevonedistat may be restarted at the next cycle at a reduced dose of 10 mg/m2. If the toxicity 
returns to ≤Grade 1 or the patient’s baseline status, pevonedistat may be re-escalated to 
15 mg/m2 for the next cycle. After 1 cycle at 15 mg/m2, further re-escalation to 20 mg/m2
may occur only after the patient’s liver function test (AST, ALT, and bilirubin) have been 
confirmed to be Grade 1, the same level as the patient’s baseline values, or a level 
considered acceptable by the investigator and the sponsor’s project clinician (or designee).
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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 (including severity 
and etiology), monitored, and treated according to institutional guidelines. 
Pevonedistat Dose Adjustment for Other Toxicities
For other ≥Grade 2 nonhematologic toxicities potentially related to pevonedistat, the 
pevonedistat dose may be reduced from 20 mg/m2 to 10 mg/m2 at the discretion of the 
investigator as clinically indicated. If the toxicity returns to ≤Grade 1 or the patient’s 
baseline status, pevonedistat may be re-escalated to 15 mg/m2 or 20 mg/m2 at the next cycle.
6.4
Excluded Concomitant Medications and Procedures
Prohibited concomitant therapies include investigational agents, androgens, 
supraphysiologic doses of corticosteroids, erythropoietin, thrombopoietin agonists (eg,
eltrombopag and romiplostim) or chemotherapeutic agents active against MDS, CMML, or 
low-blast AML.
Medications that are generally excluded but are allowed with certain exceptions listed in 
Table 6.a (for the Single-Agent Azacitidine Arm) and Table 6.b (for the Combination 
Pevonedistat Plus Azacitidine Arm).
Table 6.a
Concomitant Medications Excluded While Receiving Study Treatment: 
Single-Agent Azacitidine Arm
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 during the study treatment phase 
may be adjusted to control the level of circulating 
blast counts to no lower than 10,000/µL while on 
study treatment. The dosing of hydroxyurea and 
changes to dosing of hydroxyurea must be recorded.
Any investigational agent for MDS, CMML, or 
low-blast AML, or commercially available agents used 
in MDS, CMML, or low-blast AML, including 
androgens, supraphysiologic doses of corticosteroids, 
erythropoietin, eltrombopag [Promacta], or 
romiplostim [Nplate]
AML= acute myelogenous leukemia, CMML=chronic myelomonocytic leukemia, MDS=myelodysplastic 
syndromes.
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Table 6.b
Concomitant Medications Excluded While Receiving Study Treatment: 
Combination Pevonedistat Plus Azacitidine Arm
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 during the study treatment phase 
may be adjusted to control the level of circulating 
blast counts to no lower than 10,000/µL while on 
study treatment. The dosing of hydroxyurea and 
changes to dosing of hydroxyurea must be recorded.
Strong CYP3A inducers 
(see Section 15.6)
Known BCRP inhibitors (ie, cyclosporine)
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), 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.
Any investigational agent other than pevonedistat, for 
MDS, CMML, or low-blast AML, or commercially 
available agents used in MDS, CMML, or low-blast 
AML, including androgens, supraphysiologic doses of 
corticosteroids, erythropoietin, eltrombopag 
[Promacta], or romiplostim [Nplate]
AML=acute myelogenous leukemia, BCRP=breast cancer resistance protein, CMML=chronic 
myelomonocytic leukemia, CYP=cytochrome P450, G-CSF=granulocyte colony-stimulating factor, 
GM-CSF=granulocyte macrophage colony-stimulating factor, MDS=myelodysplastic syndromes. 
6.5
Permitted Concomitant Medications and Procedures
Medications and procedures that are specifically permitted during the study are listed in 
Table 6.c.
Table 6.c
Concomitant Medications and Procedures Permitted During the Study
Therapy
Comment
Anti-platelet agents (eg, aspirin, 
clopidogrel) and anticoagulants
May be used in patients who have controlled coagulopathy at baseline, as 
well as those who develop a coagulopathy on study. Note that patients with 
active uncontrolled coagulopathy are excluded from enrollment as per 
Section 5.2. 
Antiemetics for azacitidine
May be administered according to institutional guidelines.
Myeloid growth factors (eg, 
In general, the use of myeloid growth factors is discouraged and should be 
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Table 6.c
Concomitant Medications and Procedures Permitted During the Study
Therapy
Comment
G-CSF, GM-CSF)
restricted. For patients in CR, CRi, or marrow CR, growth factors may be 
used in specific circumstances after discussion with the project clinician or 
designee. Use of growth factors may also be used in patients with Grade 3 or 
Grade 4 febrile neutropenia after discussion and agreement with the project 
clinician or designee. Additionally, to avoid dose delays, patients who 
experience Grade 4 neutropenia (ANC <500/µL) with or without fever may 
receive granulocyte colony-stimulating factor (G-CSF) or granulocyte 
macrophage colony-stimulating factor (GM-CSF) between days 28-42 days 
of azacitidine monotherapy or combination after discussion and agreement 
with the sponsor’s project clinician (or designee). 
Patients who receive myeloid growth factors will not be included in 
assessment of neutrophil response.
Platelet transfusion
Permitted as medically necessary per institutional guidelines (eg, for 
platelets <10,000/µL in the absence of clinical bleeding); see Section 6.7.
Red blood cell transfusion
To be considered for all patients with anemia, especially those with 
hemoglobin values ≤8 g/dL; see Section 6.7.
G-CSF=granulocyte colony-stimulating factor, GM-CSF=granulocyte macrophage colony-stimulating factor.
6.6
Precautions and Restrictions
Concomitant medications and procedures that are excluded or must be used with caution are 
described in Sections 6.4 and 6.5, respectively.
Certain situations may warrant further caution, such as modifying the dose of study drug(s). 
Dose modification guidelines are provided in Section 6.3.
Refer to the package insert for VIDAZA USPI USPI) [35] or EU SmPC [66], for 
precautions and restrictions related to azacitidine use.
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 15.4) through defined 
periods during and after study treatment as specified below.
Female patients must meet 1 of the following:

Postmenopausal (see Section 15.3) for at least 1 year before the Screening visit, or

Surgically sterile, or
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
If they are of childbearing potential, 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 study 
drug, 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 to not donate eggs (ova) during the course of this study 
or 4 months after receiving their last dose of study drug(s). 
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following:

Practice highly effective barrier contraception during the entire study treatment 
period and through 4 months after the last dose of study drug, or

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 to not donate sperm during the course of this study or 4 months 
after receiving their last dose of study drug(s).
6.7
Management of Clinical Events
6.7.1
Azacitidine
The most common adverse drug reactions for azacitidine are described in Section 1.6.1. For 
the single-agent azacitidine treatment arm, refer to the VIDAZA USPI [35] or EU SmPC
SmPC) [66], as applicable, for details regarding the management of clinical events attributed 
to azacitidine.
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6.7.2
Combination Pevonedistat Plus Azacitidine
Common AEs reported for patients receiving the combination of pevonedistat and 
azacitidine are listed in Section 1.6. Also see the most recent IB. For the Combination 
Pevonedistat Plus Azacitidine Arm, follow the guidance in the following subsections of this 
protocol.
Guidance for Clinical Assessment and Management of Hemodynamic Compromise 
It is essential that the patients receiving the combination of pevonedistat and 
azacitidine are carefully evaluated at Screening and before each dose of study drug 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 the combination of 
pevonedistat and azacitidine 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 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. 
Similarly, for patients with clinically significant thrombocytopenia, especially those 
with platelet count <10,000/µL, a platelet transfusion should be considered. Any RBC 
or platelet transfusion must 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.
Guidance Management of Leukostasis 
Pevonedistat treatment should be withheld for patients who develop symptoms of 
leukostasis (see Section 6.3.2.2). Treatment may include leukapheresis and hydroxyurea 
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administration, per institutional guidelines. When the WBC of the patient is <50,000/L and 
symptoms are improved, pevonedistat treatment may be restarted after consulting with the 
sponsor’s project clinician (or designee). Azacitidine treatment may continue as clinically 
indicated.
Guidance for Management of 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.
6.8
Blinding and Unblinding
This is an open-label study; investigators and patients will know the individual treatment 
assignments.
6.9
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.
6.9.1
Azacitidine
Azacitidine may be supplied by the site from commercial sources, depending on regional 
availability. Commercially available azacitidine is supplied as lyophilized powder in 100-mg 
single-use vials. Refer to the Study/Pharmacy Manual and the VIDAZA USPI [35] or EU 
SmPC [66], as applicable, for additional information regarding azacitidine.
6.9.2
Pevonedistat
The drug product is labeled Pevonedistat (TAK-924/MLN4924) Concentrate for Solution 
for Infusion.
Pevonedistat Concentrate for Solution for Infusion will be supplied by the sponsor as 
detailed in the Study/Pharmacy Manual. 
Each Pevonedistat Concentrate for Solution for Infusion vial contains 50 mg Pevonedistat, 
as free base, formulated with the following excipients: citric acid (anhydrous), trisodium 
citrate dihydrate, Betadex Sulfobutyl Ether Sodium (Captisol®), and water for injection.
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Details are available in the IB.
6.10
Preparation, Reconstitution, and Dispensation
Before use, Pevonedistat Concentrate for Solution for Infusion vials should be brought to 
ambient conditions (15C-30°C) by removing the vials from the refrigerator and placing 
them at room temperature. Accelerated warming methods such as a water bath must not be 
used. Pevonedistat Concentrate for Solution for Infusion is stable at ambient temperature for 
6 hours before dilution. If the drug product vial is not to be used within the 6-hour 
timeframe, the vial should be returned to storage. Each vial is for single use only.
Each Pevonedistat Concentrate for Solution for Infusion vial contains nominally 5 mL 
(50 mg) Pevonedistat, as free base. Using sterile technique, the appropriate volume of drug 
should be withdrawn from vial(s) and injected into a 250-mL IV bag containing a 5% 
dextrose solution. The bag must be gently inverted repeatedly to mix the contents. The 
prepared Pevonedistat IV bag must be used within 6 hours if stored at room temperature or 
discarded. Alternatively, the prepared IV bag is chemically stable and may be stored for up 
to 18 hours at 2C to 8°C. After 18 hours of storage at 2C to 8°C, the prepared IV bag must 
be used within 3 hours upon coming to room temperature or must be discarded.
The vial must not be shaken at any time during dose preparation.
Discard bag, needle, and syringe in a proper biohazard container according to institutional 
guidelines.
Detailed reconstitution and dosage preparation instructions are provided in the Directions for 
Use located in the Pharmacy Manual.
Instructions for the preparation, reconstitution, and dispensation of azacitidine are provided 
in the VIDAZA USPI [35] or EU SmPC [66].
6.11
Packaging and Labeling
Pevonedistat Concentrate for Solution for Infusion will be provided in 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.
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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.
6.12
Storage, Handling, and Accountability
All investigational supplies are to be kept in a secure area with controlled access.
Vials of Pevonedistat Concentrate for Solution for Infusion are to be stored at 2°C to 8°C.
Details of the storage and handling of azacitidine are provided in the VIDAZA USPI [35] or 
EU SmPC [66].
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 Conference on Harmonisation (ICH) 
guidelines.
7.1
Study Personnel and Organizations
The contact information for the sponsor’s project clinician for this study, the central 
laboratory and any additional clinical laboratories or vendors participating on the study 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.
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7.3
Treatment Group Assignments 
Patient eligibility will be established before randomization into the study as patients will not 
be permitted to re-enroll. Confirmation of patient eligibility by the sponsor’s project 
clinician (or designee) following review and approval of a Patient Eligibility Checklist is 
required prior to randomization. A centralized randomization and stratification using an 
interactive web response system (IWRS) will be used. Patients will be randomized strictly 
sequentially at a center as they become eligible for randomization and will be stratified as 
detailed in Section 8.1.2. The study drug regimen must be initiated within 5 days of 
randomization on study. If a patient discontinues from the study, his/her randomization code 
will not be reused, and the patient will not be allowed to re-enter the study. 
7.4
Study Procedures
Refer to the Schedule of Events for timing of assessments. Additional details are provided as 
necessary in the sections that follow, and in the Study and Laboratory Manuals. When 
applicable, specific visit windows for study procedures are provided in the footnotes to the 
study schedules.
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. 
Reconsent of Patients Who Meet the Criteria for PD and Continue Study Treatment
Patients with HR MDS or CMML may be allowed to continue study treatment (either 
treatment arm) if they meet the criteria for PD based only on bone marrow blast count 
(without AML transformation) if, in the clinical judgment of the investigator, the patient is 
still receiving clinical benefit from this treatment, and the continuation is endorsed by the 
sponsor’s project clinician (or designee). Patients with low-blast AML in this study may also 
be allowed to continue study treatment (either treatment arm), even if they meet the criteria
for PD based only on bone marrow blast counts if, in the clinical judgment of the 
investigator, the patient is still receiving clinical benefit from this treatment, and the 
continuation is endorsed by the sponsor’s project clinician (or designee). Patients who 
continue on study under these conditions must be reconsented before continuing study 
treatment.
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7.4.2
Inclusion/Exclusion Confirmation
During the screening process, a Patient Eligibility Checklist must be completed and 
submitted by the investigator for review and approval by the sponsor or designee prior to 
patient randomization. Completion of the eligibility checklist is necessary to verify that the 
patient has met all of the inclusion and exclusion criteria. Source documentation allows for 
independent verification that patient eligibility has been determined by the proper 
methodology. Unless specifically requested, additional source documentation does not need 
to be submitted with the checklist for the assessment of eligibility related to the other 
inclusion and exclusion criteria.
7.4.3
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.
7.4.4
Medical History and IPSS-R Risk Categorization
During Screening, a complete medical history will be compiled for each patient. The history 
will emphasize the background and progress of the patient’s HR MDS or CMML or 
low-blast AML (see inclusion criteria 2 and 3, Section 5.1, for definitions), including an 
assessment of bone marrow morphology (see Section 7.4.20 for additional details on bone 
marrow sample collection and evaluation). Information regarding any prior therapy for HR 
MDS or CMML or low-blast AML, including start and stop dates of each therapeutic agent 
and response to therapy, will be collected in the eCRF. In addition, all blood transfusions 
related to HR MDS or CMML or low-blast AML that the patient received within 8 weeks 
prior to randomization will be recorded to document baseline transfusion dependence. 
For patients with HR MDS or CMML (but not for patients with low-blast AML), screening 
assessments must include risk categorization (for patients both with HR MDS and with 
CMML) according to the IPSS-R [2]. Source documents supporting the prognostic risk 
category determination may be requested with the Patient Eligibility Checklist for review by 
the sponsor prior to randomization (see Section 7.4.2).
The IPSS-R Prognostic Score values based on specific criteria are provided in Table 7.a, and 
the IPSS-R cytogenetic risk groups are provided in Table 7.b. Cytogenetic risk groups and 
bone marrow blast percentages will be based upon results from the local laboratory, while 
clinical lab values (hemoglobin, platelets and ANC) should be from the central laboratory 
results. Criteria and score values from these tables are used to determine the overall risk 
category as listed in Table 7.c. These 3 tables have been adapted from: 
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www.mds-foundation.org/ipss-r-calculator/ (accessed 05 January 2015), based on Greenberg 
et al., 2012 [2].
Additional details and instructions for determining the prognostic risk category are provided 
in the Study Manual.
Table 7.a
IPSS-R Prognostic Score Values
Prognostic Variable
0
0.5
1
1.5
2
3
4
Cytogenetics (a)
Very Good
Good
Intermediate
Poor
Very Poor
BM Blast %
≤2
>2 - <5
5-10%
>10%
Hemoglobin
≥10
8 - <10
<8
Platelets
≥100
50 - <100
<50
ANC
≥0.8
<0.8
Source: Greenberg et al., 2012 [2].
BM=bone marrow; ANC=absolute neutrophil count.
(a) Patients with indeterminate cytogenetics findings at Screening should be assigned a cytogenetics 
prognostic variable of 2 points (ie, intermediate) for determining overall Prognostic Risk Category/Score. 
Table 7.b
IPSS-R Cytogenetic Risk Groups
Cytogenetic prognostic 
subgroups
Cytogenetic abnormalities
Very good
-Y, del(11q)
Good
Normal, del(5q), del(20q), double including del(5q)
Intermediate
del(7q), +8, +19, i(17q), any other single or double independent 
clones
Poor
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q),
Complex: 3 abnormalities
Very poor
Complex: >3 abnormalities
Sources: Greenberg et al., 2012 [2] and Schanz J et al., 2012 [71].
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Table 7.c
IPSS-R Prognostic Risk Categories/Scores
Risk Category
Risk Score
Very low
≤1.5
Low
>1.5 - 3
Intermediate
>3 – 4.5
High
>4.5 – 6
Very high
>6
Source: Greenberg et al., 2012 [2]. 
7.4.5
Modified Charlson Comorbidity Index Assessment
Patients will be assessed during screening using the modified Charlson comorbidity index 
(refer to Section 15.7).
7.4.6
Physical Examination
A complete physical examination will be performed per standard of care at Screening and at 
the EOT visit. A symptom-directed physical examination will be completed per standard of 
care at the times specified in the Schedule of Events, and as clinically indicated.
7.4.7
Patient Height
Height will be measured only during Screening.
7.4.8
Patient Weight
Weight will be measured during Screening, within 3 days before Day 1 dosing in all cycles, 
and at the EOT visit. If the screening assessment was done within 3 days before Cycle 1 
Day 1, an assessment at Cycle 1 Day 1 is not necessary. 
The amount of study drug (pevonedistat and/or azacitidine, as applicable) to be administered 
will be based on BSA. BSA will be calculated using a standard formula (see example in 
Section 15.8) 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.
7.4.9
Eastern Cooperative Oncology Group Performance Status
ECOG performance status will be assessed at the times specified in the Schedule of Events. 
Refer to Section 15.1 for the performance status grading scale.
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7.4.10
Vital Signs
Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature 
will be collected at Screening, predose on Days 1, 3, and 5 on each treatment arm of each 
treatment cycle, at EOT, and as clinically indicated. Vital sign measurements will be taken 
with the patient in the supine or sitting position.
7.4.11
Electrocardiogram
A 12-lead ECG will be administered at the time points specified in the Schedule of Events.
Additional ECGs may be performed as clinically indicated.
7.4.12
Chest X-ray 
A chest X-ray will be performed during Screening. If a chest X-ray or chest CT scan was 
done within 2 months prior to randomization, the chest X-ray does not need to be done 
during Screening.
7.4.13
Enrollment
Enrollment is achieved when the patient is randomized onto study treatment.
Procedures for completion of the enrollment information are described in the Pharmacy and 
Study Manuals.
7.4.14
Clinical Laboratory Evaluations
Handling and shipment of clinical laboratory samples will be outlined in the Laboratory 
Manuals. 
Clinical laboratory evaluations will be performed by a central laboratory. The central 
laboratory results also should be used for determination of eligibility criteria by the 
sponsor’s project clinical (or designee) before randomization. For dosing decisions, local 
hematology and chemistry laboratory results may be used; however, samples must still be 
sent to the central laboratory as well. Local laboratory evaluations may be done more 
frequently at the investigator’s discretion, for instance management of anemia. Central 
laboratory results may not be available due to (but not limited to) the following reasons:

Samples are not able to be analyzed by central laboratory (for various reasons).
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
Laboratory-dependent decisions needed for patient treatment have to be made before 
the availability of central lab results.
In the instance when a local laboratory is used and central laboratory results are 
subsequently available, a retrospective review will be completed by the sponsor’s project 
clinician (or designee) to determine any significant difference between those results. In the 
event of a significant difference, the sponsor may provide further advice to the clinical site.
Coagulation testing (prothrombin time and activated partial thromboplastin time) will be 
done at Screening and sent to the central laboratory.
Blood samples for analysis of the following hematology parameters will be obtained as 
specified in the Schedule of Events:
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential, including percent circulating blasts 

Neutrophils (ANC); ANC will be calculated from the leukocyte 
count with differential count; see Section 15.9.
Blood samples for analysis of reticulocyte counts and ferritin levels will be obtained as 
specified in the Schedule of Events and sent to the central laboratory.
Blood samples for analysis of the following serum chemistry parameters will be obtained as 
specified in the Schedule of Events: 
Complete Serum Chemistry Panel

BUN

Creatinine

Bilirubin (total)

Direct bilirubin

Urate

Lactate dehydrogenase 
(LDH)

Phosphate

Albumin

Alkaline phosphatase (ALP)

AST

ALT

Glucose 

Sodium

Potassium

Calcium

Chloride

Carbon dioxide 
(CO2)

Magnesium
Select Serum Chemistry Panel

BUN

Creatinine

Bilirubin (total)

ALP

AST

ALT
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Blood phosphate tests will be performed on Day 5 of each treatment cycle or the day on 
which the third dose of pevonedistat is given if it is not Day 5 (to be performed by the 
central laboratory).
Urine samples for urinalysis will be obtained as specified in the Schedule of Events and sent 
to the central laboratory. 
Urinalysis with Microscopic Analysis

Turbidity and color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult blood

Nitrite

Glucose

Leukocytes

Microscopic assessment of 
leukocytes, erythrocytes, bacteria, 
casts, and crystals 
7.4.15
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening. 
A pregnancy test must also be performed for women of childbearing potential at every cycle 
(typically performed on Day 1 of the cycle; however, if a serum pregnancy test is used, this 
may be performed up to 3 days before Day 1) with negative results available before the first 
dose is administered in that cycle. A pregnancy test will also be performed for women of 
childbearing potential at the EOT visit to exceed the end of systemic exposure, which is 
2 days for pevonedistat.
Pregnancy tests may also be repeated during the study if requested by an IEC/IRB or if 
required by local regulations.
7.4.16
Health-Related Quality of Life Questionnaires
To compare the impact of treatment between the 2 treatment arms in this study, 
patient-reported HRQOL will be assessed by 3 instruments: EORTC-QLQ-C30 and 
EQ-5D-5L (all patients) and QOL-E (US patients only). During study treatment and EFS 
follow-up periods for HR MDS/CMML patients or response follow-up for patients with 
low-blast AML, patient-reported HRQOL will be collected from all patients as indicated in 
the Schedule of Events.
The patient should be given the paper version of the questionnaires to be completed at the 
scheduled visit before other clinical assessments are conducted. The questionnaires should 
be completed in the language most familiar to the respondent, at the scheduled visit, before 
the patient sees the investigator for clinical assessments. The patient should be given 
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sufficient space and time to complete the questionnaires. The patient should complete the 
questionnaires on their own without any assistance from site staff or a caregiver. The 
questionnaires are intended to be self-reported and should not be interviewer administered.
The study coordinator should check the questionnaire for completeness and encourage the 
patient to complete any missing responses. Detailed instructions relating to the 
administrative procedures of the questionnaires will be provided to the sites. Patient’s 
refusal to complete all or any part of a questionnaire should be documented in the eCRF. 
EORTC-QLQ-C30
The EORTC-QLQ-C30 incorporates 5 functional scales (physical functioning, role 
functioning, emotional functioning, cognitive functioning, and social functioning), 1 global 
health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 
6 individual items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). Most of the 30 items have 4 response levels (not at all, a little, quite a bit, and 
very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are 
converted into scale scores ranging from 0 to 100. For the functional scales and the global 
health status scale, higher scores represent better HRQOL; whereas for the symptom scales 
lower scores represent better HRQOL. All items in this questionnaire relate to a recall period 
of 1 week.
QOL-E
The QOL-E assesses HRQOL in 5 general domains (general well-being, physical 
well-being, functional well-being, social well-being, sexual well-being) and disease-related 
issues, with a recall period of 1 week with the exception of 1 general health item (1 month). 
A higher score indicates a better HRQOL for that domain. The QOL-E will be administered 
to American English-speaking patients in the US only.
EQ-5D-5L
The EQ-5D-5L is a self-administered preference-based measure of health status suitable for 
calculating QALYs to inform economic evaluations. EQ-5D-5L includes 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and 5 response 
levels for each domain (no problems, slight problems, moderate problems, severe problems, 
and extreme problems). Patients are asked to indicate their health state by selecting the most 
appropriate level of severity on each of the 5 dimensions. Patient responses to the 
5 dimensions of the EQ-5D-5L represent the patient’s health state that is transformed to a 
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utility score using preferably country-specific value sets for the calculation of QALYs that 
are used to inform economic evaluations. There is also a visual analogue scale used by 
respondents to rate their health on a scale from best (100) to worst (0).
7.4.17
Hospitalization Assessment
During study treatment and EFS follow-up periods for HR MDS/CMML patients or 
response follow-up for patients with low-blast AML, all hospitalizations since the previous 
assessment will be collected from all patients as indicated in the Schedule of Events. 
Examples of data to be collected are number and duration of inpatient hospitalizations,
location of admission (eg, ICU, hospital floor bed), and reason(s) for admission and primary 
diagnosis at discharge. Transfusion data will also be collected. For example, the number of 
patients who received pRBCs and number of units received, number of patients who 
received a platelet transfusion and number of units received, and location of transfusion 
(inpatient vs outpatient).
7.4.18
Pharmacokinetic Measurements
Blood samples (approximately 3 mL each) for the determination of pevonedistat (and its 
metabolites, if appropriate) plasma concentrations will be collected from all patients in the 
Combination Pevonedistat Plus Azacitidine Arm at the time points indicated in the Schedule 
of Events. The exact date and time of each sample collection, as well as the actual start and 
stop times of the study drug administration, should be recorded accurately, and particular 
care should be 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 to a patient’s IV infusion. In the case that only a single arm is 
available, blood should be drawn as distal to the site of 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. 
7.4.19
 
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7.4.20
Bone Marrow Aspirate and Biopsy Collection and Analysis
Bone Marrow Sample Collection for Disease Assessment
Bone marrow aspirates and biopsies will be required during the study as detailed in the Bone 
Marrow Collection and Assessment Schedule. 
In addition, a bone marrow assessment will be performed for disease assessment at relapse 
(or suspected relapse) or PD, and if otherwise clinically indicated (eg, major changes in the 
patient’s underlying hematological disease are suspected). Note that the detection of 
circulating blasts is not by itself a sufficient criterion for relapse, but should trigger a bone 
marrow examination to determine whether a relapse has occurred. Other examples of 
triggers for ad hoc bone marrow examination may include a 50% reduction from maximum 
remission/response in granulocytes or platelets or a reduction in hemoglobin by ≥2 g/dL that 
is not considered drug related (eg, do not recover), or the hematologic values prompt new or 
more frequent transfusion support than the patient’s baseline status. 
A bone marrow biopsy (in addition to bone marrow aspirate) is required only at Screening to 
confirm the diagnosis. 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. If 
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bone marrow biopsy is not collected routinely per country/institutional guidelines, it is not 
required.
Bone marrow samples will be analyzed locally at the clinical site to: 
!
Determine blast count on aspirate samples: Samples will be evaluated locally for 
blast count per institutional standard practice to inform disease burden assessment. 
Samples will also be sent to a central laboratory for confirmation of bone marrow 
blast count. 
!
Analyze cytogenetics for IPSS-R score determination and disease response 
assessment for patients with HR MDS and CMML. 
 
 A portion of the bone marrow aspirate 
sample at Screening will also be sent to each site’s preferred cytogenetic laboratory 
for cytogenetics assessment according to institutional guidelines (by karyotype 
and/or fluorescence in situ hybridization [FISH]). Chromosomal abnormalities and 
translocations that are routinely assessed for the diagnosis of MDS and AML and are 
included in the IPSS-R Prognostic Risk Score include, for example, trisomy 8, 
del(5)q, monosomy 7, del(20)(q), +6, +13, +21, t(5;12)(q33;p13), other 12p changes, 
t(3;5)(q25;q34), inv(3)(q21q26), rearrangements involving 1q, 11q23, 17p-/-17 and 
X chromosome.
The bone marrow pathology reports, cytogenetics reports, 
 
from the local laboratories will be submitted to the sponsor.
In addition to submitting bone marrow samples to the local laboratory (as per institutional 
guidelines), the samples should be submitted to the central laboratory, as follows:
!
Whenever a bone marrow aspirate is collected, 2 to 3 unstained aspirate smears 
(either uncharged or charged slides) should be submitted to the central laboratory.
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!
Whenever a bone marrow biopsy is collected, it should be submitted to the central 
laboratory.
Acceptable bone marrow biopsy samples in order of preference are as follows:
1. 5 unstained slides (charged slides) from core biopsy specimen 3 to 5 microns thick.
2. Formalin-fixed paraffin embedded tissue block.
3. Core biopsy in formalin-filled container.
These bone marrow samples that are being sent to the central laboratory are for:
!
Quality control evaluation of blast count assessments: Bone marrow samples will 
also be sent to a central laboratory, in addition to those sent for local laboratory 
examination, for evaluation of blast count. The procedure for handling, preparation 
and shipment of samples is outlined in the Study Manual. Samples will be evaluated 
by the central laboratory at each time point (including any unscheduled samples) and 
results will be reported to the sponsor. This evaluation will not be a real-time 
confirmation of progression, and results will not be routinely available to the clinical 
sites. Clinical decisions will be based on local laboratory blast count results. 
Discrepancies between local study site results and central laboratory results will be 
reviewed by the sponsor. 
Following Cycle 4, bone marrow collection will be performed only as clinically indicated in 
patients who achieve CR. In all other patients who do not achieve CR, bone marrow 
assessments will be performed after completion of every third treatment cycle. Additional 
bone marrow aspirates may be performed if warranted by changes in peripheral blood 
counts.
Details regarding the preparation, handling, and shipping of these samples are provided in 
the Laboratory Manual.
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Details regarding the preparation, handling, and shipping of these samples are provided in 
the Laboratory Manual.
7.4.21
Disease Assessment 
Formal disease assessments for study endpoints will be determined based on local bone 
marrow aspirate blast counts and transfusions, and central lab data (local lab data may be 
used for time-sensitive clinical decisions). The investigator’s assessment of disease status 
will be entered into the eCRF for each time point.
Transformation to AML may occur in both MDS and CMML. In this study, transformation 
to AML is defined, according to WHO Classification [72] as a patient having >20% blasts in 
the blood or marrow AND increase of blast count by 50%. To illustrate: 
!
For patients with 5% to 10% blasts pretreatment: a >50% increase to >10% blasts 
constitutes progression of MDS.
!
For patients with 10% to 20% blasts pretreatment: a >50% increase to >20% blasts 
constitutes transformation to AML.
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Note: The principal investigator should make all efforts to perform the disease assessment 
by a bone marrow examination. However, in the exceptional circumstance that it is not 
possible to have a bone marrow examination from patients for disease assessment, 
transformation to AML will also be defined as >20% blasts in peripheral blood AND an 
increase of blast count by 50% from pretreatment.
Note that, according to the WHO Classification [72]:
The blast percentage and assessment of degree of maturation and dysplastic 
abnormalities in the neoplastic cells should be determined, if possible, from a 
200-cell leukocyte differential performed on a peripheral blood smear and a 500-cell 
differential performed on marrow aspirate smears stained with Wright Giemsa or 
May-Grunwald Giemsa. The blast percentage should be correlated with an estimate 
of the blast count from the marrow biopsy section. In addition to myeloblasts, the 
monoblasts and promonocytes in acute monoblastic/monocytic and acute and chronic 
myelomonocytic leukemia and the megakaryoblasts in acute megakaryoblastic 
leukemia are considered as ‘blast equivalents’ when the requisite percentage of blasts 
is calculated for the diagnosis of AML.
As defined in Table 7.d and Table 7.e, additional assessment(s) of disease response for 
patients with MDS or CMML are based on the criteria outlined in the Modified IWG 
Response Criteria for MDS [3]; and additional assessments of disease response for patients 
with low-blast AML are based on 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 (Table 7.f.).
Note that standard MDS guidelines [33] also recommend treatment for 6 cycles without 
altering dose or frequency of azacitidine regardless of cytopenias. Therefore, in this study, 
patients with HR MDS or CMML may be allowed to continue study treatment (either 
treatment arm), even if they meet the criteria for progressive disease based only on bone 
marrow blast counts (without AML transformation), if, in the clinical judgment of the 
investigator, the patient is still receiving clinical benefit from this treatment, and the 
continuation is endorsed by the sponsor’s project clinician (or designee). Patients who meet 
the criteria for PD and continue on study under these conditions must be reconsented before 
continuing study treatment.
Investigators should note that some AML patients may benefit from continued treatment 
even though their bone marrow blast counts may fluctuate over the course of the first 
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4 cycles. For example, 2 of the 6 responders in the single-agent pevonedistat study in 
relapsed/refractory AML had asymptomatic transient increases in bone marrow blasts after 
achieving a response. In these 2 cases, bone marrow blasts increased from less than 5% to 
more than 20%, and then declined. 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, patients 
with low-blast AML, in this study, also may be allowed to continue study treatment (either 
treatment arm), even if they meet the criteria for progressive disease based only on bone 
marrow blast counts, if, in the clinical judgment of the investigator, the patient is still 
receiving clinical benefit from this treatment and the continuation is endorsed by the 
sponsor’s project clinician (or designee). Patients who meet the criteria for PD and continue 
on study under these conditions must be reconsented before continuing study treatment. If a 
patient has <50% increase in blast count from pretreatment, then this is stable disease and 
the patient should remain on study.
A minimum of 6 cycles of treatment is strongly encouraged. In the event that early 
removal from the study is being considered for toxicity or stable disease, contact the 
sponsor's project clinician (or designee) to discuss before the patient is removed from 
the study.
Table 7.d
Response Criteria for Altering Natural History of MDS and CMML
Category
Response Criteria
Complete remission 
(CR)
Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines (a) 
Persistent dysplasia will be noted (a)
Peripheral blood (b)
Hgb ≥11 g/dL
Platelets ≥100109/L
Neutrophils ≥1.0109/L
Blasts 0%
Partial remission 
(PR)
All CR criteria if abnormal before treatment except:
Bone marrow blasts decreased by ≥50% over pretreatment but still >5%
Cellularity and morphology not relevant
Marrow CR
Bone marrow: ≤5% myeloblasts and decrease by ≥50% over 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 wks
If a patient has <50% increase in blast count from pretreatment, then this is stable 
disease and the patient should remain on study.
Failure
Death during treatment or PD (as defined below), or progression to AML or a more 
advanced MDS or CMML FAB/WHO subtype than pretreatment
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Table 7.d
Response Criteria for Altering Natural History of MDS and CMML
Category
Response Criteria
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
Cytogenic response
Complete
Disappearance of the chromosomal abnormality without appearance of new ones
Partial
At least 50% reduction of the chromosomal abnormality 
Progressive disease 
(PD)
Note: Transient cytopenias during chemotherapy courses should not be 
considered PD, as long as they recover to the previous levels. Progression based on 
blood values should not be considered at all until after the post-Cycle 4 marrow 
draw.
If a patient has ≥50% increase in blast count from pretreatment (without AML 
transformation) but is still deriving benefit from this treatment (eg, improvement in 
peripheral blood counts), the patient may continue on study as agreed by the 
investigator and the sponsor’s project clinician (or designee).
For patients with:
Less than 5% blasts: ≥50% increase in blasts to >5% blasts
5% - 10% blasts: ≥50% increase to >10% blasts
10% - 20% blasts: ≥50% increase to >20% blasts
20% - 30% blasts: see Table 7.f "Response Criteria for AML"
Any of the following:
At least 50% decrement from maximum remission/response in granulocytes or 
platelets
Reduction in Hgb by ≥2 g/dL
New transfusion dependence
Survival
Endpoints:
Overall: death from any cause
Event free: failure or death from any cause
PFS: PD or death from MDS
DFS: time to relapse
Cause-specific death: death related to MDS
To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
AML=acute myelogenous leukemia, CMML=chronic myelomonocytic leukemia, CR=complete remission, 
DFS=disease-free survival, FAB=French-American-British, Hgb=hemoglobin, HI=hematologic 
improvement, MDS=myelodysplastic syndromes, PD=progressive disease, PFS=progression-free survival, 
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). 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.e
Response Criteria for Hematologic Improvement for MDS and CMML
Hematologic Improvement (a)
Response criteria (responses must be at least 8 weeks in duration)
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/8 wks compared with the 
pretreatment transfusion number in the previous 8 wks. Only RBC 
transfusions given for a 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 HI (b)
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
To convert hemoglobin levels from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
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. 
The revised recommendations of the IWG for Diagnosis, Standardization of Response 
Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute 
Myeloid Leukemia will be used for assessment of disease response [4]. Investigators are 
encouraged to consult the reference for more detailed explanation of response criteria.
Table 7.f
Response Criteria for AML
Category
Response Criteria
Morphologic 
Complete Remission 
(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 
Complete Remission 
with Incomplete 
Blood Count 
Recovery (CRi)
After chemotherapy, some patients fulfill all of the criteria for CR except for residual 
neutropenia (< 1,000/μL) or thrombocytopenia (< 100,000/μL).
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Table 7.f
Response Criteria for AML
Category
Response Criteria
Partial Remission 
(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 5% to 25% in the bone marrow aspirate. 
Thus, if the pretreatment bone marrow blast percentage was 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%, they 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.
Progressive disease 
(PD)
Because the IWG criteria for AML do not provide a standardized definition for PD, [4]
in this protocol, PD is defined as one 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
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.
7.4.22
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events. Refer to Section 10 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs. 
7.4.23
Concomitant Medications and Procedures
All concomitant medications and procedures (excluding transfusions) will be recorded from 
the time of the first dose of any study drug through 30 days after the last dose of any study
drug. RBC and platelet transfusions will be recorded from 8 weeks before randomization 
through 30 days after the last dose of any study drug. See Section 6.4 and Section 6.5 for 
additional details regarding excluded and permitted concomitant medications and 
procedures. 
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7.5
Completion of Treatment
A patient has completed the treatment if they discontinue treatment for any of the reasons 
listed in Section 7.7. Note that PD includes transformation to AML, relapse after CR for 
patients with low-blast AML, or other PD as defined in Section 7.4.21.
As detailed in Section 1.3, some patients in Study C15003 (single-agent pevonedistat in 
patients with relapsed/refractory AML) derived clinical benefit from continuing study 
treatment despite changes in their bone marrow blast counts. Standard MDS guidelines [36]
also recommend treatment for 6 cycles without altering dose or frequency of azacitidine 
regardless of cytopenias. Therefore, in this study, patients may be allowed to continue 
study treatment (either treatment arm), even if they meet the criteria for PD based 
only on bone marrow blast counts (without AML transformation), if, in the clinical 
judgment of the investigator, the patient is still receiving clinical benefit from this 
treatment, and the continuation is endorsed by the sponsor’s project clinician (or 
designee). If a patient has <50% increase in blast count from pretreatment, then this is 
stable disease and the patient should remain on study. If a patient has ≥50% increase 
in blast count from pretreatment (without AML transformation), but is still deriving 
benefit, the patient may continue on study as agreed by the investigator and the 
sponsor’s project clinician (or designee). Patients who meet the criteria for PD and 
continue on study under these conditions must be reconsented before continuing study 
treatment.
A minimum of 6 cycles of treatment is strongly encouraged. In the event that early 
removal from the study is being considered for toxicity or stable disease, contact the 
sponsor's project clinician (or designee) to discuss before the patient is removed from 
the study.
Patients will attend an EOT visit 30 days (+10 days) after the last dose of study drug or 
before the start of subsequent antineoplastic therapy if that occurs sooner; refer to the 
Schedule of Events for EOT visit assessments. All patients will then continue to be followed 
as specified in the Schedule of Events: 

Patients who have not transformed to AML (for patients with HR MDS or CMML at 
study entry) or who have not progressed (patients with low-blast AML at study 
entry) at the time of the EOT visit will enter EFS Follow-up. If a patient with HR 
MDS or CMML at study entry subsequently transforms to AML (as defined in 
Section 7.4.21) or initiates subsequent therapy during the EFS Follow-up period, the 
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patient will then enter OS Follow-up. If a patient with low-blast AML subsequently 
progresses or relapses (as defined in Section 7.4.21) or initiates subsequent therapy 
during the EFS Follow-up period, the patient will then enter OS Follow-up period.

Patients with HR MDS or CMML at study entry that has transformed to AML and 
patients with low-blast AML at study entry who have experienced progressive 
disease or relapse after CR at the time of the EOT visit will enter OS Follow-up 
immediately. 
7.6
Completion of Study
Patients will be considered to have completed the study if they are followed until death or 
until the sponsor terminates the study. 
7.7
Discontinuation of Treatment With Study Drug, and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons: 

Adverse event

Protocol violation

Progressive disease
Note: Patients with progressive disease based on bone marrow blasts counts may be 
allowed to remain on study, after discussion between the investigator and project 
clinician or designee, if it is judged that they are deriving clinical benefit from doing 
so. Patients who continue on study under these conditions must be reconsented 
before continuing study treatment.

Disease relapse

Subsequent anti-cancer therapy

Initiation of hematopoietic stem cell transplant

Study terminated by sponsor

Withdrawal by subject

Lost to follow-up
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
Other
Once study drug has been discontinued, all study procedures outlined for the EOT visit will 
be completed as specified in the Schedule of Events. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Patients who are randomized to a treatment arm but do not receive study drug for any reason 
will not 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

Study terminated by sponsor

Withdrawal by subject

Death

Other
Millennium or their designee must be notified in writing if a patient is withdrawn from study 
treatment or from the study. The reason(s) for withdrawal must be documented in the 
patient’s medical records. The investigators will make every reasonable effort to keep each 
patient on the study until all planned treatments and assessments have been performed. If a 
patient withdraws from study treatment, every attempt should be made to follow the patient 
until death or administrative study closure. Final treatment assessments will be performed 
before any other therapeutic intervention if possible. Additionally, any planned alternative 
treatments should be documented on the patient’s medical records and CRF.
7.9
Study Compliance
Study drug will be administered 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 administration.
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7.10
Posttreatment Follow-up Assessments (Event-Free Survival, Response 
Follow-up, and Overall Survival) 
Patients who discontinue study treatment will complete the EOT visit 30 days (+10) after the 
last dose of study drug(s) or before the start of subsequent antineoplastic therapy if that 
occurs sooner. After the EOT visit, patients will continue to be followed for EFS (for 
patients with HR MDS/CMML), response follow-up (for patients with AML), and OS 
endpoints as detailed in the Schedule of Events. All subsequent therapies for MDS, CMML, 
and/or AML (as applicable) will be recorded, regardless if they are initiated before or after 
PD or transformation to AML.
NOTE: Related SAEs must be reported to Millennium Department of Pharmacovigilance or 
designee. This includes deaths that the Investigator considers related to study drug that occur 
during the posttreatment follow up. Refer to Section 10 for details regarding definitions, 
documentation, and reporting of SAEs.
7.11
Posttrial Access
7.11.1
Posttrial Access
If an open-label, rollover, posttrial access (PTA) study should become an option and the 
investigator and the sponsor agree that a patient would derive benefit from continued 
treatment or would be harmed without continued access to the medication, the patient may 
be given the opportunity to enroll. The patient would then be able to continue receive 
pevonedistat (if randomized to the combination arm).
7.11.2
Duration of PTA
In the event of a rollover PTA study, continued access to pevonedistat for participants will 
be terminated for those individuals who no longer benefit from treatment (eg, their disease 
has progressed or treatment is no longer tolerable), the benefit-risk no longer favors the 
individual, an appropriate alternative therapy becomes available, or pevonedistat becomes 
available either commercially or via another access mechanism. PTA may be terminated in a 
country or geographical region where the development of pevonedistat has been suspended 
or stopped by the sponsor, or pevonedistat can no longer be supplied.
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8.
STATISTICAL AND QUANTITATIVE ANALYSES
8.1
Statistical Methods
A formal statistical analysis plan (SAP) will be developed and finalized before database 
lock. This plan will outline all data handling conventions and specify all statistical methods 
to be used for safety and efficacy data analysis. 
Deviations from the statistical analyses outlined in this protocol will be indicated in this 
plan; any further modifications will be noted in the final clinical study report.
8.1.1
Determination of Sample Size
Approximately 117 patients will be randomized in a 1:1 ratio to receive either the 
combination of pevonedistat and azacitidine or single-agent azacitidine.
8.1.2
Randomization and Stratification
Patients will be randomized to receive the combination of pevonedistat and azacitidine or 
azacitidine alone in a 1:1 ratio, stratified into 4 categories: low-blast AML, IPSS-R risk 
groups of very high, high, or intermediate for MDS/CMML [2]. (Note that patients with 
indeterminate cytogenetics findings at Screening should be assigned a cytogenetics 
prognostic variable of 2 points, ie, intermediate, for determining overall Prognostic Risk 
Category/Score; see Section 7.4.4).
8.1.3   Populations for Analysis
The populations used for analysis will include the following:

Safety population: The safety population is defined as all patients who receive at 
least 1 dose of pevonedistat plus azacitidine or azacitidine alone. Patients will be 
analyzed according to the actual treatment they received. Patients who received any 
dose of pevonedistat will be included in the Combination Pevonedistat Plus 
Azacitidine Arm, and patients who did not receive any dose of pevonedistat, but
received at least 1 dose of azacitidine, will be included in the Single-Agent 
Azacitidine Arm, regardless of their randomized treatment.

Intent-to-treat (ITT) population: The ITT population is defined as all patients who 
are randomized. Patients in this population will be analyzed according to the 
treatment they were randomized to receive, regardless of any dosing errors.
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
Response-evaluable population: The response-evaluable population is defined as
patients who receive at least 1 dose of study drug, have a disease assessment at
Baseline, and at least 1 postbaseline disease assessment.
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. 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. Details on any sensitivity analyses and data handling 
details regarding issues such as missing data will be discussed in the SAP.
8.1.5
Demographic and Baseline Characteristics
Demographics and baseline characteristics will be summarized descriptively, including 
gender, age, race, weight, height, and other parameters as appropriate. No inferential 
statistics will be carried out.
Throughout this study, baseline assessments are defined as those performed at the closest 
time before the start of study drug administration.
8.1.6
Efficacy Analysis
8.1.6.1
General Methodology
Summary tabulations will be presented by treatment group and will display the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, and the number and percent per category for categorical data. The Kaplan-Meier 
survival curves and Kaplan-Meier medians (if estimable) will also be provided, along with 
their 2-sided 95% CIs for time to event data.
All efficacy primary analyses will be based on investigator assessments. Any sensitivity 
analysis will be specified in the SAP.
8.1.6.2
Analyses of Primary Efficacy Endpoints
The analysis of the primary efficacy endpoint, OS, will be based on HR MDS/CMML 
patients and the ITT population separately.
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OS will be analyzed when approximately 60% of patients with HR MDS/CMML have 
experienced OS events, or termination of the study by the sponsor.
OS will be calculated from date of randomization to the date of patient death due to any 
cause. Patients without documented death at the time of the analysis will be censored at the 
date that the patient was last known to be alive. Unstratified log-rank test will be used to 
compare OS between the 2 treatment arms. Hazard ratios, along with the 2-sided 95% CIs,
will be estimated using the unadjusted, unstratified Cox model. The proportional hazard 
assumptions will be examined and sensitivity analysis will be conducted if appropriate. 
Kaplan-Meier curves and Kaplan-Meier medians (if estimable), together with the 95% CIs, 
will be calculated for each treatment group.
8.1.6.3
Analyses of Secondary Efficacy Endpoints
If the secondary efficacy endpoint is response related, such as CR, the response-evaluable 
population of patients with HR MDS/CMML, patients with low-blast AML, and the overall 
patient population will be used separately, if appropriate. Duration of the response-related 
endpoint will be analyzed based on the corresponding responders; otherwise, the analysis 
will be based on HR MDS/CMML patients and the ITT population separately.
For patients with low-blast AML, composite CR + CRi, CR as well as CRi will be analyzed.
Refer to Section 7.4.21 for response definitions (eg, complete remission, transformation to 
AML, PD).
EFS
The analysis of EFS, will be based on patients with HR MDS/CMML and the ITT 
population separately.
For patients with HR MDS/CMML, an event is defined as death or transformation to AML; 
for patients with low-blast AML, an event is defined as death. EFS is defined as the time 
from randomization to the occurrence of an event. Unstratified log-rank test will be used to 
compare EFS between the 2 arms. The hazard ratios along with the 2-sided 95% CIs will be 
estimated using the unadjusted, unstratified Cox model. The proportional hazard 
assumptions will be examined and sensitivity analysis will be conducted if appropriate. The 
Kaplan-Meier survival curves and Kaplan Meier medians (if estimable), along with the 95% 
CIs, will also be provided for each treatment group.
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Six-Month and One-Year Survival Rate
Kaplan-Meier estimates and the 95% CIs of 6-month and 1-year survival rates will be 
provided based on patients with HR MDS/CMML and the ITT population separately.
Time to AML Transformation
Time to AML transformation is defined as time from randomization to documented AML 
transformation. This definition only applies to patients with HR MDS and CMML, so this 
analysis will only be carried out in this subgroup. Patients who died before progression to 
AML will be censored. Unstratified log-rank test will be used to compare time to AML 
transformation between the 2 arms. Hazard ratio and its 2-sided 95% CI will be calculated 
using the unstratified Cox model. Kaplan-Meier survival curves and Kaplan-Meier medians 
(if estimable), together with the 95% CIs, will be calculated for each treatment group.
CR (CR for HR MDS and CMML, CR + CRi [composite CR] for low-blast AML)/CR 
(CR for HR MDS and CMML, CR + CRi for low-blast AML) + PR/overall response 
(CR + PR + HI for HR MDS and CMML; CR + CRi + PR for low-blast AML)/CR (not 
including CRi) in low-blast AML
CR/CR + PR (composite CR + PR for patients with low-blast AML)/overall response/CR 
(not including CRi) in low-blast AML calculations will be based on the response-evaluable 
population of patients overall, the response-evaluable patients with HR MDS/CMML, and 
the response-evaluable patients with low-blast AML, if appropriate.
The number and percentage of patients who achieved CR/CR + PR (composite CR + PR for 
patients with low-blast AML)/overall response (CR + PR + HI for patients with HR 
MDS/CMML, composite CR + PR for patients with low-blast AML)/CR (not including 
CRi) in low-blast AML, respectively, will be summarized by treatment group. CR rate/CR + 
PR rate (composite CR + PR for patients with low-blast AML)/overall response rate/CR rate 
(not including CRi) in low-blast AML between the 2 treatment arms, respectively, will be 
compared using the unstratified Cochran-Mantel-Haenszel (CMH) chi-square test. The 
relative risk with its 2-sided 95% CI will be calculated. The absolute rate difference will be 
provided with its 95% CI.
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CR (CR for HR MDS and CMML, CR + CRi [composite CR] for low-blast AML)/CR 
(CR for HR MDS and CMML, CR + CRi for low-blast AML) + PR/overall response 
(CR + PR + HI for HR MDS and CMML; CR + CRi + PR for low-blast AML)/CR (not 
including CRi) in low-blast AML by Cycle 4
The number and percentage of patients who achieved CR/CR + PR (composite CR + PR for 
low-blast AML)/overall response (CR + PR + HI for patients with HR MDS/CMML, 
composite CR + PR for patients with low-blast AML)/CR (not including CRi) in low-blast 
AML by Cycle 4, respectively, will be summarized by treatment group. CR rate/CR + PR 
(composite CR + PR for patients with low-blast AML) rate/overall response rate/CR rate 
(not including CRi) in low-blast AML by Cycle 4 between the 2 treatment arms, 
respectively, will be compared using the unstratified CMH chi-square test. The relative risk 
with its 2-sided 95% CI will be calculated. The absolute rate difference will be provided 
with its 95% CI.
Duration of CR (CR for HR MDS and CMML, CR + CRi [composite CR] for low-blast 
AML)/CR (CR for HR MDS and CMML, CR + CRi for low-blast AML) + PR/overall 
response (CR + PR + HI for HR MDS and CMML; CR + CRi + PR for low-blast 
AML)/CR (not including CRi) in low-blast AML
Calculations of duration of responses will be based on responders from the overall patient
population, responders from patients with HR MDS/CMML, and responders from patients 
with low-blast AML, if appropriate.
Duration of CR/CR + PR/overall response (CR + PR + HI for patients with HR 
MDS/CMML, CR + CRi + PR for patients with low-blast AML)/CR (not including CRi) in 
low-blast AML, respectively, will be analyzed using standard survival analysis techniques 
based on Kaplan-Meier estimates.
Time to First CR or PR
Analysis of time to first CR (composite CR for patients with low-blast AML) or PR will be 
based on the response-evaluable patients with HR MDS/CMML and the response-evaluable 
population for the overall patient population separately.
Time to first CR or PR is defined as time from randomization to first documented CR or PR, 
whichever occurs first. Unstratified log-rank test will be used to compare time to first CR or 
PR between the 2 arms. Hazard ratio and its 2-sided 95% CI will be calculated using the 
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unstratified Cox model. Kaplan-Meier survival curves and Kaplan-Meier medians (if 
estimable), together with the 95% CIs, will be calculated for each treatment group.
Time to Subsequent Therapy
Analysis of time to subsequent therapy will be based on patients with HR MDS/CMML and 
the ITT population separately.
Time to subsequent therapy is defined as time from randomization to the date of the first 
subsequent therapy. Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS 
activity (eg, cytarabine, anthracyclines, purine analogues, and hypomethylating agents other 
than azacitidine). Patients who discontinue study treatment to receive single-agent 
azacitidine off study would not be counted as receiving subsequent therapy.
Unstratified log-rank test will be used to compare time to subsequent therapy between the 
2 arms. Hazard ratio and its 2-sided 95% CIs will be calculated using unstratified Cox 
model. Kaplan-Meier survival curves and Kaplan-Meier medians (if estimable), together 
with the 95% CIs will be calculated for each treatment group.
Rate of Transfusion Independence
Analysis of RBCs and platelet-transfusion independence will be based on patients with HR 
MDS/CMML and the ITT population separately.
A patient is defined as RBC or platelet-transfusion independent if he/she receives no RBC or 
platelet transfusions for a period of at least 8 weeks [13,73]. Rate of transfusion 
independence is defined as number of patients who become transfusion independent divided 
by the number of patients who are transfusion dependent at Baseline. The number of patients 
who are transfusion dependent/independent at Baseline and post Baseline, as well as rate of 
transfusion independence, will be summarized by treatment group. Rate of transfusion 
independence between the 2 treatment arms will be compared using unstratified CMH test. 
The relative risk with its 2-sided 95% CIs will be provided. 
Percent of Inpatient Hospitalizations Related to HR MDS, CMML, or AML
Analysis of number of inpatient hospital admissions related to HR MDS, CMML, or AML 
will be based on patients with HR MDS/CMML and the ITT population separately. Inpatient 
hospital admission data will be collected through transformation to AML (patients with HR 
MDS/CMML) or disease progression (patients with low-blast AML) or until initiation of 
subsequent therapy (all patients), whichever occurs first.
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The number and percentage of patients who have any hospitalizations related to HR MDS, 
CMML, or AML will be summarized by treatment group. The absolute rate difference will 
be provided with its 95% CI.
Time to PD, Relapse, or Death
Analysis of time to PD, relapse, or death will be based on patients with HR MDS/CMML 
and the ITT population separately.
Time to PD, relapse, or death is defined as the time from randomization until disease 
progression, or relapse, or death due to any cause, whichever occurs first. Unstratified log-
rank test will be used for comparison between the 2 arms. The hazard ratios along with the 
2-sided 95% CIs will be estimated using the unadjusted unstratified Cox model. The
Kaplan-Meier survival curves and Kaplan-Meier medians (if estimable), along with the 95%
CIs, will also be provided for each treatment group.
8.1.7
Analyses of Health-related Quality of Life
Analyses of HRQOL data for EORTC-QLQ-C30 and EQ-5D-5L will be performed based on 
patients with HR MDS/CMML and the ITT population separately; and for QOL-E data, the 
American English-speaking US patient population only will be used.
The PRO analysis will be performed based on subscale scores from EORTC-QLQ-C30 and 
QOL-E. The actual value and change from baseline of the subscale scores for 
EORTC-QLQ-C30 and QOL-E will be summarized using descriptive statistics by treatment 
group over time. The EORTC-QLQ-C30 and QOL-E subscale scores will also be analyzed 
using linear mixed models by incorporating the measurements across different time points. 
Data from the EQ-5D-5L will be assessed using descriptive statistics by treatment group 
over time.
8.1.8
Pharmacokinetics/Pharmacodynamics/
Pharmacokinetic Analysis
Individual pevonedistat plasma concentration-time data collected in this study will be listed.
Data will be pooled to describe the population PK of pevonedistat. As data permit, a 
nonlinear mixed effects modeling approach (NONMEM software) will be used to assess 
pevonedistat exposure in patients who receive the combination of pevonedistat and 
azacitidine. As appropriate, historical data may be used in this analysis to increase the 
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robustness of the model and precision of estimated PK parameters and compare with 
single-agent pevonedistat data. Details of the modeling approach will be provided in a 
separate analysis plan, and the results of these analyses will be reported separately.
8.1.9
Safety Analysis
Safety population will be used for all safety analyses.
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from baselinein the patient’s vital signs, weight, ECOG performance status, ECG results, 
and clinical laboratory results using the safety population. Exposure to study drug and 
reasons for discontinuation will be tabulated.
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All treatment-emergent adverse events (TEAEs) will be tabulated. TEAEs are AEs that 
occur after administration of the first dose of any study drug and through 30 days after the 
last dose of any study drug. AEs will be tabulated according to the Medical Dictionary for 
Regulatory Activities (MedDRA) by system organ class (SOC), high-level term (HLT), and 
preferred term (PT) and will include the following categories: 

TEAEs.

Drug-related TEAEs.

Treatment-emergent drug-related Grade 3, 4, and 5 AEs (presented by grade and
overall).

Treatment-emergent Grade 3, 4, and 5 AEs (presented by grade and overall).

TEAEs resulting in study drug discontinuation.

The most commonly reported TEAEs (ie, those events reported by 10% of all
patients).

Treatment-emergent SAEs.
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 
grade from Baseline to the worst postbaseline value. Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst postbaseline values, may be used 
to understand the safety profile of pevonedistat plus azacitidine.
Baseline and change from baseline ECOG performance status will be summarized.
All concomitant medications collected from Screening through the study period will be 
classified to preferred terms according to the WHO drug dictionary. All blood (RBC, 
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platelet) transfusions (which will be reported on an eCRF) will also be reviewed to 
determine transfusion dependence or independence, as detailed in Section 8.1.6.3. 
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of pevonedistat plus azacitidine.
Electrocardiogram Analysis
Descriptive statistics for the actual values and changes from baseline in ECGs will be 
tabulated by time point, including any unscheduled measurements.
8.1.10
Interim Analysis
There are two interim analyses (IA) planned for this study. 
The first IA is planned for safety, based on 60-day mortality. It is planned when 60 patients 
are on study for 60 days or do not survive 60 days. This safety evaluation, together with 
other safety and efficacy data, will be reviewed by the independent data monitoring 
committee (IDMC) that will make recommendations regarding whether the study should 
continue as planned or discontinue based on the overall data. The IDMC will review the 
overall profile and if it is deemed unacceptable, the study will stop. Otherwise, enrollment 
and study procedures will continue as planned during this IA.
The second IA is for evaluation of both efficacy and safety data when approximately 23 EFS 
events have occurred. The IDMC will review the overall data and if it is deemed 
unacceptable, the study will stop. Otherwise, enrollment and study procedures will continue 
as planned.
9.
STUDY COMMITTEES
9.1
Millennium Safety Monitoring
Safety data will be reviewed and assessed periodically by a Global Pharmacovigilance 
Safety Team and a Safety Management Committee throughout the conduct of the study. 
These reviews will include a Global Safety Lead from the study team, as well as other 
representation from the Clinical Research, Pharmacovigilance, Biostatistics, Clinical 
Pharmacology, and Clinical Operations departments at Millennium.
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9.2
Independent Data Monitoring Committee
An IDMC will review safety and efficacy data at the first IA and safety and efficacy data at 
the second IA. The IDMC will provide a recommendation regarding study continuation 
based on the overall analysis of safety and efficacy parameters and if it is deemed 
unacceptable, the study will stop. In the event that the study is terminated early based on an 
IDMC recommendation, Millennium will notify the appropriate regulatory authorities. 
Additionally, the IDMC will periodically review data per 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
Adverse event (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. 
10.1.3
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.
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
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 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 [68]. Clarification should be 
made between a serious AE (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 
function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For 
example, a white blood cell 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.
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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
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial 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.
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Intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [68]. 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 the first dose of any study drug through 30 days after 
administration of the last dose of any 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.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from the first dose of study drug through the EOT 
visit, 30 (+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 
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designee (see Section 10.2). Every effort should be made to follow the pregnancy for the 
final pregnancy outcome.
10.5
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, investigators, 
and IRBs or IECs, as applicable, in accordance with national regulations in the countries 
where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as an expedited reported within 7 calendar days for fatal and life-threatening 
events and 15 calendar days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where 
these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational 
medicinal product’s administration or in the overall conduct of the trial. The investigational 
site also will forward a copy of all expedited reports to his or her IRB or IEC in accordance 
with national regulations.
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 that 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.
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 
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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.
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 
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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. Patients with 
progressive disease based on bone marrow blasts counts may be allowed to remain on study, 
after discussion between the investigator and project clinician or designee, if it is judged that 
they are deriving clinical benefit from doing so. Patients who meet the criteria for PD and 
continue on study under these conditions must be reconsented before continuing study 
treatment.
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 
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modification is needed to eliminate an immediate hazard or hazards to patients. Millennium, 
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 (DLLS) and report the 
complaint. The contact information is as follows: 
Call center
Phone number
E-mail
Fax
DLSS
1-844-662-8532 
Non-toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo
@takeda.com 
1-800-881-6092
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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 
 (refer to Section 10.2).
11.12
Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the IECs in all member states 
where the study is being carried out that the study has ended, as well as the competent 
authorities, where required.
Within 1 year of the end of the study, a summary of the clinical trial results will be 
submitted to the competent authorities and IECs in all member states involved in 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 enter 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.
CCI
mber sta
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may be p
ay be
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Within 15 days of premature closure, Millennium must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for 
study closure. 
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 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified. 
12.
USE OF INFORMATION
All information regarding pevonedistat 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 pevonedistat 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-2001 Amendment 04: A Phase 2, Randomized, 
Controlled, Open-Label, Clinical Study of the Efficacy and Safety of Pevonedistat Plus 
Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-Risk Myelodysplastic 
Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myelogenous 
Leukemia.
I agree to conduct the study as detailed herein and in compliance with International 
Conference on 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.
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15.
APPENDICES
15.1
Eastern Cooperative Oncology Group (ECOG) 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 et al, 1982 [74]. 
15.2
Cockcroft-Gault Equation 
For male patient/subject: 
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 patient/subject:
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])
15.3
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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15.4
Methods of Contraception Considered to be Effective
Acceptable 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 as highly effective. Such methods include:

combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 1:

oral

intravaginal

transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation 1:

oral

injectable

implantable 2
intrauterine device (IUD)2
intrauterine hormone-releasing system (IUS)2
bilateral tubal occlusion2
vasectomised partner2,3
sexual abstinence 4
Methods that are Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include:
progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action
male or female condom with or without spermicide5
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cap, diaphragm or sponge with spermicide5
_________________________________________________________________________
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
1)
Hormonal contraception may be susceptible to interaction with the investigational medicinal product, 
which may reduce the efficacy of the contraception method.
2)
Contraception methods that in the context of this guidance are considered to have low user 
dependency.
3)
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.
4)
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.
5)
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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15.5
New York Heart Association Classification of Cardiac Disease 
The following table presents the New York Heart Association classification of cardiac 
disease [75].
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
15.6
Excluded CYP3A Inducers 
Use of strong CYP3A inducers listed in Table 15.a should be avoided during pevonedistat 
therapy.
Table 15.a
In Vivo Inducers of CYP3A
Strong Inducers
(≥80% decrease in AUC)
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Rifabutin
Rifampin
Rifapentine
St. John’s wort
Abbreviations: AUC=area under the plasma concentration-time curve.
Please refer to the following sources for additional information: medicine.iupui.edu/clinpharm/ddis/main-
table/ and 
fda.gov/drugs/developmentapprovalprocess/developmentresources/%20druginteractionslabeling/ucm093
664.htm.
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15.7
Modified Charlson Comorbidity Index
Table 15.b
Modified Charlson Comorbidity Index
Point
Comorbid Condition
1
Myocardial infarction
1
Congestive heart failure
1
Cerebrovascular disease
1
Ulcer
1
Hepatic disease (mild)
1
Diabetes (mild or moderate)
1
Pulmonary disease (moderate or severe)
1
Connective tissue disease
2
Diabetes (severe with end-organ damage)
2
Renal disease (moderate or severe)
2
Solid tumor (without metastases)
3
Hepatic disease (moderate or severe)
6
Solid tumor (with metastases)
Total score
Source: From Etienne et al, 2007 [76].
15.8
Body Surface Area Calculation 
Body surface area (BSA) should be calculated using a standard formula. An example 
formula follows:
15.9
Formula for Absolute Neutrophil Count Calculation 
ANC=total leukocyte count×total percentage of neutrophils (segmented neutrophils+band 
neutrophils)
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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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15.10
Amendment 01 Rationale and Purposes
Rationale for Amendment 01
The original protocol received approval signatory on 25 February 2015. Based on the need 
to clarify information, modifications and/or revisions to the text were required. The study
has not enrolled any patients.
The rationale for including low-marrow blast count (20%-30%) World Health Organization
(WHO)-defined acute myelogenous leukemia (AML) is based on the fact that it had been 
previously classified as refractory anemia with excess blasts in transformation (RAEB-t), 
which was part of the myelodysplastic syndromes (MDS) spectrum, and that it is often 
treated with azacitidine-based therapy. In a phase 3 randomized trial, azacitidine 
significantly prolonged overall survival compared with conventional care regimens in 
patients with higher-risk MDS. In that trial, in a subgroup analysis of the 113 elderly 
patients previously classified as RAEB-t (now re-classified as low marrow blast AML), 
azacitidine significantly prolonged survival and was associated with fewer total days in the 
hospital than conventional care regimens.
The rationale for simplifying the schedule of events is based on the review of information 
presented in the last Development Safety Update Report (DSUR) (cumulative to 22 January 
2015) where there was no change to the benefit-risk evaluation for pevonedistat. The 
sponsor also conducted preliminary analyses (data available as of 19 July 2015) of select 
safety parameters, including gamma glutamyl transpeptidase (GGT), urinalyses (including 
urobilinogen), and vital signs (including systolic blood pressure, diastolic blood pressure, 
and heart rate), and no safety concerns were identified.
The rationale for instituting the 4-month requirement for female contraception after the last 
dose of study drug in women of childbearing potential is primarily because some may 
experience longer than the average 28-day menstrual cycle, and the extension to 4 months 
would adequately and safely cover these patients. In addition, pevonedistat is a first-in-class 
molecule warranting a more cautious approach, and the 4-month requirement for females 
matches the contraception recommendation for males. 
The rationale for removing the Quality of Life in Hematological Patients (myelodysplastic 
syndromes) (QOL-E) assessment at study centers outside the United States (US) is because 
validated translations of the questionnaire are not available for all countries in which the 
sponsor intends to enroll patients. 
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The definition of transformation to AML has been clarified to point out that peripheral blood 
samples can be used for patients for whom bone marrow examination is not possible. 
Specifications for sample handling have been added.
Purposes for Amendment 01
The purposes of this amendment are to:
Study Population:
!
Revise study population to include patients with low-blast AML.
!
Revise the number of patients expected to be enrolled in the study.
!
Clarify definition of progressive disease for patients with low-blast AML.
!
Clarify timing of EFS visit for patients with HR MDS, CMML, or AML.
Study Objectives:
!
Revise primary objective to reflect the addition of patients with low-blast AML.
!
Revise secondary objectives to reflect the addition of patients with low-blast AML.
!
!
Revise secondary objective to clarify that blood samples will be collected for
determination of pevonedistat plasma concentration-time data to contribute to future
population pharmacokinetic analyses of pevonedistat.
Study Endpoints:
!
Revise primary endpoint to reflect the addition of patients with low-blast AML.
!
Revise secondary endpoints to reflect the addition of patients with low-blast AML.
!
Delete secondary endpoint regarding collection of pevonedistat plasma concentrations
since this information is captured in a secondary objective.
!
Add / revise secondary endpoints.
!
Add / revise exploratory endpoints.
Inclusion/Exclusion Criteria:
!
Revise inclusion criteria to allow for patients with low-blast AML.
!
Revise inclusion criterion regarding direct bilirubin values for patients with Gilbert’s
syndrome.
CCI
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
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!
Update exclusion criteria to exclude patients with acute promyelocytic leukemia from 
enrolling in the study.
!
Update exclusion criteria to exclude patients with prothrombin time (PT) or activated 
partial thromboplastin time (aPTT) > 1.5 upper limit of the normal range (ULN).
Study Drug Administration:
!
Revise wording to emphasize that adherence to study drug dosing on specific days is 
strongly recommended. However, dosing may be delayed for safety reasons or 
unavoidable circumstances such as weather conditions affecting clinic accessibility.
Study Procedures:
!
Revise study figure for patients with higher-risk myelodysplastic syndromes (HR 
MDS) and chronic myelomonocytic leukemia (CMML) (Diagram 1) and add a study 
figure for patients with low-blast AML (Diagram 2).
!
Increase numbers of buccal swabs to be collected.
!
Remove the QOL-E assessment for investigative centers outside the US.
!
Revise language regarding the EORTC-QLQ-C30.
!
Remove GGT from serum chemistry analytes from Cycle 2 and beyond. 
!
Remove urobilinogen from all urinalyses analytes from Cycle 2 and beyond. 
!
Update section on bone marrow aspirate and biopsy collection and analysis to reconcile 
language in the protocol.
!
Revise language to emphasize that the investigator should make all efforts to obtain 
bone marrow samples for assessment of disease.
!
Update section on bone marrow sample collection for disease assessment to indicate 
that cytogenetic assessments to determine Revised International Prognostic Scoring 
System (IPSS-R) will be performed for patients with higher-risk myelodysplastic 
syndromes (HR MDS) or chronic myelomonocytic leukemia (CMML).
 
!
Revise section on prohibited concomitant medications.
!
Revise language regarding administration of myeloid growth factors to indicate that the 
use of myeloid growth factors should be limited. 
!
Revise language on pregnancy testing to 1) remove the requirement for pregnancy 
testing at the EOT visit and 2) indicate that additional pregnancy testing may be 
required if requested by an institutional review board (IRB)/ independent ethics 
committee (IEC).
!
Clarify that the Screening chest X-ray will not be done to confirm eligibility if it had 
been performed within 2 months before Screening.
!
Add phosphate blood tests to Day 5 of each cycle (to be performed by a central 
laboratory).
!
Revise timing of vital sign measurements to reflect that vital sign measurements will 
now be taken on select dosing days only instead of on all dosing days for both 
pevonedistat or azacitidine.
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Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
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Statistical Methods:

Update statistical methods section to revise hazard ratio calculations and confidence 
intervals along with the estimated number of event-free survival (EFS) events required. 

Add description of analyses for secondary efficacy endpoints.

Revise section on timing of interim analyses (IA).
Administrative:

Revise language regarding study duration.

Delete text from the introduction that proposes karyotypes and molecular alterations, 
rather than blast counts, form the basis for the separation of MDS and AML since in 
this study, blast counts are being used to differentiate between HR MDS and low-blast 
AML.

Update section on clinical data from the ongoing study with pevonedistat plus 
azacitidine.

Update section on discontinuation of study drug treatment and patient replacement to 
indicate that patients with progressive disease may remain on study if they are deriving 
clinical benefit and that patients who do not receive study drug will not be replaced.

Update section on reasons for withdrawal of patients from study.

Add section on safety monitoring.

Update section on study completion to indicate that a minimum of 6 cycles of 
treatment is strongly encouraged.

Modify the period of contraception use after the last dose of study drug for women of 
childbearing potential to 4 months.

Revise section on collection of hospitalization assessments.

Revise section regarding the Independent Data Monitoring Committee (IDMC).

Revise the section on packaging and labeling. 

Add the suspected unexpected serious adverse reactions (SUSARs) reporting section in 
order to expand the sponsor’s responsibilities for reporting expected and unexpected 
adverse events (AEs).

Update contact information for product complaints.

Update the list of references.

Update the protocol approval signatories.

Structure text and clarify wording within the modified sections for improved clarity 
and readability. 
Correct typographical errors, punctuation, grammar, and formatting.
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15.11
Amendment 02 Rationale and Purposes
Rationale for Amendment 02
This protocol was revised to comply with requests received by regulatory agencies and the 
investigative sites. To mitigate reproductive and developmental hazards, additional 
pregnancy testing has been added at Day 1 of each Cycle and at end of treatment (EOT). 
Patients will also not be allowed to donate ova or sperm during the study and for 4 months 
following the last dose of study drug(s). In addition, examples of highly effective birth 
control methods have been included. 
In this study, patients with higher-risk myelodysplastic syndromes (MDS) or chronic 
myelomonocytic leukemia (CMML) may be allowed to continue study treatment if they 
meet the criteria for progressive disease (PD) based only on bone marrow blast count 
(without transformation to acute myelogenous leukemia [AML]) if, in the clinical judgment 
of the investigator, the patient is still receiving clinical benefit from this treatment, and the 
continuation is endorsed by the sponsor’s project clinician (or designee). Patients with 
low-blast AML may also be allowed to continue study treatment even if they meet the 
criteria for PD based only on bone marrow blast counts if, in the clinical judgment of the 
investigator, the patient is still receiving clinical benefit from this treatment, and the 
continuation is endorsed by the sponsor’s project clinician (or designee). Patients with PD 
who continue on study at the investigator’s discretion should be reconsented before 
continuing study treatment.
The rationale to allow patients with therapy-related MDS, CMML, or low-blast AML 
associated with previous cytotoxic chemotherapy to be included in the study is based on the 
fact that patients with therapy-related MDS or AML have an equivalent outcome to certain 
patients with de novo disease. This is because cytogenetics has an important impact on the 
prognosis of patients with AML or MDS and is the strongest prognostic factor for overall 
survival. In patients with de novo MDS with similar adverse cytogenetics, survival is 
comparable to patients with therapy-related MDS.
Purposes for Amendment 02
The purposes of this amendment are to:
Clarify timing/consistency:

Clarify the collection period for concomitant medications and procedures.
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!
Clarify the collection period for red blood cell and platelet transfusions (8 weeks before
randomization through 30 days after the last dose of any study drug).
!
Clarify the collection period for adverse events.
!
Clarify that patients with low-blast AML at study entry will enter event-free survival
follow-up when they have experienced PD.
!
Add a window for the Cycle 1 Day 15 visit (±1 day).
!
Add a window for the Cycle 1 Day 21 visit (±1 day).
!
Clarify the window for screening assessments (within 28 days before randomization).
!
Clarify the collection time for the Cycle 2 Day 22 bone marrow aspirate sample for
molecular analysis.
!
Change the minimum time between pevonedistat dosing from 48 hours to 1 full
calendar day.
!
Clarify the collection time for the bone marrow aspiration for blast count (eligibility)
versus for molecular analysis.
!
Add a window for pevonedistat administration (60±10 minutes).
Clinical Experience:
!
Clarify that final data for Study C15009 are not yet available.
!
Clarify pevonedistat nonclinical pharmacokinetics and risk assessment for drug-drug
interactions.
Rationale:
!
Provide the rationale for the azacitidine dosing schedule.
!
Provide the rationale for including minimal residual disease assessment as a
measurement of depth of response.
!
Clarify the rationale for using the EORTC-QLQ-30 and QOL-E as health-related
quality of life (HRQOL) instruments.
Objectives/Endpoints:
!
Clarify that relapse includes relapse from complete remission (CR) and partial
remission (PR) for patients with MDS/CMML, and relapse from CR for patients with
AML.
!
!
Inclusion/Exclusion Criteria:
!
Specify that clinical laboratory values used for eligibility will need to be repeated if
performed more than 3 days before the first dose of study drug.
! Allow patients with therapy-related MDS, CMML, or low-blast AML associated with
previous cytotoxic chemotherapy (eg, alkylating agents, topoisomerase inhibitors) to
be included in the study.
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
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! Include lenalidomide as an example of an excluded antileukemic/anti-MDS drug. 
! Specify that treatment with other antileukemic/anti-MDS drugs is not allowed within 
14 days before the first dose of any study drug. 
! Provide definition of postmenopausal. 
! Specify highly effective contraception methods. 
! Specify that patients who have received systemic antineoplastic therapy or 
radiotherapy for other malignant conditions within 12 months before the first dose of 
any study drug, except for hydroxyurea, will be excluded from the study.
! Specify that donation of ova is excluded during the study and for 4 months after the 
last dose of study drug(s).
! Specify that donation of sperm is excluded during the study and for 4 months after the 
last dose of study drug(s).
Study Procedures:
!
Specify that additional electrocardiograms may be performed as clinically indicated.
!
Specify that clinical laboratory evaluations used for eligibility should be performed by 
a central laboratory.
!
Add pregnancy tests at Day 1 of each cycle and at EOT.
!
Specify that HRQOL questionnaires will be paper-based.
!
Clarify that patients should complete the patient-reported outcome questionnaires on 
their own.
!
Specify that translation and validation of the QOL-E is now available outside of the 
United States.
!
Clarify the description of the EQ-5D-5L.
!
Add transfusion data collection to hospitalization assessments.
!
Specify that acceptable bone marrow biopsy samples will include 5 unstained slides 
(charged slides) from core biopsy samples. 
!
Clarify that hematologic improvement is relevant to MDS/CMML but not AML.
!
Specify that patients with PD based only on bone marrow blast counts who continue 
on study at the investigator discretion must be reconsented before continuing study 
treatment. 
!
Clarify that mutation analysis is not required if it is not performed routinely per 
country/institutional guidelines.
!
Specify that the PD response criterion for altering the natural history of MDS and 
CMML includes new transfusion dependence.
!
Add relapse after CR as a response criterion for AML.
!
Add bone marrow aspirate for molecular analysis at the end of Cycle 4 and at the end 
of Cycle 7 (for patients who do not have a confirmed CR at Cycle 4).
Pevonedistat Labeling and Storage:
!
Update the Pevonedistat product description and labeling.
C
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Pevonedistat (MLN4924; TAK-924)
Clinical Study Protocol Pevonedistat-2001 Amendment 04, EudraCT: 2015-000221-37
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
Update the storage/stability requirements for Pevonedistat/IV preparation to be 
consistent with directions for use in the Pharmacy Manual. 

Remove the vial size specified for Pevonedistat Concentrate for Solution for Infusion. 
Administrative:

Specify that current information on azacitidine may also be found in the European Union 
Summary of Product Characteristics.

Correct the serum electrolyte toxicity grade needed to permit continued administration of 
azacitidine. 

Specify that transfusions will be collected on an electronic case report form (eCRF), not 
on a concomitant medication eCRF. 

Update contact information for product complaints.

Update the list of references.

Correct typographical errors, punctuation, grammar, and formatting.
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15.12
Amendment 03 Rationale and Purposes
Rationale for Amendment 03
This document describes the changes in reference to the protocol incorporating 
Amendment 03. The primary reason for this amendment is to employ a definition of 
event-free survival (EFS) that is consistent with the global registration 
Study Pevonedistat-3001 and provide a more clearly defined clinical endpoint for patients 
with low-blast acute myelogenous leukemia (AML). This change will facilitate integration 
of this supportive study with the global registration study results. This change in EFS 
definition affects the primary objective and primary endpoint of the study. For patients with 
low-blast AML, progressive disease or relapse after complete remission (CR) has been 
removed from the definition of an event and an event in patients with low-blast AML is now 
defined only as death.
Changes in Amendment 03
1. Realign the analysis of the primary objective and endpoint as related to the change in the
definition of an event for patients with low-blast AML.
2. Specify the change in the follow-up process for patients with low-blast AML.
3. Specify the trigger initiating the timing of the overall survival final analysis and other
factor(s) that might affect the duration of the study.
4. Specify the changes used for determination of sample size.
5. Specify the timing of the second interim analysis to a specific number of events.
6. Clarify that Kaplan-Meier estimates and CIs of 6-month and 1-year survival rates will be
provided based on the intent-to-treat population.
7. Append “relapse from CR” to Study Overview Diagram 2 for patients with AML.
8. Update the investigator responsibilities for compliance with updated International
Council for Harmonisation guidelines.
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15.13
Amendment 04 Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment 04 are 
indicated. The corresponding text has been revised throughout the protocol.
Change 1: Update the pharmacokinetic profile of pevonedistat and risk assessment for 
drug-drug interactions.
The primary change occurs in Section 1.4.1 Nonclinical Pharmacokinetics and Risk 
Assessment for Drug-Drug Interactions
Initial 
wording:
In vitro pevonedistat is metabolized via hydroxylation and oxidation, 
predominantly by CYP3A4 with a small contribution from CYP2D6.
Preliminary PK evaluations from 26 patients with advanced solid tumors 
in an ongoing open-label drug-drug interaction (DDI) study (Study 
C15011) showed that steady-state fluconazole (classified as a moderate 
CYP3A inhibitor) appeared to have minimal effect (13% increased area 
under the plasma concentration versus time curve from zero to infinity 
[AUCinf] on average) on the single IV PK of pevonedistat, while 
systemic exposure of pevonedistat appeared to increase by 23% on 
average in the presence of itraconazole (classified as a strong CYP3A 
[and P-gp] inhibitor). On the basis of these findings, administration of 
pevonedistat with strong CYP3A inhibitors or inducers should be 
avoided.
Amended or 
new wording: 
In vitro pevonedistat is metabolized via hydroxylation and oxidation, 
predominantly by CYP3A4 with a small contribution from CYP2D6.
Preliminary PK evaluations from 26 patients with advanced solid tumors 
in an ongoing open-label Results from the completed drug-drug 
interaction (DDI) study (Study C15011) showed indicated that steady-
state multiple-dose administration of fluconazole, (classified as a 
moderate CYP3A inhibitor, appeared to have minimal effect (13% 
increased area under the plasma concentration versus time curve from 
zero to infinity [AUCinf] on average) on the single IV had no clinically 
relevant effects on the PK of pevonedistat., while Pevonedistat
systemic exposure of pevonedistat appeared to increase by 23% on 
average in the presence of itraconazole, (classified as a strong CYP3A 
[and P-gp] inhibitor), On the basis of these findings, administration of 
pevonedistat with strong CYP3A inhibitors or inducers should be 
avoided. was only minimally increased compared with that in the 
absence of itraconazole (geometric mean dose-normalized
AUC∞ratio of 1.14 [90% CI, 1.07 to 1.23]). The 14% increase in the 
pevonedistat geometric mean dose-normalized AUC was not 
considered clinically meaningful when viewed in the context of 
pevonedistat overall PK variability (coefficient of variation in AUC∞,
16%-34%), supporting inference of the lack of a clinically relevant 
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effect of itraconazole, a strong CYP3A inhibitor on total systemic 
exposure (AUC) of pevonedistat (see Section 1.6.3).
Rationale for Change: Update pevonedistat PK to reflect most current information on 
DDIs.
Section 1.6.3 Potential for Drug-Drug Interactions also contains this change.
Change 2: Update the primary objective and endpoint of the study to OS.
Primary changes occur in Section 2.1 Primary Objective and Section 3.1 Primary 
Endpoint.
Initial 
wording:
2.1
Primary Objective
The primary objective is:

To determine in patients with HR MDS, CMML, and low-blast AML
whether the combination of pevonedistat and azacitidine improves
event-free survival (EFS) when compared to single-agent azacitidine;
for patients with HR MDS or CMML, an event is defined as death or
transformation to AML; for patients with low-blast AML, an event is
defined as death (see Section 7.4.21).
3.1
Primary Endpoint
The primary endpoint is:

EFS; for patients with HR MDS or CMML, an event is defined as
death or transformation to AML; for patients with low-blast AML, an
event is defined as death (see Section 7.4.21).
Amended or 
new wording: 
2.1
Primary Objective
The primary objective is:

To determine in patients with HR MDS, CMML, or CMML and
low-blast AML whether the combination of pevonedistat and
azacitidine improves event-free survival (EFS) overall survival (OS)
when compared towith single-agent azacitidine; for patients with HR
MDS or CMML, an event is defined as death or transformation to
AML; for patients with low-blast AML, an event is defined as death
(see Section 7.4.21).
3.1
Primary Endpoint
The primary endpoint is:

EFS; for patients with HR MDS or CMML, an event is defined as
death or transformation to AML; for patients with low-blast AML, an
event is defined as death (see Section 7.4.21).
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
OS
Rationale for Change: OS is a clearly defined endpoint that is commonly used in studies 
with patients who have HR MDS, CMML, or low-blast AML.
The Protocol Summary also contains the change in the primary objective.
Change 3: Update secondary objectives and endpoints of the study, including addition of 
EFS, and clarify definitions of response to the study treatment in the secondary endpoints.
Primary changes occur in Section 2.2 Secondary Objectives and Section 3.2 Secondary 
Endpoints.
Initial 
wording:
2.2
Secondary Objectives
The secondary objectives are:

To determine in patients with HR MDS, CMML, and low-blast AML
whether the combination of pevonedistat and azacitidine improves
overall survival (OS) when compared to single-agent azacitidine.

To determine in patients with HR MDS, CMML and low-blast AML
whether the combination of pevonedistat and azacitidine improves
6-month and 1-year survival rates when compared to single-agent
azacitidine.

To determine in patients with HR MDS and CMML whether the
combination of pevonedistat and azacitidine delays time to AML
transformation when compared to single-agent azacitidine.

To determine in patients with HR MDS, CMML, and low-blast AML
whether the combination of pevonedistat and azacitidine, when
compared to single agent azacitidine, improves the rate of: CR, CR
plus partial remission (CR+PR), and/or overall response. Overall
response in HR MDS and CMML is defined as CR+PR+hematologic
improvement [HI]); overall response in low-blast AML is defined as
CR+PR.

To determine in patients with HR MDS, CMML and low-blast AML
whether the combination of pevonedistat and azacitidine, when
compared to single agent azacitidine, improves the rate of CR,
CR+PR, as well as the ORR by Cycle 4.

To determine in patients with HR MDS, CMML, and low-blast AML
whether the combination of pevonedistat and azacitidine, when
compared to single-agent azacitidine, improves duration of CR,
CR+PR, and/or overall response.

To determine in patients with HR MDS, CMML, and low-blast AML
whether the combination of pevonedistat and azacitidine improves
time to first CR or PR when compared to single-agent azacitidine.

To determine in patients with HR MDS, CMML, and low-blast AML
whether the combination of pevonedistat and azacitidine delays time
to subsequent therapy when compared to single-agent azacitidine.
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Subsequent therapy is defined as agent(s) with antileukemic/anti-
MDS activity (eg, cytarabine, anthracyclines, purine analogues, and 
hypomethylating agents other than azacitidine). Patients who 
discontinue study treatment to receive single-agent azacitidine off 
study would not be counted as receiving subsequent therapy.

To determine in patients with HR MDS, CMML, and low-blast AML 
whether the combination of pevonedistat and azacitidine improves 
rate of transfusion independence when compared to single-agent 
azacitidine. RBC or platelet transfusion independence requires that 
the patient receive no RBC or platelet transfusions, respectively, for a 
period of at least 8 weeks.

To determine in patients with HR MDS, CMML and low-blast AML 
whether the combination of pevonedistat and azacitidine reduces the 
percent of patients who have at least one inpatient hospital 
admission(s) related to HR MDS, CMML, or low-blast AML when 
compared to single-agent azacitidine.

To determine in patients with HR MDS, CMML and low-blast AML 
whether the combination of pevonedistat and azacitidine delays time 
to PD, relapse, or death when compared to single-agent azacitidine.

To evaluate in patients with HR MDS, CMML and low-blast AML, 
the safety of the combination of pevonedistat and azacitidine when 
compared to single-agent azacitidine.

To collect in patients with HR MDS, CMML, and low-blast AML, 
plasma concentration-time data for pevonedistat to contribute to 
future population PK analyses of pevonedistat.
   
3.2
Secondary Endpoints
The secondary endpoints are:

OS.
   

Time to AML transformation in HR MDS and CMML patients.

CR, CR+PR, overall response (CR+PR+HI for HR MDS and 
CMML; CR+PR for low-blast AML).

CR, CR+PR, overall response (CR+PR+HI for HR MDS and 
CMML; CR+PR for low-blast AML) by Cycle 4.

Duration of CR, duration of CR+PR, duration of overall response 
(CR+PR+HI for HR MDS and CMML; CR+PR for low-blast AML).

Time to first CR or PR.
Amended or 
new wording: 
2.2
Secondary Objectives
The secondary objectives are:

To determine in patients with HR MDS, CMML, and low-blast AML 
whether the combination of pevonedistat and azacitidine improves 
overall survival (OS) when compared to single-agent azacitidine.
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
To determine in patients with HR MDS or CMML and low-blast 
AML whether the combination of pevonedistat and azacitidine 
improves event-free survival (EFS) when compared with single-
agent azacitidine; for patients with HR MDS or CMML, an event 
is defined as death or transformation to AML; for patients with 
low-blast AML, an event is defined as death (see Section 7.4.21).

To determine in patients with HR MDS, or CMML and low-blast 
AML whether the combination of pevonedistat and azacitidine 
improves 6-month and 1-year survival rates when compared towith
single-agent azacitidine.

To determine in patients with HR MDS and or CMML whether the 
combination of pevonedistat and azacitidine delays time to AML 
transformation when compared towith single-agent azacitidine.

To determine in patients with HR MDS, or CMML, and low-blast 
AML whether the combination of pevonedistat and azacitidine, when 
compared towith single-agent azacitidine, improves the rate of: CR, 
complete remission (CR) (composite CR [CR + Cri] in patients 
with low-blast AML), CR plus partial remission (composite CR +
PR for patients with low-blast AML), overall response, and/or CR
(not including CRi) in low-blast AML. Overall response in HR 
MDS and or CMML is defined as CR + PR + hematologic 
improvement ([HI]); overall response in low-blast AML is defined as 
CR + CRi + PR.

To determine in patients with HR MDS, or CMML and low-blast 
AML whether the combination of pevonedistat and azacitidine, when 
compared towith single-agent azacitidine, improves the rate of CR,
CR+PR, as well as he ORR (composite CR [CR + Cri] in patients 
with low-blast AML), CR + PR (composite CR + PR in patients 
with low-blast AML), the overall response rate (ORR), as well as 
CR (not including Cri) in low-blast AML by Cycle 4.

To determine in patients with HR MDS, or CMML, and low-blast 
AML whether the combination of pevonedistat and azacitidine, when 
compared towith single-agent azacitidine, improves duration of 
CR,CR+PR,and/or (composite CR [CR + CRi] in patients with 
low-blast AML), CR + PR (composite CR + PR in patients with 
low-blast AML), overall response, and/or CR (not including Cri) 
in patients with low-blast AML.

To determine in patients with HR MDS, or CMML, and low-blast 
AML whether the combination of pevonedistat and azacitidine 
improves time to first CR (CR for HR MDS/CMML and low-blast 
AML; CR + CRi [composite CR] for low-blast AML), or PR when 
compared with single-agent azacitidine.

To determine in patients with HR MDS, or CMML, and low-blast 
AML whether the combination of pevonedistat and azacitidine delays 
time to subsequent therapy when compared towith single-agent 
azacitidine. Subsequent therapy is defined as agent(s) with 
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antileukemic/anti-MDS activity (eg, cytarabine, anthracyclines, 
purine analogues, and hypomethylating agents other than 
azacitidine). Patients who discontinue study treatment to receive 
single-agent azacitidine off study would not be counted as receiving 
subsequent therapy.

To determine in patients with HR MDS, or CMML, and low-blast 
AML whether the combination of pevonedistat and azacitidine 
improves rate of transfusion independence when compared towith
single-agent azacitidine. RBC or platelet transfusion independence 
requires that the patient receive no RBC or platelet transfusions, 
respectively, for a period of at least 8 weeks.

To determine in patients with HR MDS, or CMML and low-blast 
AML whether the combination of pevonedistat and azacitidine 
reduces the percent of patients who have at least one inpatient 
hospital admission(s) related to HR MDS, or CMML, or low-blast 
AML when compared towith single-agent azacitidine.

To determine in patients with HR MDS, or CMML and low-blast 
AML whether the combination of pevonedistat and azacitidine delays 
time to PD, relapse, or death when compared towith single-agent 
azacitidine.

To evaluate in patients with HR MDS, or CMML and low-blast 
AML, the safety of the combination of pevonedistat and azacitidine 
when compared towith single-agent azacitidine.

To collect in patients with HR MDS, or CMML, and low-blast AML,
plasma concentration-time data for pevonedistat to contribute to 
future population PK analyses of pevonedistat.
   
3.2
Secondary Endpoints
The secondary endpoints are:

OS.

EFS; for patients with HR MDS or CMML, an event is defined as 
death or transformation to AML; for patients with low-blast 
AML, an event is defined as death (see Section 7.4.21).
   

Time to AML transformation in patients with HR MDS or and
CMML patients.

CR, CR+ (CR for HR MDS and CMML; CR + CRi [composite 
CR] for low-blast AML), CR (CR for HR MDS and CMML; CR 
+ CRi for low-blast AML) + PR, overall response (CR+PR+HI for 
HR MDS and CMML; CR+ CRi + PR for low-blast AML), CR (not 
including CRi) in low-blast AML.

CR, CR+ (CR for HR MDS and CMML; CR + CRi [composite 
CR] for low-blast AML), CR (CR for HR MDS and CMML; CR 
+ CRi for low-blast AML) + PR, overall response (CR + PR + HI 
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for HR MDS and CMML; CR+ + CRi + PR for low-blast AML) by 
Cycle 4, CR (not including CRi) in low-blast AML by Cycle 4.
!
Duration of CR, duration of CR+ (CR for HR MDS and CMML,
CR + Cri [composite CR] for low-blast AML), CR (CR for HR
MDS and CMML; CR + CRi for low-blast AML) + PR, duration
of overall response (CR + PR + HI for HR MDS and CMML; CR +
CRi + PR for low-blast AML), and duration of CR (not including
CRi) in low-blast AML.
!
Time to first CR or PR (CR for HR MDS/CMML and low-blast
AML; CR + CRi [composite CR] for low-blast AML) or PR for
HR MDS/CMML and low-blast AML.
Rationale for Change: Update secondary objectives and endpoints to include EFS and 
clarify definitions of response.
The Protocol Summary also contains the changes in the secondary objectives.
Change 4: Update exploratory objectives and endpoints. 
 
Primary changes occur in Section 2.3 Exploratory Objectives and Section 3.3 Exploratory 
Endpoints
Initial 
wording:
2.3
Exploratory Objectives
The exploratory objectives include:
CCI
CCI
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ry Objec
Obje
y
d s
t to the applicable Terms of Use
last
ast
PR for
PR fo
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objec i
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Amended or 
new wording: 
2.3
Exploratory Objectives
The exploratory objectives include:
CCI
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Rationale for Change: Update exploratory objectives and endpoints, also 
 
The Protocol Summary also contains the changes to exploratory objectives.
Change 5: Update the percentage of patients with OS events initiating the timing of the 
OS analysis and duration of the study.
Primary change Section 4.3 Duration of Study
Initial 
wording:
Patients, including those who achieve a CR, may receive study treatment 
until they experience PD or discontinuation for any other reason outlined 
in Section 7.5. Patients will be followed until approximately 60 OS 
events have occurred or 24 months after the enrollment of the last 
patient, whichever occurs first, or termination of the study by the 
sponsor.
Amended or 
new wording:
Patients, including those who achieve a CR, may receive study treatment 
until they experience PD or discontinuation for any other reason outlined 
in Section 7.5. Patients will be followed until approximately 60% of 
patients with HR MDS/CMML have experienced OS events have 
occurred or 24 months after the enrollment of the last patient, whichever 
occurs first, or termination of the study by the sponsor. Patients who are 
still receiving study treatment and continuing to derive clinical 
benefit may continue to receive pevonedistat at the discretion of the 
sponsor; the continuation of treatment may occur in a manner other 
than under the study protocol, in accordance with local regulations.
Rationale for Change: To provide sufficiently mature OS data at the time of final 
analysis.
The Protocol Summary also contains this change.
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bjective
ectiv
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init
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Change 6: Update table for concomitant medications that are excluded while receiving 
single-agent azacitidine study treatment.
Primary change occurs in Section 6.4 Excluded Concomitant Medications and Procedures
Initial 
wording:
Table 6.a
Concomitant Medications Excluded During the Study: 
Single-Agent Azacitidine Arm
Therapy
Any investigational agent including agents commercially available for 
indications other than MDS, CMML, or low-blast AML, including but 
not limited to androgens, supraphysiologic doses of corticosteroids, 
erythropoietin, eltrombopag [Promacta], or romiplostim [Nplate]
Amended or 
new wording:
Table 6.a
Concomitant Medications Excluded During the While 
Receiving Study Treatment: Single-Agent Azacitidine Arm
Therapy
Any investigational agent including agents for MDS, CMML, or low-
blast AML, or commercially available for indications other than agents 
used in MDS, CMML, or low-blast AML, including but not limited to
androgens, supraphysiologic doses of corticosteroids, erythropoietin, 
eltrombopag [Promacta], or romiplostim [Nplate]
Rationale for Change: Clarify the exclusion of investigational or commercially available 
agents used to treat patients with HR MDS/CMML or low-blast AML while patients are 
receiving study treatment.
Change 7: Update table for concomitant medications that are excluded while receiving 
combination treatment pevonedistat + azacitidine.
Primary change occurs in Section 6.4 Excluded Concomitant Medications and Procedures, 
Table 6.b Concomitant Medications Excluded While Receiving Study Treatment: 
Combination Pevonedistat Plus Azacitidine Arm
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Initial 
wording:
Table 6.b
Concomitant Medications Excluded During the Study: 
Combination Pevonedistat Plus Azacitidine Arm
Therapy
Strong CYP3A inhibitors or 
inducers (see Section 15.6)
Comment/Exceptions
Excluded, but limited use of the azole 
antifungal agent, voriconazole, is 
permitted only if clinically necessary and 
no suitable alternative exists. The patient 
may receive voriconazole 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), Friday (Day 5) 
schedule, then voriconazole 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.
Any investigational agent 
other than pevonedistat, 
including agents 
commercially available for 
indications other than MDS, 
CMML, or low-blast AML
including but not limited to 
androgens, supraphysiologic 
doses of corticosteroids, 
erythropoietin, eltrombopag 
[Promacta], or romiplostim 
[Nplate]
Amended or 
new wording:
Table 6.b
Concomitant Medications Excluded During the While 
Receiving Study Treatment: Combination Pevonedistat Plus 
Azacitidine Arm
Therapy
Strong CYP3A inhibitors or
inducers (see Section 15.6)
Comment/Exceptions
Excluded, but limited use of the azole 
antifungal agent, voriconazole, is 
permitted only if clinically necessary and 
no suitable alternative exists. The patient 
may receive voriconazole from 24 hours 
after the last pevonedistat dose until 72 
hours before the next pevonedistat dose. 
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For example, if a patient receives 
pevonedistat on a Monday (Day 1), 
Wednesday (Day 3), Friday (Day 5) 
schedule, then voriconazole 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.
Any investigational agent 
other than pevonedistat, 
including agents for MDS, 
CMML, or low-blast 
AML, or commercially 
available for indications 
other than agents used in 
MDS, CMML, or low-blast 
AML, including but not 
limited to androgens, 
supraphysiologic doses of 
corticosteroids, 
erythropoietin, eltrombopag 
[Promacta], or romiplostim 
[Nplate]
Rationale for Change: Include in the table only strong CYP3A inducers that may reduce 
pevonedistat exposures (remove restriction on CYP3A inhibitors on the basis of results of 
recent studies)
Change 8: Add section for posttrial access to study medication.
Primary change occurs in Section 7.11 Posttrial Access
Added text:
7.11
Post-Trial Access
7.11.1 Post-Trial Access
If an open-label, rollover, posttrial access (PTA) study should 
become an option and the investigator and the sponsor agree that a 
patient would derive benefit from continued treatment or would be 
harmed without continued access to the medication, the patient may 
be given the opportunity to enroll. The patient would then be able to 
continue receive pevonedistat (if randomized to the combination 
arm).
7.11.2 Duration of PTA
In the event of a rollover PTA study, continued access to 
pevonedistat for participants will be terminated for those individuals 
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who no longer benefit from treatment (eg, their disease has 
progressed or treatment is no longer tolerable), the benefit-risk no 
longer favors the individual, an appropriate alternative therapy 
becomes available, or pevonedistat becomes available either 
commercially or via another access mechanism. PTA may be 
terminated in a country or geographical region where the 
development of pevonedistat has been suspended or stopped by the 
sponsor, or pevonedistat can no longer be supplied.
Rationale for Change: Text added for information on program-level PTA for
pevonedistat.
Change 9: Specify changes for determination of sample size to align with new primary 
endpoint.
Primary change occurs in Section 8.1.1 Determination of Sample Size
Initial 
wording:
Assuming an exponential distribution for EFS, a total of approximately 
60 EFS events will be required to detect a hazard ratio of 0.585 (median 
EFS of 22.2 months in the Combination Pevonedistat Plus Azacitidine 
Arm versus 13 months in the Single-Agent Azacitidine Arm) with 
approximately 85% power using a 1-sided log-rank test at a 15% overall 
significance level. Approximately 117 patients will be randomized in a 
1:1 ratio to receive either the combination of pevonedistat and azacitidine 
or single-agent azacitidine, assuming an enrollment rate that increases 
from an initial 1 patient per month to 12 patients per month after 
7 months. Sixty EFS events are estimated to occur within approximately 
28 months from the enrollment of the first patient. This estimated period 
includes a 14-month accrual period and an additional 14-month 
follow-up from the last patient enrolled.
EFS assumptions for single-agent azacitidine are based on a phase 3 
study of azacitidine in 
MDS(https://clinicaltrials.gov/ct2/show/NCT00071799?term=azacitidine
+MDS&no_unk=Y&rank=32, accessed 13 February 2015).
Amended or 
new wording:
Assuming an exponential distribution for EFS, a total of approximately 
60 EFS events will be required to detect a hazard ratio of 0.585 (median 
EFS of 22.2 months in the Combination Pevonedistat Plus Azacitidine 
Arm versus 13 months in the Single-Agent Azacitidine Arm) with 
approximately 85% power using a 1 sided log-rank test at a 15% overall 
significance level. Approximately 117 patients will be randomized in a 
1:1 ratio to receive either the combination of pevonedistat and azacitidine 
or single-agent azacitidine, assuming an enrollment rate that increases 
from an initial 1 patient per month to 12 patients per month after 
7 months. Sixty EFS events are estimated to occur within approximately 
28 months from the enrollment of the first patient. This estimated period 
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includes a 14 month accrual period and an additional 14-month follow-
up from the last patient enrolled.
EFS assumptions for single-agent azacitidine are based on a phase 3 
study of azacitidine in 
MDS(https://clinicaltrials.gov/ct2/show/NCT00071799?term=azacitidine
+MDS&no_unk=Y&rank=32, accessed 13 February 2015).
Rationale for Change: Remove the previous specification of EFS event size because EFS 
is no longer the primary endpoint.
Change 10: Clarify definition of safety population for purposes of analysis.
Primary change occurs in Section 8.1.3 Populations for Analysis
Initial 
wording:

Safety population: The safety population is defined as all patients
who receive at least 1 dose of pevonedistat plus azacitidine or
azacitidine alone. Patients will be analyzed according to the actual
treatment they received. Patients who received any dose of study
drug (pevonedistat or azacitidine) will be included in the
Combination Pevonedistat Plus Azacitidine Arm, and patients who
did not receive any dose of pevonedistat will be included in the
Single-Agent Azacitidine Arm, regardless of their randomized
treatment.
Amended or 
new wording:

Safety population: The safety population is defined as all patients
who receive at least 1 dose of pevonedistat plus azacitidine or
azacitidine alone. Patients will be analyzed according to the actual
treatment they received. Patients who received any dose of study
drug (pevonedistat or azacitidine) will be included in the
Combination Pevonedistat Plus Azacitidine Arm, and patients who
did not receive any dose of pevonedistat, but received at least 1
dose of azacitidine, will be included in the Single-Agent Azacitidine
Arm, regardless of their randomized treatment.
Rationale for Change: Change made for clarification.
Change 11: Specify changes in general methodology for analysis of efficacy.
Primary change occurs in Section 8.1.6.1 General Methodology
Initial 
wording:
The Kaplan-Meier survival curves and Kaplan-Meier medians (if 
estimable) will also be provided, along with their 2-sided 70% CIs and 
2-sided 95% CIs for time to event data. P values from statistical tests will
be based on 2-sided tests with a 30% significance level, which is
equivalent to 1 sided tests with a 15% significance level.
Amended or 
new wording:
The Kaplan-Meier survival curves and Kaplan-Meier medians (if 
estimable) will also be provided, along with their 2-sided 70% CIs and 2-
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sided 95% CIs for time to event data. P values from statistical tests will 
be based on 2-sided tests with a 30% significance level, which is 
equivalent to 1 sided tests with a 15% significance level.
Rationale for Change: To align the general methodology for analysis of efficacy with the 
removal of EFS as the primary endpoint. 
Change 12: Specify analyses of primary efficacy endpoint OS.
Primary change occurs in Section 8.1.6.2 Analyses of Primary Efficacy Endpoints
Initial 
wording:
The analysis of the primary efficacy endpoint, EFS, will be based on the 
ITT population.
For patients with HR MDS/CMML, an event is defined as death or 
transformation to AML; for patients with low-blast AML, an event is 
defined as death. EFS is defined as the time from randomization to the 
occurrence of an event. Stratified log-rank test will be used to compare 
EFS between the 2 arms (see Section 8.1.2 for stratification factors). The 
hazard ratios along with the 2-sided 70% CIs and 95% CIs will be 
estimated using the unadjusted stratified Cox model. The proportional 
hazard assumptions will be examined and sensitivity analysis will be 
conducted if appropriate. The Kaplan-Meier survival curves and Kaplan 
Meier medians (if estimable), along with the 70% and 95% CIs, will also 
be provided for each treatment group.
Amended or 
new wording:
The analysis of the primary efficacy endpoint, OS EFS, will be based on 
HR MDS/CMML patients and the ITT population separately.
For OS will be analyzed when approximately 60% of patients with HR 
MDS/CMML, an event is defined as death or transformation to AML; for 
patients with low blast AML, an event is defined as death. EFS is defined
as the time from randomization to the occurrence of an event. Stratified
have experienced OS events, or termination of the study by the 
sponsor.
OS will be calculated from date of randomization to the date of 
patient death due to any cause. Patients without documented death 
at the time of the analysis will be censored at the date that the 
patient was last known to be alive. Unstratified log-rank test will be 
used to compare OS EFS between the 2 treatment arms (see Section 
8.1.2 for stratification factors). The hazard Hazard ratios, along with the 
2-sided 70% CIs and 95% CIs, will be estimated using the unadjusted,
stratified unstratified Cox model. The proportional hazard assumptions
will be examined and sensitivity analysis will be conducted if
appropriate. The Kaplan-Meier survival curves and Kaplan-Meier
medians (if estimable), along together with the 70% and 95% CIs, will
also be provided calculated for each treatment group.
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Rationale for Change: To align with OS as the primary endpoint.
Change 13: Clarify methodology for analysis of secondary efficacy endpoints, including 
those that are response-related.
Primary change occurs in Section 8.1.6.3 Analyses of Secondary Efficacy Endpoints
Initial 
wording:
If the secondary efficacy endpoint is response related, such as CR or 
duration of CR, the response-evaluable population will be used.
Otherwise the analysis will be based on the ITT population.
For low-blast AML patients, all CR includes both complete remission 
(CR) and complete remission with incomplete count recovery (CRi).
Overall Survival
OS will be calculated from date of randomization to the date of patient 
death due to any cause. Patients without documented death at the time of 
the analysis will be censored at the date that the patient was last known 
to be alive. Stratified log-rank test will be used to compare OS between
the 2 treatment arms. Hazard ratios, along with the 2-sided 70% and 95% 
CIs will be estimated using the unadjusted stratified Cox model. The 
proportional hazard assumptions will be examined and sensitivity 
analysis will be conducted if appropriate. Kaplan-Meier curves and 
Kaplan-Meier medians (if estimable), together with the 70% and 95% 
CIs, will be calculated for each treatment group.
Six-Month and One-Year Survival Rate
Kaplan-Meier estimates and the 70% and 95% CIs of 6-month and 1-year 
survival rates will be provided based on the ITT population.
Time to AML Transformation
Time to AML transformation is defined as time from randomization to 
documented AML transformation. This definition only applies to HR 
MDS and CMML patients, so this analysis will only be carried out in this 
subgroup. Patients who died before progression to AML will be 
censored. Stratified log-rank test will be used to compare time to AML 
transformation between the 2 arms. Hazard ratio and its 2-sided 70% and 
95% CI will be calculated using the stratified Cox model. Kaplan-Meier 
survival curves and Kaplan-Meier medians (if estimable), together with 
the 70% and 95% CIs, will be calculated for each treatment group.
CR/CR+PR/Overall Response (CR+PR+HI)
CR/CR+PR/overall response calculations will be based on the response-
evaluable population. 
The number and percentage of patients who achieved CR/CR+PR/overall 
response (CR+PR+HI for patients with HR MDS/CMML, CR+PR for 
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patients with low-blast AML), respectively, will be summarized by 
treatment group. CR rate/CR+PR rate/overall response rate, respectively, 
will be tested using the stratified Cochran-Mantel-Haenszel (CMH) chi 
square test. The CMH chi-square test p-value, the relative risk with its 
2-sided 70% and 95% CI will be calculated. The absolute rate difference 
will be provided with its 70% and 95% CI.
CR/CR+PR/Overall Response (CR+PR+HI) by Cycle 4
The number and percentage of patients who achieved CR/CR+PR/overall 
response (CR+PR+HI for patients with HR MDS/CMML, CR+PR for 
patients with low-blast AML) by Cycle 4, respectively, will be 
summarized by treatment group. CR rate/CR+PR rate/overall response 
rate by Cycle 4, respectively, will be tested using the stratified 
Cochran-Mantel-Haenszel (CMH) chi-square test. The CMH chi-square 
test p-value, the relative risk with its 2-sided 70% and 95% CI will be 
calculated. The absolute rate difference will be provided with its 70% 
and 95% CI.
Duration of CR/CR+PR/Overall Response (CR+PR+HI)
Calculations of duration of responses will be based on the response-
evaluable population.
Duration of CR/CR+PR/overall response (CR+PR+HI for patients with 
HR MDS/CMML, CR+PR for patients with low-blast AML), 
respectively, will be analyzed using standard survival analysis techniques 
based on Kaplan-Meier estimates.
Time to First CR or PR
Analysis of time to first CR or PR will be based on the response-
evaluable population.
Time to first CR or PR is defined as time from randomization to first 
documented CR or PR, whichever occurs first. Stratified log-rank test 
will be used to compare time to first CR or PR between the 2 arms. 
Hazard ratio and its 2-sided 70% and 95% CI will be calculated using the 
stratified Cox model. Kaplan-Meier survival curves and Kaplan-Meier 
medians (if estimable), together with the 70% and 95% CIs, will be 
calculated for each treatment group.
Time to Subsequent Therapy
Analysis of time to subsequent therapy will be based on the ITT 
population.
   
Stratified log-rank test will be used to compare time to subsequent 
therapy between the 2 arms. Hazard ratio and its 2-sided 70% and 95% 
CIs will be calculated using stratified Cox model. Kaplan-Meier survival 
curves and Kaplan-Meier medians (if estimable), together with the 70% 
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and 95% CIs will be calculated for reach treatment group.
Rate of Transfusion Independence
Analysis of RBCs and platelet-transfusion independence will be based on 
the ITT population.
A patient is defined as RBC or platelet-transfusion independent if he/she 
receives no RBC or platelet transfusions for a period of at least 8 weeks 
[13,73]. Rate of transfusion independence is defined as number of 
patients who become transfusion independent divided by the number of 
patients who are transfusion dependent at Baseline. The number of 
patients who are transfusion dependent/independent at Baseline and post 
Baseline, as well as rate of transfusion independence, will be 
summarized by treatment group. Rate of transfusion independence will 
be tested using stratified CMH test. P values and 2-sided 70% and 95% 
CIs of the relative risk will be provided.
Percent of Inpatient Hospitalizations Related to HR MDS, CMML, 
or AML
Analysis of number of inpatient hospital admissions related to HR MDS, 
CMML, or AML will be based on the ITT population. Inpatient hospital 
admission data will be collected through transformation to AML (HR 
MDS/CMML patients) or disease progression (low-blast AML patients) 
or until initiation of subsequent therapy (all patients), whichever occurs 
first.
The number and percentage of patients who have any hospitalizations 
related to HR MDS, CMML, or AML will be summarized by treatment 
group. The absolute rate difference will be provided with its 70% and 
95% CI.
Time to PD, Relapse, or Death
Analysis of time to PD, relapse, or death will be based on the ITT 
population.
Time to PD, relapse, or death is defined as the time from randomization 
until disease progression, or relapse, or death due to any cause, 
whichever occurs first. Stratified log-rank test will be used for 
comparison between the 2 arms. The hazard ratios along with the 2 sided 
70% and 95% CIs will be estimated using the unadjusted stratified Cox 
model. The Kaplan-Meier survival curves and Kaplan-Meier medians (if 
estimable), along with the 70% and 95% CIs, will also be provided for 
each treatment group.
Amended or 
new wording:
If the secondary efficacy endpoint is response related, such as CR or 
duration of CR, the response-evaluable population will be used. 
Otherwise of patients with HR MDS/CMML, patients with low-blast 
AML, and the overall patient population will be used separately, if 
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appropriate. Duration of the response-related endpoint will be 
analyzed based on the corresponding responders; otherwise, the 
analysis will be based on HR MDS/CMML patients and the ITT 
population separately.
For patients with low-blast AML patients, all CR includes both 
complete remission (CR) and complete remission with incomplete count 
recovery (CRi), composite CR + CRi, CR as well as CRi will be 
analyzed.
Overall Survival
OS will be calculated from date of randomization to the date of patient 
death due to any cause. Patients without documented death at the time of 
the analysis will be censored at the date that the patient was last known 
to be alive. Stratified log-rank test will be used to compare OS between 
the 2 treatment arms. Hazard ratios, along with the 2-sided 70% and 95% 
CIs will be estimated using the unadjusted stratified Cox model. The 
proportional hazard assumptions will be examined and sensitivity 
analysis will be conducted if appropriate. Kaplan-Meier curves and 
Kaplan-Meier medians (if estimable), together with the 70% and 95% 
CIs, will be calculated for each treatment group.
EFS
The analysis of EFS, will be based on patients with HR MDS/CMML 
and the ITT population separately.
For patients with HR MDS/CMML, an event is defined as death or 
transformation to AML; for patients with low-blast AML, an event 
is defined as death. EFS is defined as the time from randomization to 
the occurrence of an event. Unstratified log-rank test will be used to 
compare EFS between the 2 arms. The hazard ratios along with the 
2-sided 95% CIs will be estimated using the unadjusted, unstratified
Cox model. The proportional hazard assumptions will be examined
and sensitivity analysis will be conducted if appropriate. The
Kaplan-Meier survival curves and Kaplan Meier medians (if
estimable), along with the 95% CIs, will also be provided for each
treatment group.
Six-Month and One-Year Survival Rate
Kaplan-Meier estimates and the 70% and 95% CIs of 6-month and 1-year 
survival rates will be provided based on patients with HR 
MDS/CMML and the ITT population separately.
Time to AML Transformation
Time to AML transformation is defined as time from randomization to 
documented AML transformation. This definition only applies to 
patients with HR MDS and CMML patients, so this analysis will only 
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be carried out in this subgroup. Patients who died before progression to 
AML will be censored. Stratified Unstratified log-rank test will be used 
to compare time to AML transformation between the 2 arms. Hazard 
ratio and its 2-sided 70% and 95% CI will be calculated using the 
stratified unstratified Cox model. Kaplan-Meier survival curves and 
Kaplan-Meier medians (if estimable), together with the 70% and 95% 
CIs, will be calculated for each treatment group.
CR/CR+PR/Overall Response (CR+PR+HI) (CR for HR MDS and 
CMML, CR + CRi [composite CR] for low-blast AML)/CR (CR for 
HR MDS and CMML, CR + CRi for low-blast AML) + PR/overall 
response (CR + PR + HI for HR MDS and CMML; CR + CRi + PR 
for low-blast AML)/CR (not including CRi) in low-blast AML
CR/CR +PR PR (composite CR + PR for patients with low-blast 
AML)/overall response/CR (not including CRi) in low-blast AML
calculations will be based on the response-evaluable population of 
patients overall, the response-evaluable patients with HR 
MDS/CMML, and the response-evaluable patients with low-blast 
AML, if appropriate.
The number and percentage of patients who achieved CR/CR+PR PR 
(composite CR + PR for patients with low-blast AML)/overall 
response (CR+PR+HI for patients with HR MDS/CMML, composite CR
+ PR for patients with low-blast AML)/CR (not including Cri) in low-
blast AML, respectively, will be summarized by treatment group. CR 
rate/CR + PR rate (composite CR + PR for patients with low-blast 
AML)/overall response rate/CR rate (not including CRi) in low-blast 
AML between the 2 treatment arms, respectively, will be tested
compared using the stratified unstratified Cochran-Mantel-Haenszel 
(CMH) chi square test. The CMH chi-square test p-value, the relative 
risk with its 2-sided 70% and 95% CI will be calculated. The absolute 
rate difference will be provided with its 70% and 95% CI.
CR/CR+PR/Overall Response (CR+PR+HI) by Cycle 4 (CR for HR 
MDS and CMML, CR + CRi [composite CR] for low-blast 
AML)/CR (CR for HR MDS and CMML, CR + CRi for low-blast 
AML) + PR/overall response (CR + PR + HI for HR MDS and 
CMML; CR + CRi + PR for low-blast AML)/CR (not including CRi) 
in low-blast AML by Cycle 4
The number and percentage of patients who achieved CR/CR+PR PR 
(composite CR + PR for low-blast AML)/overall response (CR + PR +
HI for patients with HR MDS/CMML, composite CR + PR for patients 
with low-blast AML)/CR (not including CRi) in low-blast AML by 
Cycle 4, respectively, will be summarized by treatment group. CR 
rate/CR+PR + PR (composite CR + PR for patients with low-blast 
AML) rate/overall response rate/CR rate (not including CRi) in low-
blast AML by Cycle 4 between the 2 treatment arms, respectively, 
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will be tested compared using the stratified unstratified Cochran-
Mantel-Haenszel (CMH) chi-square test. The CMH chi-square test 
p-value, the relative risk with its 2-sided 70% and 95% CI will be 
calculated. The absolute rate difference will be provided with its 70% 
and 95% CI.
Duration of CR/CR+PR/Overall Response (CR+PR+HI) (CR for HR 
MDS and CMML, CR + CRi [composite CR] for low-blast 
AML)/CR (CR for HR MDS and CMML, CR + CRi for low-blast 
AML) + PR/overall response (CR + PR + HI for HR MDS and 
CMML; CR + CRi + PR for low-blast AML)/CR (not including CRi) 
in low-blast AML
Calculations of duration of responses will be based on the response-
evaluable population responders from the overall patient population, 
responders from patients with HR MDS/CMML, and responders 
from patients with low-blast AML, if appropriate.
Duration of CR/CR + PR/overall response (CR +PR + HI for patients 
with HR MDS/CMML, CR + CRi + PR for patients with low-blast 
AML)/CR (not including CRi) in low-blast AML, respectively, will be 
analyzed using standard survival analysis techniques based on 
Kaplan-Meier estimates.
Time to First CR or PR
Analysis of time to first CR (composite CR for patients with low-blast 
AML) or PR will be based on the response-evaluable patients with HR 
MDS/CMML and the response-evaluable population for the overall 
patient population separately.
Time to first CR or PR is defined as time from randomization to first 
documented CR or PR, whichever occurs first. Stratified Unstratified 
log-rank test will be used to compare time to first CR or PR between the 
2 arms. Hazard ratio and its 2-sided 70% and 95% CI will be calculated 
using the stratified unstratified Cox model. Kaplan-Meier survival 
curves and Kaplan-Meier medians (if estimable), together with the 70% 
and 95% CIs, will be calculated for each treatment group.
Time to Subsequent Therapy
Analysis of time to subsequent therapy will be based on patients with 
HR MDS/CMML and the ITT population separately.
   
Stratified Unstratified log-rank test will be used to compare time to 
subsequent therapy between the 2 arms. Hazard ratio and its 2-sided 70% 
and 95% CIs will be calculated using stratified unstratified Cox model. 
Kaplan-Meier survival curves and Kaplan-Meier medians (if estimable), 
together with the 70% and 95% CIs will be calculated for reach each
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treatment group.
Rate of Transfusion Independence
Analysis of RBCs and platelet-transfusion independence will be based on 
patients with HR MDS/CMML and the ITT population separately.
A patient is defined as RBC or platelet-transfusion independent if he/she 
receives no RBC or platelet transfusions for a period of at least 8 weeks 
[13,73]. Rate of transfusion independence is defined as number of 
patients who become transfusion independent divided by the number of 
patients who are transfusion dependent at Baseline. The number of 
patients who are transfusion dependent/independent at Baseline and post 
Baseline, as well as rate of transfusion independence, will be 
summarized by treatment group. Rate of transfusion independence
between the 2 treatment arms will be tested compared using stratified
unstratified CMH test. P values and The relative risk with its 2-sided 
70% and 95% CIs of the relative risk will be provided.
Percent of Inpatient Hospitalizations Related to HR MDS, CMML, 
or AML
Analysis of number of inpatient hospital admissions related to HR MDS, 
CMML, or AML will be based on patients with HR MDS/CMML and
the ITT population separately. Inpatient hospital admission data will be 
collected through transformation to AML (patients with HR 
MDS/CMML patients) or disease progression (patients with low-blast 
AML patients) or until initiation of subsequent therapy (all patients), 
whichever occurs first.
The number and percentage of patients who have any hospitalizations 
related to HR MDS, CMML, or AML will be summarized by treatment 
group. The absolute rate difference will be provided with its 70% and
95% CI.
Time to PD, Relapse, or Death
Analysis of time to PD, relapse, or death will be based on patients with 
HR MDS/CMML and the ITT population separately.
Time to PD, relapse, or death is defined as the time from randomization 
until disease progression, or relapse, or death due to any cause, 
whichever occurs first. Stratified Unstratified log-rank test will be used 
for comparison between the 2 arms. The hazard ratios along with the 
2-sided 70% and 95% CIs will be estimated using the unadjusted 
stratified unstratified Cox model. The Kaplan-Meier survival curves and 
Kaplan-Meier medians (if estimable), along with the 70% and 95% CIs, 
will also be provided for each treatment group.
Rationale for Change: Clarify the definitions of CR and composite CR (CR plus CRi) in 
patients with low-blast AML, provide data on both HR MDS/CMML and the ITT 
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populations, and update the analyses accordingly.
Change 14: Clarify populations for analyses of health-related quality of life.
Primary change occurs in 8.1.7 Analyses of Health-related Quality of Life
Initial 
wording:
Analyses of HRQOL data for EORTC-QLQ-C30 and EQ-5D-5L will be 
performed using the ITT population; and for QOL-E data, the American 
English-speaking US patient population only will be used.
Amended or 
new wording:
Analyses of HRQOL data for EORTC-QLQ-C30 and EQ-5D-5L will be 
performed using based on patients with HR MDS/CMML and the ITT 
population separately; and for QOL-E data, the American English-
speaking US patient population only will be used.
Rationale for Change: Clarification of populations for analyses.
Change 15: Specify 
 
Primary change occurs in Section 8.1.8 Pharmacokinetics/Pharmacodynamics/Biomarkers
Initial 
wording:
Amended or 
new wording
CCI
CCI
CCI
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an
an
5L will
wi
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Rationale for Change: 
 
Change 16: Delete the exclusion of CYP3A inhibitors from the concomitant medicines 
table during administration of pevonedistat therapy.
Primary change occurs in Section 15.6 Excluded CYP3A Inducers
Initial 
wording:
15.6
Excluded CYP3A Inhibitors and Inducers
Use of strong CYP3A inhibitors or inducers listed in Table 15.a should 
be avoided during pevonedistat therapy. Note that HIV medications that 
are strong CYP3A inhibitors or inducers are not included in this list 
because HIV-positive patients are excluded from study participation.
CCI
CCI
Property of Takeda: For non-commercial use only
CYP3A
CYP3
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Excl
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and subject to the applicable Terms of
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Table 15.a
In Vivo Inhibitors or Inducers of CYP3A
Strong Inhibitors
(5-fold increase in AUC)
Clarithromycin
Itraconazole
Ketoconazole
Nefazodone
Voriconazolea
Posaconazole
Telithromycin
Conivaptan
Strong Inducers
(≥80% decrease in AUC)
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Rifabutin
Rifampin
Rifapentine
St. John’s wort
  
a Permitted only if the patient’s clinical condition requires the use of an azole 
antifungal agent. The patient may receive voriconazole 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), Friday (Day 5) 
schedule, then voriconazole 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.
Amended or 
new wording:
15.6
Excluded CYP3A Inhibitors and Inducers 
Use of strong CYP3A inhibitors or inducers listed in Table 15.a should 
be avoided during pevonedistat therapy. Note that HIV medications that 
are strong CYP3A inhibitors or inducers are not included in this list 
because HIV-positive patients are excluded from study participation.
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Table 15.a
In Vivo Inhibitors or Inducers of CYP3A
Strong Inhibitors
(5-fold increase in AUC)
Clarithromycin
Itraconazole
Ketoconazole
Nefazodone
Voriconazolea
Posaconazole
Telithromycin
Conivaptan
Strong Inducers
(≥80% decrease in AUC)
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Rifabutin
Rifampin
Rifapentine
St. John’s wort
  
a  Permitted only if the patient’s clinical condition requires the use of an azole 
antifungal agent. The patient may receive voriconazole 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), Friday (Day 5) 
schedule, then voriconazole 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.
Rationale for Change: To reflect recent data that indicates moderate or strong CYP3A 
inhibitors do not affect pevonedistat exposures.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety 
of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients with Higher-Risk 
Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute 
Myelogenous Leukemia
NCT Number: NCT02610777
SAP Approve Date: 06 August 2019 
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Pevonedistat-2001
A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of 
Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients with Higher-Risk 
Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute 
Myelogenous Leukemia
PHASE 2
Version: Amendment 01
Date: 06 August 2019 
Prepared by:
Based on:
Protocol Version: Amendment 04
Protocol Date: 27 July 2018
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
the Effi
the E
in Patie
in Pati
ukemia,
ukemia
mendm
mendm
06 Aug
06 Au
Protoco
otoc
Prot
Pro
n-com
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Statistical Analysis Plan Amendment 01
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1.1
Approval Signatures
Study Title:
A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the 
Efficacy and Safety of Pevonedistat Plus Azacitidine Versus Single-Agent 
Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes, 
Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myelogenous 
Leukemia
Date
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ent t 
s, 
s, 
genous
genous
he applicable
subject to th


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Statistical Analysis Plan Amendment 01
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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Exploratory Objectives ..............................................................................................9
4.4
Study Design ...........................................................................................................10
5.0
ANALYSIS ENDPOINTS.............................................................................................13
5.1.1
Primary Endpoints .............................................................................................13
5.1.2
Secondary Endpoint ...........................................................................................13
5.1.3
Exploratory Endpoints .......................................................................................14
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................15
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................16
7.1
General Principles....................................................................................................16
7.1.1
Blinding and Unblinding....................................................................................16
7.1.2
Randomization and Stratification .......................................................................16
7.1.3
Definition of Study Days....................................................................................16
7.1.4
Definition of Study Visit Windows ....................................................................16
7.1.5
Conventions for Missing dates in Adverse Event................................................16
7.1.6
Conventions for Missing Concomitant Medication/ Subsequent Therapies 
Dates..................................................................................................................17
7.1.7
Missing/Partial Dates in Screening Visit ............................................................18
7.1.7
Definition of Baseline Values.............................................................................18
7.2
Analysis Sets ...........................................................................................................18
7.2.1
Intent-to-Treat Population ..................................................................................18
7.2.2
Safety Population...............................................................................................19
7.2.3
Response-evaluable Population..........................................................................19
7.3
Disposition of Subjects ............................................................................................19
7.4
Demographic and Other Baseline Characteristics.....................................................20
7.4.1
Demographics....................................................................................................20
7.4.2
Inclusion/Exclusion Criteria...............................................................................20
7.4.3
Baseline Disease Status......................................................................................20
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Statistical Analysis Plan Amendment 01
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7.5
Medical History and Concurrent Medical Conditions...............................................21
7.6
Medication History..................................................................................................21
7.7
Concomitant Medications ........................................................................................22
7.8
Study Drug Exposure and Compliance.....................................................................22
7.8.1
Extent of Exposure.............................................................................................22
7.8.2
Treatment Compliance and Modifications..........................................................23
7.8.3
Duration of Follow-up........................................................................................24
7.9
Efficacy Analysis.....................................................................................................24
7.9.1
Primary Efficacy Endpoints ...............................................................................24
7.9.2
Secondary Efficacy Endpoint .............................................................................26
7.9.3
Additional Efficacy Endpoint(s).........................................................................32
7.10
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................32
7.10.1 Pharmacokinetic Analysis ..................................................................................32
7.10.2 Pharmacodynamic Analysis ...............................................................................32
7.11
Other Outcomes.......................................................................................................32
7.11.1 Patient-Reported Outcomes (PROs) ...................................................................33
7.11.2 Health Economics (Health Care Resource Use)..................................................35
7.11.3
..........................................................................................................35
7.12
Safety Analysis........................................................................................................36
7.12.1 Adverse Events ..................................................................................................36
7.12.2 Clinical Laboratory Evaluations .........................................................................41
7.12.3 60-day Mortality ................................................................................................44
7.12.4 Vital Signs .........................................................................................................44
7.12.5 12-Lead ECGs ...................................................................................................44
7.12.6 Other Observations Related to Safety.................................................................45
7.12.7 Protocol Deviations............................................................................................45
7.13
Interim Analysis ......................................................................................................45
7.14
Changes in the Statistical Analysis Plan...................................................................45
8.0
REFERENCES..............................................................................................................47
LIST OF IN-TEXT TABLES
Table 7.a
List of Subgroups...............................................................................................26
Table 7.b
Handling of Missing Assessments and Censoring for HR MDS/CMML 
Patients for EFS Key Analysis Based on The FDA Rules...................................27
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
22
......
......22
22
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Statistical Analysis Plan Amendment 01
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Table 7.c
Handling of Missing Assessments and Censoring for HR MDS/CMML 
Patients for EFS Sensitivity Analysis Based on The EMA Rules........................28
Table 7.d
Description of EORTC QLQ-C30 domain scores...............................................33
Table 7.e
Description of Subscale Scores of QOL-E..........................................................34
Table 7.f
Selected Labs.....................................................................................................42
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Statistical Analysis Plan Amendment 01
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3.0
LIST OF ABBREVIATIONS
Abbreviation
Term
AE
adverse event
AML
acute myelogenous leukemia
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CMML
chronic myelomonocytic leukemia
CR
complete remission
DOR
duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EFS
event-free survival
ELN
European LeukemiaNet
EORTC
European Organization for Research and Treatment of 
Cancer 
EOT
End of Treatment (visit)
EQ-5D
EuroQol 5-Dimensional Health Questionnaire
FA
final analysis
HRMDS
higher-risk myelodysplastic syndromes
HU
health utilization
IA
interim analysis
IB
Investigator’s Brochure
IDMC
independent data monitoring committee
IPSS-R
Revised International Prognostic Scoring System
ITT
intent-to-treat
IV
intravenous; intravenously
IVRS
interactive voice response system
K-M
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
ORR
overall response rate
OS
overall survival
PD
progressive disease (disease progression)
PK
pharmacokinetic(s)
PR
partial remission
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Page 7 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
Abbreviation
Term
PRO
patient-reported outcome
PSMB1
Proteasome subunit beta type-1
QLQ
Quality of Life Questionnaire (EORTC)
Abbreviation
Term
QTc
rate-corrected QT interval (millisec) of 
electrocardiograph
SAE
serious adverse event
SAP
statistical analysis plan
SC
Subcutaneous
SD
stable disease
SMQs
Standardised MedDRA Queries
SQ
Subcutaneous
TEAE
treatment-emergent adverse event
US
United States
WBC
white blood cell
WHO
World Health Organization
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Page 8 of 47
Statistical Analysis Plan Amendment 01
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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objectives are:

To determine in patients with HR MDS or CMML, and low-blast AML whether the 
combination of pevonedistat and azacitidine improves overall survival (OS) when compared 
with single-agent azacitidine.
4.2
Secondary Objectives
The secondary objectives are:

To determine in patients with HR MDS or CMML, and low-blast AML whether the 
combination of pevonedistat and azacitidine improves event-free survival (EFS) when 
compared with single-agent azacitidine; for patients with HR MDS or CMML, an event is 
defined as death or transformation to AML; for patients with low-blast AML, an event is 
defined as death.

To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine improves 6-month and 1-year survival rates 
when compared with single-agent azacitidine.

To determine in patients with HR MDS or CMML whether the combination of pevonedistat 
and azacitidine delays time to AML transformation when compared with single-agent 
azacitidine.

To determine in patients with HR MDS or CMML, and low-blast AML whether the 
combination of pevonedistat and azacitidine, when compared to single-agent azacitidine, 
improves the rate of complete remission (CR) (composite CR [CR+ CRi] in patients with 
low-blast AML), CR plus partial remission ((composite CR + PR for patients with low-blast 
AML), overall response, and/or CR (not including CRi) in low-blast AML. Overall response 
in HR MDS or CMML is defined as CR+PR+hematologic improvement [HI]; overall 
response in low-blast AML is defined as CR+CRi +PR.

To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine, when compared with single-agent azacitidine, 
improves the rate of CR (composite CR [CR+ CRi] in patients with low-blast AML), CR + 
PR (composite CR + PR in patients with low-blast AML), overall response, as well as CR 
(not including CRi) in low-blast AML by Cycle 4.

To determine in patients with HR MDS or CMML, and low-blast AML whether the 
combination of pevonedistat and azacitidine, when compared with single-agent azacitidine, 
improves duration of CR (composite CR [CR+ CRi] in patients with low-blast AML), CR + 
PR (composite CR + PR in patients with low-blast AML), overall response, and/or CR (not 
including CRi) in patients with low-blast AML.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


P2001
Page 9 of 47
Statistical Analysis Plan Amendment 01
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!
To determine in patients with HR MDS or CMML, and low-blast AML whether the 
combination of pevonedistat and azacitidine improves time to first CR (CR for HR 
MDS/CMML and low-blast AML; CR + CRi [composite CR] for low-blast AML), or PR 
when compared with single-agent azacitidine.
!
To determine in patients with HR MDS or CMML, and low-blast AML whether the 
combination of pevonedistat and azacitidine delays time to subsequent therapy when 
compared with single-agent azacitidine. Subsequent therapy is defined as agent(s) with 
antileukemic/anti-MDS activity (eg, cytarabine, anthracyclines, purine analogues, and 
hypomethylating agents other than azacitidine). Patients who discontinue study treatment to 
receive single-agent azacitidine off study would not be counted as receiving subsequent 
therapy.
!
To determine in patients with HR MDS or CMML, and low-blast AML whether the 
combination of pevonedistat and azacitidine improves rate of transfusion independence when 
compared with single-agent azacitidine. RBC or platelet transfusion independence requires 
that the patient, receive no RBC or platelet transfusions, respectively, for a period of at least 
8 weeks. 
!
To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine reduces the percent of patients who have at least 
one inpatient hospital admission(s) related to HR MDS or CMML, or low-blast AML when 
compared with single-agent azacitidine.
!
To determine in patients with HR MDS or CMML and low-blast AML whether the 
combination of pevonedistat and azacitidine delays time to PD, relapse after CR or PR (HR 
MDS/CMML) or CR (low-blast AML), or death when compared to single-agent azacitidine.
!
To evaluate in patients with HR MDS or CMML and low-blast AML, the safety of the 
combination of pevonedistat and azacitidine when compared with single-agent azacitidine.
!
To collect in patients with HR MDS or CMML, and low-blast AML, plasma concentration-
time data for pevonedistat to contribute to future population PK analyses of pevonedistat.
4.3
Exploratory Objectives
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Page 10 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
4.4
Study Design
This study is a multicenter, global, randomized, controlled, open-label, phase 2 clinical study of 
the combination of pevonedistat and azacitidine versus single-agent azacytidine administered in 
patients with HR MDS or CMML and low-blast AML who have not previously received a 
hypomethylating agent. Patients with nonproliferative CMML (ie, white blood cell [WBC] 
<20,000/μL) are included because these patients were also included in both randomized studies 
of azacitidine conducted in the US and the European Union with similar response rates to 
patients with MDS.
General eligibility may be assessed prior to the formal Screening period if it is part of standard 
clinical practice. However, per the Schedule of Events, formal screening will occur during the 
Screening period, which may last up to 28 days prior to randomization. The sponsor’s project 
clinician (or designee) will confirm patient eligibility prior to randomization by the investigator.
It is expected that approximately 117 patients will be enrolled in this study. Once enrolled,
patients (MDS, CMML, and low-blast AML) will be randomized at a 1:1 ratio to receive study 
drug (either single-agent azacitidine or the combination of pevonedistat and azacitidine) in 
28-day treatment cycles. All patients will be stratified into 4 categories: low-blast AML, IPSS-R 
risk groups of very high, high, or intermediate for MDS/CMML. Note that patients with HR 
MDS/CMML with indeterminate cytogenetics findings at Screening should be assigned a 
cytogenetics prognostic variable of 2 points, ie, intermediate, for determining overall Prognostic 
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P2001
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Statistical Analysis Plan Amendment 01
06 August 2019
Risk Category/Score. All patients will receive azacitidine (75 mg/m2 [IV or SC]) on Days 1 
through 5, Day 8, and Day 9. Patients randomized to the combination arm will also receive 
pevonedistat (20 mg/m2 via 60 ([±10]-minute infusion) on Days 1, 3, and 5. Modifications to the 
dose and schedule may be allowed as detailed in the Schedule of Events.
Patients, including those who achieve a CR, may receive study treatment until they experience 
unacceptable toxicity, relapse, transformation to AML, or PD. Patients with HR MDS or CMML 
may be allowed to continue study treatment (either treatment arm) if they meet the criteria for 
progressive disease based only on bone marrow blast count (without AML transformation) if, in 
the clinical judgment of the investigator, the patient is still receiving clinical benefit from this
treatment and the continuation is endorsed by the sponsor’s project clinician (or designee). 
Patients with low-blast AML in this study may also be allowed to continue study treatment 
(either treatment arm), even if they meet the criteria for progressive disease based only on bone 
marrow blast counts, if, in the clinical judgment of the investigator, the patient is still receiving 
clinical benefit from this treatment and the continuation is endorsed by the sponsor’s project 
clinician (or designee). Patients who meet the criteria for PD and continue on study under these 
conditions must be reconsented before continuing study treatment. Patients may choose to 
discontinue therapy at any time.
Patients will attend the End-of-Treatment (EOT) visit 30 days (+10 days) after the last dose of 
study drug or before the start of subsequent antineoplastic therapy if that occurs sooner. After the 
EOT visit, patients will enter EFS follow-up (for patients with HR MDS or CMML) or response 
follow-up (for patients with low-blast AML), with study visits every 3 months, to include 
physical exam, clinical blood tests, HRQOL assessments, hospitalization assessment, bone 
marrow aspirate sampling, and disease assessment, if their disease has not transformed to AML 
(for patients with HR MDS or CMML) or progressed (for patients with low-blast AML), and 
they have not started subsequent therapy. Patients will enter OS follow-up (contacted every 
3 months to document subsequent therapies and survival status) when they have confirmed 
transformation to AML (for patients with HR MDS or CMML) or experienced progressive 
disease (for patients with low-blast AML) or have started subsequent therapy.
Disease response assessments for all patients with HR MDS or CMML will be based on the
Modified International Working Group (IWG) response criteria for MDS. Disease response 
assessments for patients with low-blast AML will be based on the Revised Recommendations of 
the IWG for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Formal disease 
assessments for study endpoints will be determined based on local bone marrow aspirate blast 
counts and transfusions, and central lab data (local lab data may be used for time-sensitive 
clinical decisions).
Inpatient hospital admissions related to HR MDS or CMML or low-blast AML, as well as
transfusion independence, will be monitored as secondary efficacy endpoints. RBC- and
platelet-transfusion independence requires that the patient receive no RBC or platelet
transfusions, respectively, for a period of at least 8 weeks. Treatment-emergent resistance will 
also be monitored.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Page 12 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
A bone marrow aspirate and biopsy will be collected at Screening, and bone marrow aspirates 
will be collected during treatment and follow-up for blast count evaluation (to inform disease 
burden assessment). Bone marrow aspirates obtained at time points described in the Bone 
Marrow Collection and Assessment Schedule will also be used 
 
 
 
 
Sparse sampling for the determination of pevonedistat plasma concentrations and, if appropriate, 
its metabolites will be collected from each patient in the Combination Pevonedistat Plus 
Azacitidine Arm to contribute to a population PK analysis of pevonedistat co-administered with 
azacitidine.
Adverse events and ECOG performance status will be assessed, and ECGs, clinical laboratory 
values, and vital signs will be obtained, to evaluate the safety and tolerability of the study drug 
treatments. 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. Dose modification guidelines are presented in Section 6.3 in the protocol.
 
CCI
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Statistical Analysis Plan Amendment 01
06 August 2019
5.0
ANALYSIS ENDPOINTS
5.1.1
Primary Endpoints
OS is the primary endpoint.
5.1.2
Secondary Endpoint
The secondary endpoints are:

EFS: for patients with HR MDS or CMML, an event is defined as death or transformation to 
AML; for patients with low-blast AML, an event is defined as death.

Six-month and 1-year survival rates.
–
Time to AML transformation in patients with HR MDS or CMML.

CR (CR for HR MDS and CMML; CR + CRi [composite CR] for low-blast AML), CR (CR 
for HR MDS and CMML; CR + CRi for low-blast AML) + PR, overall response (CR + PR + 
HI for HR MDS and CMML; CR + CRi + PR for low-blast AML), CR (not including CRi) in 
low-blast AML.

CR (CR for HR MDS and CMML; CR + CRi [composite CR] for low-blast AML), CR (CR 
for HR MDS and CMML; CR + CRi for low-blast AML) + PR, overall response (CR + PR + 
HI for HR MDS and CMML; CR + CRi + PR for low-blast AML) by Cycle 4, CR (not 
including CRi) in low-blast AML by Cycle 4.

Duration of CR (CR for HR MDS and CMML, CR + CRi [composite CR] for low-blast 
AML), CR (CR for HR MDS and CMML; CR + CRi for low-blast AML) + PR, overall 
response (CR + PR + HI for HR MDS and CMML; CR + CRi + PR for low-blast AML), and 
duration of CR (not including CRi) in low-blast AML.

Time to first CR (CR for HR MDS/CMML and low-blast AML; CR + CRi [composite CR] 
for low-blast AML) or PR for HR MDS/CMML and low-blast AML.

Time to subsequent therapy.

RBCs and platelet-transfusion independence.

Percentage of patients with at least 1 inpatient hospital admissions related to HR MDS or 
CMML (collected through transformation to AML or until initiation of subsequent therapy, 
whichever occurs first) or low-blast AML (collected through AML progression or until 
initiation of subsequent therapy, whichever occurs first).

Time to PD, relapse, or death.

AEs and serious adverse events (SAEs), abnormal clinical laboratory values, Eastern 
Cooperative Oncology Group (ECOG) performance status, ECGs, and vital sign 
measurements.
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P2001
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Statistical Analysis Plan Amendment 01
06 August 2019
5.1.3
Exploratory Endpoints 
CCI
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mmercial use only and subject to the applicable Terms of


P2001
Page 15 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
6.0
DETERMINATION OF SAMPLE SIZE
Approximately 117 patients will be randomized in a 1:1 ratio to receive either the combination of 
pevonedistat and azacitidine or single-agent azacitidine.
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P2001
Page 16 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
In general, 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 percentage (of nonmissing) per category for categorical data, unless specified otherwise.
7.1.1
Blinding and Unblinding
This is an open-label study; investigators and patients will know the individual treatment
assignments. 
7.1.2
Randomization and Stratification 
The randomization scheme will be generated by an independent statistician at Millennium who is 
not on the study team. Before dosing, a randomization number will be assigned to each patient.
The randomization assignment will be implemented by an interactive web-based response 
system (IWRS).
Patients will be randomized to receive the combination of pevonedistat and azacitidine or
azacitidine alone in a 1:1 ratio, stratified into 4 categories: low-blast AML, IPSS-R risk groups 
of very high, high, or intermediate for HR MDS/CMML [1]. (
7.1.3
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
7.1.4
Definition of Study Visit Windows
All data will be categorized based on the scheduled visit at which they were collected. These 
visit designators are predefined values that appear as part of the visit tab in the electronic case 
report form (eCRF). The analysis of PK data will be based on the actual elapsed time post dose.
7.1.5
Conventions for Missing dates in Adverse Event 
Every effort will be made to avoid missing/partial dates in on-study data. 
Adverse events with stop dates that are completely or partially missing will be imputed as 
follows:
!
If the stop date has a month and year but the day is missing, the last day of the month will be 
imputed.
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P2001
Page 17 of 47
Statistical Analysis Plan Amendment 01
06 August 2019

If the stop date has a year but the day and month are missing, the 31st of December will be 
imputed.
After the imputation, the imputed dates will be compared against the date of death, if available. 
If the date is later than the date of death, the date of death will be used as the imputed date 
instead.
Adverse events with start dates that are completely or partially missing will be imputed as 
follows:

If the start date has a month and year but the day is missing, the first day of the month will be 
imputed.
–
If this date is earlier than the first dose date, then the first dose date will be used instead.
–
If this date is later than the stop date (possibly imputed), then the stop date will be used 
instead.

If the start date has a year, but the day and month are missing, the 15th of June will be 
imputed.
–
If this date is earlier than the first dose date, then the first dose date will be used instead.
–
If this date is later than the stop date (possibly imputed), then the stop date will be used 
instead.

If the start date of an event is completely missing, then it is imputed with the first dose date.
7.1.6
Conventions for Missing Concomitant Medication/ Subsequent Therapies Dates
Concomitant therapies with start dates that are completely or partially missing will be analyzed 
as follows:

If the start date has a month and year but the day is missing, the therapy will be included in 
the summary table if the month and year of the start date of the event are: 
–
On or after the month and year of the date of the first dose of study drug.
and 
–
On or before the month and year of the date of the last dose of study drug plus 30 days.
a) If the start date has the year but the day and month are missing, the therapy will be included 
in the summary table if the year of the start date of the event is:
–
On or after the year of the date of the first dose of study drug.
and 
–
On or before the year of the date of the last dose of study drug plus 30 days.
If the start date of an event is completely missing, then the therapy will be included in the 
summary table.
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P2001
Page 18 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
Subsequent therapies with start dates that are completely or partially missing will be analyzed as 
follows:

When the month and year are present but the day is missing:
–
If the onset month and year are the same as the month and year of the last dose of study 
drug, the day of the last dose + 1 will be imputed.
–
If the onset month and year are not the same as the month and year of the last dose of 
study drug, the first day of the month is imputed. 

When only a year is present:
–
If the onset year is the same as the year of the last dose of study drug, the date of last dose 
+ 1 will be imputed.
–
If the onset year is not the same as the year of the last dose of study drug, the first day of 
the year is imputed. 

If no components of the onset date are present, the date of the last dose of study drug + 1 will 
be imputed.
7.1.7
Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded in the Screening visits: 

If only the day component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of study drug; otherwise, the 15th will be 
used. 

If only a year is present, and it is the same as the year of the first dose of study drug, the 15th 
of January will be used unless it is later than the first dose, in which case the date of the first 
of January will be used, unless other data indicate that the date is earlier.

If only a year is present, and it is not the same as the year of the first dose of study drug, the 
15th of June will be used, unless other data indicate that the date is earlier. 
7.1.7
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 screening value. 
7.2
Analysis Sets
7.2.1
Intent-to-Treat Population
The Intent-to-Treat (ITT) population is defined as all patients who are randomized. Patients will 
be analyzed according to the treatment they were randomized to receive, regardless of any errors 
of dosing. 
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P2001
Page 19 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
The ITT population will be used for the primary and secondary efficacy analyses, and resource 
utilization and patient-reported outcome analysis. 
7.2.2
Safety Population
The safety population is defined as all patients who receive at least 1 dose of pevonedistat plus 
azacitidine or azacitidine alone. Patients will be analyzed according to the actual treatment they 
received. That is, those patients who are randomized to Arm B but received the regimen in Arm 
A will be included in Arm A; those patients who are randomized to Arm A but received the 
regimen in Arm B will be included in Arm B for safety analyses. Patients who received any dose 
of pevonedistat will be included in the combination pevonedistat plus azacitidine arm, and 
patients who did not receive any dose of pevonedistat and received at least 1 dose of azacitidine 
will be included in the single-agent azacitidine arm, regardless of their randomized treatment.
The safety population will be used for all safety-related analyses such as AEs, concomitant 
medications, laboratory tests, and vital signs.
7.2.3
Response-evaluable Population
The response-evaluable population is defined as patients who receive at least 1 dose of study 
drug, have a disease assessment at baseline, and at least 1 postbaseline disease assessment.
The response evaluable population will be used for the analyses of response rates, and time to 
response. The response-evaluable patients must have disease assessment at baseline, which is 
defined by:
!
 
7.3
Disposition of Subjects
Patient disposition includes the number and percentage of patients for the following categories: 
patients randomized, patients in each of the study populations, patients discontinued from 
treatment, primary reason for discontinuation from treatment, patients discontinued from the 
study, primary reason for discontinuation from the study, and completion of study. All 
percentages will be based on the number of patients in the ITT population or the subset of 
patients with HR MDS/CMML, HR MDS and CMML separately. 
Patients will be considered to have completed the study if they are followed until death or until 
the sponsor terminates the study.
Disposition will be generated for the ITT population, patients with HR MDS/CMML, HR MDS 
and CMML separately.
A listing will present data concerning patient disposition.
The stratification strata at randomization is based on the disease diagnose at screening, for the 
patients whose disease diagnose were changed after screening and before randomization, a 
listing will be provided. 
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P2001
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Statistical Analysis Plan Amendment 01
06 August 2019
7.4
Demographic and Other Baseline Characteristics
7.4.1
Demographics
Baseline demographics will be summarized for the ITT population, patients with HR 
MDS/CMML, patients with HR MDS and CMMLseparately. Baseline demographic data to be 
evaluated will include age at date of informed consent, sex, ethnicity, race, height, weight, body 
surface area (BSA), and other parameters as appropriate. 
Patient enrollment by region and country will also be summarized by treatment arms.
BSA is calculated using the following formula based on the patient’s height and weight collected 
at baseline. If a weight at Cycle 1 Day 1 pre-dose is not available, the screening weight can be 
used.
BSA = 
No inferential statistics will be generated.
Demographic data will also be presented in a by-patient listing.
7.4.2
Inclusion/Exclusion Criteria
All inclusion/exclusion information on enrolled patients will be included in a by-patient listing 
for the ITT patients, patients with HR MDS/CMML, and patients with HR MDS separately. 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.
7.4.3
Baseline Disease Status
Analysis on baseline disease characteristics will be performed for the ITT patients, patients with 
HR MDS/CMML, and patients with HR MDS separately.
Baseline disease characteristics (HR MDS/CMML, HR MDS, CMML : disease type of de novo 
or secondary, disease subtype if secondary, French-American-British (FAB) category, WHO 
classification of tumors, Modified Charlson Comorbidity Index, and IPSS-R category; low-blast 
AML: disease type of de novo or secondary, disease subtype if secondary, revised WHO 
classification of AML, evidence of extramedullary disease; HR MDS/CMML, HR MDS, 
CMML, AML: months from initial diagnosis) and ECOG performance status will be 
summarized for all patients by treatment arm. Separate by-patient listings will also be presented 
for baseline disease characteristics and ECOG performance status. 
HR MDS/CMML patients, HR MDS patients, CMML patients will be classified into 3 categories 
based on the IPSS-R score: intermediate, high, very high. 
Separate tables for HR MDS/CMML patients, HR MDS patients, CMML patients and low-blast 
AML patients will summarize the numbers and percentages of patients who had prior therapy, 
prior radiation (including the total lifetime dose of radiation received and months from last prior 
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P2001
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Statistical Analysis Plan Amendment 01
06 August 2019
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. Separate by-
patient listings will also be presented for prior therapies, prior radiation, prior surgery, and prior 
transplants. 
Months from diagnosis to the randomization date for each treatment is calculated by: 
randomization date - date of diagnosis 
365.25/12
Distribution of stratification factor will also be summarized. 
A listing will be generated for patients who receive hydroxycarbamide (hydroxyurea) at 
enrollment, which includes screening WBC and screening bone marrow aspirate myeloblasts.
7.5
Medical History and Concurrent Medical Conditions
General medical history and prior medications will be listed for all patients.
7.6
Medication History 
General medical history and prior medications will be listed for the ITT patients, patients with 
HR MDS/CMML and HR MDS separately.
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P2001
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Statistical Analysis Plan Amendment 01
06 August 2019
7.7
Concomitant Medications
Analysis on concomitant medications will be performed for the ITT patients, patients with HR 
MDS/CMML, and patients with HR MDS separately.
Concomitant medications will be coded by Preferred Term using the World Health Organization 
(WHO) Drug Dictionary. The number and percentage of patients taking concomitant medications 
from the first dose through the end of the on-treatment period will be tabulated by Anatomical 
Therapeutic Chemical (ATC) classification pharmacological subgroup and WHO drug generic 
term for each treatment arm in the Safety population. A by-patient listing will also be presented 
for concomitant medications.
Concomitant procedures will not be coded but will be presented in a data listing for the Safety 
population.
7.8
Study Drug Exposure and Compliance
Analysis on extent of exposure will be performed for the ITT patient, patients with HR 
MDS/CMML, and patients with HR MDS separately.
7.8.1
Extent of Exposure
Pevonedistat
An overall summary of drug exposure for pevonedistat will be presented, including the number 
of cycles, the mean number of doses per cycle, and the distribution of the number of cycles 
(numbers and percentages of patients who are treated for at least 1 cycle, 2 cycles, 3 cycles, …), 
for the treatment arm of pevonedistat plus azacitidine in the safety population. 
Patients will be considered to have been treated for a cycle if they receive at least one dose of 
pevonedistat during the 28 days of that cycle.
The mean number of doses per cycle will be calculated for each patient and then summarized for 
the treatment arm of pevonedistat plus azacitidine in the safety population. 
Dosing intensity will be summarized for the treatment arm of pevonedistat plus azacitidine in the 
safety population. Percent Dosing Intensity will be calculated using the following equations for 
Daily Expected Dose (mg), Daily Prepared Dose (mg), and Daily Dose Received (mg): 
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 on Cycle 1, Day 1, and at subsequent visits if 
the patient experiences a >5% change in body weight from the weight used for the most recent 
BSA calculation. 
)
Volume
Prepared
(mL)
infused
actually 
bag
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of
Volume
(
*
Dose
Prepared
Daily 
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Area
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*
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Level
Dose
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Dose
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


P2001
Page 23 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
Total Dose Received, Total Dose Expected, and Dosing Intensity for pevonedistat will be based 
on the following formulas: 
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 for the treatment arm of 
pevonedistat plus azacitidine.
Azacitidine
For azacitidine dosing, the percentage of all doses that were administered IV or SC will be 
summarized by treatment arm. The extent of exposure will be summarized by treatment arm in a 
similar manner as pevonedistat. 
Daily Expected Dose, Daily Prepared Dose for Aza IV, Daily Dose Received for Aza IV, Daily 
Dose Received for Aza SC, Total Dose Received, Total Dose Expected, and Dosing Intensity for 
azacitidine will be based on the following formulas: 
Dosing intensity for azacitidine will be summarized by treatment arm in a similar manner to 
pevonedistat dosing intensity. 
Dosing data will also be presented in by-patient listings.
7.8.2
Treatment Compliance and Modifications
The actions on study drugs will be summarized by treatment arm in the safety population. Data 
will be summarized for Cycle 1 only as well as all cycles. A patient will count only once for each 
type of action.
Analysis on treatment compliance and modifications will be performed for the ITT patients, 
patients with HR MDS/CMML, and patients with HR MDS separately.
100
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Dose
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Percent 
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Dose
Total
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Dose
Total
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Dosing
Percent 
cycles
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Expected
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Total
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Dose
Actual
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Sum
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Dose
Total
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Dose
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SC)
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Volume
Prepared
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
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


P2001
Page 24 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
7.8.3
Duration of Follow-up
The duration of follow-up is defined as time from randomization to the date of death or last 
known visit. If a subject die, the duration will equal the date of death minus the date of study 
start + 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 study start + 1, 
with a censor variable = 0 (event for follow-up). 
Analysis on duration of follow-up will be performed for the ITT population, patients with HR 
MDS/CMML, and patients with HR MDS separately.
7.9
Efficacy Analysis
All efficacy evaluations will be conducted for the ITT patients, patients with HR MDS/CMML,
and patients with HR MDS separately. Analyses based on other subsets of patients will be 
specified when needed.
7.9.1
Primary Efficacy Endpoints
OS is the primary endpoint. Analysis on OS will be presented for ITT patients, HR MDS/CMML 
patients, HR MDS patients and CMML patients separately. OS also will be assessed separately 
in patients with LB AML.
Primary Analysis
OS will be analyzed and tested at the final analysis when approximately 60% of patients with HR 
MDS/CMML have experienced OS events, or termination of the study by the sponsor. 
OS will be calculated from date of randomization to the date of death due to any cause. Patients 
without documented death at the time of the analysis will be censored at the date that the patient 
was last known to be alive. Unstratified log-rank test will be used to compare OS between the 
2 treatment arms. Hazard ratios, along with the 2-sided 95% CIs will be estimated using the 
unadjusted unstratified Cox models. Kaplan-Meier curves, Kaplan-Meier medians (if estimable), 
and survival probability at 6 months and 1 year, together with the 95% CIs, will be calculated for 
each treatment group.
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P2001
Page 25 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
In addition, an unstratified Cox regression model will be used to further evaluate the treatment 
effects on OS after adjusting for some prognostic factors. Besides treatment, the following 
prognostic factors will be included in the model simultaneously: age (<65, 65-74, >=75), de novo 
versus secondary, disease risk group (IPSS-R risk categories for HR MDS/CMML: very high, 
high, intermediate;
 
Additional exploratory analyses may be performed if deemed 
necessary. 
Sensitivity Analysis
To adjust for the potential confounding effects of post-treatment transplantation after patients
discontinued study treatment, unstratified log-rank tests and unstratified Cox model will be 
applied to OS with censoring at the start of post-treatment transplantation.
To adjust for the potential confounding effects of subsequent therapies after patients discontinue 
study treatment, the following 2 methods will be used:
1. Marginal Structural Models (MSMs) by Robins et al., 2000.
2. Inverse Probability of Censoring Weighted (IPCW) method by Robins and Finkelstein, 2009.
In the MSM and IPCW analyses, in order to derive weights adjusting for the time-fixed and 
time-varying confounding effects due to taking alternative therapies, the covariates that affect 
disease progression and post-progression treatment, and the OS endpoint will be used. Baseline 
covariates include region (North America (NA) vs ex NA), age (< 65 years, >=65 and 
<= 74 years, >= 75 years), race (white, non-white), ECOG score (0 or 1, 2), disease type 
(de novo or secondary, baseline peripheral WBC, baseline platelets, disease risk group (for 
AML, ELN 2017, adverse, intermediate, favorable, for HR MDS/CMML, IPSS-R, very high, 
high, intermediate). Time-varying covariates include duration of treatment exposure, disease 
progression status at each study visit, RBC Transfusion at each study visit, platelet transfusion at 
each study visit, indication of subsequent therapy (yes or no), additional therapy with 
transplantation. The final criteria for selected covariates would need to be statistically have a 
p-value of less than or equal to 0.1 in the multivariate Cox regression models for weight 
calculations, and in the final Cox model for OS. If there are more than 5% missing in the 
covariate, then this covariate will be dropped from the weighting calculation and final OS model. 
For both MSM and IPCW analyses, logistic regression models on repeated measurements will be 
used to approximate the Cox models in the weight derivations from which stabilized weights will 
be derived per subject per observation. Adjusted K-M curves will also be presented along with
hazard ratios (HRs), 95% confidence intervals for HRs, and adjusted p-values based on MSM 
and IPCW approaches. SAS proc PHREG procedure with counting process type of data input, 
which takes multiple observations per subject, will be used as the final Cox model for OS for 
both MSM and IPCW approaches. 
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Subgroup Analysis
Subgroup analyses will be performed for OS relative to baseline stratification factors, 
demographic data such as sex, race, and age, and disease characteristics such as de novo or 
secondary. The subgroup analysis for OS will be presented for ITT patients, HR MDS/CMML 
patients, HR MDS patients and CMML patients separately. 
The statistical model will be adjusted accordingly to fit the subgroup analyses. The details on 
subgroups are presented in the following:
Table 7.a
List of Subgroups
Subgroup
Definition of Group
Age
< 65 years, ≥65 and 74 years, ≥75 years
Sex
male vs female
Region
North America (NA) vs ex NA
IPSS-R risk category & low-blast AML 
very high, high, intermediate, or low-blast AML
Indication
HR MDS/CMML, HR MDS, CMML, or low-blast AML
Low-blast AML ELN risk
adverse, intermediate and favorable
ECOG performance status
0 or 1 vs 2
Disease type 
de novo, secondary
peripheral WBC
<15,000 per µL vs ≥15,000 per µL
Platelet
<100,000 vs ≥100,000 per µL
7.9.2
Secondary Efficacy Endpoint
Event-Free Survival (EFS)
EFS event is defined as death or transformation to AML for HR MDS/CMML patients, 
whichever occurs first, or defined as death for low-blast AML patients. EFS is defined as the 
time from the date of randomization to the date of the occurrence of an event.
Transformation to AML for HR MDS/CMML patients is defined according to WHO 
Classification [1]. 
For HR MDS/CMML patients, patients without documentation of transformation to AML will be 
censored at the date of the last response assessment. Stem cell transplantation (SCT) is not 
considered as alternate antineoplastic therapy. Following Cycle 4, bone marrow disease 
assessment will be performed only as clinically indicated at the suspicion of relapse in patients 
with HR MDS/CMML who achieve CR. Bone marrow disease assessment is not required to be 
regularly assessed after Cycle 4 for patients with HR MDS/CMML who achieve CR. Therefore, 
EFS event after more than 3 cycles or equivalent from the last disease assessment which is 
Cycle 4 or beyond for patients with HR MDS/CMML who achieve CR is considered as an event. 
HR MDS/CMML patients with no response assessment will be censored at the date of 
randomization.
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For low-blast AML patients, patients without documentation of death will be censored at the date 
that the patient was last known to be alive. 
The details regarding the handling of missing assessments and censoring for HR MDS/CMML 
patients for the EFS key analysis are based on the FDA rules and presented in Table 7.b.
Table 7.b
Handling of Missing Assessments and Censoring for HR MDS/CMML 
Patients for EFS Key Analysis Based on The FDA Rules
Situation
Date of Event or Censoring
Outcome
No baseline and/or no post baseline assessment, no subsequent 
anticancer therapy after study treatment, no death
Date of Randomization 
Censored
Transformation to AML documented between scheduled visits 
Date of documented transformation 
to AML
Event
No documented EFS event 
Date of last adequate assessmenta
Censored
Lost to follow-up, withdraw consent before any documented 
EFS event
Date of last adequate assessmenta
Censored 
EFS event after more than 1 missed visit (excluding HR 
MDS/CMML patients who achieve CR and last disease 
assessment is Cycle 4 or beyond prior to the EFS event) 
Date of last adequate assessmenta
Censored
EFS event after more than 1 missed visit from the last disease 
assessment which is Cycle 4 or beyond for HR MDS/CMML 
patients who achieve CR 
Date of documented EFS event
Event
Alternate antineoplastic therapy started prior to transformation to 
AML (excluding stem cell transplantation) 
Date of last adequate assessment 
prior to starting alternate 
antineoplastic therapy
Censored
Death before first assessment
Date of death
Event
Death between adequate assessment visits
Date of death
Event
a
Adequate disease assessment is defined as there is sufficient data to evaluate a patient’s disease status.
Key Analysis
Key analysis on EFS will be performed for the ITT patient, patients with HR MDS/CMML,
patients with HR MDS and patients with CMML separately.
Unstratified log-rank test will be used to compare EFS between the 2 treatment arms. 
Unstratified Cox models will be used to estimate the hazard ratio and its 2-sided 95% CIs for the 
treatment effect. The Kaplan Meier (K-M) survival curves and K-M medians (if estimable), 
along with their 2-sided 95% CIs, will also be provided for each treatment arm.
In addition, an unstratified Cox regression model will be used to further evaluate the treatment 
effects on EFS after adjusting for some prognostic factors. Besides treatment, the following 
prognostic factors will be included in the model simultaneously: age (<65, 65-74, ≥75), de novo 
versus secondary, disease risk group (IPSS-R risk categories for HR MDS/CMML: very high, 
high, intermediate; ELN 2017 cytogenetic risk categories for low-blast AML: adverse, 
intermediate, favorable), region (North America vs ex North America), baseline ECOG score 
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(0-1 vs 2), baseline peripheral WBC (<15,000 per µL vs ≥15,000 per µL), baseline platelet 
(<100,000 vs ≥100,000 per µL). Additional exploratory analyses may be performed if deemed 
necessary.
For patients with EFS events, the reasons leading to the determination of EFS will be tabulated. 
For patients without EFS events, the main reason for censoring will also be tabulated.
The proportional hazard assumptions will be examined and sensitivity analysis will be conducted 
if appropriate. 
Subgroup analyses will be performed using subgroups defined for OS analyses.
Sensitivity Analysis
EFS using different censoring mechanisms for patients with HR MDS/CMML will be analyzed, 
for example, not censoring for patients who discontinue treatment and go on alternative 
antineoplastic therapy. The details of the handling of missing assessments and censoring for 
patients with HR MDS/CMML based on the EMA rules for sensitivity analyses are presented in
Table 7.c. Sensitivity analyses for EFS based on the EMA rules will be performed based on the 
alterations of the handling of missing assessment and censoring in Table 7.c, on the basis of 
combined alterations, as well as 1 alteration at a time. 
Table 7.c
Handling of Missing Assessments and Censoring for HR MDS/CMML 
Patients for EFS Sensitivity Analysis Based on The EMA Rules
Situation
Date of Event or Censoring
Outcome
Alternate antineoplastic therapy started 
prior to transformation to AML 
Date of documented transformation to AML 
Event
EFS event after more than one missed visit
Date of documented EFS event 
Event
Additional sensitivity analyses for EFS using other censoring mechanisms for patients with HR 
MDS/CMML include:

SCT is considered as alternate antineoplastic therapy for patients with HR MDS/CMML, and 
patients with HR MDS/CMML who have SCT prior to transformation to AML will be 
censored at the date of last adequate assessment prior to starting SCT.

If HR MDS/CMML patients who achieve CR have EFS event after more than 1 missed visit 
from the last disease assessment which is Cycle 4 or beyond, these patients will be censored 
at the date of last adequate disease assessment.

Combine the above 2 scenarios: (1) SCT is considered as alternate antineoplastic therapy for 
patients with HR MDS/CMML, and patients with HR MDS/CMML who have SCT prior to 
transformation to AML will be censored at the date of last adequate assessment prior to 
starting SCT; (2) If HR MDS/CMML patients who achieve CR have EFS event after more 
than 1 missed visit from the last disease assessment which is Cycle 4 or beyond, these 
patients will be censored at the date of last adequate disease assessment.
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
If there is no documented EFS events, HR MDS/CMML patients with CR will be censored at 
the date of the last visit with hematological evaluation, or the date of last bone marrow 
disease assessment, whichever occurs later.
Six-Month and One-Year Survival Rate
Kaplan-Meier estimates and the 95% CIs of 6-month and 1-year survival rates will be provided 
by treatment arm based on the ITT population, patients with HR MDS/CMML, and patients with 
HR MDS.
Time to AML Transformation
Time to AML transformation is defined as time from randomization to documented AML 
transformation. This definition only applies to HR MDS and CMML patients, so this analysis 
will only be carried out in this subgroup of the ITT population and separately for HR MDS 
patients and CMML patients. Patients who died before progression to AML will be censored at 
the date of death. Patients without documented AML transformation at the time of the analysis 
will be censored at the date of the last assessment. Time to AML transformation is a time-to-
event variable, which will be analyzed using a similar method as OS.
CR (CR for HR MDS and CMML, CR + CRi [composite CR] for low-blast AML)/CR (CR for HR 
MDS and CMML, CR + CRi for low-blast AML)+PR/Overall Response (CR+PR+HI for HR 
MDS and CMML; CR+CRi+PR for low-blast AML)/ CR (not including CRi) in low-blast AML
Rate of CR/CR+PR (composite CR + PR for patients with low-blast AML)/overall response /CR 
(not including CRi) in low-blast AML respectively, are defined as the proportion of patients who 
achieve CR/PR or better /overall response/ CR (not including CRi) in low-blast AML. Overall 
response is defined as HI or PR or better for HR MDS/CMML patients, and PR or better for 
low-blast AML patients. For low-blast AML patients, composite CR includes both complete 
remission (CR) and complete remission with incomplete count recovery (CRi). 
The number and percentage of patients who achieved CR/CR+PR/overall response/CR (not 
including CRi) in low-blast AML, respectively, will be summarized by treatment group. CR 
rate/CR+PR rate/overall response rate/CR (not including CRi) rate in low-blast AML, 
respectively, will be tested using the unstratified Cochran-Mantel-Haenszel (CMH) chi-square 
test. The CMH chi-square test p-value, the relative risk with its 2-sided 95% CIs will be 
calculated. The absolute rate difference will be provided with its 95% CIs.
The key analysis will be based on the ITT population, patients with HR MDS/CMML, patients 
with HR MDS and patients with CMML separately, with response non-evaluable patients treated 
as non-responders. Sensitivity analysis will be performed using the response-evaluable 
population and response-evaluable patients with HR MDS/CMML and HR MDS separately.
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CR (CR for HR MDS and CMML, CR + CRi [composite CR] for low-blast AML)/CR (CR for HR 
MDS and CMML, CR + CRi for low-blast AML) +PR/Overall Response (CR+PR+HI for HR 
MDS and CMML; CR+CRi+PR for low-blast AML)/ CR (not including CRi) in low-blast AMLby 
Cycle 4
Rate of CR/CR+PR/overall response/CR (not including CRi) in low-blast AML by cycle 4, 
respectively, are defined as the proportion of patients who achieve CR/PR or better / overall 
response/CR (not including CRi) in low-blast AML, respectively, by cycle 4. 
The number and percentage of patients who achieved CR/CR+PR/overall response/CR (not 
including CRi) in low-blast AML by Cycle 4, respectively, will be summarized by treatment
group. CR rate/CR+PR rate/overall response rate/ CR (not including CRi) rate in low-blast AML 
by cycle 4 are binary outcome variables, which will be analyzed similarly as CR rate/CR+PR 
rate/overall response rate/CR (not including CRi) rate in low-blast AML.
The key analysis will be based on the ITT population, patients with HR MDS/CMML, and 
patients with HR MDS separately, with response non-evaluable patients treated as 
non-responders. Sensitivity analysis will be performed using the response-evaluable population, 
response-evaluable patients with HR MDS/CMML and HR MDS separately.
MDS and CMML, CR + CRi [composite CR] for low-blast AML)/CR (CR for HR MDS and 
CMML, CR + CRi for low-blast AML) +PR/Overall Response (CR+PR+HI for HR MDS and 
CMML; CR+CRi+PR for low-blast AML)/ CR (not including CRi) in low-blast AML
Duration of CR/CR+PR/overall response/CR (not including CRi) rate in low-blast AML, 
respectively, is defined as the time from the date of first documentation of a CR/PR or better/ 
overall response/CR (not including CRi) rate in low-blast AML, respectively, to the date of first 
documentation of PD (HR MDS/CMML, low-blast AML), relapse from CR or PR (HR 
MDS/CMML), or relapse from CR (low-blast AML), whichever comes first, for responders of 
CR/PR or better/ overall response/CR (not including CRi) rate in low-blast AML, respectively. 
Responders without documentation of PD or relapse from CR (low-blast AML), or relapse from 
CR or PR (HR MDS/CMML) will be censored as below: 

key analysis: censored at the date of the last visit with hematological evaluation, or the date 
of last bone marrow disease assessment that is SD or better, whichever occurs later.

sensitivity analysis: censored at the date of the last response assessment that is SD or better. 
Duration of CR/CR+PR/overall response/CR (not including CRi) rate in low-blast AML will be 
summarized descriptively using the K-M method and separately for the overall responders, 
responders of HR MDS/CMML, responders of HR MDS, responders of CMML, responders of 
low-blast AML. Kaplan Meier (K-M) survival curves and K-M medians (if estimable) will be 
provided for each treatment arm.
Time to First CR or PR
Time to first CR (CR and composite CR for patients with low-blast AML) or PR is defined as the 
time from the date of randomization to the first documentation of PR or better. Patients who do 
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not develop any CR or PR will be censored at the date of their last disease assessment. Time to 
first CR or PR is a time-to-event variable, which will be analyzed based on the 
response-evaluable population and response-evaluable patients with HR MDS/CMML, 
HR MDS, CMML and AML separately, using a similar method as OS.
Time to Subsequent Therapy
Time to subsequent therapy is defined as the time from the date of randomization to the date of 
the first documented subsequent therapy (excluding stem cell transplantation). Subsequent 
therapy is defined as agent(s) with antileukemic/anti-MDS activity (eg, cytarabine, 
anthracyclines, purine analogues, and hypomethylating agents other than azacitidine). Patients 
who discontinue study treatment to receive single-agent azacitidine off study would not be 
counted as receiving subsequent therapy. Patients who do not receive subsequent therapy at the 
time of the analysis will be censored at the date of death or last contact. Time to subsequent 
therapy is a time-to-event variable, which will be analyzed based on the ITT population, patients 
with HR MDS/CMML, and patients with HR MDS separately, using a similar method as OS.
Rate of Transfusion Independence
A patient is defined as RBC or platelet-transfusion independent if he/she receives no RBC or 
platelet transfusions for a period of at least 8 weeks [4,5] during the time period from 
randomization through 30 days after the last dose of any study drug. Rate of transfusion 
independence is defined as the number of patients who become transfusion independent divided 
by the number of patients who are transfusion dependent at Baseline (ie, patients received RBC 
or platelet transfusion within 8 weeks before randomization). The number of patients who are 
transfusion dependent/independent at Baseline and post Baseline, as well as rate of transfusion 
independence, will be summarized by treatment group. Rate of transfusion independence will be 
tested using unstratified CMH test. P values and 2-sided 95% CIs of the relative risk will be 
provided. The absolute rate difference will be provided with its 95% CIs.
Analysis of rate of transfusion independence will be performed for the ITT patients, patients with 
HR MDS/CMML, and patients with HR MDS separately.
Percent of Inpatient Hospitalizations Related to HR MDS, CMML, or AML
Inpatient hospital admission data will be collected through transformation to AML (HR 
MDS/CMML patients) or disease progression (low-blast AML patients) or until initiation of 
subsequent therapy (all patients), whichever occurs first. The analysis will be based on the ITT 
population.
The number and percentage of patients who have any hospitalizations related to HR MDS,
CMML, or AML will be summarized by treatment group. The absolute rate difference will be 
provided with its 95% CI.
Analysis will be performed for the ITT patients, patients with HR MDS/CMML, and patients 
with HR MDS separately.
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Time to PD, Relapse After CR or PR (HR MDS/CMML), Relapse After CR (LB AML), or Death
Time to PD, relapse after CR or PR, relapse from CR, or death is defined as the time from the 
date of randomization until the date of the first documentation of disease progression, or relapse 
after CR or PR, or relapse from CR, or death due to any cause. Time to PD, relapse after CR or 
PR, relapse from CR, or death is a time-to-event variable, which will be analyzed based on the 
ITT population, patients with HR MDS/CMML, and patients with HR MDS separately, using a 
similar method as OS.
7.9.3
Additional Efficacy Endpoint(s)
Transfusion Independence
KM figure and table will be provided for the longest duration of transfusion independence for 
ITT patients, patients with HR MDS/CMML, and patients with HR MDS separately. 
The transfusion rate per month (ie, number of transfusion received divided by the time [in month 
unit] from randomization through 30 days after the last dose of study dug) will also be 
summarized for both RBC and platelet separately. 
Duration of HI
Table and figure will be provided for duration of HI, duration of HI-Neutrophil, duration of 
HI-Erythroid, duration of HI-Platelet for HR MDS/CMML and HR MDS population separately. 
Allogeneic Stem Cell Transplantation
Rate of overall response and Allogeneic Stem Cell Transplantation will be summarized for ITT, 
HR MDS/CMML, HR MDS, CMML, low-blast AML. 
7.10
Pharmacokinetic/Pharmacodynamic Analysis
7.10.1 Pharmacokinetic Analysis
Pevonedistat plasma concentration-time data will be presented in listings. Pharmacokinetic data 
will be used to perform future population PK analyses of pevonedistat using a nonlinear mixed 
effects modeling approach and to assess the effect of various covariates on pevonedistat PK. 
These analyses may additionally include data collected in other pevonedistat clinical studies. The 
analysis plan for the population PK analysis will be separately defined, and the results of these 
analyses will be reported separately.
7.10.2 Pharmacodynamic Analysis
Not applicable.
7.11
Other Outcomes
Not applicable.
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7.11.1 Patient-Reported Outcomes (PROs)
Patient reported outcome assessments using the EORTC-QLQ-C30 and the QOL-E will be 
analysed using patients with PRO measurements at baseline and at least one post baseline 
measurement in the ITT population. For QOL-E data, the American English-speaking US patient 
population only will be used for analysis.
The descriptive statistics of actual values and changes from baseline of the subscale scores for 
the EORTC QLQ-C30 and QOL-E will be summarized by treatment arm over time in a table and 
accompanying sets of figures. The descriptive analyses will be conducted in the full population, 
the population of HR MDS/CMML patients, HR MDS patients, and the population of low blast 
AML patients. Additionally, the descriptive statistics of actual values and changes from baseline 
of global health status/quality of life (QOL) will be summarized by treatment arm over time by 
clinical response (responders and nonresponders). Responders are HR MDS/CMML patients 
who achieve HI, PR, or CR, or low-blast AML patients who achieve PR, CRi or CR. The 
subscales of the EORTC QLQ-C30 are defined in Table 7.d. The summary score of EORTC 
QLQ-C30 will be calculated from the mean of 13 of the 15 QLQ-C30 scales (the Global Health 
Status/QoL scale and the Financial Difficulties scale are not included). The subscales of the 
QOL-E are defined as in Table 7.e. 
Table 7.d
Description of EORTC QLQ-C30 domain scores
Subscale
Individual Items
Physical functioning
1-5
Role functioning
6-7
Emotional functioning
21-24
Cognitive functioning
20, 25
Social functioning
26-27
Quality of life
29- 30
Fatigue
10, 12, 18
Nausea and vomiting
14-15
Pain
9, 19
Dyspnea
8
Insomnia
11
Appetite loss 
13
Constipation 
16
Diarrhea
17
Financial difficulties 
28
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Table 7.e
Description of Subscale Scores of QOL-E
The number and percentage of patients with a change in EORTC QLQ C30 subscale scores from 
baseline achieving the published minimally important difference (MID) of 10 points will be 
summarized by treatment group over time in a table and figure. Specifically, patients with a 
change in score from baseline ≥MID in a direction reflecting deteriorating functioning or 
increased symptoms at a given time point will be classified as “worsened”, whereas those with a 
change in score from baseline ≥MID in a direction reflecting improved QOL/functioning or 
decreased symptoms at a given time point will be classified as “improved”. Those with no 
change in score from study entry or a change in score within MID will be classified as “stable”. 
The MID analyses will be conducted in the full population, the population of HR MDS/CMML 
patients and HR MDS patients.
The change in score from baseline to any post-baseline visit will be presented using cumulative 
distribution function (CDF) figures. The patient’s largest improvement from baseline will be 
determined first, and CDF curves will then be used to display the cumulative percentage of 
patients experiencing that improvement by treatment arm. The CDF figures for all subscales will 
be presented in the full population, the population of HR MDS/CMML patients and HR MDS 
patients. Additionally, CDF curves will be generated for global health status/QOL score by 
treatment arm among responders and nonresponders, respectively.
The change from baseline in subscale scores of EORTC QLQ-C30 and QOL-E will be also 
analysed using the repeated-measures linear mixed-effects (random-intercept only) models by 
incorporating the measurements across different time points, including treatment arm, time (a 
discrete variable), the interaction between treatment arm and time, baseline score, and 
stratification factor as covariates. The estimated mean in the changes from baseline in the 
2 treatments and the 95% CIs will be provided at each time point and overall. In addition, the 
mean differences between treatment groups along with 95% CIs and p values will be presented at 
each time point and overall in a table and accompanying set of figures. The analyses using 
repeated-measures linear mixed-effects models will be conducted for all subscales in the full 
population, the population of HR MDS/CMML and HR MDS patients.
Subscale
Individual Items
Physical (QOL-FIS)
3a, 3b, 3c, 3d
Functional (QOL-FUN)
4a, 4b, 5
Social (QOL-SOC)
6a, 6b, 6c, 7
Sexual (QOL-SES)
8, 14f
Fatigue (QOL-FAT)
9, 10, 11a, 11b, 11c, 11d, 12
MDS-Specific (QOL-SPEC)
13, 14a, 14b, 14c, 14d, 14e, 14g
General (QOL-GEN)
QOL-FIS, QOL-FUN, QOL-SOC, QOL-SES, QOL-FAT
ALL
QOL-FIS, QOL-FUN, QOL-SOC, QOL-SES, QOL-FAT, QOL-SPEC
Treatment-outcome index (TOI)
QOL-FIS, QOL-FUN, QOL-SPEC
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Details of scoring and initial handling of missing data are included in the EORTC QLQ-C30 and 
QOL-E scoring guidelines. Further investigation of missing patterns and details of imputation, 
including subsequent sensitivity analysis, may be conducted.
Compliance rates for EORTC QLQ-C30, QQL-E and EQ-5D-5L based on the full ITT 
population will be summarized over time by treatment arm. Compliance rates will be presented 
in the full population, the population of HR MDS/CMML patients and HR MDS patients. If 
compliance is less than 50% at baseline or at either of the first 2 visits, we will not move forward 
with additional analyses.
7.11.2 Health Economics (Health Care Resource Use)
EQ-5D-5L quality of life questionnaire scores (including 5-dimension descriptive system, VAS 
score and utilities) will be summarized in descriptive statistics for treatment arms over time. In 
addition, the change from baseline of VAS score and utilities (time tradeoff) will also be 
summarized in descriptive statistics for treatment arms over time. Analyses of EQ-5D-5L will be 
conducted in the full population, the population of HR MDS/CMML patients and HR MDS 
patients. Specifically, utilities for UK, France, Germany, Italy, and Spain are of interest. The 
directly elicited value sets will be used for these country-specific utilities calculations, if 
available, otherwise, the crosswalk value sets will be used. 
Healthcare utilization data will be summarized in descriptive statistics of medical encounters. 
Specifically, the number of hospitalizations, number of ICU stays, number of emergency room 
stays, length of hospital stay, length of stay in ICU, length of stay in hospital floor bed, visit
reasons and primary diagnosis at discharge by treatment arm will be summarized by treatment 
group over time. The summary of the healthcare utilization data will be conducted in the full 
population, the population of HR MDS/CMML patients and HR MDS patients. 
Transfusion data will be summarized in descriptive statistics. Transfusions will be categorized as 
platelet (pooled platelet concentrate or plateletpheresis (single donor)) or red blood cell. For each 
type of transfusion, we will present the number of patients receiving a transfusion, the number of 
transfusions per patient, the location of the transfusion (in hospital vs. outpatient), and the 
number of units per transfusion by treatment arm. The summary of the transfusion data will be 
conducted in the full population, the population of HR MDS/CMML patients and HR MDS 
patients. 
Further modeling will be performed separately at post hoc analyses.
7.11.3 Biomarker
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Property of Takeda: For non
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7.12
Safety Analysis
Safety evaluations will be based on the incidence, severity, type of AEs, clinically significant 
changes or abnormalities in the patient’s physical examination, vital signs, ECG, and clinical 
laboratory results. 
These analyses will be performed using the safety population for all patients, patients with HR 
MDS/CMML, and patients with HR MDS, separately. All analyses will be performed for by 
treatment arm.
7.12.1 Adverse Events
7.12.1.1 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 through 30 days after the last dose of any study drug. 
AEs will be tabulated by system organ class (SOC), high level term (HLT), and preferred term 
(PT) by treatment arm. Summary tabulations include the following categories:
!
Treatment emergent AEs.
!
Drug-related treatment emergent AEs. 
!
Treatment-emergent Grade 3, 4 and 5 AEs (presented by grade and overall).
!
Treatment-emergent drug-related Grade 3, 4 and 5 AEs (presented by grade and overall).
!
Treatment-emergent AEs resulting in study drug discontinuation.
!
Treatment-emergent AEs that required dose modification of pevonedistat.
!
Treatment emergent AEs that required dose modification of azacytidine.
CCI
Property of Takeda: For non-commercial use only and subject
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P2001
Page 37 of 47
Statistical Analysis Plan Amendment 01
06 August 2019

SAEs. 

Treatment-emergent drug related SAEs. 
Patients with the same AE more than once will have that event counted only once within each 
body system, once within each High Level Term (HLT), and once within each Preferred Term 
(PT).
Treatment emergent AEs will be tabulated by SOC, HLT, PT, and highest intensity. Most 
commonly reported (at least 10% of all patients) treatment emergent AEs will be presented by 
preferred term. 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 8-9, Cycle 10-11, Cycle 12-13, Cycle 14+). 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 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.
A by-patient listing of the AEs will be presented (the patient listing will contain all AEs, 
including a flag indicating treatment emergent status).
7.12.1.2 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. 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.
7.12.1.3 Deaths
A by-subject listing of the deaths will be presented. All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment emergent AE status). 
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P2001
Page 38 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
All deaths will be summarized by treatment arm, including deaths occurring on-study and death 
during follow-up separately.
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.
7.12.1.4 Adverse Events Resulting in Discontinuation of Study Drug
The number and percentage of patients experiencing at least one adverse event resulting in 
discontinuation of study drug will be summarized by MedDRA SOC, HLT, and PT.
A by-patient listing of treatment emergent AEs resulting in discontinuation of study drug will be 
presented. 
7.12.1.5 Haemorrahges (SMQ)
Patients with haemorrhages will be summarized respectively for occurrences of 
thrombocytopenia, platelet count decreased, and lab platelet toxicity grade of at least 2.
By-patient line listing for patients with Thrombocytopenia/Platelet Count Decreased and 
Haemorrhages (defined by SMQ Haemorrhages) concurrently occurred within 5 days will be 
provided.
7.12.1.6 Myalgia and Musculoskeletal Events
A listing of patients who experience treatment emergent myalgia (PT) events or treatment 
emergent musculoskeletal pain and discomfort (PT) will be presented.
7.12.1.7 Acute Renal Failure Events
A listing of treatment-emergent acute renal failure events will be generated. 
7.12.1.8 Liver Function Test (LFT) Elevations
Listing and summary table of treatment-emergent LFT elevations will be generated. The 
corresponding preferred and HLG terms are listed as below:

Acute hepatic failure (PT).

Blood alkaline phosphatase (PT).

Blood alkaline phosphatase abnormal (PT).

Blood alkaline phosphatase increased (PT).

Hyperbilirubinemia (PT).

Hepatic function abnormal (PT).

Liver function analyses (HLT).
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P2001
Page 39 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
7.12.1.9 Tachycardia Events
A listing of treatment-emergent tachycardia events will be generated. The corresponding 
preferred terms are listed as below:

Heart rate increased.

Rebound tachycardia.

Sinus tachycardia.

Supraventricular tachyarrhythmia.

Tachyarrhythmia.

Tachycardia.

Tachycardia paroxysmal.

Palpitations.
7.12.1.10
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 diastolic decreased.

Blood pressure orthostatic abnormal.

Blood pressure orthostatic decreased.

Blood pressure systolic decreased.

Hypotension.

Orthostatic hypotension.
7.12.1.11
Anaemia
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:

Anaemia of chronic disease.

Anaemia of malignant disease.

Anaemia.

Red blood cell count decreased.

Haemoglobin decreased.

Mean cell haemoglobin decreased.

Haematocrit decreased.
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P2001
Page 40 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
7.12.1.12
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.

Neutropenia.

Neutropenic infection.

Neutropenic sepsis.

Neutrophil count abnormal.

Neutrophil count decreased.

Neutrophil percentage abnormal.

Neutrophil percentage decreased.
By- patient line listing for patients with Febrile neutropenia and Infections (defined by SOC 
Infections and Infestations. or HLGT Respiratory Tract Infections, or HLT Lower Respiratory 
Tract Inflammatory and Immunologic Conditions) concurrently occurred within 5 days will be 
generated. The listing will include: subject ID, Treatment group, Febrile neutropenia (reported 
term and PT, Start date/End date, Days from first dose/Days from last dose, Seriousness), 
Infections (reported term and PT, Start date/End date; Days from first dose/Days from last dose; 
Seriousness).
By- patient line listing for Patients with Grade 3 or Higher TEAE of Neutropenia (defined by PT 
Neutropenia, PT Neutrophil Count Decreased, PT White Cell Count Decreased) and Infections 
(defined by SOC Infections and Infestations. or HLGT Respiratory Tract Infections, or HLT 
Lower Respiratory Tract Inflammatory and Immunologic Conditions) concurrently occurred 
within 5 days will be generated. The listing will include: subject ID, Treatment group, 
Neutropenia (reported term and PT, Start date/End date, Days from first dose/Days from last 
dose, Seriousness), Infections (reported term and PT, Start date/End date; Days from first 
dose/Days from last dose; Seriousness).
7.12.1.13
Change in Transfusion
A listing will be generated for patients who take platelets and/or red blood cells as concomitant 
medications during study to display transfusion trend over time (Week 1-4, Week 5-8, 
Week 9-12, and Week 13+).
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P2001
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Statistical Analysis Plan Amendment 01
06 August 2019
7.12.1.14
Overall Summary
The number and percentage of patients who experience any of the following groups will be 
summarized by treatment arm and azacitidine route:

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.

Adverse events resulting in study drug discontinuation.

Adverse events that required dose modification.

On-study deaths. 
The summary tables will also be provided for overall TEAE summary by age (<65, >=65 and 
<75, and >=75), including on-study deaths, Grade 3 or higher TEAEs, drug related adverse 
events, serious adverse events, drug related serious adverse events, adverse events leading to 
treatment discontinuations. 
7.12.2 Clinical Laboratory Evaluations
For the purposes of summarization in both the tables and listings, 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 summary statistics, ignoring the non-numeric qualifier. 
Laboratory test results from the central laboratory will be used when they are available. 
Laboratory test results from local laboratory will be used only when no central laboratory test 
result exists at the same scheduled sample collection time point.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory test results will be summarized according to the scheduled sample collection time 
point. Change from baseline will also be presented. Unscheduled laboratory test results will be 
listed and included in laboratory shift tables. 
Shift tables of the change in NCI CTC from baseline to the post baseline worst CTC grade will 
be generated for relevant measurements. 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 individual tests over time by treatment arm.
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P2001
Page 42 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
2. Scatter plots of baseline versus worst post-baseline values for all patients. Separate plotting 
characters will be used for each treatment arm. These will be generated for only selected labs 
(see table below).
Table 7.f
Selected Labs
Panel
Test
CTCAE Shift 
Table
Box Graphs
Scatter 
Plots
Summary 
Tables
Chemistry
Albumin
X
X
ALT
X
X
X
AST
X
X
X
Alkaline Phosphatase
X
X
Direct Bilirubin
X
X
Total Bilirubin
X
X
X
Blood urea nitrogen
X
X
Calcium
X
X
Chloride
X
X
Creatinine
X
X
Creatinine Clearance
X
X
X
Glucose
X
X
Lactate dehydrogenase 
(LDH)
X
X
Magnesium
X
X
Phosphate
X
X
X
Potassium
X
X
X
Sodium
X
X
Urate
X
X
Hematology
Platelets
X
X
X
Hemoglobin
X
X
Leukocytes
X
X
Neutrophils (ANC)
X
X
X
Monocytes
X
Additional
Reticulocyte
X
X
Ferritin
X
X
Additional graphical representations to compare trajectories of platelet count, absolute neutrophil 
count, and hemoglobin values (eg, median and IQR) over time (eg, by cycle) between treatment 
arms will be provided. 
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P2001
Page 43 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
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)
Example: 
If total leukocyte count = 4.3 x 103; segmented neutrophils = 48%; band neutrophils = 2% Then:
4300 × (0.48 + 0.02) = 4300 × 0.5 = ANC of 2150
Creatinine clearance will be derived using one of the Cockcroft-Gault and CKD-epi formulas as 
follows:
Cockcroft-Gault equation:
For males:
OR 
For females:
OR
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:
, 
where Scr = serum creatinine (mg/dL).
For black males:
,
where Scr = serum creatinine (mg/dL).
)
mol/L]
[
creatinine
serum
(
81
.0
[kg]
 weight 
)
age[years]
-
(140
(mL/min)
Clearance
Creatinine




)
[mg/dL]
creatinine
serum
(
72
[kg]
 weight 
)
age[years]
-
(140
(mL/min)
Clearance
Creatinine



)
mol/L]
[
creatinine
serum
(
81
.
0
[kg]
 weight 
)
age[years]
-
(140
0.85
(mL/min)
Clearance
Creatinine





)
[mg/dL]
creatinine
serum
(
72
[kg]
 weight 
)
age[years]
-
(140
0.85
(mL/min)
Clearance
Creatinine




  
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

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

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P2001
Page 44 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
For females:
, 
where Scr = serum creatinine (mg/dL).
For black females:
,
where Scr = serum creatinine (mg/dL).
All chemistry and hematology lab data will also be presented in by-patient listings.
The percentage of marrow progenitor cells in peripheral blood will be presented in by-patient 
listings, including leukemic blasts, myeloblasts, promyelocytes, myelocytes, metamyelocytes, 
and uncharacterized blasts.
In addition, the urinalysis parameters will be presented in by-patient listings. These include 
turbidity and color, pH, specific gravity, protein, ketones, bilirubin, occult blood, nitrite, 
urobilinogen, glucose, erythrocytes, leukocyte esterase, and leukocytes.
7.12.3 60-day Mortality
Sixty-day mortality rate is defined as the proportion of patients who survive at most 60 days 
from the first dose of study drug, which will be summarized by treatment arm based on the safety 
population.
7.12.4 Vital Signs
Boxplots over time for temperature, DBP, SBP, and heart rate during Cycle 1 will be generated. 
Vital sign data will also be presented in a by-patient listing.
Summary table of weight and percent change from baseline in weight over time will be provided. 
7.12.5 12-Lead ECGs
The number and percent of patients experiencing abnormal ECG results will be summarized for 
each time point and unscheduled visits by treatment arm.
QTcF and QTcB will be derived using the following formulas.
ECG findings will also be presented in by-patient listings.
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

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 
3
/
1
d
uncorrecte
Rate
r 
Ventricula
60
QT
QTcF







Rate
r 
Ventricula
60
QT
QTcB
d
uncorrecte

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P2001
Page 45 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
7.12.6 Other Observations Related to Safety
Eastern Cooperative Oncology Group (ECOG) performance status and change from baseline will 
be summarized. Shifts from baseline to the worst postbaseline score will be tabulated by 
treatment arm.
7.12.7 Protocol Deviations
A listing will be presented for significant protocol deviation for ITT population, ordered by 
disease type. 
7.13
Interim Analysis
There are two interim analyses (IA) planned for this study.
The first IA is planned for safety, based on 60-day mortality. It is planned when 60 patients are 
on study for 60 days or do not survive 60 days. This safety evaluation together with the overall 
data will be reviewed by the independent data monitoring committee (IDMC) that will make 
recommendations regarding whether the study should continue as planned or discontinue based 
on the overall data. The IDMC will review the overall profile and if it is deemed unacceptable, 
the study will stop. Otherwise, enrollment and study procedures will continue as planned during 
this IA.
The second IA is for evaluation of both efficacy and safety data when approximately 23 EFS 
events have occurred. The IDMC will review the overall data, and if it is deemed unacceptable, 
the study will stop. Otherwise, enrollment and study procedures will continue as planned.
7.14
Changes in the Statistical Analysis Plan 
Reference materials for this statistical plan include Clinical Study Protocol P-2001 Amendment 4 
(Protocol dated 27 July 2018). Additional major changes include:

Section 7.9.1 prespecify statistical testing procedures to control type I error for US 
submission and ex-US submission separately.

Section 7.11.1 by response analysis on patient reported outcomes.

Section 7.11.1 MID and CDF analyses on the EORTC QLQ C30 subscale scores.
Additional change in SAP Amendment 01, referring the SAP version 1.0 (dated 22 February 
2019) include:

The addition of analyses and summaries for HR MDS patients is to further define results in 
this subpopulation.

Section 7.11.1 Patient-Reported Outcomes, clarify the definition of responders for AML
patients (CR+PR+CRi).
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P2001
Page 46 of 47
Statistical Analysis Plan Amendment 01
06 August 2019

Section 7.12.1.9 Tachycardia Events, remove heart rate irregular from the PT search criteria. 

Section 7.12.1.5 Haemorrahges (SMQ) and section7.12.1.12 Neutropenia, clarify that the by-
patient line listings are for the concurrent events. 
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P2001
Page 47 of 47
Statistical Analysis Plan Amendment 01
06 August 2019
8.0
REFERENCES
1. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised 
international prognostic scoring system for myelodysplastic syndromes. Blood 
2012;120(12):2454-65.
2. 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.
3. 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.
4. Liu Y, Hu MX. Testing multiple primary endpoints in clinical trials with sample size 
adaptation. Pharmaceutical Statistics 2016; 15(1):37-45.
5. Dohner H, Estey E. et al. Diagnosis and management of AML in adults. Blood 2017; 
129(4):424-427.
6. Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics 1999;55(3):853-7.
7. Robins JM, Hernan M, Brumback B. Marginal strucural models and causal inference in 
epidemiology. Epidemiology 2000; 11(5): 550-560.
8. Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an 
AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank tests. 
Biometrics 2000;56(3):779-88.
9. 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 
Oncology 2009;10(3):223-32.
10. Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, et al. 
Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 
8421, 8921, and 9221 by the Cancer and Leukemia Group B. Journal of Clinical Oncology 
2006;24(24):3895-903.
11. Fayers PM, Aaronson NK, Bjordal K, et al. The EORTC QLQ-C30 Scoring Manual (3rd 
Edition). Brussels: European Organisation for Research and Treatment of Cancer; 2001
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