Conditions: Acute Myeloid Leukemia (AML)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This research is being done to find out the toxicity and efficacy of a combination of Pevonedistat and Azacitidine as post allogeneic hematopoietic stem cell transplant maintenance therapy for non-remission AML and to see the overall diseases free survival, relapse, and GVHD after treatment.

Detailed description:
In preclinical studies Pevonedistat has shown significant single agent activity against mouse xenograft models of AML cell Line HL-60. Also this effect seemed to be synergistically enhanced by combining it with Azacitidine. In clinical arena, Pevonedistat has shown single agent activity in heavily pretreated patients with AML. In Study C15003, responses (complete responses \[CRs\] and partial responses \[PRs\]) were observed in a variety of patient settings, including post allogeneic transplant, therapy-related AML, and primary refractory AML, although some of the responses were of relatively short duration. Study C15009 is an ongoing phase 1b study evaluating the MTD of Pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2 Azacitidine (administered on a 5-on/2-off \[weekend\]/2-on schedule) in a 28-day treatment cycle in patients 60 years of age or older with treatment naïve AML who are unlikely to benefit from standard induction therapy. As of 22 June 2017, enrollment had completed and 15 patients remained on study. As of 22 January 2017, preliminary data are available for 64 patients enrolled in the study who received at least 1 dose of Pevonedistat in combination with Azacitidine; these patients had completed a total of approximately 360 cycles, with a median of 4 cycles of treatment In the dose escalation cohorts, 6 patients received 20 mg/m2 Pevonedistat, and 3 patients received 30 mg/m2. The most common events (reported by ≥ 25% of patients) were constipation (45%), nausea (42%), fatigue (39%), anemia (34%), febrile neutropenia (30%), decreased appetite (28%), and thrombocytopenia (27%). The MTD in this study was determined to be 20 mg/m2 Pevonedistat given on Days 1, 3, and 5, in combination with 75 mg/m2 Azacitidine given on Days 1 through 5, 8, and 9, in 28 day treatment cycles. A total of 45 (70%) patients experienced at least 1 SAE A total of 14 SAEs were reported for more than 1 patient, including: febrile neutropenia (16 patients); pneumonia (8 patients); pyrexia (4 patients); AML and sepsis (3 patients); and acute myocardial infarction, cellulitis, diverticulitis, dyspnea, embolism, hypoxia, mental status changes, multi-organ failure, and transaminase increased (2 patients each). A total of 19 patients treated with Pevonedistat (either 20 mg/m2 or 30 mg/m2), discontinued from Study participation because of a TEAE. No other events leading to discontinuation were assessed by study investigators as at least possibly related to study drug treatment. 11 on-study deaths had been reported; none assessed as related to study treatment. A total of 31 patients experienced PR or better. Eighteen patients had a best response of CR, 4 patients had a best response of CRi, and 9 patients had a best response of PR. One patient in the 30 mg/m2 dose level group achieved a CR; all other responses occurred in patients treated with 20 mg/m2.

The following studies are currently enrolling.

* Study 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.
* Study 1012: A phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as Single Agent and in Combination with Azacitidine in adult East Asian patients with acute myeloid leukemia or myelodysplastic syndromes

Hence owing to the current knowledge of clinical and preclinical experience with Azacitidine and Pevonedistat alone and in combination, this combination appears feasible for testing in patients post-transplant with at very high risk of relapse.

The Investigator proposes a study using a combination of Pevonedistat and Azacitidine for maintenance therapy after allogeneic HSCT for non-remission. Patients will receive up to five 28 day cycles of the investigational maintenance therapy. Maintenance therapy will begin between days +30 to +45 post-transplant.

Arms:
arm 1: The study period is from the start of study treatment, cycle 1 day 1 until 28 days after the last treatment dose. (Cycle 5 day 9). Treatment will be continued until cycle 5 is completed or the study is terminated for the patient. The cycles will be repeated every 28 days. Cycle 1 Day 1 of study treatment will be between day +30 and day +45 post-transplant. Each 28-day cycle is comprised of Pevonedistat at 20 mg/m2 IV infusion over 1 hour on days 1, 3 and 5 and Azacitidine at 25 mg/m2 IV infusion over 30 minutes on days 1, 2, 3, 4, 5, 8 and 9. The drugs can be administered either through a central catheter or a peripheral line.

Interventions: intervention 1: Pevonedistat intervention 2: transplant intervention 3: Azacitidine
Intervention descriptions: intervention 1: To assess the toxicity and efficacy of a combination of Pevonedistat and Azacitidine as post allogeneic hematopoietic stem cell transplant maintenance therapy for non-remission AML. intervention 2: Although hematopoietic stem cell transplantation (HSCT) is curative for many patients with AML, AML in relapse at the time of transplant is still a major challenge with low rates of leukemia-free survival even with an intensive myeloablative conditioning. intervention 3: To assess the toxicity and efficacy of a combination of Pevonedistat and Azacitidine as post allogeneic hematopoietic stem cell transplant maintenance therapy for non-remission AML.

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 75 (V.1.8.5, 07/26/2018)
Protocol Title: PSCI 17-056
A Phase II Study of Pevonedistat (MLN4924, TAK924) and Azacitidine as Maintenance 
Therapy after Allogeneic Stem Cell Transplantation for Non-Remission Acute 
Myelogenous Leukemia
Principal Investigator:
Shin Mineishi, M.D. 
Professor and Director, Blood and Marrow Transplant Program
500 University Drive, CH46
Hershey, PA 17111
717-531-8678 (Office)
717-531-4969 (Fax)
Email:smineishi@pennstatehealth.psu.edu
Site PIs
Additional sites may be added in the future.
Co-Investigators:
David Claxton, M.D. 
Hong Zheng, M.D. Ph.D.
Seema Naik, M.D.
Muhammad Khawaja, M.D.
Jason Liao, Ph.D.
Co-Investigator/MD Coordinator
Kevin Rakszawski, MD
Fellow, Hematology & Oncology
Email:krakszawski@pennstatehealth.psu.edu
Version Date:
Version 1.8.5, 07-26-2018
Clinicaltrials.gov Registration #:
 03709576
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Contents
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS......................................................................................................6
1.0
Objectives .......................................................................................................................................................10
1.1.
Primary Objective.................................................................................................................................................10
1.2.
Secondary Objectives ...........................................................................................................................................10
1.3.
Primary Endpoint..................................................................................................................................................10
1.4.
Secondary Endpoints ............................................................................................................................................10
2.0
Background ....................................................................................................................................................10
2.1.
Background...........................................................................................................................................................10
2.1.1.
High-risk AML particularly Non-remission AML..............................................................................10
2.1.2.
Intensification of conditioning – experience with CloBu4 conditioning trials for Non-remission AML
11
2.1.3.
Relapsed AML after allogeneic HSCT, another population with Poor Prognosis ..............................12
2.1.4.
Maintenance therapy after allogeneic stem cell transplantation.........................................................12
2.1.5. Use of Azacitidine post-transplant........................................................................................................................13
2.2.
Scientific Background of Pevonedistat.................................................................................................................13
2.3.
Preclinical Experience with Pevonedistat.............................................................................................................14
2.4.
Clinical Experience with Pevonedistat .................................................................................................................16
2.4.1.
Pharmacokinetics ................................................................................................................................17
2.4.2.
Pharmacodynamics .............................................................................................................................18
2.4.3.
Phase 1 Monotherapy Studies .............................................................................................................18
2.4.4.
Phase 1 Combination Studies ..............................................................................................................19
2.5.
Potential risks of Pevonedistat..............................................................................................................................21
2.5.1.
Potential Risks from Phase 1 Studies ..................................................................................................21
2.5.2.
Potential Risks Confounded by Underlying Disease or Malignancy ...................................................22
2.5.3.
Potential Risks Primarily Based on Findings from Animal Studies....................................................22
2.5.4.
Additional Safety Considerations........................................................................................................23
Experience with Pevonedistat in AML induction and post-transplant treatment .............................................................25
2.6.
Azacitidine and Pevonedistat as combination therapy for AML ..........................................................................25
2.7.
Proposed Study...............................................................................................................................................26
3.0
Inclusion and Exclusion Criteria....................................................................................................................26
3.1.
Inclusion Criteria for Study Registration..............................................................................................................26
3.2.
Exclusion Criteria for Study Registration.............................................................................................................27
3.3.
Additional Eligibility Criteria for Initiating Study Treatment ..............................................................................29
3.4.
Inclusion of Women and Minorities:....................................................................................................................29
3.5.
 Vulnerable Populations........................................................................................................................................29
3.6.
 Registration and Early Withdrawal/Discontinuation of the Study.......................................................................29
3.6.1. 
REGISTRATION PROCEDURES.....................................................................................................29
3.6.2. 
Discontinuation of the Study/Withdrawal...........................................................................................30
3.6.3.  
Follow-up for withdrawn subjects.......................................................................................................30
4.0 Recruitment Methods...........................................................................................................................................30
4.1. 
Identification of subjects.......................................................................................................................................30
4.2. 
Recruitment process .............................................................................................................................................30
4.3. 
Recruitment materials...........................................................................................................................................30
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4.4. 
Eligibility/screening of subjects............................................................................................................................30
5.0 Consent Process and Documentation ...................................................................................................................30
5.1. 
Consent Process....................................................................................................................................................30
5.1.1.
Obtaining Informed Consent ..............................................................................................................31
5.1.2
Waiver or alteration of the informed consent requirement ................................................................31
5.2.
Consent Documentation........................................................................................................................................31
5.2.1.
Written Documentation of Consent.....................................................................................................31
5.2.2.
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.) ...................................31
5.2.3. Consent – Other Considerations ...........................................................................................................................31
6.0.
HIPAA Research Authorization and/or Waiver or Alteration of Authorization ...........................................31
6.1.
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI......................31
6.2.
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI........................................................32
7.0.
Study Design and Procedures.........................................................................................................................32
7.1.
Study Treatment ...................................................................................................................................................32
7.2.
Study Drug Administration...................................................................................................................................34
7.3.
Delay of Medications/Dose Modifications at each cycle:.....................................................................................34
7.4.
Other Dose-Modification Guidelines....................................................................................................................36
7.4.1.
General Guideline for dose modification.............................................................................................36
7.4.2.
Criteria for Retreatment and Dose Delays..........................................................................................36
7.4.3.
Dose Modifications for Hematologic Toxicities ...................................................................................37
7.4.4.
Dose Modifications for Non-hematologic Toxicities............................................................................38
7.5.
GVHD and Immunosuppression...........................................................................................................................38
7.6.
Excluded Concomitant Medications and Procedures............................................................................................38
7.7.
Permitted Concomitant Medications and Procedures ...........................................................................................39
7.8.
Study Treatment Period ........................................................................................................................................40
7.9.
Treatment Cycles..................................................................................................................................................40
7.10.
Evaluable patients.................................................................................................................................................40
7.11.
Removal from the study........................................................................................................................................40
7.12.
Withdrawal from the study ...................................................................................................................................41
7.13.
Precautions and Restrictions.................................................................................................................................41
7.14.
Test Article(s) (Study Drug(s) and/or Study Device(s)).......................................................................................42
7.14.1.
Pevonedistat (MLN4924, TAK924) .....................................................................................................42
7.14.2.
Azacitidine (Vidaza) ............................................................................................................................46
7.15.
Method for Assigning Subject to Treatment Groups............................................................................................48
7.16.
Subject Compliance Monitoring...........................................................................................................................48
7.17.
Blinding of the Test Article ..................................................................................................................................48
7.18.
Receiving, Storage, Dispensing and Return .........................................................................................................48
7.18.1.
Receipt of Test Article.........................................................................................................................48
7.18.2.
Storage.................................................................................................................................................48
7.18.3.
Preparation and Dispensing ................................................................................................................49
7.18.4.
Return or Destruction of the Test Article............................................................................................49
7.19.
Required Observations...................................................................................................................................49
7.19.1.
Pre-Transplant / Study Registration:..................................................................................................49
7.19.2.
Post-Transplant / Day +30: .................................................................................................................50
7.19.3.
Study Treatment Initiation: ................................................................................................................50
7.19.4
During Study Treatment:....................................................................................................................50
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7.19.5.
At Study Treatment Completion Visit (Day 42-56 after day 1 of the last cycle) .................................50
7.19.6. 
Yearly visits after stem cell transplant (±1 month of 1 to 5 years after transplant)............................50
7.19.7.
Post study-treatment required observations and follow-up plans.......................................................51
8.0.
Subject Numbers and Statistical Plan ............................................................................................................51
8.1.
Simon’s two stage design .....................................................................................................................................51
8.2.
Statistical Analysis plan:.......................................................................................................................................51
10.0.
Confidentiality, Privacy and Data Management ............................................................................................52
10.0.
DATA REPORTING / REGULATORY REQUIREMENTS ........................................................................52
10.1.
Confidentiality of Records:...................................................................................................................................52
10.2.
Patient Consent Form: ..........................................................................................................................................52
10.3.
Registration Eligibility Worksheet: ......................................................................................................................52
10.4.
Data Collection Forms and Submission Schedule: ...............................................................................................52
10.5.
Site Monitoring:....................................................................................................................................................53
10.6.
Institutional Review Board Approval:..................................................................................................................53
10.7.
Records Retention: ...............................................................................................................................................54
10.8.
Data Safety Monitoring Plan ................................................................................................................................54
11.0
Risks ................................................................................................................................................................54
12.0
Potential Benefits to Subjects and Others ........................................................................................................54
12.1
Potential Benefits to Subjects .............................................................................................................................54
12.2
Potential Benefits to Others................................................................................................................................54
13.0
Sharing Results with Subjects...........................................................................................................................55
14.0
Subject Stipend (Compensation) and/or Travel Reimbursements.....................................................................55
15.0
Economic Burden to Subjects...........................................................................................................................55
15.1
Costs .....................................................................................................................................................................55
15.2
Compensation for research-related injury..........................................................................................................55
16.0
Resources Available .........................................................................................................................................55
16.1
Facilities and locations.........................................................................................................................................55
16.2
Feasibility of recruiting the required number of subjects ..................................................................................55
16.3
PI Time devoted to conducting the research ......................................................................................................55
16.4
Availability of medical or psychological resources .............................................................................................55
16.5
Process for informing Study Team ......................................................................................................................55
17.0.
Other Approvals.............................................................................................................................................55
17.1.
Other Approvals from External Entities ...............................................................................................................55
17.2.
Internal PSU Committee Approvals .....................................................................................................................56
18.0.
Adverse Event Reporting................................................................................................................................56
18.1.
Definition of Adverse events................................................................................................................................56
18.2.
Required Adverse Events Reporting.....................................................................................................................57
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18.3.
Serious Adverse Event Reporting Procedures ......................................................................................................57
18.4.
Procedures for Reporting Serious Adverse Events to Supporting Company (Millennium/Takeda).....................58
18.5.
ADMINISTRATIVE REQUIREMENTS ............................................................................................................60
18.5.1.
Product Complaints.............................................................................................................................60
18.6 Reporting of Adverse Reactions and Unanticipated Problems to the FDA ............................................................60
18.7 Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB..............................................61
18.8 Unblinding Procedures............................................................................................................................................61
18.9 Stopping Rules.........................................................................................................................................................61
19.0 Study Monitoring, Auditing and Inspecting.......................................................................................................61
Quality Assurance and Quality Control ....................................................................................................................61
20.0.
Future Undetermined Research: Data and Specimen Banking......................................................................61
21.0.
References.......................................................................................................................................................61
APPENDIX A ............................................................................................................................................................67
APPENDIX B.............................................................................................................................................................68
APPENDIX E
 STUDY CALENDAR..................................................................................................................74
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Common abbreviations used in oncology protocols are provided below.  Program-specific or protocol-specific 
abbreviations must be added to this list, and unnecessary abbreviations removed, as applicable.  Abbreviations 
that are retained should not be changed. 
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
API
active pharmaceutical ingredient
aPTT
activated partial thromboplastin time
Ara-C
Cytarabine
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC24 hr
area under the plasma concentration versus time curve from zero to 24 hours
AUCinf
area under the plasma concentration versus time curve from zero to infinity
AUCτ
area under the plasma concentration versus time curve from zero to next dose
BCRP
breast cancer resistance protein
hCG
beta-human chorionic gonadotropin
BCRP
BID
breast cancer-resistance protein
bis in die; twice a day
BM
bone marrow
BSA
body surface area
BUN
blood urea nitrogen
BZD
Benzodiazepines
CBC
complete blood count
CFR
Code of Federal Regulations
CL
clearance, IV dosing
CLP
plasma clearance
CLTotal
total clearance
Cmax
single-dose maximum (peak) concentration  
CNS
central nervous system
CO2
carbon dioxide
CR
complete remission   
CRi
CRM
complete remission with incomplete blood count recovery
continual reassessment method
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Abbreviation
Term
CRP
C-reactive protein
CSF-1R
colony-stimulating factor 1 receptor
CT
computed tomography
Ctrough
single-dose end of dosing interval (trough) concentration
CV
coefficient of variation
CYP
cytochrome P450
DLT
dose-limiting toxicity
DME
drug metabolizing enzymes
DNA
deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EOS
End of Study (visit)
EOT
End of Treatment (visit)
EU
European Union
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GM-CSF
GGT
granulocyte macrophage colony-stimulating factor.  
gamma glutamyl transferase
GI
Gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
GMP
Good Manufacturing Practice
Hb
Hemoglobin
Hct
Hematocrit
HDPE
high-density polyethylene
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
HNSTD
highest nonseverely toxic dose
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
ITT
intent-to-treat
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Abbreviation
Term
IV
intravenous; intravenously
IVRS
interactive voice response system
Ki
inhibition constant
KPS
Karnofsky Performance Status
LDH
lactate dehydrogenase
LFT
liver function test(s)
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MRI
magnetic resonance imaging
MRU
medical resource utilization
MTD
maximum tolerated dose
MUGA
multiple gated acquisition (scan)
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NPO
nothing by mouth
NYHA
New York Heart Association
OATPs
organic anion-transporting proteins
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
PR
partial remission
PRO
patient-reported outcome
PSA
prostate-specific antigen
QD
quaque die; each day; once daily
QID
quater in die; 4 times a day
QOD
quaque altera die; every other day
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SC
Subcutaneous
SD
stable disease
SmPC
Summary of Product Characteristics
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Abbreviation
Term
t1/2
terminal disposition half-life
TGI
tumor growth inhibition
Tmax
single-dose time to reach maximum (peak) concentration
UK
United Kingdom
ULN
upper limit of the normal range
US
United States
Vz
volume of distribution in the terminal phase
WBC
white blood cell
WHO
World Health Organization
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1.0
Objectives
1.1.
Primary Objective
To assess the toxicity and efficacy of a combination of Pevonedistat and Azacitidine as post 
allogeneic hematopoietic stem cell transplant maintenance therapy for non-remission AML.
1.2.
Secondary Objectives
To assess the overall disease free survival, relapse, and GVHD after the above noted treatment.
1.3.
Primary Endpoint 

One year overall survival 
1.4.
Secondary Endpoints

One-year disease-free survival

Cumulative incidence of relapse at 2 years

Two-year and five-year disease-free and overall survival

Treatment related mortality/morbidity

Toxicity related to Pevonedistat

Incidence and severity of acute and chronic GVHD
2.0
Background
2.1.
Background
2.1.1.
High-risk AML particularly Non-remission AML
Although hematopoietic stem cell transplantation (HSCT) is curative for many patients 
with AML, AML in relapse at the time of transplant is still a major challenge with low 
rates of leukemia-free survival even with an intensive myeloablative conditioning. In 
1997 Seattle data suggested that long term survival rate is quite low in AML with 
peripheral circulating blasts at the time of transplant1.  Similar data have been reported 
from EBMT. Also, in our own historical data, these patients are very difficult to achieve 
long term remission. 
Recently, reduced intensity transplant have shown that even elderly patients can undergo 
allogeneic stem cell transplantation2-5.  It is associated much less complications compared 
to myeloablative conditioning therapy, but anti-tumor effect may also be weaker. More 
recently, it has been shown that reduced intensity transplant may be associated with more 
relapse, particularly in non-remission malignancies6, 7. 
FluBu4 conditioning regimen was developed as a full intensity, reduced toxicity 
conditioning regimen8, 9. It has been associated with much less toxicity compared to 
conventional myeloablative regimens, and may be stronger compared to reduce intensity 
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regimens in terms of anti-leukemic effect, but still may be associated with relatively high 
rate of relapse in non-remission malignancies. 
There are a large number of elderly patients with non-remission AML because of the 
complete remission rate with induction chemotherapy decreases with age10, and such 
older patients do not tolerate conventional myeloablative conditioning regimens. Thus, an 
effective and tolerable way of conducting stem cell transplantation for non-remission 
AML patient is a great unmet need for current transplant practice.
 
2.1.2.
Intensification of conditioning – experience with CloBu4 conditioning trials for Non-
remission AML
Clofarabine is a second generation nucleoside analogue, similar to fludarabine and 
cladribine, with promising activity in refractory AML. Clofarabine has been shown to be 
well-tolerated with manageable side effects, particularly in elderly patients11.  The drug’s 
main toxicity is bone marrow suppression, and non-hematologic toxicities are relatively 
mild.  
The University of Michigan BMT program has conducted a phase I/II study using 
Clofarabine/Busulfan 4 (CloBu4) for non-remission hematologic malignancies (PI, Shin 
Mineishi, M.D.)12.  All patients had a hematologic malignancy that was not in remission 
at the time of transplant. Busulfan was administered once daily at 3.2 mg/kg IV x 4days 
(days -5 to -2) and Clofarabine once daily at 20, 30 or 40 mg/m2 IV x 5days (days -6 to -
2) with the specific dose determined by the Time to Event-Continuous Reassessment 
Method (TITE-CRM).  Of 46 patients enrolled, 31 patients had AML. Among AML 
patients, the median age was 53 years (range 1-68).  A quarter of patients had previous 
allogeneic HSCT, 45% had high risk cytogenetics, and 71% had circulating blasts at the 
time of transplant. In this very high-risk population, overall survival at 12 months was 
48%. As seen in the figure, the relapse rate in this population was much lower than 
historical control. 
Figure: Cumulative Incidence of relapse in AML patients, compared to historical control. 
Solid line: CloBu4, Broken line: Other myeloablative regimens. P=0.04
Using CloBu4 conditioning, we were successful in suppressing the relapse rate in this 
population, but some of these patients still relapse. To decrease the relapse rate 
furthermore, another approach to overcome aggressive leukemia should be sought.  
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2.1.3.
Relapsed AML after allogeneic HSCT, another population with Poor Prognosis 
Relapsed AML after allogeneic HSCT would conform another population of the patients 
with very poor prognosis¸ to median survival of only 3-4 months without active 
treatment. Particularly patients who relapsed within 6 months have <5% 1 year survival13-
15. Various treatment strategies such as decreasing immunosuppression, DLI, Azacitidine 
or second transplant can be employed in such patients. Second transplant could 
potentially provide with an opportunity for cure but the results in this highly selected 
group of patient who are eligible for second transplant are still disappointing with <20% 
6 month survival with especially poor survival in patient with residual disease at 
transplant. A recent study suggested superiority of second HSCT over chemotherapy(58 
vs 14%, 1 year survival) but the advantage was lost at 2 years due to relapse of disease16. 
Another study showed that remission could be achieved in all patients with second HSCT 
but was lead to failure again by disease relapse17. These patients can possibly achieve a 
remission with a second transplant more difficulty is in maintaining remission. A 
maintenance treatment strategy would theoretically of benefit in such population to 
achieve longer remission.
2.1.4.
Maintenance therapy after allogeneic stem cell transplantation
Although maintenance therapies are commonly used in the treatment of hematologic 
malignancies, such as acute lymphoblastic leukemia or multiple myeloma, the concept of 
maintenance therapy in AML after allogeneic HSCT is relatively new. One reason is that 
allogeneic HSCT has been considered as the “final” therapy, and physicians doing 
transplant have not been interested in giving any therapy after transplant.  This tendency 
was also supported by the idea of “graft-versus-leukemia (GVL) effect18. GVL effect 
itself is a sort of “maintenance therapy”, thus it was assumed that no other therapy is 
necessary. The other reason is that, because allogeneic HSCT itself has been associated 
with many complications, such as toxicity from high-dose chemotherapy, or graft-versus-
host disease (GVHD), physicians have been hesitating to give any treatment after 
allogeneic HSCT.  
This has been changing recently.  As maintenance therapy has become a standard after 
autologous stem cell transplantation for multiple myeloma, there have been studies giving 
salvage/maintenance therapy for myeloma, even after allogeneic stem cell 
transplantation19.  As stated above, allogeneic stem cell transplantation itself has many 
complications, so maintenance therapy agents should be less toxic. This has been 
impossible when mainstay of the leukemia/lymphoma/myeloma therapy has been 
cytotoxic chemotherapy. More recently, there have been many new agents, such as 
bortezomib (Velcade) or lenalidomide (Revlimid), introduced in the treatment of 
hematologic malignancies, most of them are targeted agents or agents with different 
mechanisms of action, and may not be very toxic. 
Azacitidine is one agent used for maintenance therapy for AML after allogeneic stem cell 
transplantation, study recently conducted at M. D. Anderson Cancer Center20. Azacitidine 
is a good agent for this purpose, but it is somewhat myelosuppressive, thus the dose being 
used for maintenance therapy is much lower (25 mg/m2/day as opposed to 75 mg/m2/day) 
than the usual dose. The study showed that in some relapsed AML cases Azacitidine was 
able to induce remissions. There is a concern if single agent Azacitidine is potent enough 
for very high risk AML remission maintenance. 
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2.1.5.
Use of Azacitidine post-transplant
Azacitidine has been used post-transplant for maintenance as well as treatment of patients 
with relapsed AML. A study recently reported by the MD Anderson group showed some 
efficacy of use of Azacitidine in post-transplant population for AML and MDS patients. 
Forty-five high-risk patients were treated. Median age was 60 years; median number of 
comorbidities was 3; 67% were not in remission. By using a Bayesian adaptive method to 
determine the best dose/schedule combination based on time to toxicity, the authors 
investigated combinations of 5 daily Azacitidine doses, 8, 16, 24, 32, and 40 mg/m2, and 
4 schedules: 1, 2, 3, or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 
started on Day +40. Reversible thrombocytopenia was the dose-limiting toxicity. The 
optimal combination was 32 mg/m2 given for 4 cycles. Median follow-up was 20.5 
months. One-year event-free and overall survivals were 58% and 77%21. In another 
recent publication, a combination of Azacitidine with gemtuzumab-ozogamicin was 
tested in ten patients with high-risk AML, eight males and two females, at a median age 
of 49.5 years (range: 17–65 years) as maintenance therapy after allogeneic stem cell 
transplant. AZA at 30 mg/m2 was administered intravenously on days 1–7, followed by 
GO at 3 mg/m2 on day 8. AZA-GO was repeated every 4 weeks or as soon as possible 
after hematological recovery. All patients developed grade IV hematological toxicities 
and received platelet transfusions. The overall survival was 70% at 1 year with disease 
free survival at 60%22. 
Studies are also published showing activity of Azacitidine in relapsed AML after 
allogeneic SCT. It has been shown to re induce complete remissions in this high 
pretreated and resistant population23. This shows the likely activity of Azacitidine alone 
and in combination post-transplant but the common toxicity in all these studies is 
hematologic toxicity which likely could be improved by reducing the dose of Azacitidine 
but that in turn would limit the leukemicidal ability of Azacitidine necessary to overcome 
the relapsing disease and to allow enough time for the GVL effect to take place to induce 
long term remission. Multiple studies have also published result in evaluating the effects 
of Azacitidine on GVHD. There is convincing evidence that Azacitidine infusion in post-
transplant population can lead to in vivo expansion of regulatory T cell (CD4+ CD25+ 
FOXP3+ T cells) which can reduce GVHD while having no significant effect on GVL 
effect24, 25. This dual purpose of Azacitidine can make it an ideal drug for post-transplant 
treatment and maintenance therapy however again as mentioned above the therapeutic 
potential in anti-leukemia activity is limited by dose limitation due to hematologic 
toxicity.
2.2.
Scientific Background of Pevonedistat
The ubiquitin-proteasome system (UPS) is responsible for much of the regulated protein turnover 
in the cell. The UPS maintains cellular homeostasis and impacts signaling pathways that regulate 
cell cycle progression and regulation of transcription. It is a complex, multi-protein system that 
utilizes distinct enzyme classes that coordinate ubiquitination and mediate ubiquitin-dependent 
degradation through the proteasome26. A proteasome inhibitor, bortezomib, was shown to be 
very effective in the treatment of various hematologic malignancies including multiple myeloma 
and mantle cell lymphoma, suggesting that compounds targeting other components of the UPS 
could prove useful in the treatment of malignancies. 
The polyubiquitination reaction involves the coordination of 3 classes of enzymes, E1 (ubiquitin 
activating), E2 (ubiquitin conjugating), and E3 (ligases). The E3 ligases are multiprotein 
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complexes whose specificity is established by the members of the protein complex. A subset of 
E3 ligases, cullin-dependent ubiquitin E3 ligases (CDLs) also undergoes neddylation and this 
modification is necessary for their activity. Activation of the Nedd8 pathway that leads to 
conjugation of the E3 ligases with Nedd8 shares similarities to the ubiquitin conjugating system. 
Nedd8-activating enzyme (NAE) is the first step in activation of the neddylation pathway and 
through transfer to the conjugating enzyme, Ubc12, leads to neddylation of the cullin family of 
proteins27. The cullin-specific ligases control the timely ubiquitination and subsequent 
degradation of many proteins with important roles in cell cycle progression (such as p27, cyclin 
E), DNA damage (chromatin licensing and DNA replication factor-1 [Cdt-1]), stress response 
(nuclear factor (erythroid derived 2)-related factor 2 [NRF-2], hypoxia-inducible factor 1alpha 
[HIF-1α]), and signal transduction (phosphorylated I kappa B alpha [pIκBα]).
Pevonedistat (also known as TAK 924 and MLN4924; hereinafter referred to as Pevonedistat) is 
a first-in-class, small molecule inhibitor of neural precursor cell expressed, developmentally 
down-regulated 8 (NEDD8)-activating enzyme (NAE) under development for the treatment of 
malignancies. The NEDD8 conjugation (neddylation) pathway is responsible for much of the 
regulated protein turnover in the cell26, 27, which is similar to the ubiquitin-proteasome system 
(UPS). However, UPS is known to regulate a myriad of processes in eukaryotic cells, whereas 
only a limited number of neddylation substrates have been described to date. VELCADE® 
(bortezomib) for Injection, a drug that acts by inhibiting the 26S proteasome, has proven utility 
in the treatment of multiple myeloma and mantle cell lymphoma28. Therefore, it is anticipated 
that other compounds directed against different components of the UPS and/or the NEDD8 
conjugation pathway may prove useful in the treatment of malignancies.
NAE, E1 ligase, is an essential component of the NEDD8 conjugation pathway, which initiates 
the neddylation to protein substrates. Specifically, NEDD8 conjugation to cullin dependent 
ubiquitin E3 ligases (CDLs) is necessary for their activity. The ligases in the NEDD8 
conjugation pathway control the timely neddylation of many substrate proteins with important 
roles in cell cycle progression and signal transduction. The ubiquitination/neddylation of proteins 
targets them for proteasomal degradation. These cellular processes are relevant to tumor cell 
growth, proliferation, and survival; as such, inhibitors of NAE activity may be of therapeutic 
value in the treatment of various cancers by inhibiting the degradation of a subset of proteins that 
are regulated by the proteasome. In nonclinical studies, treatment of cells with Pevonedistat 
results in the accumulation of CDL substrates, followed by a deoxyribonucleic acid (DNA) 
damage response and cell death. Pevonedistat treatment results in tumor growth inhibition (TGI) 
in mouse tumor xenograft models of solid tumors, lymphoma, and acute myeloid leukemia 
(AML).
2.3.
Preclinical Experience with Pevonedistat
Pevonedistat is a potent and selective inhibitor of NAE activity (Pevonedistat was at least 300- 
and 1800- fold more selective for NAE than for the closely related ubiquitin activating enzyme 
and sumo activating enzyme, respectively). Pevonedistat treatment of cultured tumor cells 
resulted in growth inhibition of a wide variety of cell lines derived from acute leukemia’s, 
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 apoptosis29-31. When administered in 
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combination with hypo ethylating agents Azacitidine and Decitabine demonstrated synergistic 
activity in AML cell lines.
Pevonedistat demonstrated pharmacodynamic and antitumor activity in solid tumor, lymphoma, 
and AML xenograft models when administered to immunocompromised mice by the 
subcutaneous (SC) route. Antitumor activity of Pevonedistat in mice bearing HL-60 and THP-1 
tumor xenografts was enhanced by combination treatment with Azacitidine. Combination 
treatment with Pevonedistat and docetaxel significantly inhibited tumor growth in the PHTX-
02B primary human breast cancer model and the LU1143 primary human squamous non-small 
cell lung cancer (sqNSCLC) xenograft model. Combination treatment with Pevonedistat and 
carboplatin in both NCI-H69 human small cell lung cancer (SCLC) xenografts and LU1143 
primary sqNSCLC xenografts resulted in significant antitumor activity.
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 800mg/m2, respectively), 
Pevonedistat was not well tolerated at doses ≥30 mg/kg (≥600mg/m2). Mortality and/or 
moribundity were observed within 24 hours post dose as a result of gastrointestinal injury at 40 
mg/kg. Increased heart rate was observed at all doses. 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 dose-limiting toxicities (DLTs) in the 2-cycle studies for rats and dogs 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 sites 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. Pevonedistat 
was not mutagenic in the bacterial reverse mutation assay (Ames assay).
Pevonedistat was highly bound in whole blood and plasma of mice, rats, dogs, monkeys and 
humans. No metabolite unique to humans was observed in vitro. In vitro, Pevonedistat is 
predominantly metabolized by the cytochrome P450 (CYP) isozyme 3A4. There is potential for 
drug drug interactions (DDIs) if Pevonedistat is co-administered with drugs that are CYP3A 
inhibitors or inducers. Pevonedistat is neither an inhibitor of CYP1A2, 2C9, 2C19, 2D6, or 
3A4/5 (IC50 > 100 µM and Ki > 50 µM) nor an inducer of CYP1A2, 2B6, or 3A4/5 (at 
concentrations up to 30 µM), but is a weak inhibitor of CYP2B6 and 2C8 (IC50 = 97.6 and 23.1 
µM, respectively). The major elimination pathway of Pevonedistat in animals is through the 
hepatic route. Pevonedistat is a substrate of P-glycoprotein (P-gp), breast cancer resistance 
protein (BCRP), and multidrug resistance protein 2 (MRP2) in Caco 2 cells. Pevonedistat is also 
a weak inhibitor of P-gp (IC50 = 41.2 to 56.0 µM) and BCRP (IC50 = 6.3 µM), but not of MRP2 
(IC50 > 200 µM). Additionally, Pevonedistat is not a substrate for organic anion-transporting 
proteins (OATPs).
Detailed information regarding the nonclinical pharmacology and toxicology of Pevonedistat is 
provided in the Investigator’s Brochure (IB).
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2.4.
Clinical Experience with Pevonedistat
The clinical development program of Pevonedistat began with 4 phase 1 studies of single agent 
Pevonedistat at doses ranging from 25 to 278 mg/m2:

Study C15001 in patients with solid tumors32.

Study C15002 in patients with lymphoma or multiple myeloma33. 

Study C15003 in patients with AML, high-grade myelodysplastic syndrome (MDS), or 
acute lymphoblastic leukemia (ALL)34.

Study C15005 in patients with melanoma35.
In these studies, toxicity involving multi organ failure on C1D1, including serious adverse events 
(SAEs) of renal, hepatic, and cardiac failure, some with a fatal outcome, was identified at doses 
equal to or above 110 mg/m2. On the basis of a comprehensive review of the available phase 1 
clinical safety data at the time, a revised risk mitigation strategy, including limiting the dose to 
no higher than 100 mg/m2 for single agent administration, was implemented across the 
Pevonedistat program in October 2012. The current understanding of the renal toxicity observed 
with Pevonedistat suggests that it is not a primary event but is likely secondary to hemodynamic 
changes occurring in the setting of a type of acute phase response.
As of January 2017, a total of 227 patients were treated in single agent phase I and a total of 451 
patients received at least one dose of Pevonedistat including combination studies, and no C1D1 
SAEs of multi-organ failure as described above have been observed. These patients received 
Pevonedistat at a dose of 50 to 100 mg/m2 as a single agent (after October 2012), a dose of 15 to 
30 mg/m2 in combination with different standard of care therapies, or a dose of 8 mg/m2 to 20 
mg/m2 in combination with a CYP3A inhibitor.
Current development is focused on Pevonedistat in combination with standard clinically 
available therapies in hematologic malignancies and solid tumors. Two phase 1b clinical studies 
are closed to enrollment but are still ongoing with active patients:

Study C15009 (phase 1b) evaluated the maximum tolerated dose (MTD) of 
Pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2 Azacitidine 
(administered on a 5-on/2-off [weekend]/2-on schedule) in a 28 day treatment cycle in 
elderly patients with treatment-naïve AML36.

Study C15010 (phase 1b) evaluated the MTD of Pevonedistat plus docetaxel, 
gemcitabine, or the combination of carboplatin and paclitaxel, in patients with solid 
tumors37, 38.
Additionally, Study C15011 (phase 1) is evaluating the effects of CYP3A mediated inhibition of 
Pevonedistat in patients with solid tumors (DDI assessment; Part A). After completion of the 
DDI assessment portion of the study, patients have the opportunity to continue in the study by 
participating in Part B (Pevonedistat plus docetaxel or the combination of carboplatin and 
paclitaxel).
The cumulative enrollment in all clinical studies through 22 January 2017 is approximately 451 
patients (defined as having received at least 1 dose of study drug).
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Two studies are currently enrolling: 

Study 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.

Study 1012: A phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as 
Single Agent and in Combination with Azacitidine in adult East Asian patients with 
acute myeloid leukemia or myelodysplastic syndromes
2.4.1.
Pharmacokinetics 
The clinical pharmacokinetics (PK) of Pevonedistat have been evaluated in 4 
monotherapy phase 1 studies in 96 patients with solid tumors (C15001 and C15005) and 
109 patients with hematologic malignancies (C15002 and C15003). These studies have 
evaluated the single- and multiple-dose PK of Pevonedistat administered via IV infusion 
across the 25 to 278 mg/m2 dose range and at various daily or intermittent dosing 
schedules within 21 day treatment cycles. 
Plasma concentrations of Pevonedistat declined in a bi-exponential manner at the end of 
IV infusion, with little or no drug accumulation following intermittent dosing or once-
daily dosing for 5 consecutive days of a 21 day cycle. Mean terminal disposition t1/2z 
was estimated to be approximately 10 hours (range 7.7-15.2) across doses and schedules. 
Consistent with in vitro data, Pevonedistat is extensively partitioned in human blood 
(mean blood-to-plasma concentration ratio of approximately 65) with whole blood and 
plasma kinetics declining in parallel over time. Pevonedistat generally exhibited linear 
PK over the dose range studied. Observed inter individual variability (IIV) was generally 
moderate with 18% to 41% coefficient of variation (CV) for maximum concentration 
(Coax), 12% to 56% CV for area under the plasma concentration-time curve from time 
zero to 24 hours post dose (AUC24), and 15% to 33% CV for the area under the plasma 
concentration-time curve from time zero to the end of the dosing interval when 
Pevonedistat was administered on Days 1, 3, and 5. Body size influences Pevonedistat 
systemic clearance and volume of distribution, thus supporting body surface area (BSA)-
normalized dosing to reduce variation in systemic exposure of Pevonedistat in cancer 
patients. Pevonedistat clearance tended to gradually decrease in elderly patients (by 
approximately 25% over the 30-90 age range). There was also no apparent effect of renal 
function status (as assessed by estimated creatinine clearance > 30 mL/min) on 
Pevonedistat PK. 
Additionally, evaluation of Pevonedistat PK is ongoing for 2 studies of Pevonedistat in 
combination with different standard-of-care therapies, and for a DDI study evaluating the 
effects of CYP3A mediated inhibition on Pevonedistat. Pevonedistat PK was not altered 
in the presence of Azacitidine when compared to historical single agent data. Also, no 
obvious changes in the PK behavior of Pevonedistat in the presence of docetaxel or 
gemcitabine have been observed whereas a trend towards increasing plasma 
concentrations of Pevonedistat in the presence of carboplatin + paclitaxel was evident 
[12-13]. This apparent drug interaction effect, which cannot be explained at this time, 
warrants further understanding of the disposition properties of Pevonedistat in humans. 
Lastly, multiple doses of fluconazole, a moderate CYP3A inhibitor, had minimal effect 
(13% increase in mean area under the plasma concentration time curve from zero to 
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infinity [AUCinf]) on the single-dose IV PK of Pevonedistat, while Pevonedistat systemic 
exposure increased by 23% on average in the presence of the strong CYP3A inhibitor, 
itraconazole.
For detailed information please consult the current IB.
   
2.4.2.
Pharmacodynamics
Preliminary data provide evidence of pathway inhibition downstream of NAE and 
biological activity of Pevonedistat in skin and tumor tissue (solid tumor or AML bone 
marrow derived blasts) at all doses tested in pharmacodynamic assays. These doses range 
from 25 to 261 mg/m2 across the various single-agent, phase 1 Pevonedistat trials.
For detailed information please consult the current IB.
   
Summary of Safety and Efficacy Data Findings Available on Takeda 
Sponsored Trials
For detailed information please consult the current IB.
   
2.4.3.
Phase 1 Monotherapy Studies
Overall, 99 patients with advanced solid tumors or melanoma in Study C15001 and Study 
C15005 were treated with single-agent Pevonedistat at doses ranging from 25 to 278 
mg/m2. Common AEs (reported by ≥ 25% of patients in either study) were fatigue, 
nausea, anemia, decreased appetite, vomiting, diarrhea, myalgia, constipation, arthralgia, 
dizziness, and peripheral neuropathy. DLTs included increased LFTs, increased 
creatinine, acute renal failure and acute hepatic failure, hypophosphatemia, and 
myocarditis. Acute renal failure occurred in 3 patients: 2 patients on Study C15001 at 196 
mg/m2 (1 patient also reported acute hepatic failure); and 1 patient on Study C15005 at 
157 mg/m2, who also reported myocarditis and hyperbilirubinemia. Deaths on study that 
were considered related to study treatment included multi-organ failure (at 61 mg/m2 QD 
× 5 consecutive days and 196 mg/m2 in Study C15001), disease progression (at 83 mg/m2 
in Study C15001), and renal failure acute (at 209 mg/m2 in Study C15005).
A total of 128 patients with hematologic malignancies (lymphoma, multiple myeloma, 
AML, MDS, or ALL) in Study C15002 and Study C15003 were treated with single-agent 
Pevonedistat at doses ranging from 25 to 261 mg/m2. Common AEs (reported by ≥ 25% 
of patients in either study) were ALT increased, anemia, AST increased, chills, 
constipation, decreased appetite, diarrhea, dizziness, dyspnea, fatigue, febrile 
neutropenia, headache, muscle spasms, myalgia, nausea, peripheral edema, pyrexia, and 
vomiting. DLTs included increased LFTs, febrile neutropenia, muscle spasms, 
thrombocytopenia, acute renal failure, orthostatic hypotension, cardiac failure, rash 
morbilliform, GI necrosis, hypotension, lactic acidosis, and myocardial ischemia. Deaths 
on study that were considered related to study treatment (all in Study C15003) included 2 
deaths from multi organ failure (at 110 and 147 mg/m2), 1 from sepsis (at 78 mg/m2), and 
1 from cardiopulmonary failure (at 45 mg/m2). 
The primary aims of the phase 1 monotherapy studies were to establish the safety profile 
and to determine the MTDs of Pevonedistat administered by several different dose 
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schedules in both hematologic and solid tumor settings. While safety, PK, and 
pharmacodynamic objectives were the primary focus of these studies, disease response 
was also assessed. A total of 12 patients experienced PRs or better in the phase 1 
monotherapy studies.
   
2.4.4.
Phase 1 Combination Studies
C15009
Study C15009 is an ongoing phase 1b study evaluating the MTD of Pevonedistat on Days 
1, 3, and 5 in combination with 75 mg/m2 Azacitidine (administered on a 5-on/2-off 
[weekend]/2-on schedule) in a 28-day treatment cycle in patients 60 years of age or older 
with treatment naïve AML who are unlikely to benefit from standard induction therapy. 
As of 22 June 2016, enrollment had completed and 15 patients remained on study. As of 
22 January 2017, preliminary data are available for 64 patients enrolled in the study who 
received at least 1 dose of Pevonedistat in combination with Azacitidine; these patients 
had completed a total of approximately 360 cycles, with a median of 4 cycles of 
treatment.   In the dose escalation cohorts, 6 patients received 20 mg/m2 Pevonedistat, 
and 3 patients received 30 mg/m2.   The most common events (reported by ≥ 25% of 
patients) were constipation (45%), nausea (42%), fatigue (39%), anemia (34%), febrile 
neutropenia (30%), decreased appetite (28%), and thrombocytopenia (27%). The MTD in 
this study was determined to be 20 mg/m2 Pevonedistat given on Days 1, 3, and 5, in 
combination with 75 mg/m2 Azacitidine given on Days 1 through 5, 8, and 9, in 28 day 
treatment cycles. A total of 45 (70%) patients experienced at least 1 SAE A total of 14 
SAEs were reported for more than 1 patient, including: febrile neutropenia (16 patients); 
pneumonia (8 patients); pyrexia (4 patients); AML and sepsis (3 patients); and acute 
myocardial infarction, cellulitis, diverticulitis, dyspnea, embolism, hypoxia, mental status 
changes, multi-organ failure, and transaminase increased (2 patients each).   A total of 19 
patients treated with Pevonedistat (either 20 mg/m2 or 30 mg/m2), discontinued from 
Study participation because of a TEAE. No other events leading to discontinuation were 
assessed by study investigators as at least possibly related to study drug treatment. 11 on–
study deaths had been reported; none assessed as related to study treatment. A total of 31 
patients experienced PR or better. Eighteen patients had a best response of CR, 4 patients 
had a best response of CRi, and 9 patients had a best response of PR. One patient in the 
30 mg/m2 dose level group achieved a CR; all other responses occurred in patients treated 
with 20 mg/m2.
C15010
Study C15010 is an ongoing phase 1b study evaluating the MTD of Pevonedistat plus 
docetaxel, gemcitabine, or a combination of carboplatin and paclitaxel, in patients with 
solid tumors. As of 22 January 2017, enrollment has completed; 2 patients remain on 
study. The treatment arms are: 

Arm 1: Pevonedistat dosing on Days 1, 3, and 5 with 75 mg/m2 docetaxel dosing 
on Day 1 in a 21-day cycle.

Arm 2 Lead-in: Pevonedistat dosing on Days 1, 3, and 5 with AUC6 carboplatin 
dosing on Day 1 in a 21-day cycle.

Arm 2: Pevonedistat dosing on Days 1, 3, and 5 with paclitaxel dosing on Day 1 
and carboplatin dosing on Day 1 in a 21-day cycle. Per protocol, the dose levels 
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for paclitaxel and carboplatin were to be based on the DLTs in the Arm 2 Lead-in 
cohort; because there were 2 DLTs in the Arm 2 Lead-in cohort doses were set at 
175 mg/m2 paclitaxel and AUC5 for carboplatin. 

Arm 3: Pevonedistat dosing on Days 1, 8, and 15 with 1000 mg/m2 gemcitabine 
dosing on Day 1, 8, and 15 in a 28-day cycle.
As of 22 January 2017, preliminary data are available for 64 patients enrolled who 
received at least 1 dose of Pevonedistat in combination with standard of care; these 
patients had completed a total of approximately 330 cycles, with medians ranging from 2 
to 6 cycles of treatment across the 4 treatment groups. The starting dose levels for dose 
escalation and determination of Pevonedistat MTD were 15 mg/m2 for Arm 1 and Arm 2, 
and 25 mg/m2 for Arm 3. Overall, the most common AEs (occurring in ≥ 25% of patients 
were fatigue (56%), nausea (48%), anemia (41%), diarrhea (34%), constipation and AST 
increased (31% each), ALT increased (30%), and vomiting (28%).
Per the data cut off, 15 patients experienced Cycle 1 DLTs in Study C15010. Increased 
ALT or AST (or both) accounted for DLTs in 11 patients, febrile neutropenia was 
reported for 3 patients, and 1 patient experienced thrombocytopenia. 
The MTD for Arm 1 was determined to be 25 mg/m2 Pevonedistat (dosing on Days 1, 3, 
and 5 with 75 mg/m2 docetaxel dosing on Day 1 in a 21 day cycle). No MTD was 
determined for the Arm 2 Lead-in per protocol, but these DLTs informed the dose 
selection for paclitaxel and carboplatin in Arm 2: paclitaxel dose 175 mg/m2 and a 
reduced dose for carboplatin of AUC5. The MTD for Arm 2 was determined to be 20 
mg/m2 Pevonedistat (dosing on Days 1, 3, and 5 with 175 mg/m2 paclitaxel and AUC5 
carboplatin dosing on Day 1 in a 21 day cycle). The gemcitabine combination arm (Arm 
3) was closed to enrollment due to lack of tolerability (MTD was not determined). A total 
of 26 (41%) patients experienced at least 1 SAE. Febrile neutropenia was the only event 
reported for at least 1 patient in each of the 4 treatment arms (reported for 2 of 26 patients 
in Arm 2 and 2 of 10 patients in Arm 3). Dyspnea was reported for 3 of the 22 patients in 
Arm 1 and for 1 patient in Arm 3. Abdominal pain was reported for 1 patient each in Arm 
1 and Arm 3 and pneumonia was reported for 2 patients in Arm 1; all other events were 
reported for only 1 patient across the treatment arms. Fifteen patients discontinued the 
Study because of TEAEs. Events that resulted in study discontinuation that were assessed 
at least possibly related to study drug treatment included ALT and AST increased, blood 
bilirubin increased, and blood creatinine increased (1 patient each in Arm 1); platelet 
count decreased, peripheral neuropathy, and neutropenia (1 patient each in Arm 2); 
leukopenia, lymphopenia, and pneumonitis (1 patient each in Arm 3), and febrile 
neutropenia (2 patients in Arm 3). Six on study deaths (within 30 days of the last dose of 
study drug) were reported with one death (Arm 3; due to febrile neutropenia) assessed as 
related to study treatment (Pevonedistat and gemcitabine). Twelve patients on Study 
C15010 had achieved PR or better. Two patients in Arm 2 achieved a CR; 3 patients in 
Arm 1, 1 patient in the Arm 2 Lead in, and 6 patients in Arm 2 achieved a PR.
C15011
Study C15011 is an ongoing phase 1 study evaluating the PK drug interaction between
pevonedistat and CYP3A inhibitors (fluconazole or itraconazole) in patients with 
advanced solid tumors (Part A). As of 22 January 2017, enrollment has completed. In 
Part A of Study C15011, patients receive a single dose of Pevonedistat given as an IV 
infusion on Day 1 and Day 8, and either concomitant oral fluconazole or itraconazole on 
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Day 4 through Day 10. Patients are assessed for eligibility to continue in Part B (optional) 
after completion of Part A during a 2- to 8 week washout period. Thirty-six of the
51 patients enrolled in Study C15011 continued into Part B of the study, with 4 patients
ongoing as of 22 January 2017. The 36 patients in Part B have received a total of
approximately 203 cycles of pevonedistat in combination with either docetaxel (n=23;
median, 4 cycles; range, 2-10) or the combination of carboplatin and paclitaxel (n=13;
median, 5 cycles; range, 2-27). Data are available for 51 patients in Study C15011 as of 
22 January 2017; 36 patients continued into Part B of the study, with 4 patients ongoing 
as of this date. Overall, the most common AEs (occurring in ≥30% of patients in Part A 
or Part B) were fatigue, vomiting, nausea, decreased appetite, dehydration, constipation, 
anemia, stomatitis, diarrhea, headache, and hypokalaemia. Most SAEs (inclusive of Part 
A and Part B) were reported for 1 patient only; events reported for 3 or more patients 
included dyspnea (6 patients); pneumonia (5 patients); abdominal pain, abdominal pain 
upper, nausea, vomiting, failure to thrive, aspiration pneumonia, hypotension (4 patients 
each); and small intestinal obstruction, hyperkalemia (3 patients each). Thirty (59%) 
patients who participated in Part A experienced an SAE; in Part B, 16 (70%) patients in 
the pevonedistat+docetaxel group and 6 (46%) patients in the carboplatin+paclitaxel 
group also experienced an SAE. All but 2 of these SAEs (esophageal hemorrhage and 
dyspnoea) occurred during the washout period. Esophageal bleeding started before the 
second dose of itraconazole; dyspnoea was reported after the last dose of fluconazole and 
within the same month as the last dose of fluconazole, so it is within 2 weeks of the 
washout period, but the exact date is unknown. Six patients experienced a total of 10 
SAEs during Part B that were assessed as related to study treatment; these events 
included pneumonia (reported for 2 patients), nausea and vomiting, chest discomfort and 
dyspnea, septic shock, failure to thrive and hypovolemic shock, and respiratory failure. 
As of 22 January 2017, 4 patients in Study C15011 achieved a PR in Part B of the study.
2.5.
Potential risks of Pevonedistat
There are potential risks in the Pevonedistat program that require monitoring. While these toxicities 
may be severe or life threatening, it is anticipated that they can be managed by clinical monitoring and 
intervention. Patients will be monitored for these potential toxicities and for unanticipated toxicities 
when they receive Pevonedistat for at least 30 days after their last dose.
   
2.5.1.
Potential Risks from Phase 1 Studies 
Events have been reported in completed phase 1 studies primarily at doses and schedules 
substantially higher than doses administered in current clinical studies. These events are being 
considered potential risks for the doses and schedules in the current studies, as follows:

Multi-organ failure that could result in death.

Renal failure.
o
The events of multi organ failure (hepatic, renal, and cardiac) with a fatal 
outcome, and renal failure alone, have been reported at doses of 
Pevonedistat ranging from 110 to 278 mg/m2.

Cardiac arrhythmias.
o
All events were supraventricular arrhythmias; all except 1 were unrelated. 
The events of supraventricular arrhythmias were all considered as 
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unrelated to Pevonedistat except for 1 event of atrial fibrillation that 
occurred in a patient with a history of risk factors for cardiac disease.

Myelosuppression with increased susceptibility to infection, bleeding, and anemia.

Acute phase response.

GI toxicity including or resulting in dehydration and/or electrolyte imbalance.

Hypophosphatemia.
2.5.2.
Potential Risks Confounded by Underlying Disease or Malignancy
Events have been reported from clinical trials that are confounded by the patient’s underlying 
medical condition, including malignancy. These events are noted in the absence of randomized, 
controlled data:

Fatigue.

Chills.

Decreased appetite.

Neutropenia.

Febrile neutropenia.

GI bleeding.
o
All events were assessed by the investigator as unrelated; the majority 
occurred in the setting of thrombocytopenia.
2.5.3.
Potential Risks Primarily Based on Findings from Animal Studies
Potential risks that are derived from findings in animal studies in rats and dogs include:

Myocardial degeneration and thrombosis.

Pulmonary hypertension.

Cardiovascular changes that could result in tachycardia, decreased or increased systolic 
blood pressure, and increased diastolic blood pressure.

Enteropathy (including dehydration and electrolyte loss) with secondary sepsis.

Effects on the testes and ovaries that represent a reproductive hazard including sterility.

Increased developmental risk to the 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 aPTT.

Local tissue injury when administered SC.

It is possible that Pevonedistat will have toxicities that were not observed in or predicted from 
the studies completed in rats and dogs, or have not yet been identified in patients, which may be 
severe or fatal.
For detailed information please consult the current IB.
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2.5.4.
Additional Safety Considerations
Cycle 1, Day 1 Toxicity/Multi Organ Failure
A comprehensive review of the clinical trial safety data has shown that C1D1 toxicity involving 
multi-organ failure, including SAEs of renal, hepatic, and cardiac failure, some with a fatal 
outcome, has been observed in phase 1, single agent Pevonedistat studies at doses equal to or 
above 110 mg/m2. Based on the observation that these events are associated with higher 
Pevonedistat doses, Millennium Pharmaceuticals, Inc. determined that all newly enrolling 
patients would receive Pevonedistat at doses equal to or below 100 mg/m2. 
The current understanding of the renal toxicity observed with Pevonedistat suggests that it is not 
a primary event but is likely secondary to hemodynamic changes occurring in the setting of a 
type of acute phase response.
Nonclinical investigative activities were undertaken to better understand the potential physiology 
behind the C1D1 events observed with Pevonedistat dosing. As summarized in the latest IB, a 
model in which a minimally toxic, single dose of Pevonedistat was administered with TNFα had 
several hallmarks associated with septic and/or cytokine-induced shock. The overall time course 
and target organs affected in this nonclinical model also appeared to closely mimic those 
observed in clinical C1D1 events at single agent doses ranging from 110 to 278 mg/m2.
In October 2012, a revised risk mitigation strategy including limiting the dose to no higher than 
100 mg/m2 for single agent administration was implemented across the Pevonedistat program. 
As of January 2016, approximately 180 additional patients have been treated in single agent and 
combination studies, and no C1D1 SAEs as described above have been observed. These patients 
received Pevonedistat at a dose of 50 to 100 mg/m2 as a single agent, a dose of 15 to 30 mg/m2 in 
combination with different standard of care therapies, or a dose of 8 mg/m2 in combination with 
a CYP3A inhibitor.
Guidance for Clinical Assessment and Management of Hemodynamic Compromise
Due to the underlying conditions of patients with advanced malignancies, patients must be 
carefully evaluated at screening and before each Pevonedistat dose for early symptoms and signs 
of hemodynamic compromise and active infection. Particular attention should be paid to 
unexplained fever, tachycardia, hypotension, orthostasis, tachypnea, recent nausea and vomiting, 
and clinical evidence of dehydration. For those 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. For all patients with anemia, and especially for patients 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 patient’s risk of inadequate oxygenation, 
underlying cardiopulmonary status, clinical judgment, and/or hospital guidelines. Patients who 
experience signs and symptoms of hemodynamic compromise after Pevonedistat dosing (e.g., 
tachycardia, hypotension, orthostasis, and changes in mental status, syncope, and dizziness) 
should be followed closely and managed with supportive care, including hospitalization as 
clinically indicated.
Guidance for Management of Patients with Blood Cell Counts Greater than 50,000/µL
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One patient died of AML complicated by leukostasis within hours after receiving the first dose 
of Pevonedistat. This patient experienced rapidly increasing blast counts (to levels greater than 
100,000/µL) before receiving the first dose of Pevonedistat on C1D1. This patient was not 
treated with hydroxyurea before receiving treatment with Pevonedistat. Patients with AML who 
experience extremely high leukemic blast cell count are at high risk of leukostasis, an AML 
complication characterized by an extremely elevated blast cell count causing symptoms of 
decreased tissue perfusion. To mitigate the risk of leukostasis, Study C15003 was amended to 
require that patients have a WBC count ≤ 50,000/µL at screening and before Pevonedistat dosing 
during the first cycle of treatment. 
In response to this event, AML clinical study protocols were updated to include a monitoring and 
treatment plan for leukocytosis and an exclusion criterion requiring a WBC count below 
50,000/µL at screening and on Pevonedistat dosing days in Cycle 1. For patients who develop 
symptoms of leukostasis while on the study, Pevonedistat treatment should be withheld until the 
leukostasis symptoms are controlled. Treatment of leukostasis symptoms may include 
leukapheresis and hydroxyurea administration per study site institutional guidelines. When the 
WBC count of the patient is < 50,000/µL and symptoms are improved, Pevonedistat treatment 
may be restarted after consulting with the project clinician.
Increases in Serum Creatinine
At current doses equal to or below 100 mg/m2 on a Day 1, 3, and 5 or a Day 1, 4, 8, and 11 
schedules, there have been reports of changes in serum creatinine from baseline levels of Grade 0 
to Grade 1, and from baseline levels of Grade 1 to Grade 2.
Increases in Liver Enzymes and Biochemical Tests
Grade 1 to Grade 4 increases in adverse events related to liver function analyses (such as for 
liver transaminases [up to Grade 4], bilirubin [up to Grade 3], and alkaline phosphatase [up to 
Grade 3]), have been noted following administration of Pevonedistat in patients with advanced 
malignancies receiving Pevonedistat as a single agent and in combination with standard of care 
cytotoxic therapies. Among the single-agent studies, one patient in Study C15001 with metastatic 
colon cancer experienced a Grade 4 adverse event related to liver function analyses (alanine 
aminotransferase increased). In Study C15009, in patients with AML treated with Pevonedistat 
in combination with Azacitidine, Grade 4 increases for adverse events related to liver function 
analyses occurred in 2 patients as DLTs (alanine aminotransferase increased, aspartate 
aminotransferase increased). A third patient in Study C15009 experienced a Grade 4 adverse 
event (aspartate aminotransferase increased) that was not assessed as a DLT. In Study C15010 in 
patients with solid tumors treated with Pevonedistat in combination with docetaxel, gemcitabine, 
or carboplatin plus paclitaxel, and also in Study C15011, a drug-drug interaction study, adverse 
events related to liver function analyses up to Grade 3 were observed. 
All patients experiencing these increases in laboratory values have been asymptomatic. The 
elevations in laboratory values have been reversible with dose modification including dose delay 
and reduction.
Drug Drug Interactions (DDIs)
Because the metabolic and excretion pathways of Pevonedistat remain to be characterized in 
humans, the risk of DDIs between Pevonedistat and concomitantly administered drugs is 
currently informed by available nonclinical and clinical data. On the basis of preliminary 
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findings, administration of Pevonedistat with moderate CYP3A inhibitors is permitted, while use 
of strong CYP3A inhibitors or inducers should be avoided. On the basis of in vitro transport 
studies, and until further investigation is performed, co administration with BCRP inhibitors 
should not be allowed in clinical studies of Pevonedistat.
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.
Experience with Pevonedistat in AML induction and post-transplant treatment 
It has been reported that there were 15 patients placed in phase I relapse or refractory AML protocol 
(Study C15003).  Among them, 3 complete remissions have been recorded.  Toxicities were not much, 
only reversible liver enzyme abnormalities. It is of note that no myelosuppression was reported. One 
patient who relapsed early after CloBu4 transplant (who was treated with Pevonedistat after relapse) 
and brought back into remission with 100% donor cells in bone marrow, without much toxicity.  She 
was treated with 25 mg dose level. Afterwards she remained in CR for more than 8 months. Another 
patient who also relapsed early after stem cell transplant, and placed on this agent, went into CRi 
(without platelet recovery).  In addition, other post-transplant patients had either hematologic 
improvement or partial response in granulocytic sarcoma. Although only a few cases, this experience 
may suggests us that Pevonedistat may work very well after allogeneic HSCT, with only little toxicity. 
An agent which is not myelosuppressive, and not too toxic after allogeneic HSCT, is ideal for 
maintenance therapy after HSCT.  
2.6.
Azacitidine and Pevonedistat as combination therapy for AML
In preclinical studies Pevonedistat has shown significant single agent activity against mouse xenograft 
models of AML cell Line HL-60. Also this effect seemed to be synergistically enhanced by combining 
it with Azacitidine. In clinical arena, Pevonedistat has shown single agent activity in heavily pretreated 
patients with AML. In Study C15003, responses (complete responses [CRs] and partial responses 
[PRs]) were observed in a variety of patient settings, including post allogeneic transplant, therapy-
related AML, and primary refractory AML, although some of the responses were of relatively short 
duration. Study C15009 is an ongoing phase 1b study evaluating the MTD of Pevonedistat on Days 1, 
3, and 5 in combination with 75 mg/m2 Azacitidine (administered on a 5-on/2-off [weekend]/2-on 
schedule) in a 28-day treatment cycle in patients 60 years of age or older with treatment naïve AML 
who are unlikely to benefit from standard induction therapy. As of 22 June 2017, enrollment had 
completed and 15 patients remained on study. As of 22 January 2017, preliminary data are available 
for 64 patients enrolled in the study who received at least 1 dose of Pevonedistat in combination with 
Azacitidine; these patients had completed a total of approximately 360 cycles, with a median of 4 
cycles of treatment In the dose escalation cohorts, 6 patients received 20 mg/m2 Pevonedistat, and 3 
patients received 30 mg/m2. The most common events (reported by ≥ 25% of patients) were 
constipation (45%), nausea (42%), fatigue (39%), anemia (34%), febrile neutropenia (30%), decreased 
appetite (28%), and thrombocytopenia (27%). The MTD in this study was determined to be 20 mg/m2 
Pevonedistat given on Days 1, 3, and 5, in combination with 75 mg/m2 Azacitidine given on Days 1 
through 5, 8, and 9, in 28 day treatment cycles. A total of 45 (70%) patients experienced at least 1 
SAE A total of 14 SAEs were reported for more than 1 patient, including: febrile neutropenia (16 
patients); pneumonia (8 patients); pyrexia (4 patients); AML and sepsis (3 patients); and acute 
myocardial infarction, cellulitis, diverticulitis, dyspnea, embolism, hypoxia, mental status changes, 
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multi-organ failure, and transaminase increased (2 patients each). A total of 19 patients treated with 
Pevonedistat (either 20 mg/m2 or 30 mg/m2), discontinued from Study participation because of a 
TEAE. No other events leading to discontinuation were assessed by study investigators as at least 
possibly related to study drug treatment. 11 on–study deaths had been reported; none assessed as 
related to study treatment. A total of 31 patients experienced PR or better. Eighteen patients had a best 
response of CR, 4 patients had a best response of CRi, and 9 patients had a best response of PR. One 
patient in the 30 mg/m2 dose level group achieved a CR; all other responses occurred in patients 
treated with 20 mg/m2.
The following studies are currently enrolling. 

Study 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.

Study 1012: A phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as Single 
Agent and in Combination with Azacitidine in adult East Asian patients with acute myeloid 
leukemia or myelodysplastic syndromes
Hence owing to the current knowledge of clinical and preclinical experience with Azacitidine and 
Pevonedistat alone and in combination, this combination appears feasible for testing in patients post-
transplant with at very high risk of relapse.
2.7.
Proposed Study 
We propose a study using a combination of Pevonedistat and Azacitidine for maintenance therapy after 
allogeneic HSCT for non-remission. Patients will receive up to five 28 day cycles of the investigational 
maintenance therapy.  Maintenance therapy will begin between days +30 to +45 post-transplant.
3.0
Inclusion and Exclusion Criteria
3.1.
Inclusion Criteria for Study Registration
1. Age ≥ 18 years (or age of majority at participating site, whichever is greater) and ≤ 75 years.
2. Non-remission AML at the time of transplant proven via bone marrow aspiration and/or biopsy. 
o
“Not in remission” is defined as “greater than 5.0% bone marrow blasts by aspirate 
morphology,” as determined by a bone marrow aspirate obtained within 2 weeks of study 
registration.
o
For primary induction failure patients: Patients must have failed at least 2 induction 
regimens.
o
For patients with relapsed disease: Patients who relapse more than 1 year after preceding 
remission must fail at least one reinduction regimen to be eligible. For patients in whom 
the preceding remission is equal to or shorter than 1 year duration, no re-induction 
regimen is required to qualify for this protocol.
o
If the pre-transplant bone marrow aspirate and biopsy are hypo plastic (less than 10% 
cellularity), and blast percentages cannot be determined, the patient is eligible if the 
preceding bone marrow met the above criteria.
o
Patients with peripheral circulating blasts or patients with extramedullary leukemia are 
eligible if bone marrow aspirate and biopsy meets the above criteria.
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3. Karnofsky Performance Scale (KPS) above or equal to 70%
4. Clinical laboratory values within the following parameters:
a) Creatinine clearance ≥ 50 mL/min
b) Hemoglobin > 8 g/dL. Patients may be transfused to achieve this value. 
c) LFTs (ALT, AST) equal or less than 2.5 times upper limit of normal value.
d) Bilirubin ≤ x 1.5 ULN
5. Female patients who:
o
Are postmenopausal for at least 1 year before the screening visit, OR
o
Are surgically sterile, OR
If they are of childbearing potential:
o
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 (female and male condoms should not be used 
together), or
o
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
post ovulation methods] withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception.) 
Male patients, even if surgically sterilized (i.e., status post vasectomy), who:
o
Agree to practice effective barrier contraception during the entire study treatment  period 
and through 4 months after the last dose of study drug (female and male condoms should 
not be used together), or
o
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
post ovulation methods for the female partner] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception.)
6. 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.
7. Patient has consented to be in the IBMTR registry study.
3.2.
Exclusion Criteria for Study Registration
 
1. Treatment with any investigational products within 21 days of study registration.
2. Known hypersensitivity to Azacitidine.
3. Active uncontrolled infections or severe infectious disease, such as severe pneumonia, 
meningitis, or septicemia. 
4. Known central nervous system (CNS) involvement.
5. Known human immunodeficiency virus (HIV) positivity.
6. Known hepatitis B surface antigen-positive, or known active hepatitis C infection.
o
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.  Patients who have positive hepatitis C antibody 
may be included if they have an undetectable hepatitis C viral load.
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7. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of study procedures
8. Major surgery within 14 days before the first dose of any study drug or a scheduled surgery 
during study period.
9. 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 
non- melanoma skin cancer or carcinoma in situ of any type are not excluded if they have 
undergone resection.
10. Life-threatening illness unrelated to cancer.
11. Patients with uncontrolled coagulopathy or bleeding disorder.
12. Known hepatic cirrhosis or severe pre-existing hepatic impairment
13. Known cardiopulmonary disease defined as:

Unstable angina; 

Congestive heart failure (New York Heart Association [NYHA] Class III or IV;

Myocardial infarction (MI) within 6 months prior to first dose (patients who had ischemic 
heart disease such as a (ACS), MI, and/or revascularization greater than 6 months before 
screening and who are without cardiac symptoms may enroll);

Cardiomyopathy;

Clinically significant arrhythmia:
a) History of polymorphic ventricular fibrillation or torsade de pointes,
b) Permanent atrial fibrillation [a fib], defined as continuous a fib for ≥ 6 months,
c) Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring 
cardioversion in the 4 weeks before screening,
d) Grade 3 a fib defined as  symptomatic and incompletely controlled medically, or 
controlled with device (e.g. pacemaker), or ablation and
e) Patients with paroxysmal a fib or < Gr 3 a fib for period of at least 6 months are 
permitted to enroll provided that their rate is controlled on a stable regimen.

Implantable cardioverter defibrillator;

Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing);

Pulmonary hypertension
14. Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic blood 
pressure > 95 mm Hg).
15. Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to institutional 
guidelines.
16. Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide 
angiography.
17. Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and 
pulmonary fibrosis. FVC, FEV1, or DLCO (corrected with hemoglobin) less than 40% of 
expected value. 
18. Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days 
before the first dose of any study drug, except for hydroxyurea.
19. Female patients who are both 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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22. Patients who need to use clinically significant CYP3A enzyme inducers (listed on Appendix A)
3.3.
Additional Eligibility Criteria for Initiating Study Treatment
The following criteria are to be met to initiate each 28 day cycle of study treatment. The assessment 
will take place on Day 1 of each cycle (except item 5, 6).
1. No treatment with clinically significant metabolic enzyme inducers (Appendix A) within 14 
days of first dose. Use of these drugs is not permitted on study.
2. Performance Status 60% KPS or above.
3. LFTs (ALT, AST) equal or less than 2.5 times upper limit of normal value.
4. Bilirubin < x 1.5 ULN limit 
5. Must have results of a day +30 (±7) post-transplant bone marrow aspirate / biopsy. The results 
will be recorded. Does not require CR to initiate study treatment. This item is only to initiate 
cycle #1.
6. White blood cell (WBC) count < 50,000/µL before administration of Pevonedistat on cycle 1 
day 1.  Note:  Hydroxyurea may be used to control the level of circulating leukemic blast cell 
counts. 
The following additional criteria need to be met to initiate each cycle of Azacitidine treatment. 
7. ANC equal to or more than 1,000/mm3
8. Platelets equal to or more than 20,000/mm3
9. Albumin >2.7 mg/dl 
10. Creatinine Clearance should be ≥ 30 ml/min
3.4.
Inclusion of Women and Minorities: 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
3.5.
 Vulnerable Populations
The following populations of patients are not enrolled into the study. 
Adults who cannot sign on consents
Pregnant Women
Prisoners
3.6.
 Registration and Early Withdrawal/Discontinuation of the Study 
3.6.1. REGISTRATION PROCEDURES
Eligible patients will be registered on study by the Penn State Hershey Cancer Institute, 
Clinical Trials Office (PSHCI-CTO) by the Study Coordinator.  The subject’s Eligibility 
Worksheet will be completed electronically in its entirety prior to registration, and source 
documentation verifying each eligibility criterion must be available.  Following 
registration, patients should begin protocol treatment within 2 weeks.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator and 
documented in the chart.  
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3.6.2. Discontinuation of the Study/Withdrawal
The study may be discontinued for following reasons. 
The patient can withdraw the consent and withdraw from the study any time.
If the patient is noncompliant or for other reasons if the treating physician determine it 
may be inappropriate to continue the study. 
3.6.3.  Follow-up for withdrawn subjects
The patients withdrawn from study treatment will be followed as a study patient as far as 
the patient allows data collection. Please see section 7.12. 
4.0 Recruitment Methods
4.1. 
Identification of subjects
Patients undergoing hematopoietic stem cell transplantation at Penn State Hershey Medical Center will be 
identified as the possibly eligible patients. 
 4.2. 
Recruitment process
Treating physicians, investigators, or coordinators will introduce the study to the patient and will discuss 
with them. If patients agree to participate, they will sign on the study consent and proceed. 
4.3. 
Recruitment materials
Consent form will be given to the patients to read beforehand and they will be given time to read and ask 
questions. 
4.4. 
Eligibility/screening of subjects
Screening tests, including blood tests, Pulmonary Functions Tests, Echocardiogram/MUGA scan 
will be ordered by transplant coordinators and results will be reviewed by them with physicians. 
Eligibility checklist will be filled to confirm that all the eligibility criteria are met before the 
registration. 
5.0 Consent Process and Documentation
Consenting process will follow  “SOP: Informed Consent Process for Research (HRP-090)”. HRP-090 can be 
accessed by clicking the Library link in CATS IRB (http://irb.psu.edu).
5.1. 
Consent Process 
 
5.1.1.
Obtaining Informed Consent
5.1.1.1. Timing and Location of Consent
Consenting will take place mainly at the Hematology/Bone Marrow Transplant 
Clinic in the Cancer Institute in average a few weeks before the transplant 
admission.  Exceptions will be allowed (For example, inpatient room if the 
patient is in the hospital at the time of consenting.).
5.1.1.2. Coercion or Undue Influence during Consent
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The treating physicians and/or Investigators, transplant coordinators will explain 
about the protocol in detail and the patients will be given time to think, discuss with 
someone else, and ask questions. Patients will be informed that participation is 
voluntary and that a decision not to participate will not be held against them.
5.1.2
Waiver or alteration of the informed consent requirement
N/A
5.2.
Consent Documentation
5.2.1.
Written Documentation of Consent
The consenting process will follow “SOP: Written Documentation of Consent (HRP-091)” for 
information about the process to document the informed consent process in writing.  HRP-091 
can be accessed by clicking the Library link in CATS IRB (http://irb.psu.edu).
5.2.2.
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.)
N/A
5.2.3.
Consent – Other Considerations 
5.2.3.1.
Non-English Speaking Subjects
N/A Non-English Speaking subjects will not be enrolled on the study. 
5.2.3.2.
Cognitively Impaired Adults
N/A Cognitively impaired adults who cannot sign the consent will not be 
enrolled on the study. 
5.2.3.3.
Subjects who are not yet adults (infants, children, teenagers) 
N/A One of the eligibility criteria is 18 years or older. 
6.0.
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1.
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of 
PHI
Check all that apply:
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
X
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ 
medical records will be accessed to determine eligibility before consent/authorization has 
been obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3]
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Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2.
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
N/A
6.3.
Waiver or alteration of authorization statements of agreement
N/A
7.0.
Study Design and Procedures
7.1.
Study Treatment
The study treatment will be started after transplant.  The definition of transplant here is “the infusion of 
donor stem cells”. It includes donor lymphocyte infusion used as the 2nd transplant if the graft includes 
mobilized donor stem cells. 
Cycle 1 Day 1 of study treatment will be between day +30 and day +45 post-transplant (but can be 
delayed up day 73 as described in Section7.3).  Each 28-day  cycle is comprised of Pevonedistat at 20 
mg/m2 IV infusion over 1 hour on days 1, 3 and 5 and Azacitidine at 25 mg/m2 IV infusion over 10 
minutes on days 1, 2, 3, 4, 5, 8 and 9. The drugs can be administered either through a central catheter or 
a peripheral line. 
Premedication for Azacitidine will be given according to the institutional standard.
Pevonedistat is known to have associated with nausea, vomiting and diarrhea and has also been 
associated with episodes of hypotension, thus patient will be pre-medicated with anti-emetics. It is 
recommended to administer Zofran at 16mg IV 30 minutes prior to the each dose of Pevonedistat. 
Patients will also have other anti-emetic and antidiarrheal medications available to be used PRN. 
For those 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 normal saline given over 2 to 4 
hours for a total of 1 to 2 L of fluid as clinically appropriate, or at the treating physician’s discretion.
For patients with hemoglobin values < 8 g/dL at the beginning of a cycle RBC transfusions should be 
considered before Pevonedistat dosing based on the patient’s risk of inadequate oxygenation, 
underlying cardiopulmonary status, treating physician judgment, and/or institutional guidelines.
Bilirubin and LFTs need to be checked before each dose of Pevonedistat.  If bilirubin is > 1 and ≤ 1.5 
of UNL, the dose of Pevonedistat will be reduced from 20 mg/m2 to 15 mg/m2.  If total bilirubin is 
again > 1 and ≤ 1.5 of UNL in the next cycle the dose of Pevonedistat will be further reduced to 10 
mg/m2.
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Table 7-1  Study Treatment / Post Transplant Maintenance Therapy
28 day cycles. 1st cycle beginning between day +30 and day +45 post-transplant and continued up to 5 
cycles.
Agent
Pre-medications; 
Precautions
Dose*
Route
Schedule
Cycle 
Length
Pevonedistat
Zofran 16 mg IV 30 
minutes prior to 
Pevonedistat.
Consider: Hydration; 
RBC transfusions if 
indicated.
20 mg/m2
15 mg/m2
10 mg/m2
Intravenous 
infusion given 
over 1 hour.
Days 1, 3, 
and 5 of each 
cycle. 
Azacitidine
Pre-meds per 
institutional 
guidelines.
25 mg/m2
Intravenous 
infusion given 
over 10 minutes.
Days 1, 2, 3, 
4, 5, 8, and 9 
of each 
cycle. 
28 days
(4 weeks)
*Please see the section 7.1 and 7.3.
7.2.
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 sub investigator(s).
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 should not be exceeded. 
The amount of study drug to be administered will be based on body surface area (BSA). BSA will be 
calculated using Mostellar’s formula 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.
7.3.
Delay of Medications/Dose Modifications at each cycle: 
Cycle 1:
If the criteria # 1, 2, 3, 4, 5, 6 noted in section 3.3 are not met within the target range of days +30 to 
+45 post-transplant, the treatment may be delayed for up to 4 weeks to allow for resolution. Cycle 1 
may begin up to day +73 post-transplant at the latest. The delay should be minimal, thus the patient 
should be assessed for eligibility to start treatment weekly. 
If the patient does not meet the criteria #1, 2, 3, 4, 5, and 6 by day 73, then the cycle 1 will be skipped 
and the patient will be assessed to start next cycle 2 two weeks later. 
If the criteria # 7, 8, 9, and 10 noted in section 3.3 are not met but the other criteria (#1, 2, 3, 4, 5, 6) are 
met, the cycle will be started with Pevonedistat only.  
Cycles 2 – 5:
If the criteria, # 1, 2, 3, 4 noted in section 3.3 are not met beginning of each subsequent cycle, then 2 
weeks of delay between cycles will be allowed.  If still not eligible after 2 week delay then that cycle 
will be skipped. The next scheduled cycle may resume if eligible at the original scheduled time, which 
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will be 2 weeks from the last skipped cycle. If 2 straight cycles are skipped before the patient receives 2 
cycles, the patient is off study and not considered evaluable for efficacy.  (Patient is still evaluable for 
toxicity if the patient received at least one dose of Pevonedistat.)
Once the cycle is initiated, the dosage of the drugs will not be modified provided that bilirubin and LFTs 
are inside the acceptable range per the inclusion criteria (please refer to Section 3.3.  However, the dose 
can be held if the treating physician thinks that the patient has unacceptable side effects due to the drugs. 
In this case PI or coordinating MD should be contacted. 
Please refer to the following diagram for delaying the cycles.
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Figure:  Schematic diagram of delays.  (A) Each cycle every 28 days (standard). (B) Cycle 1 (C1) failed 
and then resumed 2 weeks later. (C) C1 failed initially and again 2 weeks later, then another 2 weeks 
later C1 was successfully started before or on day 73. (D) C1 failed initially then 2 weeks and 4 weeks 
later, thus C1 was skipped and C2 was started another 2 weeks later. C1 can be delayed up to 4 weeks 
but in subsequent cycles (C2-C5) delays are allowed only up to 2 weeks. (E) C1 was skipped and C2D1 
was delayed by 2 weeks. (F) C1 was skipped and C2 was also skipped, at that point the patient comes 
off study. (G) C1 was given on schedule; C2 was delayed by 2 weeks. (H) C1 was given on schedule, 
but C2 was delayed but 2 weeks later eligibility criteria were not met again, thus C2 was skipped. (I) C1 
was given, C2 was skipped, and C3 was delayed by 2 weeks but then C3 was started with 2 weeks delay. 
(J) C1 was given on schedule, but C2 and C3 were skipped, then this patient comes off study. (K, L) The 
patient already received C1 and C3 thus can stay on study until completion.
7.4. Other Dose-Modification Guidelines
7.4.1.
General Guideline for dose modification 
If the section 7.1 determines the dose modification, that will be prioritized above the rule in this 
section.
If patient bilirubin values before dosing are >1 and ≤1.5 of UNL, the dose of Pevonedistat will 
be reduced from 20 mg/m2 to 15 mg/m2. If total bilirubin is again >1 and ≤1.5 of UNL in the 
next cycle the dose of Pevonedistat will be further reduced to 10 mg/m2. 
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE).
7.4.2.
   Criteria for Retreatment and Dose Delays
   
Retreatment within a Cycle
If dosing of either drug is delayed for safety reasons, retreatment may be resumed upon 
resolution of the safety condition. For Pevonedistat, a minimum of 1 full calendar day between 
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any 2 doses should be maintained. A maximum of 3 doses of Pevonedistat should not be 
exceeded.
If dosing is interrupted within a cycle because of drug-related toxicity, and if the sponsor 
investigator (or designee) agrees 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 in the next cycle. 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 investigator (or designee).
Initiation of a New Cycle
Treatment with study drugs will be repeated every cycle. For therapy to resume, toxicity 
considered related to treatment with study drugs must have resolved to Grade 1, to the patient’s 
baseline values, or to a level considered acceptable by the sponsor investigator.
If a patient fails to meet the criteria for retreatment, initiation of the next cycle of treatment may 
be delayed for up to 2 weeks. At the end of that time, the patient should be reevaluated to 
determine whether the criteria for retreatment have been met. A dose reduction 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 investigator (or designee).
For toxicity not related to drug (eg, disease-related toxicity), although a similar dose reduction is 
permitted, in general it is discouraged. If the 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.
For hematologic toxicity a delay in the initiation of a cycle by 4 weeks or greater because of lack 
of recovery from treatment-related hematologic toxicity (resolved to Grade 1, to patient’s 
baseline values, or to a level considered acceptable by the sponsor investigator) that is not related 
to leukemic infiltration will trigger a dose reduction if treatment resumes. If indicated, bone 
marrow evaluation will be performed to establish whether continued myelosuppression is related 
to persistent or progressing leukemic infiltration. The Pevonedistat dose should be reduced by at 
least 1 dose level. (if applicable)
7.4.3.
Dose Modifications for Hematologic Toxicities
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 one dose level. The Pevonedistat dose may be re-escalated at 
the next cycle, if the toxicity has recovered to ≤Grade 1 or the patient’s baseline. 
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 investigator. (if applicable)
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7.4.4.
Dose Modifications for Non-hematologic Toxicities
7.4.4.1.
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. 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. If the toxicity 
returns to ≤Grade 1 or the patient’s baseline status, Pevonedistat may be re-escalated.
7.4.4.2. 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.
7.4.4.3. Pevonedistat Dose Adjustment for Other Toxicities
For other ≥Grade 2 non-hematologic toxicities potentially related to Pevonedistat, the 
Pevonedistat dose may be reduced at the discretion of the sponsor investigator as clinically 
indicated. If the toxicity returns to ≤Grade 1 or the patient’s baseline status, Pevonedistat 
may be re-escalated at the next cycle.
7.5.
GVHD and Immunosuppression
At any point during the study treatment, if patient experiences acute GVHD grade III to IV, 
study treatment will be held until the GVHD improves to grade II or lower, then the study 
treatment can be resumed.
If the patient has any liver or gut GVHD, Pevonedistat should not be given. 
7.6.
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:
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Table 7-6
Concomitant Medications Excluded During the Study
Therapy
Comment/Exceptions
Acetaminophen and acetaminophen-containing 
products
May be used judiciously but should not exceed a 
dose of 2 g in 24 hours.
Systemic antineoplastic therapy, except for 
hydroxyurea
Hydroxyurea dosing 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.
Clinically significant metabolic enzyme inducers
Excluded. 
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. Tacrolimus is permitted. 
Any investigational agent other than Pevonedistat, 
including but not limited to androgens, 
supraphysiologic doses of corticosteroids, 
erythropoietin, eltrombopag [Promacta], or 
romiplostim [Nplate]
BCRP=breast cancer resistance protein, CYP=cytochrome P450, 
7.7.
Permitted Concomitant Medications and Procedures
Table 7-7
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. 
Myeloid growth factors (eg, 
G-CSF, GM-CSF)
In general, the use of myeloid growth factors is discouraged and should be 
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 investigator (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 (e.g., for 
platelets <10,000/µL in the absence of clinical bleeding) 
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Table 7-7
Concomitant Medications and Procedures Permitted During the Study
Therapy
Comment
Red blood cell transfusion
To be considered for all patients with anemia, especially those with 
hemoglobin values ≤8 g/dL.
G-CSF=granulocyte colony-stimulating factor, GM-CSF=granulocyte macrophage colony-stimulating factor.
7.8.
Study Treatment Period 
The “Study Treatment Period” is from the start of study treatment, cycle 1 day 1 until the study 
treatment completion visit.  Last treatment dose of azacitidine is being given on day 9 of the last cycle, 
and study treatment completion visit will be scheduled between 42 days and 56 days after the day 1 of 
the last treatment cycle.  
AEs and SAEs will be reported during the Study Treatment Period. AEs and SAEs initiated during this 
period will be followed until they resolve. 
7.9.
Treatment Cycles
Treatment will be continued until cycle 5 is completed or the study is terminated for the patient. The 
cycles will be repeated every 28 days. 
7.10.
Evaluable patients 
Patients who received at least one dose of Pevonedistat will be considered evaluable for toxicity 
assessment. Patients who received at least 2 cycles of Pevonedistat treatment will be considered as 
evaluable for efficacy.  
The patients who were registered and/or underwent transplant but did not receive study drug will be 
considered unevaluable and replaced.  
7.11.
Removal from the study
Patients will be removed from the study in the following cases.  If the patient receives at least one dose 
of Pevonedistat the patient is evaluable for toxicity assessment. 

Unequivocal progression of AML after the initiation of the study drug.  One of the following 
criteria should be met: (a) if the patient was in CR when the study drug was started, overt 
relapse would be considered “unequivocal” progression.  (b) if the patient was not in CR when 
the drug was started, more than double the blast percentage would be defined as 
“unequivocal”. 

The occurrence of unacceptable toxicity indicating the need for cessation of treatment.

Non-compliance by the patient with protocol requirements.

Patient is lost to follow-up. If a patient does not return for scheduled visits, every effort should 
be made to re-establish contact. If patient cannot be contacted and removed from the study, 
every effort should be made to document patient outcome.

Patient becomes pregnant.
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
Termination of the study by investigator or sponsor agency.
7.12.
Withdrawal from the study
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons:

Adverse event

Protocol violation

Lost to follow-up

Progressive disease

Note: patients with PD may remain on the study, after discussion with Millennium Inc., if it is 
judged that they are deriving a clinical benefit from doing so.

Initiation of hematopoietic stem cell transplant

Subsequent anti-cancer therapy

Withdrawal by subject

Study terminated 

Other
Patients will be offered alternative options at that time. Even if the patient withdraws, patient may be 
evaluable based on criteria 7.10. If a subject withdraws consent completely, we will stop collecting their 
health information for this study; however, we may continue to use and share the subject’s health 
information that was already obtained as necessary for safety and scientific soundness of the research 
study. We will not be able to take back information that has already been used or shared with others.
7.13.
Precautions and Restrictions
Pregnancy
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 through defined periods during and after 
study treatment as specified below.
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the Screening visit, or

Surgically sterile, or

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, post ovulation methods] 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.)
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
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 (i.e., status post vasectomy), 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 [e.g., calendar, ovulation, symptothermal, post ovulation 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).
7.14.
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.14.1. Pevonedistat (MLN4924, TAK924) 
Chemical Characteristics
The chemical name of the drug substance, Pevonedistat, is ((1S, 2S, 4R)-4-{4-[(1S)-2, 3-
dihydro-1H-inden-1-ylamino]-7H-pyrrolo [2, 3-d] pyrimidin-7-yl}-hydroxycyclopentyl) methyl 
sulfamate hydrochloride. 
Structure of Pevonedistat
Available Forms
The drug product is labeled Pevonedistat (TAK-924/MLN4924) Concentrate for Solution for Infusion. 
The MLN4924-003 Injection Drug Product formulation consists of 10 mg/mL (as free base) of 
MLN4924-003 in an aqueous solution of 7.45 mg/mL citric acid (anhydrous),
3.29 mg/mL trisodium citrate dihydrate and 100 mg/mL ß-Cyclodextrin sulfobutyl ether
(Captisol®) at pH 3.3. Each USP Type I glass vial nominally contains 5 mL of compounded sterile 
solution, sealed with a Teflon®-coated butyl rubber stopper and over sealed with an aluminum seal and a 
plastic cap. 
Each MLN4924-003 Injection Drug Product vial contains nominally 5 mL (50 mg
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MLN4924-003 as free base). Pevonedistat (TAK-924/MLN4924) will be provided in 10-mL glass vials 
at a concentration of 10 mg/mL.
Full details are available in the IB.
Storage and Handling
The study agent Pevonedistat (MLN4924) is provided by the manufacturer.  MLN4924-003 Injection 
Drug Product is a cytotoxic anticancer drug.  As with other potentially toxic compounds, caution should 
be exercised when handling MLN4924. All investigational supplies are to be kept in a secure area with 
controlled access.
Refer to institutional guidelines regarding the proper handling and disposal of cytotoxic agents. 
MLN4924-003 Injection Drug Product vials should be stored refrigerated at 2°C to 8°C. 
Before use, MLN4924-003 Injection Drug Product 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.
The vial must not be shaken at any time during dose preparation.
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. Discard bag, needle, and syringe in a proper biohazard container according to 
institutional guidelines.
MLN4924-003 Injection Drug Product is stable at ambient temperature for 8 hours before dilution.  
Once it is diluted in 5% dextrose, the prepared MLN4924-003 IV bag must be used within 6 hours (time 
to the end of an injection) if stored at ambient temperature.  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 (time to the end of an injection) upon coming 
to ambient temperature.
Study drug will be administered only to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).  The amount of drug to be administered will be based on body surface 
area (BSA).  BSA will be calculated using a standard nomogram 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.
The pharmacist will maintain records of drug receipt (if applicable), drug preparation, and dispensing, 
including the applicable lot numbers, and total drug administered in milliliters and milligrams.  
All patients will receive Pevonedistat diluted with 5% dextrose in a 250-mL IV bag via IV infusion via a 
60-minute IV infusion. 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. Doses of Pevonedistat must be separated by at least 1 full calendar day.
Toxicity
Safety information gained from clinical studies and toxicology studies has been used to guide the safety 
evaluation of Pevonedistat. 
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Potential risks of Pevonedistat from phase 1 studies conducted at higher doses than currently 
investigated in the clinical development program are multi-organ failure that could result in death, renal 
failure, cardia arrhythmias, acute phase response, GI toxicity including or resulting in dehydration 
and/or electrolyte imbalance, hypophosphatemia, and myelosuppression with increased susceptibility to 
infection, bleeding, and anemia. 
Potential risks of Pevonedistat confounded by underlying disease or malignancy are fatigue, chills, 
decreased appetite, neutropenia, febrile neutropenia, and GI bleeding. 
Potential risks of Pevonedistat primarily based on findings from animal studies are myocardial 
degeneration and thrombosis, pulmonary hypertension, effects on the testes and ovaries that represent a 
reproductive hazard including sterility, increased developmental risk to the fetus or embryo, decreased 
trabecular bone without fractures, prolongation of the activated partial thromboplastin time, local tissue 
injury (when administered SC), and cardiovascular changes that could result in tachycardia, decreased or 
increased systolic blood pressure, and increased diastolic blood pressure.
Tumor lysis may occur if the patient with active leukemia is given pevonedistat.  Tumor lysis syndrome 
is caused by the acute lysis of leukemia cells and is characterized by high potassium, high phosphorus, 
low calcium, high uric acid, high BUN, and may be associated with coagulopathy.  It can be 
prevented/appropriately treated with awareness of this condition.  It should be treated with hydration, 
correction of electrolytes, allopurinol, and may require rasburicase in severe cases. 
Drug-drug interaction
Pevonedistat is metabolized by the liver predominantly through the CYP isozyme CYP3A4, with a small 
contribution from CYP2D6 (approximately 3%).  There is a potential risk for a drug-drug interaction 
when Pevonedistat is co-administered with drugs that are CYP3A inhibitors or inducers (Appendix A).  
Consequently, co-administration of strong CYP3A inhibitors or inducers is not permitted in clinical 
studies of Pevonedistat.  Per protocol, treatment with strong CYP3A inhibitors or inducers must be 
discontinued 14 days before initiation of Pevonedistat therapy.  Patients must have no history of 
amiodarone use in the 6 months before the first dose of Pevonedistat. 
Adverse Drug Reactions
All the events included in this section are considered expected for the purpose of regulatory reporting 
and must remain unchanged throughout the DSUR reporting period.
Cardiac disorders:
Increased heart rate
Gastrointestinal disorders:
Diarrhea
Nausea
Vomiting
General disorders and administration site conditions:
Pyrexia
Investigations:
Liver function test abnormal
Musculoskeletal and connective tissue disorders:
Musculoskeletal pain/myalgia
Warnings and Precautions 
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Acetaminophen:
For patients in the dose-escalation phase of a clinical study, agents such as acetaminophen and 
acetaminophen-containing products should not be administered 24 hours before, on the day of, and 24 
hours after dosing with Pevonedistat.  For patients not in dose escalation, agents such as acetaminophen 
and acetaminophen-containing compounds may be used judiciously and should not exceed a dose of 2 g 
of acetaminophen in a 24-hour period.
Statins:
Use of statins had been restricted to hold dosing on the day before, day of, and day after administration 
of Pevonedistat.  Because this restriction on statins was instituted, further analyses have been performed 
supporting the lifting of this restriction.  
Hepatotoxicity:
Hepatotoxicity has been noted following administration of Pevonedistat in patients with advanced 
malignancy, including elevations of liver transaminases, ALP, and bilirubin. 
Grade 1, 2, and 3 increases in ALT and AST have been observed in patients receiving the
50-mg/ m2 dose on Days 1, 3, and 5 in Schedule E of Study C15003.  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 re-challenged at lower doses.
Guidance for Clinical Assessment and Management of Hemodynamic Compromise
Patients must be carefully evaluated at screening and before each Pevonedistat dose for early symptoms 
and signs of hemodynamic compromise and active infection.  Particular attention should be paid to 
unexplained fever, tachycardia, hypotension, orthostasis, tachypnea, recent nausea and vomiting, and 
clinical evidence of dehydration.  For those 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.  For all patients 
with anemia, and especially for patients 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 
patient’s risk of inadequate oxygenation, underlying cardiopulmonary status, clinical judgment, and/or 
hospital guidelines.  Patients who experience signs and symptoms of hemodynamic compromise after 
Pevonedistat dosing (e.g., tachycardia, hypotension, orthostasis, and changes in mental status, syncope, 
and dizziness) should be followed closely and managed with supportive care, including hospitalization 
as clinically indicated.
 
Guidance for Management of Leukostasis
Pevonedistat treatment should be withheld for patients who develop symptoms of leukostasis. Treatment 
may include leukapheresis and hydroxyurea administration, per institutional guidelines. When the WBC 
of the patient is <50,000/µL and symptoms are improved, Pevonedistat treatment may be restarted after 
consulting with the sponsor investigator (or designee). 
Guidance for Management of Extravasation
Based on nonclinical findings as detailed in the IB, Pevonedistat is considered a non-vesicant drug. 
Although no published guidelines are available for extravasation of non-vesicants, 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.
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7.14.2. Azacitidine (Vidaza)
Chemical Characteristics
Azacitidine for injectable suspension contains Azacitidine, which is a pyrimidine 
nucleoside analog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-
2(1H)-one. The structural formula is as follows:
The empirical formula is C8 H12 N4 O5. The molecular weight is 244. Azacitidine is a white to off-
white solid. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly 
soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, 
water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 
in water; and soluble in dimethyl sulfoxide (DMSO).
Available Forms
Azacitidine for injection is commercially available as Vidaza and is supplied as Lyophilized powder in 
100 mg single-use vials.
The product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or 
reconstitution as a solution with further dilution for intravenous infusion.  Vials of contain 100 mg of 
Azacitidine and 100 mg mannitol as a sterile lyophilized powder.
Storage and Handling
Azacitidine for injection is commercially available and will be prescribed for this trial.  Store un-
reconstituted vials at 25º C (77º F); excursions permitted to 15º-30º C.  
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Procedures for proper handling and disposal of anticancer drugs should be applied.  Several guidelines 
on this subject have been published30-32.There is no general agreement that all of the procedures 
recommended in the guidelines are necessary or appropriate. 
Reconstitute the appropriate number of vials to achieve the desired dose. Reconstitute each vial with 10 
mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The 
resulting solution will contain Azacitidine 10 mg/mL. The solution should be clear. Parenteral drug 
product should be inspected visually for particulate matter and discoloration prior to administration, 
whenever solution and container permit. Withdraw the required amount of Vidaza solution to deliver the 
desired dose and inject into a 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or 
Lactated Ringer’s Injection.
Toxicity
Anemia, Neutropenia and Thrombocytopenia
Vidaza 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
Vidaza Toxicity in Patients with Severe Pre-existing Hepatic Impairment
Because Azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic
impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to 
metastatic disease have been reported to experience progressive hepatic coma and death during 
Azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is 
contraindicated in patients with advanced malignant hepatic tumors.
Renal Toxicity
Patients with renal impairment may be at increased risk for renal toxicity. Also, Azacitidine and its 
metabolites are primarily excreted by the kidney. Therefore, these patients should be closely monitored 
for toxicity.
Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in 
patients treated with intravenous Azacitidine in combination with other
chemotherapeutic agents for non-MDS conditions. In addition, 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 CML treated with Azacitidine and etoposide. If 
unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine 
occur, the dosage should be reduced or held.
Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia,
thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, 
neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, 
rigors, weakness and hypokalemia.
Administration
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Azacitidine solution is administered intravenously.  Administer the total dose over a period of 10 
minutes.  The administration must be completed within 1 hour of reconstitution of the Azacitidine vial. 
Azacitidine reconstituted for intravenous administration may be stored at 25°C (77°F), but 
administration must be completed within 1 hour of reconstitution. 
Incompatibilities
Azacitidine is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate.  
These solutions have the potential to increase the rate of degradation of Azacitidine and should therefore 
be avoided. 
Drug-Drug Interactions
No formal clinical drug interaction studies with Azacitidine have been conducted.
An in vitro study of Azacitidine incubation in human liver fractions indicated that Azacitidine may be 
metabolized by the liver.  Whether Azacitidine metabolism may be affected by known microsomal 
enzyme inhibitors or inducers has not been studied. An in vitro study with cultured human hepatocytes 
indicated that Azacitidine at concentrations up to 100 µM (IV Cmax = 10.6 µM) does not cause any 
inhibition of CYP2B6 and CYP2C8. The potential of Azacitidine to inhibit other cytochrome P450 
(CYP) enzymes is not known. In vitro studies with human cultured hepatocytes indicate that Azacitidine 
at concentrations of 1.0 µM to 100 µM does not induce CYP 1A2, 2C19, or 3A4/5.
7.15.
Method for Assigning Subject to Treatment Groups
N/A
7.16.
Subject Compliance Monitoring
Subjects will be followed at BMT clinic regularly and compliance will be monitored as a 
standard procedure after allogeneic stem cell transplant. 
7.17.
Blinding of the Test Article
N/A
7.18.
Receiving, Storage, Dispensing and Return 
7.18.1. Receipt of Test Article 
Pevonedistat will be distributed by Takeda to Investigational Drug Pharmacy Service. (IDS) of 
PSCI. 
Commercial supply will be used for azacitidine. 
7.18.2. Storage
MLN4924-003 Injection Drug Product vials should be stored refrigerated at 2°C to 8°C. 
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Before use, MLN4924-003 Injection Drug Product 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.
7.18.3. Preparation and Dispensing
Pevonedistat is a cytotoxic anticancer drug, and as with the other potentially toxic 
compounds, caution should be exercised when handling Pevonedistat. 
The specified number of Injection Drug Product vials should be removed and allowed to 
equilibrate to room temperature prior to dilution. The vial must not be shaken at any time 
during dose preparation. 
Using aseptic technique, the appropriate volume of drug should be withdrawn from 
vials(s), then injected into a 250-mL IV bag containing 5% dextrose solution, and then 
gently inverted repeatedly to mix. The Pevonedistat prepared IV bag must be used within 
6 hours (time to the end of an injection) if stored at ambient temperature. 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 (time to the end of an injection) upon coming to ambient temperature. Discard bag, 
needle and syringe in a proper biohazard container according to institutional guidelines.  
7.18.4. Return or Destruction of the Test Article
Pevonedistat will be returned to Takeda after the study, or appropriately destroyed 
according to the manufacturer’s direction. 
 
7.19.
Required Observations
Required observations will be monitored as follows:
7.19.1. Pre-Transplant / Study Registration:
Pre-Transplant required observations (performed within 35 days prior to study 
registration and/or day of final evaluation before transplant).
1. History and physical exam (including Vital Signs (VS) and Karnofsky Performance 
Status (KPS) score). 
2. CBC with differential (diff), Complete Metabolic Panel (CMP) with LDH, 
Magnesium, Phosphate, Uric Acid and Direct Bilirubin. 
3. Echocardiogram or MUGA.
4. 12 lead ECG. 
5.
Unilateral bone marrow aspirate and biopsy (morphology, and cytogenetics) performed 
within 2 weeks before study registration to confirm non-remission AML. 
6.
Urinalysis with microscopic analysis 
7.
Coagulation including PT, PTT, INR
8.
Serum pregnancy test for women with childbearing potential. 
CMP includes: Na, K, Bicarbonate (HCO3), BUN, Creatinine, Glucose, Calcium, ALT, 
AST, Alkaline Phosphatase, Total Bilirubin, Albumin, and Total Protein. 
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7.19.2.
Post-Transplant / Day +30:
1. History and physical exam (including VS and KPS score). 
2. CBC with diff, CMP with LDH, Magnesium, Phosphate, Uric Acid, and Direct 
Bilirubin. 
3. Unilateral bone marrow aspirate and biopsy (morphology, and cytogenetics) at day 30 
(±7) post-transplant.
7.19.3.
Study Treatment Initiation:
Study treatment will be initiated between day +30 and day +45 post-transplant, after bone 
marrow aspiration/biopsy morphology result is obtained. 
7.19.4
During Study Treatment:
1. History and physical exam (including VS and KPS score) on each day when 
Pevonedistat is given 
2. CBC with diff, CMP with LDH, Magnesium, Phosphate, Uric Acid, and Direct 
Bilirubin., on each day when Pevonedistat is given and weekly during the Treatment 
Cycles (days 1, 3, 5, 8, 15 and 22.). The bilirubin assessment must be performed and read 
prior to dosing Pevonedistat.
3. On each cycle, the results of assessment on Day 1 will be used to meet the criteria 3.3. 
4. Tumor Lysis Labs (CMP, LDH, Phosphate, Uric Acid) will be drawn every 8 hours 
during the first cycle of Pevonedistat treatment if the disease is not in remission at the 
time of initiation of Pevonedistat. In this case the patient will be admitted to the hospital 
and allopurinol will be given. Tumor Lysis Labs will be stopped when the risk of tumor 
lysis is determined minimal. 
5. Urinalysis with microscopic analysis and Coagulation (including PT and aPTT) on day 
1 of each cycle.
6. 12-lead ECG on day 1 of each cycle 
7. Serum Pregnancy Test at day 1 of each cycle for women with childbearing potential. 
7.19.5.
At Study Treatment Completion Visit (Day 42-56 after day 1 of the last cycle) 
1. History and physical exam (including VS and KPS score). 
2. CBC with diff, CMP with LDH, Magnesium, Phosphate. 
3. Unilateral bone marrow aspirate and biopsy (morphology, and cytogenetics) ±15days 
of the study completion visit.  
4. Urinalysis with microscopic analysis and Coagulation (including PT and aPTT)
5. 12-lead ECG 
7.19.6. 
Yearly visits after stem cell transplant (±1 month of 1 to 5 years after transplant)
Yearly visits are based on transplant date, not study initiation date. 
1. History and physical exam (including VS and KPS score). 
2. CBC with diff, CMP with LDH, Magnesium, Phosphate. 
3. Unilateral bone marrow aspirate and biopsy (morphology, and cytogenetics) 1 month 
of the 1-year post transplant yearly visit.  
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7.19.7.
Post study-treatment required observations and follow-up plans
Recommended follow-up is once a week until day 100, once in 2 weeks to once a month 
until day 365, then once a month to once in 2-6 months until year 3, then at least once a 
year until year 5.  The patient who progressed on this protocol will be followed only for 
survival. 
Regimen-related toxicity (RRT) will be recorded using the definition of CTCAE version 
5. Acute and chronic GVHD will be recorded using the standard criteria (Appendix C, 
D)39. Overall and disease-free survival will be analyzed using the method of Kaplan and 
Meier. One-year, two-year and five-year overall and disease-free survival will be 
examined. Cumulative incidence of relapse will be calculated.
8.0.
Subject Numbers and Statistical Plan
8.1.
Simon’s two stage design
The primary endpoint is one year overall survival rate. The one-year survival rate for the historic 
control of in this population is 10% and is assumed to be 34% for this treatment. We shall use 
Simon’s (Simon 1989) two-stage design so that a quick termination can be made if the new 
treatment does not outperform historical control. The main outcome of one year survival, however, 
requires to wait potentially for one full year for a patient. To speed up the trial, for the conduct of 
this trial, we shall use the half-year survival rate as the primary outcome (Note, however, all 
patients will be followed for at least one year when the trial is complete so that the one year-
survival probability can be estimated). For this purpose, we assume that the half-year survival rate 
is 33% for the historic control and 60% for the new treatment. The Simon’s two stage design based 
on Ho: P0=0.33 and H1: P1=0.60 is then
Stopping Rules:
Stage 1:
Enroll 20 subjects. Stop and accept the null hypothesis if the survival rate is less than or equal to 
7/20.  Otherwise, continue to stage 2.
Stage 2:
Enroll 10 additional subjects. Accept the null hypothesis if the survival rate is less than or equal to 
14/30.  Otherwise, reject the null hypothesis.
8.2.
Statistical Analysis plan: 
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The primary decision rules for the effectiveness of the new treatment are the two-stage rule described 
above. 
For time-to-event variables such as overall survival and progression free survival, the Kaplan-Meier 
plots will be provided to describe the complete survival process. One year survival rate and cumulative 
incidence at 2 years will be estimated with 95% confidence intervals. Summaries of the number and 
percentage of patients survived at different time points along with median OS will be presented. These 
survival curves will be compared to that of the historic controls.
All patients who receive treatment in this study will be included in the ongoing safety analysis. 
Descriptive statistics will be used to summarize the safety and efficacy variables collected and the 
baseline demographic data. Continuous variables will be summarized using mean, standard deviation, 
minimum, median, and maximum. Categorical variables will be summarized using frequency counts 
and percentages and corresponding exact 95% confidence intervals will be estimated for the secondary 
endpoints. The detailed tabulation of adverse events will be provided and reported for safety 
monitoring.
10.0. Confidentiality, Privacy and Data Management 
See the Research Data Plan Review Form
10.0. DATA REPORTING / REGULATORY REQUIREMENTS
10.1.
Confidentiality of Records:  
The original data collection forms will be stored in secured cabinets at the originating institution.  
Institutional policy and guidance on requirements for managing clinical research data will be followed, 
including the appropriate levels of safeguard to ensure the confidentiality, integrity and availability of 
clinical research data.
10.2.
Patient Consent Form:  
Prior to commencement of any screening activities, written, signed and dated patient consent must be 
obtained.  A copy of the signed and dated consent form must be provided to the patient.  The original signed 
consent form and additional copies must be maintained per institutional standards (i.e., with research 
records, medical chart).  
10.3.
Registration Eligibility Worksheet:  
At the time of registration, the information requested on the On-Study/Eligibility Form will be completed.  
Confirmation of eligibility will be confirmed by the investigator’s signature on the completed worksheet. 
The investigator is responsible for enrolling only those patients who have met protocol eligibility criteria. 
10.4.
Data Collection Forms and Submission Schedule:  
Direct data entry into to the Penn State Cancer Institute OnCore CTMS will be utilized for this study.  
Electronic data capture will occur via electronic case report forms in OnCore®. OnCore® (On-line Clinical 
Oncology Research Environment) is the primary data management system for clinical trials activity at PSCI.  
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OnCore® was developed by Forte, Inc., and is a highly secure, web-based, customizable system that 
provides fully integrated clinical data management and protocol management capabilities.  OnCore® houses 
regulatory tracking information, study management activity and clinical data.  Data entry requirements are 
as follows:
Event
Data Entry Timeline
Subject registration
48 hours
On-study form completion
Within 2 weeks of subject on study
Each course of treatment, all required forms 
completion (includes response evaluation, 
where applicable)
Within 2 weeks of course completion
Follow-up per protocol
Within 2 weeks of follow-up time point
The data to be transcribed and entered into the study database will include but is not limited to 
demographics, medical history, concomitant medications, safety data, and those data needed to answer the 
study objectives.   Eligibility assessment will be coded as met or not met with reasons rather than including 
each criterion related data.   The assessments and interventions noted in the Table of Interventions and 
Assessments (Appendix C) e.g. data related to dates and results of physical examinations, vital signs, 
performance status, laboratory results (CBC, Chemistry, etc.), etc will not be entered into the database.  
However, any abnormal results of the assessments will be captured as an AE according to the criteria noted 
in Section 18.0.  For those who consent but are not eligible (screen failure) only data related to failure 
reason and demography will be captured. 
10.5.
Site Monitoring:  
To ensure compliance with current federal regulations and the ICH guidelines, data generated by this study 
must be available for inspection upon request by representatives of the FDA, national and local health 
authorities, the Sponsor-Investigator and duly authorized representative of any entity providing support for 
this trial. Routine monitoring or audit activities for this study will be conducted by representatives of the 
PSCI Clinical Trials Office. The general scope of such visits would be to inspect study data (regulatory 
requirements), source documentation and CRF completion in accordance with current FDA Good Clinical 
Practices (GCP), the ICH guidelines and the respective local and national government regulations and 
guidelines. 
10.6.
Institutional Review Board Approval:  
This protocol, the informed consent document, relevant supporting information and all types of patient 
recruitment and advertisement information must be submitted to the local IRB for review and must be 
approved before the study is initiated. An amendment to remove a life-threatening situation can by 
implemented by the Investigator prior to obtaining IRB approval by the site. In such situations, the IRB 
must be notified immediately and the amendment forwarded to the IRB for their consideration.
The investigator is responsible for keeping their local IRB informed of the progress with study renewal at 
least once a year. The investigator must also keep the local IRB informed of any significant adverse events, 
per local institutional guidelines. Adverse event reporting guidelines can be found in Section 18.0, 
Reporting Adverse Events.
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10.7.
Records Retention:  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all study-related documentation, 
including source document and CRFs, long enough to allow the sponsor to use the data to support marketing 
applications.  If this study is conducted under an IND, all records must be maintained for:
Two years after the FDA approved the marketing application, or
Two years after the FDA disapproves the application for the indicating being studied, or 
Two years after the FDA is notified by the sponsor of the discontinuation of trials and that an 
application will not be submitted.
For all studies, including studies with FDA-IND exemption, the Investigator/Institution/Sponsor will take 
measures to prevent accidental or premature destruction of study documents.   For such studies conducted 
under IND exemption, records will be retained for a minimum of seven (7) years past official study 
termination.
10.8.
Data Safety Monitoring Plan
The Penn State Hershey Cancer Institute Data and Safety Monitoring Committee (PSCI DSMC) will 
serve as the internal DSMC for data and safety review for this protocol. The principal investigator (PI) 
will continuously monitor study progress for safety and will hold routine meetings with the study team 
and disease center personnel to review overall conduct and progress of this study.  The frequency of 
such meetings will be dependent upon accrual to the trial and issues that arise.  Study team and disease 
team meetings will include discussion of accrual, adverse events/safety issues, response and overall 
progress of the trial.  
On an annual basis, the PI will provide the PSCI DSMC with reports showing the number of subjects 
enrolled, SAE assessments, information on any protocol deviations or breaches of confidentiality, 
response if appropriate, and overall status of the trial. The PSCI DSMC meets quarterly as well as on 
an ad hoc basis.  The investigator will be asked for a report for the DSMC sufficiently in advance of 
annual IRB renewal in order to include DSMC findings with annual IRB submission.  Adverse event 
reporting to the IRB will occur in compliance with IRB guidelines.  A summary of all adverse events 
will be reported to the IRB annually; unexpected adverse events will be reported as they arise as well 
as any significant literature reporting developments that may affect the safety of participants in this 
study. Serious and unexpected adverse events will be reported to PSCI DMSC simultaneously with the 
IRB reporting.
11.0
Risks
There are additional risks related to study treatment Pevonedistat and Azacitidine, in addition to the risks 
associated with standard allogeneic stem cell transplantation. 
12.0
Potential Benefits to Subjects and Others
12.1
Potential Benefits to Subjects
There may not be any direct benefits to the subjects. 
12.2
Potential Benefits to Others
Future patients may benefit from the knowledge obtained through this study. 
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13.0
Sharing Results with Subjects
The results will not be shared with subjects or others. 
14.0
Subject Stipend (Compensation) and/or Travel Reimbursements
N/A
15.0
Economic Burden to Subjects
15.1 Costs 
There will be no additional costs for this research. 
15.2 Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment for 
research-related injury. In the event of injury resulting from this research, medical treatment is available 
but will be provided at the usual charge. Costs for the treatment of research-related injuries will be 
charged to subjects or their insurance carriers.
16.0
Resources Available
16.1 Facilities and locations
The research will be conducted in the inpatient and outpatient unit of Penn State Cancer Institute.
16.2 Feasibility of recruiting the required number of subjects
We have about 2 cases/months of patients who may qualify for this protocol, including the relapse/2nd 
transplant cases. Most of these patients will be enrolled into this study. 
16.3 PI Time devoted to conducting the research
Five % of PI time will be devoted to this protocol. 
16.4 Availability of medical or psychological resources
All medical and psychological consulting services are available.  PSU Blood and Marrow Transplant 
Program is accredited with FACT (Foundation for the Accreditation of Cell Therapy) which requires all 
the consultation resources are available. 
16.5 Process for informing Study Team
We will have a Site Initiation Meeting and also will have repeated lectures in Science Meetings of 
hematology/BMT Program. 
17.0. Other Approvals
17.1.
Other Approvals from External Entities
N/A
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17.2.
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library.
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or 
gene therapy). 
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that had 
been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of HRP-901 
- Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. This form 
is available in the CATS IRB Library.
  Clinical Research Center (CRC) Advisory Committee– All campuses – Research involves the use of 
CRC services in any way.  
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a copy of 
HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library.
X  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
X   Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific 
review requirement may be fulfilled by one of the following: (1) external peer-review process; (2) 
department/institute scientific review committee; or (3) scientific review by the Clinical Research Center 
Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute Scientific Review 
Committee is required if the study involves cancer prevention studies or cancer patients, records and/or 
tissues. For more information about this requirement see the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/investigator 
18.0. Adverse Event Reporting
Adverse events occurring following study registration, but prior to beginning study agent therapy will 
not be reported. Protocol related therapy does not begin until patients receive their first dose of study 
agent. 
18.1.
Definition of Adverse events
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered a 
medicinal product; the untoward medical occurrence does not necessarily have a causal relationship 
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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.  
Reporting requirements may include the following considerations: 
1. The characteristics of the adverse event including the grade (severity); 
2. The relationship to the study therapy (attribution); and 
3. The prior experience (expectedness) of the adverse event.
Expected events are those that have been previously identified as resulting from administration of the 
agent. For commercially available agents, an adverse event is considered unexpected, for reporting 
purposes only, when either the type of event or the severity of the event is not listed in the current NCI 
Agent-Specific Adverse Event List located in the drug package insert. Except where otherwise 
specified, Common Terminology Criteria for Adverse Events (CTCAE) v.5 will be used to grade 
adverse events in this study.
18.2.
Required Adverse Events Reporting 
Therapy for hematological malignancies, with or without stem cell transplantation, is associated with 
significant toxicity. These toxicities are generally viewed as an anticipated consequence of therapy 
rather than an adverse event. To summarize, adverse events with severity grades 1, 2 will not be 
reported to the IRB, as they are expected in patients undergoing stem cell transplantation for 
hematological malignancies. Only grade 3, 4 toxicity events with a possible, probable or definite 
relation to the study drug and all grade 5 events will be reported to IRB.
18.3.
Serious Adverse Event Reporting Procedures 
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event.  It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or surgical 
intervention to prevent 1 of the outcomes listed above, or involves suspected transmission via a 
medicinal product of an infectious agent.   Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse; any organism, virus, or infectious particle (e.g., prion protein 
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transmitting Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.  
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 are 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.
All serious adverse events (SAE) which require reporting must be reported immediately (i.e. within 24 
hours of awareness) to the Principal Investigator of the Coordinating Center or designee, followed by 
written documentation to each IRB from the Principal Investigator (including the PI’s or designee’s 
medical summary of the SAE) within 4 days of the Investigator’s knowledge of occurrence to the Penn 
State Cancer Institute CTO.  The staff of the PSCI CTO will coordinate the reporting process between 
the investigators, PIs and each IRB as well as other applicable reporting agencies (such as FDA), 
including the reporting of SAEs on a MEDWATCH 3500A form to FDA. Copies of all correspondence 
and reporting documents will be maintained in a regulatory file held by the PSCI CTO.  Institution and 
Investigator understand and agree that Investigator and Institution are obligated under applicable law 
and regulations to report any serious and related adverse event, if any, which occurs during treatment 
with Pevonedistat and Azacitidine to the Institution’s IRB/Ethics Committee and to the governing 
regulatory authority in accordance with applicable filing timelines promptly after any such event 
occurs. 
 
18.4.
Procedures for Reporting Serious Adverse Events to Supporting Company (Millennium/Takeda)
Adverse Events may be spontaneously identified by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other diagnostic procedures.  
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 one comprehensive event. 
 
Adverse Events which are serious must be reported to Millennium Pharmacovigilance (or designee) 
from the first dose of Pevonedistat up to and including 30 days after administration of the last dose of 
Pevonedistat.  Any SAE that occurs at any time after completion of Pevonedistat treatment or after the 
designated follow-up period that the sponsor-investigator and/or sub-investigator considers to be 
related to any study drug must be reported to Millennium Pharmacovigilance (or designee).  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 (e.g., surgery was performed earlier or later than planned).  All 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).
Since this is an investigator-initiated study, the principal investigator Dr. Shin Mineishi also referred to 
as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to any regulatory 
agency and to the sponsor- investigator’s EC or IRB.   
Regardless of expectedness or causality, all SAEs must also be reported in English to Millennium 
Pharmacovigilance or designee:
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Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s observation or 
awareness of the event
All other serious (non-fatal/non life threatening) events within 4 calendar days of the sponsor-
investigator’s observation or awareness of the event
The SAE report must include at minimum:

Event term(s)

Serious criteria

Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s determination.  Intensity 
for each SAE, including any lab abnormalities, will be determined by using the NCI CTCAE 
version specified in the protocol, as a guideline, whenever possible.  The criteria are available 
online at http://ctep.cancer.gov/reporting/ctc.html.

Causality of the event(s): Sponsor-investigator’s or sub-investigator’s determination of the 
relationship of the event(s) to study drug administration. 
Follow-up information on the SAE may be requested by Millennium Pharmacovigilance (or designee).  
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that the SAE 
reports are sent to Millennium Pharmacovigilance (or designee) from all sites participating in the study.  
Sub-investigators must report all SAEs to the sponsor-investigator so that the sponsor-investigator can 
meet his/her foregoing reporting obligations to the required regulatory agencies and to Millennium 
Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and sub-investigator(s).  
Relationship to all study drugs for each SAE will be determined by the investigator or sub-investigator 
by responding yes or no to the question: Is there a reasonable possibility that the AE is associated with 
the study drug(s)?
Suggested Reporting Form:  
•
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm
•
Any other form deemed appropriate by the sponsor-investigator
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-investigator 
must fax a completed Pregnancy Form to the Millennium  Pharmacovigilance or designee immediately.  
US and Canada
Toll-Free Fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
All other countries (Rest of World)
Fax #: 1 202 315 3560
E-mail: takedaoncocases@cognizant.com
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The pregnancy must be followed for the final pregnancy outcome (i.e., delivery, still birth, miscarriage) 
and Millennium Pharmacovigilance or designee will request this information from the sponsor-
investigator.
If a female partner of a male patient becomes pregnant during the male patient’s participation in this 
study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to the 
Millennium Pharmacovigilance or designee.  Every effort should be made to follow the pregnancy for 
the final pregnancy outcome.
18.5.
ADMINISTRATIVE REQUIREMENTS
18.5.1. 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 Millennium (see below) and report 
the event.  Whenever possible, the associated product should be maintained in accordance with the 
label instructions pending further guidance from a Millennium Quality representative.
For Product Complaints, call
Phone 1-844-ONC-TKDA (1-844-662-8532)
Email: GlobalOncologyMedinfo@takeda.com
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 Millennium Pharmacovigilance.
18.6 Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
18.6.1 Written IND/IDE Safety Reports
Initial reporting: IND application sponsor must report any suspected adverse reaction or 
adverse reaction to study treatment that is both serious and unexpected. 
Unexpected serious suspected adverse reactions and observations from animal studies 
suggesting significant risk to human subjects must be reported to FDA as soon as 
possible but no later than within 15 calendar days following the sponsor’s initial receipt 
of the information.
Unexpected fatal or life-threatening suspected adverse reactions represent especially 
important safety information and must be reported to FDA as soon as possible but no 
later than 7 calendar days following the sponsor’s initial receipt of the information.
•Follow-up reporting: Any relevant additional information obtained by the sponsor that 
pertains to a previously submitted IND safety report must be submitted as a Follow-up 
IND Safety Report. Such report should be submitted without delay, as soon as the 
information is available but no later than 15 calendar days after the sponsor receives the 
information.
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All IND safety reports must be submitted on Form 3500A  and be accompanied by Form 
1571. The type of report (initial or follow-up) should be checked in the respective boxes 
on Forms 3500A and 1571. 
The submission must be identified as:
•“IND safety report” for 15-day reports, or
•“7-day IND safety report” for unexpected fatal or life-threatening suspected adverse 
reaction reports, or
•“Follow-up IND safety report” for follow-up information.
18.6.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
In addition to the subsequent submission of a written IND Safety Report, the sponsor shall notify 
the FDA by telephone or by facsimile transmission of any human adverse event that is (i) 
Associated with the use of the drug; (ii) Unexpected; and (iii) Fatal or Life-threatening.
18.7 Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) experienced 
by a subject or other individual, which in the opinion of the investigator is determined to be (1) 
unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
18.8 Unblinding Procedures
N/A
18.9 Stopping Rules
Stopping rule is incorporated in the Simon’s two-step design (Section 8.1). 
19.0 Study Monitoring, Auditing and Inspecting
Quality Assurance and Quality Control
The study will be monitored by the Clinical Trial Monitoring Team from the Department of Public Health 
Sciences at Penn State Hershey College of Medicine. The monitors will provide an independent review of the 
regulatory and subject records and the data collected to assure compliance with the protocol, GCP, and 
applicable federal regulations. The monitoring will occur at regular intervals after the enrollment of the first 
subject and the times will be predetermined by the monitoring plan developed by the Clinical Trial Monitoring 
Team. 
Research Quality Assurance (RQA) office will conduct post-approval monitoring after the first and 3rd subjects 
are enrolled.  PI will notify RQA at that time. 
20.0. Future Undetermined Research: Data and Specimen Banking
N/A
21.0. References
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Transplantation of marrow cells from unrelated donors for treatment of high-risk acute 
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leukemia: the effect of leukemic burden, donor HLA-matching, and marrow cell dose. 
Blood 1997; 89(11): 4226-4235. 
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Giralt S, Estey E, Albitar M, van Besien K, Rondon G, Anderlini P et al. Engraftment of 
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Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. 
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7.
Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A et al. 
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Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C et al. Once-daily 
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Magenau J, Tobai H, Pawarode A, Braun T, Peres E, Reddy P et al. Clofarabine and 
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13.
Kobayashi K, Kami M, Murashige N, Kusumi E, Kishi Y, Hamaki T et al. Outcomes of 
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Mineishi S, Kanda Y, Saito T, Nakai K, Makimoto A, Kami M et al. Impact of graft-
versus-host disease in reduced-intensity stem cell transplantation (RIST) for patients with 
haematological malignancies. British journal of haematology 2003; 121(2): 296-303. 
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19.
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marrow transplantation 2010; 45(2): 349-353. doi: 10.1038/bmt.2009.155
20.
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Swords RT, Erba HP, DeAngelo DJ, Bixby DL, Altman JK, Maris M et al. Pevonedistat 
(MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute 
myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. British journal of 
haematology 2015; 169(4): 534-543. doi: 10.1111/bjh.13323
35.
Bhatia S, Pavlick AC, Boasberg P, Thompson JA, Mulligan G, Pickard MD et al. A 
phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat 
(TAK-924/MLN4924) in patients with metastatic melanoma. Investigational new drugs 
2016; 34(4): 439-449. doi: 10.1007/s10637-016-0348-5
36.
Swords RT CS, Maris M, Zeidner JF, Foran JM, Cruz JC, Erba HP, Berdeja JG, Tam W, 
Vardhanabhuti S, Dobler I, Faessel HM, Dash AB, Sedarati F, Dezube BJ, and Savona 
MR. Results of Clinical Study of Pevonedistat (Pev), a First-in-Class NEDD8-Activating 
Enzyme (NAE) Inhibitor, Combined with Azacitidine (Aza) in Older Patients with 
Acurte Myeloid Leukemia (AML)  ASH anual meeting abstract 98 2016. 
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37.
Bauer TM HD, Lee CB, Aggarwal C, Cohen RB, Sedarati F, Nip K, Fassel HM, Dash 
AB, Dezube BJ, Santillana S, Dowlati A, Lockhart CA. Investigational NEDD8-
activating enzyme inhibitor pevonedistat plus chemotherapy in patients with solid tumors 
(phase 1b study): Activity of pevonedistat plus carboplatin/paclitaxel. . ASCO Annual 
Meeting, 2016. Poster presentation from Abstract #2580. 2016. 
38.
Lockhart CA BT, Harvey D, Lee CB, Aggarwal C, Cohen RB, Sedarati F, Teng, X, 
Fassel HM, Dezube BJ, Santillana S, Dowlati A. . Phase 1b trial of investigational 
NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in 
combination with docetaxel, paclitaxel/carboplatin, or gemcitabine in patients with solid 
tumors. . AACR-NCI-EORTC - 27th International Symposium - Molecular Targets and 
Cancer Therapeutics (November 5-9, 2015 - Boston, Massachusetts, USA). Poster 
presentation from Abstract #B26. 2015. 
39.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National 
Institutes of Health Consensus Development Project on Criteria for Clinical Trials in 
Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group 
report. Biology of blood and marrow transplantation : journal of the American Society 
for Blood and Marrow Transplantation 2015; 21(3): 389-401 e381. doi: 
10.1016/j.bbmt.2014.12.001
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APPENDIX A
Prohibited Medications
                  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 versus time curve; CYP=cytochrome P450.
Please refer to the following sources for additional information: http://medicine.iupui.edu/clinpharm/ddis/main-table/ and 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/%20druginteractionslabeling/ucm093664.htm 
1.
Corticosteroids may be administered as required for the treatment of GVHD or for other clinical concerns
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 APPENDIX B
Karnofsky performance status scale
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA
  100  Normal no complaints; no evidence of 
disease.
90
Able to carry on normal activity; minor signs 
or symptoms of disease.
Able to carry on normal activity and to work; no special 
care needed.
80
Normal activity with effort; some signs or 
symptoms of disease. 
70
Cares for self; unable to carry on normal 
activity or to do active work.
60
Requires occasional assistance, but is able to 
care for most of his personal needs.
Unable to work; able to live at home and care for most 
personal needs; varying amount of assistance needed.
50
Requires considerable assistance and 
frequent medical care. 
40
Disabled; requires special care and 
assistance.
30
Severely disabled; hospital admission is 
indicated although death not imminent.
20
Very sick; hospital admission necessary; 
active supportive treatment necessary.
10
Moribund; fatal processes progressing 
rapidly.
Unable to care for self; requires equivalent of institutional 
or hospital care; disease may be progressing rapidly.
0
Dead
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Appendix C
Acute GVHD
Acute GVHD will be described as follows: 
“Skin 2, Liver 0, Gut 1, Overall Grade 2”
 
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Appendix D 
Chronic GVHD (From Reference 39)
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APPENDIX E
STUDY CALENDAR
Day 1 
(#5)
Day 2
Day 3 
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 15
Day 22
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X (#4)
X
X
X(#8)
X
X
X
X
X
X
Pevonedistat
X
X
X
Azacitidine
X
X
X
X
X
X
X
X
X
Tumor Lysis Lab (#7)
First cycle of Pevonedistat (if not CR) every 8 hours until risk of tumor lysis is minimal
Echo or MUGA
At  Study 
Treatment 
Completion
Yearly Visits 
after 
Transplant
CMP with LDH, 
Magnesium, Phosphate, 
Uric Acid and Direct 
Bilirubin (#3)
CBC with diff
Physical Exam (#2)
History
Pre-
Transplant 
Registration 
(#1)
Post-
Transplant 
Day 30
Treatment Cycle (#6)
AE, Concurrent Meds
Pulmonary Function Test
Study 
Treatment
Bone Marrow Aspiration 
and Biopsy
12 lead ECG
Urinalysis with microscopic 
analysis
Coagulation Labs including 
PT, PTT, INR
Serum Pregnancy Test for 
Women in childbearing age


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#1.  Performed within 35 days prior to study registration and/or day of final evaluation before transplant.
#2.  Includes Vital Signs and Karnofsky Performance Status score.
#3.  CMP = Comprehensive Metabolic Panel (please see section 7.19.4)
#4.  Performed within 2 weeks before study registration to confirm non-remission AML.
#5.  Pre-treatment assessments are performed on Day 1 of each cycle (Section 3.3 and 7.19.4).
#6.  Follow Section 7.1.
#7.  Please see section 7.19.4
#8.  Performed ±1 month of 1-year post transplant visit only. 
Note:   Serum pregnancy test will be done for females of childbearing potential prior to first infusion of each cycle.    


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APPENDIX F.  REQUIRED DATA COLLECTION 
For the purpose of this study, the following data will be collected and entered in the Oncore study database.  Other 
data needed to answer the study objectives may be added as needed.  Information from the standard evaluations noted 
in the above Appendix E e.g. physical examinations, performance status, vital signs, general (CBC, Chemistry) 
laboratory results, etc. will not be entered into the database.  Any abnormal results of the assessments will be captured 
as an AE according to the criteria noted in Section 18.
Unique Identification Number
Date of Consent
Eligibility met?  Yes or No with reason (identify as screen failure if not met)
General demographics (e.g. age, gender, race, etc.)
Modifications made to prescribed conditioning or GVHD med regimen? No or Yes, specify
Safety data/AEs/SAEs as defined in Section 18.0.
Survival status – cause of death if applicable; date of last known alive (mm/dd/yy),
Study status – on study date, off evaluation, withdrawal/off study with reason, etc.
The following data is collected and entered into CIBMTR by a BMT Primary Data Collection and 
Analysis Coordinator at Penn State Cancer Institute. Therefore, the patients in this study will be 
required to participate in this research database trial maintained by CIBMTR, entitled “Protocol for 
a research database for hematopoietic cell transplantation, other cellular therapies and marrow toxic 
injuries” IRB #2002-198EP). The CIBMTR is a voluntary organization of basic and clinical 
scientists who share information on results of blood and marrow transplants and cellular therapies. 
The following data entered in CIBMTR will be extracted and utilized for the purpose of this study.
Significant Past medical history 
Medications taken within past 30 days 
Concomitant medications as described in Section 7.6 and 7.7
Donor Type/relationship (unrelated, sibling, mother, father, aunt, uncle, cousin, other, specify)
Donor demographics (as identified in recipients chart only e.g. gender, age if known) 
Donor product cell counts (e.g. CD3, CD34, MNC)
Date of initiation of conditioning regimen (mm/dd/yy)
Date of HSCT infusion Date(s)  (mm/dd/yy)
Cyclophosphamide infusion dates 
Cyclophosphamide doses (mg/kg)
Any interruption or modification in the cyclophosphamide?  No or Yes with reason. 
Number of days to ANC engraftment
Graft failure prior to Day 100? Yes or No
Acute GVHD by Day 100 Yes or No.    If yes, start date (mm/dd/yy), site, max grade, duration
Chronic GVHD - Yes or No.    If yes, start date (mm/dd/yy), site, max grade, duration
Stem cell boost administered?  If yes, date (mm/dd/yy)
Donor Lymphocyte Infusions? if yes, doses, date(s), and indication for administration 
Routine immune reconstitution results (CD34, CD3, etc.)
Chimerism results (donor/host)
Ongoing disease status evaluation with dates 
Research specific immune results will be maintained in the laboratory investigators database.
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