Clinical trial NCT03813147
Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Recurrent Myelodysplastic Syndrome Refractory Acute Myeloid Leukemia Refractory Myelodysplastic Syndrome
Sponsor: National Cancer Institute (NCI)
Start date: 2019-05-17; Completion date: 2023-12-31
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I trial studies the side effects and how well pevonedistat, azacitidine, fludarabine phosphate, and cytarabine work in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (relapsed) or has not responded to treatment (refractory). Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, fludarabine phosphate, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) and pevonedistat may work better in treating patients with acute myeloid leukemia or myelodysplastic syndrome.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the tolerability and feasibility of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine phosphate (fludarabine), and cytarabine re-induction for pediatric patients with recurrent/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

II. To define and describe the toxicities of MLN4924 (pevonedistat) when given in combination with azacitidine, fludarabine, and cytarabine to pediatric patients with relapsed/refractory AML and MDS.

III. To characterize the pharmacokinetics of MLN4924 (pevonedistat) in children with recurrent or refractory AML and MDS.

SECONDARY OBJECTIVE:

I. To describe the antitumor activity of MLN4924 (pevonedistat) in combination with azacitidine, fludarabine, and cytarabine within the confines of a feasibility study.

EXPLORATORY OBJECTIVES:

I. To describe the effect of MLN4924 (pevonedistat) administered on this schedule on messenger ribonucleic acid (mRNA) transcript levels of genes known to be induced by MLN4924 (pevonedistat) mediated NEDD8 activating enzyme (NAE) inhibition.

II. To describe the effect of MLN4924 (pevonedistat) on NEDDylation of proteins in the NEDD8 pathway that are likely to be affected by NAE inhibition with MLN4924 (pevonedistat).

OUTLINE:

Patients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of each cycle. Patients then receive azacitidine intravenously (IV) over 15 minutes once daily (QD) on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients with central nervous system (CNS)2 or CNS3 receive cytarabine intrathecally or methotrexate intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and 11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable toxicity. Patients with stable or greater with non-hematologic toxicities probably or definitely related to pevonedistat may receive an additional cycle of treatment.

After completion of study treatment, patients are followed up for 30 days.

Arms: arm 1: Patients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of each cycle. Patients then receive azacitidine IV over 15 minutes QD on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients with CNS2 or CNS3 receive cytarabine intrathecally or methotrexate intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and 11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable toxicity. Patients with stable or greater with non-hematologic toxicities probably or definitely related to pevonedistat may receive an additional cycle of treatment.
Interventions: intervention 1: Azacitidine intervention 2: Cytarabine intervention 3: Fludarabine Phosphate intervention 4: Methotrexate intervention 5: Pevonedistat intervention 6: Therapeutic Hydrocortisone
Intervention descriptions: intervention 1: Given IV intervention 2: Given intrathecally and IV intervention 3: Given IV intervention 4: Given intrathecally intervention 5: Given IV intervention 6: Given intrathecally

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Pediatric Early Phase Clinical Trial 
Network (PEP-CTN) and  
Developmental Therapeutics (DVL) 
Chair 
Brenda J. Weigel, M.D. 
weige007@umn.edu 
 
PEP-CTN and  
Developmental Therapeutics (DVL) 
Vice Chair  
Elizabeth Fox, M.D. 
elizabeth.fox@stjude.org 
 
PEP-CTN Operations  
Data & Statistics Center Director 
Thalia Beeles, MPH 
tbeeles@childrensoncologygroup.org 
 
PEP-CTN Statistician  
Charles G. Minard, Ph.D. 
minard@bcm.edu 
 
 
PEP-CTN and  
DVL Chair’s Office 
University of Minnesota/ 
Masonic Cancer Center 
Masonic Children’s Hospital 
420 Delaware Street, SE 
MMC 366 
Minneapolis, MN  55455 
 
P 612 626 5501 
F 612 624 3913 
 
 
Children’s Oncology Group 
Group Chair 
Douglas S. Hawkins, MD 
Seattle Children’s Research 
Institute  
Mailstop: JMB 9 
1900 9th Avenue 
Seattle, WA 98101 
P 206 884 1107 
doug.hawkins@seattlechildrens       
.org  
 
 
 
PEP-CTN Operations Data & 
Statistics Center 
800 Royal Oaks Drive 
Suite 210  
Monrovia, CA 91016 
 
P 626 241 1500 
F 626 445 4334 
 
 
A National Cancer Institute-  
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
 
 
 
 
 
 
i 
 
August 27, 2020 
 
 
Martha Kruhm, M.S., RAC  
Head, Protocol and Information Office (PIO) 
National Institutes of Health/NCI/DCTD/CTEP/OIB/PIO 
9609 Medical Center Drive, OIB MSC 9742, Room #5W246 
Bethesda, MD 20892-9742 
 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #3A to ADVL1712, A Feasibility Trial of 
MLN4924 (pevonedistat, TAK 924) given in Combination with Azacitidine, 
Fludarabine, and Cytarabine, in Children, Adolescents, and Young Adults with 
Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic 
Syndrome. 
 
This amendment is being submitted in response to a Request for Rapid 
Amendment (RRA) from Dr. John J. Wright (wrightj@ctep.nci.nih.gov), dated 
August 7, 2020. In this amendment, the revised CAEPR for MLN4924 
(Pevonedistat HCl) (Version 2.3, July 10, 2020) has been inserted in the 
protocol, and the associated risk information in the informed consent document 
has been revised. All revisions are detailed in the summary of changes below. 
 
Please let me know if you have any questions or need additional information. 
 
Sincerely,  
Jennifer Knothe, Protocol Coordinator (for) 
Katherine Tarlock, M.D., ADVL1712 Study Chair, and 
Brenda Weigel, M.D., PI, PEP-CTN 


 
ii 
 
SUMMARY OF CHANGES: PROTOCOL 
In accordance with the above discussion, the following specific revisions have been made to the protocol. 
Additions are in boldfaced font and deletions in strikethrough font. 
 
# 
Section 
Page(s) 
Change 
1.  
General 
Throughout 
Updated protocol version date in the footer.  
2.  
Cover Page 
1 
Updated version date and amendment number.  
3.  
9.1.10 
40-43 
Inserted revised CAEPR for MLN4924 (Pevonedistat HCl) 
(Version 2.3, July 10, 2020). 
 
Specific changes are as follows: 
 
• 
Added New Risk:  
• 
Also Reported on MLN4924 Trials But With 
Insufficient Evidence for Attribution: Ascites; 
Hypertension; Non-cardiac chest pain; 
Treatment related secondary malignancy; 
Urinary retention; White blood cell decreased 
 
• 
Increase in Risk Attribution:  
• 
Changed to Less Likely from Also Reported on 
MLN4924 Trials But With Insufficient Evidence 
for Attribution: Urinary tract infection 
 
• 
Decrease in Risk Attribution:  
o 
Changed to Less Likely from Likely: 
Constipation; Dizziness 
o 
Changed to Also Reported on MLN4924 Trials 
But With Insufficient Evidence for Attribution 
from Less Likely: Rash maculo-papular 
 
 


                             
ADVL1712 
                                                                                                                                                                
 
Version Date: 08/27/2020 
 
 
1 
 
Activated: 
05/01/19 
Version Date: 
08/27/20 
Closed: 
 
Amendment # 
3A 
 
 
 
 
 
 
 
 
 
 
 CHILDREN’S ONCOLOGY GROUP 
 
 
 
ADVL1712 
 
A FEASIBILITY TRIAL OF MLN4924 (PEVONEDISTAT, TAK 924) GIVEN IN 
COMBINATION WITH AZACITIDINE, FLUDARABINE, AND CYTARABINE, IN 
CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH RELAPSED OR REFRACTORY 
ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROME 
 
Lead Organization: COG Pediatric Early Phase Clinical Trials Network (PEP-CTN) 
 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
STUDY CHAIR 
 
Katherine Tarlock, MD 
Seattle Children’s Hospital 
4800 Sand Point Way NE 
Seattle, WA 98105 
Phone: (206) 987-2106  
Fax: (206) 987-3946 
 
Email: katherine.tarlock@seattlechildrens.org 
 
 
 
For PEP-CTN Operations and Data/Statistics Contacts see: http://members.childrensoncologygroup.org 


                             
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2 
TABLE OF CONTENTS 
SECTION 
PAGE 
 
TABLE OF CONTENTS 
2 
STUDY COMMITTEE 
5 
STUDY COMMITTEE, CONT. 
6 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Aims 
9 
1.2 
Secondary Aim 
9 
1.3 
Exploratory Aims 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Preclinical Studies 
11 
2.3 
Adult Studies 
13 
2.4 
Pediatric Studies 
14 
2.5 
Overview of Proposed Pediatric Study 
15 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
16 
3.1 
Current Study Status 
16 
3.2 
IRB Approval 
16 
3.3 
Patient Registration 
17 
3.4 
Reservation and Contact Requirements 
17 
3.5 
Informed Consent/Assent 
17 
3.6 
Screening Procedures 
17 
3.7 
Eligibility Checklist 
17 
3.8 
Institutional Pathology Report 
18 
3.9 
Study Enrollment 
18 
3.10 
Dose Assignment 
18 
4.0 
PATIENT ELIGIBILITY 
18 
4.1 
Inclusion Criteria 
19 
4.2 
Exclusion Criteria 
21 
5.0 
TREATMENT PROGRAM 
23 
5.1 
Overview of Treatment Plan 
23 
5.2 
Treatment Details (Cycles 1 & 2) 
24 
5.3 
Criteria for Starting Cycle 2 
26 
5.4 
Dosing Schema 
26 
5.5 
Grading of Adverse Events 
27 
5.6 
Definition of Dose-Limiting Toxicity (DLT) 
27 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
28 
6.1 
Dose Modifications for Hematological Toxicity 
28 
6.2 
Dose Modifications for Non-Hematological Toxicity 
28 
6.3 
Modifications and Supportive Care Recommendations for Toxicity Related to Protocol 
Therapy (Cycle 1 and Cycle 2) 
29 


                             
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3 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
31 
7.1 
Concurrent Anticancer Therapy 
31 
7.2 
Investigational Agents 
31 
7.3 
Supportive Care 
31 
7.4 
Concomitant Medications 
32 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
32 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
32 
8.2 
Pharmacology (Required) 
33 
8.3 
Pharmacodynamics - mRNA Transcript Levels (Optional) 
35 
8.4 
Pharmacodynamics - NEDDylated Protein Analysis (Optional) 
35 
9.0 
AGENT INFORMATION 
37 
9.1 
MLN4924 (Pevonedistat) 
37 
9.2 
Azacitidine – Injection 
44 
9.3 
Cytarabine        (07/13/15) 
50 
9.4 
Fludarabine         (01/10/18) 
52 
9.5 
Intrathecal Triples (Methotrexate/Hydrocortisone/Cytarabine, IT-3)            (05/08/12) 55 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
57 
10.1 
Criteria for Removal from Protocol Therapy 
57 
10.2 
Off Study Criteria 
58 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
58 
11.1 
Sample Size and Study Duration 
58 
11.2 
Definitions 
59 
11.3 
Dose Confirmation and Determination of MTD/RP2D 
59 
11.4 
Inclusion of Children, Women and Minorities 
60 
11.5 
Pharmacokinetic and Response Analysis 
60 
12.0 
EVALUATION CRITERIA 
61 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
61 
12.2 
Response Criteria for Patients with Leukemia 
61 
12.3 
CNS Leukemia at Diagnosis 
62 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
63 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
63 
13.2 
When to Report an Event in an Expedited Manner 
65 
13.3 
Expedited Reporting Methods 
66 
13.4 
Definition of Onset and Resolution of Adverse Events 
66 
13.5 
Other Recipients of Adverse Event Reports 
66 
13.6 
Reporting Secondary AML/MDS 
67 
13.7 
Data and Safety Monitoring Plan 
67 
13.8 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
68 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
69 
14.1 
Categories of Research Records 
69 
14.2 
CDUS 
69 
14.3 
CRADA/CTA/CSA 
69 
14.4 
Data and Safety Monitoring Plan 
71 
REFERENCES 
73 


                             
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4 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
75 
APPENDIX II: CORRELATIVE STUDIES GUIDE 
76 
APPENDIX III: TOXICITY-SPECIFIC GRADING 
78 
APPENDIX IV-A: PHARMACOKINETIC STUDY FORM FOR PATIENTS < 10 KG 
79 
APPENDIX IV-B: PHARMACOKINETIC STUDY FORM FOR PATIENTS > 10 KG 
80 
APPENDIX V: PHARMACODYNAMICS (MRNA TRANSCRIPT LEVELS) STUDY FORM 
82 
APPENDIX VI-A: PHARMACODYNAMICS (NEDDYLATED PROTEIN ANALYSIS) STUDY 
BLOOD SAMPLE INSTRUCTIONS 
83 
APPENDIX VI-B: PHARMACODYNAMICS (NEDDYLATED PROTEIN ANALYSIS) STUDY 
FORM – BLOOD SAMPLES 
85 
APPENDIX VII: PHARMACODYNAMICS (NEDDYLATED PROTEIN ANALYSIS) STUDY FORM 
– BONE MARROW SAMPLES 
86 
APPENDIX VIII-A: THERAPY DELIVERY MAP FOR CYCLE 1 
87 
APPENDIX VIII-B: THERAPY DELIVERY MAP FOR CYCLE 2 
92 
APPENDIX IX: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
96 
APPENDIX X:  PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
98 
APPENDIX XI: NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC DISEASE
 
100 
APPENDIX XII: CTEP AND CTSU REGISTRATION PROCEDURES 
101 
APPENIX XIII: GUIDELINES FOR SHIPPING SAMPLES TO COVANCE – MADISON 
104 
 
 


                     
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Version Date: 08/27/2020 
 
 
5 
STUDY COMMITTEE 
STUDY CHAIR 
Elizabeth Fox, MD 
Katherine Tarlock, MD 
Vice Chair, Developmental Therapeutics 
Seattle Children’s Hospital 
Saint Jude Children’s Research Hospital 
4800 Sand Point Way NE 
262 Danny Thomas Place 
Seattle, WA 98105 
Memphis, TN 38105 
Phone: (206) 987-2106 
Phone:   (901) 595-3300 
Fax: (206) 987-3946 
 
Fax:  
 (901) 595-7031 
e-mail: katherine.tarlock@seattlechildrens.org 
Email: elizabeth.fox@stjude.org  
 
 
 
 
STUDY VICE CHAIR  
STUDY PHARMACIST 
Todd Cooper, DO 
Sarah Menig, PharmD 
Seattle Children’s Hospital 
Seattle Children’s Hospital 
4800 Sand Point Way NE 
4800 Sand Point Way NE 
Seattle, WA 98105 
Seattle, WA 98105 
Phone: (206) 987-2106  
Phone: (206) 987-2033  
Fax: (206) 987-3946 
 
Fax: (206) 987-5058 
 
e-mail: todd.cooper@seattlechildrens.org 
E-mail:  sarah.menig@seattlechildrens.org  
 
 
 
 
SENIOR STATISTICIAN 
STUDY NURSE 
Charles Minard, PhD 
Sharon Bergeron, RN, BSN, CPON 
Baylor College of Medicine  
Children’s Hospital of Orange County 
One Baylor Plaza, BCM 122 
1201 West La Veta 
Houston, TX 77030 
Orange, CA 92868 
Phone:   (713) 798-2353 
Phone: (714) 509-4396 
Fax:  
 (713) 798-2813 
Fax: (714) 509-4365 
Email: minard@bcm.edu 
E-mail: sbergeron@choc.org 
 
 
 
 
STUDY COMMITTEE MEMBERS  
STUDY CRA 
Brenda J. Weigel, MD 
CRA NAME 
Chair, Developmental Therapeutics  
Address 
Hematology/Oncology 
Address 
University of Minnesota Medical Center - Fairview 
Address 
Department of Pediatrics 
Address 
420 Delaware Street, SE  MMC 366 
Phone:  
Minneapolis, MN 55455 
Fax:  
Phone:   (612) 626-5501 
E-mail:  
Fax:  
 (612) 624-3913 
 
E-mail: weige007@umn.edu 
 
 
 
 
 
 


                     
ADVL1712 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 08/27/2020 
 
 
6 
  STUDY COMMITTEE, CONT. 
 
COG OPERATIONS STAFF 
 
 
 
PROTOCOL COORDINATOR 
 
MASTER STATISTICIAN 
Alina Stout, BS 
Xiaowei Liu, MS 
Children’s Oncology Group – Operations Center 
Children’s Oncology Group – Operations Center 
Phone: (626) 241-1566 
Phone: (626) 241-1535 
Fax: 
(626) 445-4334 
Fax: 
(626) 445-4334 
E-mail:  astout@childrensoncologygroup.org 
E-mail:  xwliu@childrensoncologygroup.org  
 
 
RESEARCH COORDINATOR 
 
Ashley Rodela, BS 
 
Phone: (626) 241-1624 
 
Fax: (626) 445-4334 
 
E-mail: arodela@childrensoncologygroup.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AGENT NSC# AND IND#’s 
 
Agent Supplied by CTEP:  
MLN4924 (NSC#793435) 
 
 
Commercial Agents:  
Azacitidine (Vidaza®, NSC#102816) 
 
Cytarabine (Cytosar®, NSC#63878) 
Fludarabine (Fludara®, NSC#103805) 
 
Hydrocortisone (Solu-cortef®, NSC#10483) 
Methotrexate (Trexall®, NSC#740) 
 
 
 
IND Sponsor: DCTD, NCI 
 
 
 
 
For PEP-CTN Operations and Data/Statistics 
Contacts see: 
http:members.childrensoncologygroup.org 
 
 
SEE SECTION 8.2.6, 8.3.6 AND 8.4.6 FOR SPECIMEN SHIPPING ADDRESSES 
 
 


                     
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THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 08/27/2020 
 
 
7 
 
This trial is covered by a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects.  The Certificate protects against the involuntary release of 
information about subjects collected during the course of our covered studies.  The researchers involved in 
the studies cannot be forced to disclose the identity or any information collected in the study in any legal 
proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or 
legislative proceedings.  However, the subject or the researcher may choose to voluntarily disclose the 
protected information under certain circumstances.  For example, if the subject or his/her guardian requests 
the release of information in writing, the Certificate does not protect against that voluntary disclosure.  
Furthermore, federal agencies may review our records under limited circumstances, such as a DHHS 
request for information for an audit or program evaluation or an FDA request under the Food, Drug and 
Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
ABSTRACT 
Outcomes for children with relapsed AML remain poor and have not significantly improved over the past 
decade.  For patients who do experience relapse, effective combination therapies that achieve complete 
remission so that patients can proceed to stem cell transplant remain the only chance for long-term survival. 
Thus, new therapies are urgently needed and as single agents are inadequate in patients with relapsed or 
refractory AML, optimal combination strategies are an important area of investigation.  MLN4924 
(pevonedistat) is a novel small molecule inhibitor of NEDD8-activating enzyme (NAE), which is involved 
in the ubiquitin-proteasome system and responsible for protein turnover within cells and has significant 
impact on cell growth and survival. Preclinical studies in AML have shown that exposure to MLN4924 
(pevonedistat), especially when combined with AML chemotherapies including cytarabine or azacitidine, 
results in potent cell death. Further, a phase I study of MLN4924 (pevonedistat) combined with azacitidine 
in adults with AML demonstrated that the regimen was well tolerated, and that the combination of the two 
drugs resulted in higher complete remission rates compared to rates previously observed with either of the 
drugs alone. This is a phase I feasibility study of MLN4924 (pevonedistat) in combination with azacitidine 
followed by fludarabine and cytarabine for children with refractory or recurrent AML. MLN4924 
(pevonedistat) will be administered in combination with azacitidine, fludarabine, and cytarabine in a 35-
day cycle. A total of 2 cycles will be allowed. Once the recommended phase 2 dose (RP2D) is determined, 
a dose-expansion cohort will further assess the safety of this combination.  This clinical trial is critical to 
evaluating this novel agent in AML and determining the safety of this combination strategy in relapsed 
AML in efforts to improve outcomes for this group of patients. 
 
 
 
 
 
 
 
 
 
 
 
 


                     
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Version Date: 08/27/2020 
 
 
8 
 
EXPERIMENTAL DESIGN SCHEMA 
 
ALL PATIENTS:  
 
 
 
 
 
 


                    
ADVL1712
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Version Date: 08/27/2020
9
1.0
GOALS AND OBJECTIVES (SCIENTIFIC AIMS)
1.1
Primary Aims
To evaluate the tolerability and feasibility of MLN4924 (pevonedistat) added to 
the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction 
for pediatric patients with recurrent/refractory AML and MDS.
To define and describe the toxicities of MLN4924 (pevonedistat) when given in 
combination with azacitidine, fludarabine, and cytarabine to pediatric patients 
with relapsed/refractory AML and MDS.
To characterize the pharmacokinetics of MLN4924 (pevonedistat) in children 
with recurrent or refractory AML and MDS.
1.2
Secondary Aim
To describe the antitumor activity of MLN4924 (pevonedistat) in combination 
with azacitidine, fludarabine, and cytarabine within the confines of a feasibility
study.
1.3
Exploratory Aims
To describe the effect of MLN4924 (pevonedistat) administered on this schedule 
on mRNA transcript levels of genes known to be induced by MLN4924 
(pevonedistat) mediated NAE inhibition.
To describe the effect of MLN4924 (pevonedistat) on NEDDylation of proteins 
in the NEDD8 pathway that are likely to be affected by NAE inhibition with 
MLN4924 (pevonedistat). 
2.0
BACKGROUND
2.1
Introduction/Rationale for Development
MLN4924 (pevonedistat) is a novel small molecule inhibitor of NEDD8-activating 
enzyme (NAE) that is currently under development for patients with hematologic and 
solid malignancies. The NEDD8 conjugation pathway is involved in the ubiquitin-
proteasome system (UPS), which is responsible for protein turnover within cells.  The 
NAE is an essential component of the NEDD8 conjugation pathway, controlling the 
activity of a subset of UPS E3 ligases that regulate the timely ubiquitination of proteins 
with key roles in cell cycle progression and a number of cellular processes integral to cell 
growth, proliferation, and survival.  In preclinical studies in both solid and hematologic 
cancer cell lines, MLN4924 (pevonedistat) resulted in NAE inhibition, decreased 
NEDD8-cullin levels, and an increase in ubiquitin ligases that require NEDD8 for 
activation.1,2  In most cases, exposure to MLN4924 (pevonedistat) resulted in DNA 
damage and cell death through apoptosis.3  AML samples with cycling cells were more 
sensitive to NAE inhibition than non-cycling cells. Phase 1 studies of MLN4924 
(pevonedistat) in adults with hematologic and non-hematologic malignancies have 
suggested promising activity with minimal adverse effects when administered on specific 


                     
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Version Date: 08/27/2020 
 
 
10 
dosing schedules.1,4  In vitro and in vivo evaluation by the Pediatric Preclinical Testing 
Program (PPTP) in cell lines and xenograft models demonstrated inhibition of tumor 
growth in some malignancies.5 Clinical development with MLN4924 (pevonedistat) in 
adults is currently focused on patients with AML and MDS due to the encouraging 
activity and safety in combination with azacitidine, as well as additional therapies in this 
patient population in Phase 1 and Phase 2 clinical trials.6,7 
The chemotherapy backbone of fludarabine (Flu) and cytarabine (AraC) has become a 
standard re-induction regimen among pediatric patients with relapsed AML.  The 
International BFM group conducted a randomized trial that compared Flu/AraC + 
filgrastim vs. Flu/AraC + filgrastim + daunoXome that randomized 394 patients, providing 
the largest amount of statistically significant data evaluating cytarabine based regimens. 
Following 2 courses of therapy with Flu/AraC vs Flu/AraC+daunoXome, the CR was 59% 
vs 69% respectively (p=0.07), with no differences in overall survival at 36% vs. 40% 
respectively (p=0.54).8 However, among patients with core binding factor AML there was 
improvement in survival observed among patients receiving daunoXome.  Many patients 
are at risk for treatment-related cardiotoxicity due to the cumulative anthracycline exposure 
during initial therapy, as well as the total body irradiation for patients who have undergone 
hematopoietic stem cell transplant.  Thus, the development of effective non-anthracycline 
regimens is critical for patients with relapsed AML. For these reasons, the Flu/AraC 
regimen has now become the standard salvage backbone for which novel agents are 
evaluated within COG as well as other cooperative groups. Single agent MLN4924 
(pevonedistat) resulted in a 9% CR/CRi rate compared to 39% for azacitidine + MLN4924 
(pevonedistat), and 44% among patients who were evaluable for disease.6,7 Given the 
encouraging data from early phase clinical trials with the combination of azacitidine + 
MLN4924 (pevonedistat), there is compelling rationale to move this combination forward 
in AML. 
 
 
Aberrant DNA methylation has been associated with disease progression and drug 
resistance, thus providing rationale for the potential of a DNA hypomethylating agent such 
as azacitidine to be added into chemotherapy regimens.9,10 Hypomethylating agents such 
as azacitidine have been found to act through a variety of mechanisms with anti-leukemic 
potential, including but not limited to induction of global hypomethylation, downregulation 
of oncogenes, reactivation of tumor suppressors, and increasing sensitivity to cytotoxic 
agents.11-13 There is also preclinical and clinical data to support the safety and potential 
increase in efficacy of azacitidine in combination with fludarabine and cytarabine in AML. 
In vivo studies have demonstrated that azacitidine administered prior to high dose AraC 
can result in hypomethylation and increased expression of certain genes, including 
deoxycytidine kinase (dCK), which results in increased cellular ara-CTP concentrations 
and sensitivity to AraC.8,14 A phase 1 trial evaluating azacitidine in combination with 
fludarabine and cytarabine in pediatric AML found this regimen to be safe and well 
tolerated with no excess toxicity compared to what is seen with standard AML salvage 
regimens, particularly Flu/AraC alone.15 Pharmacodynamic studies demonstrated a 
decrease in methylation following azacitidine exposure in the peripheral blood of all 
patients treated with this regimen.15 Taken together, this pre-clinical data as well as phase 
1 adult and pediatric studies demonstrate the biologic rational for azacitidine given with 
MLN4924 (pevonedistat), and demonstrate the safety of this regimen. The azacitidine 
prime prior to standard chemotherapy is also being evaluated in the upfront setting of the 
St. Jude’s trial AML16 (NCT03164057). Given the importance of the epigenome in AML 
and the global hypermethylation that is often seen in AML, there is significant interest in 


                    
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the use of epigenetic modulation in combination with chemotherapy. This trial will further 
the COG’s investigation in the safety and potential efficacy of this strategy.  Based on 
results of this study, the cassette of MLN4924 (pevonedistat) + azacitidine in combination 
with flu/AraC could move into the phase II setting where it is evaluated against the 
combination of azacitidine + Flu/AraC to determine the efficacy signal attributable to the 
MLN4924 (pevonedistat) + azacitidine combination. 
Regimens used in relapsed AML are very intensive with known toxicities, especially 
myelosuppression. Given the intensity of myelosuppression for many relapsed AML 
regimens, there is no consensus measure of what duration is excessively toxic. Recent 
review of the COG trial AAML0531 is in line with TACL’s findings, as on this study the 
median time to platelet > 50,000 and ANC > 500 was 38 and 37 days, respectively, and 
evaluation of approximately 2 standard deviations of this is approximately 50 days.  More 
recent COG trials for relapsed AML, including the current first line relapse trial, have set 
a duration of greater than 50 days from the start of therapeutic cycle as excessively 
myelosuppresive and a DLT based on the recovery times for multi-agent intensive 
regimens. Fludarabine and cytarabine is comparable in intensity to this regimen, therefore 
for this trial a time of 50 days from the start of therapy without hematologic recovery 
(ANC>500 and a non-transfusion platelet count > 20,000) as a hematologic DLT. 
2.2
Preclinical Studies
Antitumor Activity
There is strong biologic rationale to utilize MLN4924 (pevonedistat) in AML.  In-
vitro studies of MLN4924 (pevonedistat) as a single agent demonstrate its ability 
to induce death of AML cells through multiple pathways, including NF-ĸB 
inhibition, reactive oxygen species generation, and DNA damage.16,17 There exists 
biologic rationale to combine MLN4924 (pevonedistat) with cytarabine, as 
MLN4924 (pevonedistat) disrupts nucleotide metabolism and promotes increased 
incorporation of cytarabine into the DNA of AML cells, and the combination led 
to observed synergy in vitro and increased survival for AML xenograft models.16,18
Among 4 AML cell lines tested, all showed increased cell death when treated with 
the drug combination, as well as patient samples (n=10) with combination indexes 
(CI) ranging from 0.5-0.8 across all combinations tested, all demonstrating 
synergy (CI < 1).18 Importantly, there was no difference seen between primary 
patient samples with prior exposure to chemotherapy (n=6) compared to treatment 
naive samples (n=4).  Preclinical data from in vitro studies demonstrates
synergistic activity of MLN4924 (pevonedistat) administered in combination with 
cytarabine.16,18 The combination of azacitidine and MLN4924 (pevonedistat) was 
evaluated in an AML xenograft model and the combination demonstrated synergy 
when compared to monotherapy with a significant decrease in tumor burden 
(p<0.05).19
MLN4924 (pevonedistat) administration in tumor-bearing immunocompromised 
mice has demonstrated anti-tumor activity in AML xenografts, as demonstrated by 
stable disease regression and inhibition of NEDDylated cullins.17 Treatment with 
MLN4924 (pevonedistat) resulted in dose dependent inhibition of the neddylation 
of cullins, as well as the stabilization of cullin-dependent ligase substrates Nrf-2 
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Pharmacodynamic studies have demonstrated that MLN4924 (pevonedistat)
exposure results in increased levels of the protein ribonucleotide reductase 
(RRM2), which can be antagonized by azacitidine, which may result in increased 
sensitivity to MLN4924 (pevonedistat). In vitro studies in AML cell lines 
demonstrated the ability of azacitidine to counter the normally seen increase in 
RRM2 following MLN4924 (pevonedistat).19 The combination was evaluated in 7 
AML cell lines and resulted in synergy (CI < 1) when evaluating cell viability.19
Animal Toxicology 
The non-clinical safety profile of MLN4924 (pevonedistat) has been characterized 
when given by SubQ injection or 30 minute IV infusion in Sprague Dawley rats 
and by 30 minute IV infusion in beagle dogs. The lethal dose in rats in a SubQ 
repeat dose 5 day study was 200 mg/kg (1200 mg/m2) within 24 hours after a single 
dose. Additionally moribundity requiring euthanasia within 24 hours after a dose 
was observed in dogs dosed at 40 mg/kg (800 mg/m2).20
The highest non-severely toxic dose (HNSTD) of MLN4924 (pevonedistat) when 
administered cyclically (2 cycles of 5 days of dosing followed by a 14 day rest 
period or 5 cycles of 4 doses given every other day followed by a 14 day rest 
period) was 15 mg/kg (300 mg/m2) in dogs and 60 mg/kg (360 mg/m2) in rats. The 
primary dose limiting toxicity of MLN4924 (pevonedistat) in rats and beagle dogs 
was GI toxicity leading to electrolyte imbalances and dehydration and 
complications associated with bone marrow suppression. An acute phase-like 
response was also observed presenting with alterations in body temperature, 
increased fibrinogen, decreased albumin, alterations in circulating neutrophils, and 
increased neutrophil infiltration in multiple tissues (dogs only). Decreased blood 
pressure, increased heart rate, and shortened PR and QT intervals followed by an 
increased diastolic blood pressure were also noted. Myocardial, renal, and 
hepatotoxicity seen at doses above the maximum tolerated dose (MTD) in rats 
were correlated with sepsis. Other adverse effects observed were injection site
necrosis of skin and soft tissues with SubQ administration, changes in trabecular 
bone formation and changes in serum chemistry. Most MLN4924 (pevonedistat) 
related adverse effects resolved during the 14 day rest period or were resolving at 
the completion of the 14 days and are considered reversible.20
Microscopic changes noted in male and female reproductive organs in rats and 
dogs indicate MLN4924 (pevonedistat) represents a significant reproductive and 
developmental hazard. MLN4924 (pevonedistat) was not mutagenic in a bacterial 
reverse mutation (Ames) test.20 Please refer to the Investigator’s brochure for full 
details of preclinical toxicology studies. 
Preclinical Pharmacokinetic Studies
In vitro, MLN4924 (pevonedistat) is predominantly metabolized by CYP3A4, with 
small contribution from the CYP2D6.  Drug-drug interaction studies indicated 
CYP3A4 inhibitors had no clinically meaningful effects on MLN4924 
(pevonedistat) pharmacokinetics, however, there is potential for drug-drug 
interactions if MLN4924 (pevonedistat) is coadministered with drugs that are 
CYP3A4 inducers.  MLN4924 (pevonedistat) is a weak and reversible inhibitor of 
CYP2B6 and 2C8.  The major elimination pathway of MLN4924 (pevonedistat)


                    
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in animals was through the hepatic route. Animal studies have demonstrated that 
MLN4924 (pevonedistat) has been shown to be primarily excreted in the feces and 
excretion is almost complete by 24 hours postdose.  MLN4924 (pevonedistat) has 
been shown to be a substrate of P-glycoprotein (P-gp), breast cancer resistance 
protein (BCRP), and multidrug resistance protein 2 (MRP2).20
2.3
Adult Studies
Phase 1 Studies
To date, MLN4924 (pevonedistat) has been evaluated in multiple phase 1 studies 
as a single agent and with combination therapy in adults with both hematologic 
and non-hematologic malignancies.  Results have demonstrated that MLN4924 
(pevonedistat) is tolerated on an intermittent dosing schedule and has promising 
results for potential efficacy.
Two single agent studies in hematologic malignancies, including one for patients 
with AML or myelodysplastic syndrome (MDS), have evaluated MLN4924 
(pevonedistat) across a range of dosing schedules as well as doses, ranging from 
25 mg/m2 – 147 mg/m2.  When MLN4924 (pevonedistat) was administered on days 
1, 3, and 5 every 21 days in 27 patients, the maximum tolerated dose (MTD) was 
determined to be 59 mg/m2.7 The most common adverse events (AE) on this 
schedule were diarrhea (52%), pyrexia (44%), febrile neutropenia (41%), 
decreased appetite (41%), fatigue (33%), myalgia (30%), increased AST (30%), 
and increased ALT (33%).7  A variety of dose limiting toxicities (DLTs) occurred, 
including hepatic toxicity, hypotension, cardiac failure, GI necrosis, lactic 
acidosis, myocardial ischemia, acute renal failure, and morbiliform rash.  For the 
23 patients treated at or below the MTD for the schedule above, there were 2 
complete remissions (CR, 9%) and additional 2 partial remissions (PR 8%), for a 
combined CR/PR rate of 17%.7 An additional 26 patients were treated on alternate 
dosing regimen that administered MLN4924 (pevonedistat) on days 1, 4, 8, and 11 
and the MTD was determined to be 83 mg/m2 and there were 2 PRs observed 
(10%). 
An additional trial evaluating MLN4924 (pevonedistat) in combination with 
azacitidine in older adult patients (> 60 years of age) with de novo AML has 
demonstrated an acceptable toxicity profile.  This study administered azacitidine 
IV or subcutaneously for a total of 7 days on days 1-5, 8-9 (5 on/2 weekend off/2 
on) at a dose of 75 mg/m2 with MLN4924 (pevonedistat) administered on days 1, 
3, and 5 in 28-day treatment cycles.  MLN4924 (pevonedistat) doses of 20 mg/m2
(n=55) and 30 mg/m2 (n=6) dosing were evaluated and the MTD was determined 
to be 20 mg/m2.  A total of 61 patients have been treated on this study, receiving a 
median of 4 cycles of therapy (range of 1-33).  The most common AEs were 
constipation (48%), nausea (42%) fatigue (42%), and anemia (39%).  A majority 
of patients (n=53, 83%) experienced a > grade 3 AE, with most common being 
anemia and febrile neutropenia (30% each), thrombocytopenia (23%), neutropenia 
(20%), and pneumonia (17%). There were DLTs observed in four patients (n=2 at 
20 mg/m2 and n=2 at 30 mg/m2).  One patient had elevated bilirubin, and the other 
3 patients had elevated AST and ALT (maximum grade 3-4).  For the 2 patients
with transaminase elevation treated at the 20 mg/m2 dose, this was a transient effect


                    
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that resolved spontaneously and the patients were successfully re-challenged at a 
lower dose and remained on study. The most common SAEs detected were febrile 
neutropenia (25%) and pneumonia (14%).  These infectious events and 
myelosuppression are commonly observed in AML regimens. None of the on-
study deaths (n=11) were attributed to MLN4924 (pevonedistat).  A total of 64 
patients were treated and included in the intent to treat (ITT) cohort, with a total of 
52 patients evaluable for response. Among the ITT cohort, the CR/CRi rate was 
39% (20 CR, 5 CRi) with 7 PRs for an overall response rate (ORR) of 50%. Among 
the patients evaluable for response, a CR/CRi rate of 48% was observed.6
Pharmacology/Pharmacokinetics/Correlative and Biological Studies
Pharmacokinetic studies with single agent MLN4924 (pevonedistat) have 
demonstrated that Cmax and AUC24 do increase in a dose proportional manner 
when evaluated from 25-147 mg/m2. However plasma concentrations are similar 
across a range of doses (25 -78 mg/m2) after 12 hours of exposure and were 
detectable at 24 hours post-dose.21 Pharmacodynamic (PD) studies with single 
agent MLN4924 (pevonedistat) have demonstrated induction of multiple target 
genes induced by MLN4924 (pevonedistat) mediated NAE inhibition across all 
dose levels tested.1,7 Pharmacodynamic data across the various single-agent 
phase 1 MLN4924 (pevonedistat) trials provide evidence of pathway inhibition 
downstream of NAE and biological activity is seen across all doses tested (range 
25-261 mg/m2) in pharmacodynamics assays. Additional data of PK and PD 
studies of single agent MLN4924 (pevonedistat), including in the presence of 
moderate CYP3A4 inhibitor also demonstrated activity of MLN4924 
(pevonedistat) at 8, 15, and 20 mg/m2 doses.  Pharmacodynamic evaluation of 8 
genes of interest that are induced by NAE inhibition demonstrated an increase in 
gene expression relative to baseline in all genes. Importantly, positive increases 
in gene expression were most notable at the higher doses of 15 and 20 mg/m2 as 
compared to the 8 mg/m2 dose, where more variability was observed.  Further, 
the time interval of maximal effect was seen at 4-8 hours following MLN4924 
(pevonedistat) administration with a similar pattern between the 15 and 20 mg/m2
doses.22
Preliminary PK studies of MLN4924 (pevonedistat) demonstrate no alterations in 
PK profiles in the presence of azacitidine compared to single agent MLN4924 
(pevonedistat) as well as in the presence of other conventional chemotherapy 
agents.6,23
2.4
Pediatric Studies
Prior Experience in Children 
There is a currently accruing phase 1 study within COG (ADVL1615) evaluating 
MLN4924 (pevonedistat) in patients with relapsed/refractory solid tumors.  The 
study is evaluating MLN4924 (pevonedistat) as a single agent and in 
combination with irinotecan and temozolomide. The study is currently accruing 
at dose level 2 (20 mg/m2) and thus far no DLTs have been reported. 


                     
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2.5 
Overview of Proposed Pediatric Study 
 
This is a feasibility study of MLN4924 (pevonedistat) in combination with azacitidine, 
fludarabine, and cytarabine for patients with recurrent or refractory AML or MDS. 
MLN4924 (pevonedistat) will be administered IV over 1 hour on days 1, 3, and 5 of a 35-
day cycle at a starting dose of 20 mg/m2 for patients > 1 year of age. For patients < 1 year 
of age, MLN4924 (pevonedistat) will be administered IV over 1 hour on days 1, 3, and 5 
of a 35-day cycle at a starting dose of 15 mg/m2. For all patients, MLN4924 (pevonedistat) 
will be administered in combination with azacitidine (75 mg/m2/dose for patients > 1 year 
of age and 2.5 mg/kg/dose for patients < 1 year of age) daily x 5 days administered on days 
1-5. Following completion of azacitidine and MLN4924 (pevonedistat), IV fludarabine (30 
mg/m2/dose for patients > 1 year of age and 1 mg/kg/dose for patients < 1 year of age) 
infused over 30 minutes, and IV cytarabine (2000 mg/m2/dose for patients > 1 year of age 
and 67 mg/kg/dose for patients < 1 year of age) infused over 1-3 hours will be administered 
daily x 5 days, with cytarabine infusion to begin 4 hours after the start of fludarabine.  A 
total of 2 cycles will be allowed. Once the RP2D is determined, a dose-expansion cohort 
will further assess the safety of this combination.  Pharmacokinetics will be obtained in all 
patients while correlative studies will be obtained in consenting patients. Based on the 
results of this study, the efficacy of this combination will be further evaluated in a phase 2 
trial for relapsed AML.   
  
 


                     
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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Oncology Patient Enrollment Network (OPEN), a web-based registration 
system available on a 24/7 basis. It is integrated with the NCI Cancer Trials Support Unit (CTSU) 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
position in the RAVE database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active Cancer 
Therapy Evaluation Program-Identity and Access Management (CTEP-IAM) account (check at < 
https://ctepcore.nci.nih.gov/iam/index.jsp >). This is the same account (user id and password) used 
for credentialing in the CTSU members' web site. To perform registrations in OPEN, the site user 
must have been assigned the 'Registrar' role on the relevant Group or CTSU roster. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
 
3.1 
Current Study Status  
Investigators should refer to the COG website to determine if the study is currently open 
for accrual.  If the study is listed as active, investigators should then access the Studies 
Requiring Reservations page to ensure that a reservation for the study is available. To 
access the Studies Requiring Reservations page:  
1. Log in to https://open.ctsu.org/open/ 
2.  Click the Slot Reservation Tab. The Site Patient page opens.  
3.  Click the Report Tab. The Slot Reservation Report opens. Available Slots are 
detailed per study strata. 
 
3.2 
IRB Approval 
NCI Pediatric CIRB approval or local IRB approval of this study must be obtained by a 
site prior to enrolling patients. Sites must submit CIRB/IRB approvals to the NCI’s Cancer 
Trials Support Unit (CTSU) Regulatory Office and allow 3 business days for processing. 
The CTSU IRB Certification Form may be submitted in lieu of the signed IRB approval 
letter. All CTSU forms can be located on the CTSU web page (www.ctsu.org). Any other 
regulatory documents needed for access to the study enrollment screens will be listed for 
the study on the CTSU Member’s Website under the Regulatory Tab. 
 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing or amendment review. This information will be provided to 
the CTSU Regulatory Office from the CIRB at the time the site’s Signatory Institution 
accepts the CIRB approval. The Signatory site may be contacted by the CTSU Regulatory 
Office or asked to complete information verifying the participating institutions on the 
study. 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
 


                     
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Regulatory Submission Portal: www.ctsu.org (members’ area)  Regulatory Tab 
 Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. For general (non-regulatory) questions, call the CTSU General Helpdesk at 
1-888-823-5923 or contact CTSU by email at ctsucontact@westat.com. 
 
Study centers can check the status of their registration packets by accessing the Site 
Registration Status page on the CTSU Member’s Website under the Regulatory Tab. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory 
Office.) 
 
3.3 
Patient Registration 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry in the OPEN system once authorization for the 
release of protected health information (PHI) has been obtained. 
 
3.4 
Reservation and Contact Requirements 
Before enrolling a patient on study, a reservation must be made through the OPEN website 
and the Study Chair or Vice Chair should be notified. (The patient will need a COG patient 
ID number in order to obtain a reservation). Patients must be enrolled within 7 calendar 
days of making a reservation.  
 
Reservations may be obtained 24-hours a day through the OPEN website.  
 
3.5 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
3.6 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through one of the following mechanisms: a) the COG screening protocol, b) an IRB-
approved institutional screening protocol or c) the study-specific protocol.  Documentation 
of the informed consent for screening will be maintained in the patient’s research chart. 
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
3.7 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 


                     
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into RAVE immediately following enrollment. 
 
3.8 
Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into RAVE. The report must 
include the associated study number and COG patient registration and accession numbers. 
Personal identifiers, including the patient’s name and initials must be removed from the 
institutional pathology report prior to submission. 
 
3.9 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Patients who give informed consent for the protocol in order to undergo 
screening for eligibility are not considered enrolled and should not be enrolled until the 
screening is completed and they are determined to meet all eligibility criteria. Study 
enrollment is accomplished by going to the CTSU OPEN (Oncology Patient Enrollment 
Network) https://open.ctsu.org/open/. For questions, please contact the COG Study 
Research 
Coordinator, 
or 
the 
CTSU 
OPEN 
helpdesk 
at 
https://www.ctsu.org/CTSUContact.aspx.  Patients must be enrolled before treatment 
begins.  The date protocol therapy is projected to start must be no later than five (5) calendar 
days after the date of study enrollment. Patients must not receive any protocol therapy 
prior to enrollment. 
 
3.10 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum  creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Bone marrow 
biopsy and/or aspirate must be obtained within 14 days prior to start of protocol therapy.  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01).  All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the 
time of audit. 
 
 


                    
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4.1
Inclusion Criteria
Age:  Patients must be ≥1 months and 21 years of age at the time of study 
enrollment.
Diagnosis:
4.1.2.1 Patients must have had histologic verification of AML at the original 
diagnosis. Patients must have one of the following: 
a)
Recurrent disease in ≥ 1st relapse with ≥ 5% blasts in the bone marrow 
(M2/M3) marrow OR immunophenotypic evidence of disease with ≥ 
0.1% blasts detected by flow cytometry, OR evidence of recurrent 
cytogenetic or molecular abnormalities consistent with relapse, with 
or without extramedullary disease.
b)
Refractory AML is defined as > 5% blasts in the bone marrow 
(M2/M3) after > 2 induction attempts (i.e., 2 cycles of chemotherapy).
4.1.2.2 Patients with advanced MDS, including MDS that has progressed to AML,
and have experienced relapse or are refractory after > 1 course of induction 
therapy, are eligible.
Performance Level:  Karnofsky 50% for patients > 16 years of age and Lansky 
50 for patients 16 years of age (See Appendix I). 
Prior Therapy:
4.1.4.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g., blood count 
criteria, the patient is considered to have recovered adequately.
a.
Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See DVL homepage for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment.
•
≥ 14 days must have elapsed after the completion of other 
cytotoxic therapy, with the exception of hydroxyurea, for 
patients not receiving standard maintenance therapy. 
Additionally, patients must have recovered from all acute 
toxic effects of prior therapy.
NOTE:
Cytoreduction 
with 
hydroxyurea 
must 
be 
discontinued ≥24 hours prior to the start of protocol 
therapy.
b.
Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥7 days after the 
last dose of agent. See DVL homepage for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 


                    
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of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment. 
c.
Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1.
d.
Hematopoietic growth factors: ≥ 14 days after the last dose of a long-
acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting 
growth factor. For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair and the 
study-assigned Research Coordinator.
e.
Interleukins, Interferons and Cytokines (other than Hematopoietic 
Growth Factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than Hematopoietic Growth Factors )
f.
Stem cell Infusions (with or without TBI):
•
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥84 
days after infusion and no evidence of GVHD.
•
Autologous stem cell infusion including boost infusion:  ≥42
days.
g.
Cellular Therapy: ≥ 30 days after the completion of any type of 
cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.)
h.
XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 42 days after TBI, craniospinal XRT or if radiation to 
50% of the pelvis; ≥ 42 days if other substantial BM radiation.
i.
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): ≥ 42 days after systemically administered 
radiopharmaceutical therapy.
j.
Patients must not have received prior exposure to MLN4924 
(pevonedistat).
Organ Function Requirements
4.1.5.1 Adequate Renal Function Defined as:
-
Creatinine clearance or radioisotope GFR 60ml/min/1.73 m2 or
-
A serum creatinine based on age/gender as follows:
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female


                    
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1 month to < 6 months
0.4
0.4
6 months to < 1 year
0.5
0.5
1 to < 2 years
0.6
0.6
2 to < 6 years
0.8
0.8
6 to < 10 years
1
1
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC.
4.1.5.2 Adequate Liver Function Defined as:
-
Bilirubin (sum of conjugated + unconjugated) upper limit of normal 
(ULN) for age.
-
Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) 2.5 X ULN. For the purpose of this study, the ULN for 
SGPT is 45 U/L. 
4.1.5.3 Adequate Cardiac Function Defined As:
-
Shortening fraction of  27% by echocardiogram, or
-
Ejection fraction of ≥ 50% by echocardiogram or radionuclide 
angiogram
-
No ventricular or supraventricular arrhythmia on EKG
-
Prolonged rate corrected QT (QTc) interval < 500 msec
4.1.5.4 Adequate Pulmonary Function Defined As: 
-
Pulse oximetry > 94% on room air if there is clinical indication for 
determination (e.g. dyspnea at rest)
4.1.5.5 Adequate Coagulation Defined As: 
-
INR < 1.5
4.1.5.6 Adequate Bone Marrow Function Defined As: 
-
Hemoglobin > 8.0 g/dL (may receive RBC transfusions)
Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines. 
4.2
Exclusion Criteria
Pregnancy or Breast-Feeding
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal and teratogenic adverse events as seen in animal/human studies, OR because
there is yet no available information regarding human fetal or teratogenic 
toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males 
or females of reproductive potential may not participate unless they have agreed 
to use 1 highly effective and 1 additional effective (barrier) method of 
contraception at the same time for the duration of study therapy and for 4 months 
after the completion of MLN4924 (pevonedistat) administration. True abstinence, 


                    
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when this is in line with the preferred and usual lifestyle of the subject, is 
acceptable. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. 
Concomitant Medications
4.2.2.1 Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible.
4.2.2.2 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible [except hydroxyurea, which may be continued until 
24 hours prior to start of protocol therapy].
4.2.2.3 Anti-GVHD agents post-transplant: 
Patients who are receiving cyclosporine, tacrolimus or other systemic
agents to prevent graft-versus-host disease post bone marrow transplant 
are not eligible for this trial. Topical immunosuppressive agents (e.g. 
topical steroids) are allowed. Physiologic replacement of hydrocortisone 
is allowed. 
4.2.2.4 Patients who are taking drugs that are strong CYP3A4 inducers and cannot 
be switched to alternative drugs 14 days prior to enrollment are not 
eligible. Strong inducers of CYP34 are not permitted during the study. See
Appendix IX for more details. 
Patients with known hepatitis B surface antigen seropositive or known or 
suspected active hepatitis C infection are not eligible. NOTE: Patients who have 
isolated positive hepatitis B core antibody (i.e. 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. 
Patients with known hepatic cirrhosis or severe pre-existing hepatic impairment 
are not eligible.
Patients with uncontrolled high blood pressure (i.e., > 99% for age, see Appendix 
XI) are not eligible. 
Patients with any of the following diagnoses:
-
Acute promyelocytic leukemia
-
Down syndrome
-
Juvenile myelomonocytic leukemia
Infection:  Patients who have a documented active uncontrolled infection are not 
eligible.
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition as the study agent. 


                    
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Patients with HIV are not eligible unless they meet all of the following criteria: 
-
CD4 count > 350 cell/mm3
-
Undetectable viral load
-
Maintained on modern therapeutic regimens utilizing non-CYP-
interactive agents
-
No history of AIDS-defining opportunistic infections
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) are not eligible. 
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) are not eligible. 
5.0
TREATMENT PROGRAM
5.1
Overview of Treatment Plan
The primary purpose of this feasibility study is to evaluate the safety and toxicity profile 
of MLN4924 (pevonedistat) in combination with azacitidine, fludarabine, and cytarabine 
in children with relapsed or refractory AML or MDS and to recommend a phase 2 dose for 
use in further studies.  A rolling 6 design will be utilized. Patients will receive 1 dose of 
intrathecal cytarabine with a diagnostic lumbar puncture to be performed prior to the start 
of each cycle of therapy. 
For patients > 1 year of age, MLN4924 (pevonedistat) will be administered at 20 
mg/m2/dose intravenously (IV) on days 1, 3 and 5. Azacitidine will be administered at 75 
mg/m2/dose IV once daily on days 1-5. On days 1, 3, and 5 when both drugs are 
administered, azacitidine will be administered first followed by MLN4924 (pevonedistat) 
infusion. The infusion of MLN4924 (pevonedistat) will begin between 30-60 minutes after 
completion of IV azacitidine. Following completion of azacitidine and MLN4924 
(pevonedistat), fludarabine 30 mg/m2/dose IV once daily and cytarabine 2000 mg/m2/dose 
IV once daily will be administered on days 6-10. Cytarabine infusion will begin 4 hours 
after the start of fludarabine.
For patients < 1 year of age, MLN4924 (pevonedistat) will be administered at 15 
mg/m2/dose intravenously (IV) on days 1, 3, and 5. Azacitidine will be administered at 2.5 
mg/kg/dose IV once daily on days 1-5. On days 1, 3, and 5 when both drugs are 
administered, azacitidine will be administered first followed by MLN4924 (pevonedistat)
infusion. The infusion of MLN4924 (pevonedistat) will begin between 30-60 minutes after 
completion of IV azacitidine. Following completion of azacitidine and MLN4924 
(pevonedistat), fludarabine 1 mg/kg/dose IV once daily and cytarabine 67 mg/kg/dose IV
once daily will be administered on days 6-10. Cytarabine infusion will begin 4 hours after 
the start of fludarabine.
Patients without additional evidence of CNS disease (CNS1) do not require additional 
CNS-directed therapy during the cycles. Patients with blasts detected in the CNS (CNS2/3) 
will receive additional intrathecal chemotherapy with IT cytarabine or IT triple therapy 
(cytarabine, hydrocortisone, methotrexate) per institutional standards at a schedule of 
2x/weekly until the CNS is clear of blasts on 2 consecutive LPs, with a minimum of 4 IT 
cytarabine or IT triple (ITT) doses administered.


                     
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NOTE: Central venous access in the form of a double lumen Broviac or Hickman is highly 
recommended.  
 
*For patients with CNS 2/3 status, IT cytarabine or ITT should be administered 2x/weekly until the CNS is clear of blasts on 2 
consecutive LPs, with a minimum of 4 IT cytarabine/IT triple doses administered. This should begin on Day 8 and should be 
repeated 2x/weekly with not less than 3 days between doses, thus any necessary subsequent doses should be given starting on 
Day 11. Days of therapy may vary depending on scheduling.  
 
 
A cycle of therapy is considered to be 35 days.  A cycle may be repeated for a total of 2 
cycles, up to a total duration of therapy of approximately 4 months. 
 
Drug doses of MLN4924 (pevonedistat), azacitidine, fludarabine, and cytarabine should be 
adjusted based on the BSA calculated from height and weight measured within 7 days prior 
to the beginning of each cycle.  Drug doses of intrathecal cytarabine and intrathecal triples 
should be based on the age at the time of administration.   
 
See Appendix VIII for Therapy Delivery Maps for each cycle.  
 
5.2 
Treatment Details (Cycles 1 & 2) 
Intrathecal cytarabine: IT 
All patients will receive 1 dose of IT cytarabine using age-based dosing below 
at the time of diagnostic lumbar puncture, or on Day 0 of each cycle. Patients may be given 
intrathecal cytarabine up to 1 week prior to Day 1, but at least 24 hours prior to the start of 
MLN4924 (pevonedistat) and azacitidine on Day 1. If IT cytarabine is given prior to 
enrollment, a separate institutional consent must be obtained. 
 
Age-based dosing: 
Age (yrs) 
Dose 
< 1 
 
20 mg 
1-1.99   
30 mg 
2-2.99   
50 mg 
≥ 3 
 
70 mg 
 
 
Triples (Methotrexate/Hydrocortisone/Cytarabine): IT 
For CNS2/3 patients only. IT triples may be given instead of IT cytarabine for CNS2/3 
patients in Cycle 1 after the Day 0 IT cytarabine dose per the details described below.  
 
Day 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11-34 
35 
IT Cytarabine 
(all patients) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Azacitidine 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Disease 
Evaluation 
MLN4924 
(Pevonedistat) 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Fludarabine 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Cytarabine 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
IT Cytarabine 
OR ITT* 
(CNS2/3) 
 
 
 
 
 
 
 
 
X* 
 
 
X* 
 


                     
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Age-based dosing:  
Age (yrs) 
Dose 
 
 
<1 
 
MTX: 7.5 mg, HC: 7.5 mg, ARAC: 15 mg 
 
 
1-1.99  
MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
 
 
2-2.99  
MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
 
 
3-8.99  
MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
 
 
> 9 
 
MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
 
 
For CNS2 or CNS3 patients: 
Patients with CNS2 or CNS3 involvement at screening will receive additional intrathecal 
chemotherapy with IT cytarabine or IT triples (doses as above) at a twice weekly schedule 
until the CNS is clear of blasts on 2 consecutive LPs. The administration of IT cytarabine 
vs IT triples is up to the treating physician’s discretion. A minimum of 4 and a maximum 
of 6 intrathecal treatments may be given. This count includes the pre-study/Day 0 dose. 
Subjects who have persistent CNS disease despite 6 doses of IT cytarabine or IT triples 
will be off study treatment and considered treatment failures (See Section 12.2.5). See 
Section 12.3 for definitions of CSF involvement. 
 
 
Azacitidine: IV over 15 minutes once daily 
Days: 1-5 
Dose: Age based dosing 
Age 
 
Dose 
<1 year  
2.5 mg/kg/dose 
> 1 year 
75 mg/m2/dose  
 
Note:  infusion must be completed within 1 hour of vial reconstitution 
On Days 1, 3, and 5 azacitidine will be given 30-60 minutes before MLN4924 
(pevonedistat) infusion. See details of the timing below.  
 
 
MLN4924 (Pevonedistat)*:  
IV over 60 minutes  
Days: 1, 3, and 5  
Starting dose: 20 mg/m2 for patients > 1 year of age; 15 mg/m2 for patients < 1 year of age 
(Dose Level 1). See Dosing Schema in Section 5.4. 
 
*NOTE: Give MLN4924 (pevonedistat) 30 – 60 minutes after the completion of the 
azacitidine infusion. If MLN4924 (pevonedistat) dosing is delayed, a minimum of 1 full 
calendar day between any 2 doses should be maintained.  
 
 
Fludarabine: IV over 30 minutes once daily 
Days: 6-10 
Dose: Age based dosing 
 
Age 
 
Dose 
< 1 year 
1 mg/kg/dose 
> 1 year 
30 mg/m2/dose 
 


                    
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High Dose Cytarabine: IV infusion over 1-3 hours once daily
Days: 6-10
Dose: Age based dosing (begin 4 hours after start of fludarabine)
Age
Dose
< 1 year
67 mg/kg/dose
> 1 year
2000 mg/m2/dose
Please note: Following/during high-dose cytarabine, chemical conjunctivitis may occur. 
Administer steroid eye drops (0.1% dexamethasone or 1% prednisolone ophthalmic 
solution), 2 drops to each eye every 6 hours, beginning immediately before the first dose 
and continuing for 24 hours after the last dose. If patient does not tolerate steroid eye drops, 
artificial tears may be administered on an every 2-4 hour schedule.
See the Chemotherapy Administration Guidelines (CAG) on the COG website at:
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf
for special 
precautions and suggestions for patient monitoring during the infusion. As applicable, also 
see the CAG for suggestions on hydration, or hydrate according to institutional guidelines.
5.3
Criteria for Starting Cycle 2
Patients may proceed to cycle 2 following completion of cycle 1 disease assessment if 
stable or greater response and if non-hematologic toxicities probably or definitely related 
to MLN4924 (pevonedistat) recover to < grade 2. Bilirubin, ALT, and AST must be 
< Grade 1 or at the patient’s baseline values prior to starting Cycle 2.
NOTE: See Appendix III for Toxicity Specific Grading.
•
Patients will have disease assessment on Day 36-39 of Cycle 1.  If a bone marrow 
aspirate cannot be evaluated (dry tap, no spicules), a follow-up bone marrow 
aspirate and biopsy must be performed within 2 weeks to assess cellularity and 
response. 
•
If aspirate and/or biopsy results indicate hypocellular marrow (<10% cellularity on 
biopsy), then continue to repeat bone marrow aspirate and/or biopsy not less than 
once every 14 days until response can be assessed.
•
If count recovery is noted within 14 days of an unevaluable marrow, there is no 
need to repeat the marrow to confirm response. 
•
If the patient meets criteria for CR, CRp, or CRi after Cycle 1 then the patient can 
proceed to Cycle 2 (See Section 12.2 for definitions of response)
•
If the bone marrow aspirate and/or biopsy performed after Cycle 1 reveals > 5% 
but < 25% blasts, then the patient should proceed to Cycle 2 of chemotherapy
5.4
Dosing Schema
Dose Confirmation Schema
The starting dose will be 20 mg/m2 for patients > 1 year of age (Dose Level 1) 
with dose levels for subsequent groups of patients as follows:


                    
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Dose Level
MLN4924 (Pevonedistat) Dose (mg/m2)
-1
15 mg/m2
1*
20 mg/m2
* Starting Dose Level
The starting dose will be 15 mg/m2 for patients < 1 year of age (Dose Level 1) with 
dose levels for subsequent groups of patients as follows: 
Dose Level
MLN4924 (Pevonedistat) Dose (mg/m2)
-1
10 mg/m2
1*
15 mg/m2
* Starting Dose Level
There will be no escalations beyond Dose Level 1 (20 mg/m2), as adult studies 
examining doses higher than 20 mg/m2 observed excess toxicity without any 
apparent disease benefit and no significant differences in pharmacokinetic 
parameters to suggest significant increase in efficacy.24
If the maximally tolerated dose (MTD) has been exceeded at the first dose level, 
then the subsequent cohort of patients will be treated at Dose Level -1. If Dose 
Level -1 is not well tolerated, further de-escalation will not occur. The study will 
be closed to accrual.
Intra-Patient Escalation
Intra-patient dose escalation is not allowed. 
5.5
Grading of Adverse Events
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can 
be 
downloaded 
from 
the 
CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
Any 
suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 
hours) to the Study Chair.
5.6
Definition of Dose-Limiting Toxicity (DLT)
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to protocol therapy.  The DLT observation period for the purposes of dose-
confirmation will be the first cycle of therapy.
Dose limiting hematological and non-hematological toxicities are defined differently.  
Non-hematological dose-limiting toxicity:
5.6.1.1 All Grade 3 or greater non-hematological toxicity not clearly related to the 
underlying disease and attributable to protocol therapy will be considered 
a DLT except:
•
Grade 3 or 4 elevation of ALT/AST that returns to Grade < 1 within 
14 days. NOTE: For the purposes of this study the ULN for ALT is 
defined as 45 U/L regardless of baseline and for AST is defined as 50 
U/L regardless of baseline. See Appendix III for values that represent 
thresholds between CTCAE grades. 


                    
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•
Grade 3 or 4 electrolyte abnormalities that resolve, with or without 
supplementation intervention, to < Grade 2 within 72 hours. 
Electrolyte supplementation is encouraged. 
•
Grade 3 arthralgia/myalgia that returns to Grade ≤ 2 within 5 days on 
analgesics
•
Grade 3 or 4 fever, febrile neutropenia, or infection with or without 
hospitalization
•
Grade 3 tumor lysis syndrome
•
Alopecia
•
Grade 3 maculo-papular or morbiliform rash that resolves to < Grade 
2 within 7 days
•
Grade 3 mucositis that resolves (with or without supportive care) to <
Grade 2 within 14 days
•
Grade 3 fatigue or anorexia responsive to supportive care within 7 
days
•
Grade 3 nausea, vomiting, and/or diarrhea responsive to supportive 
care within 72 hours
•
Early intervention with TPN or enteral tube feeding for anorexia, 
nausea, or concern for poor nutritional status
Hematological dose-limiting toxicity:
Hematological dose limiting toxicity attributable to protocol therapy is defined as 
failure to recover to a peripheral ANC > 500/m3 and platelets > 20,000/mm2 by 50 
days from the start of fludarabine and cytarabine administration, not due to 
presence of leukemia or severe infection (defined as Grade > 3).
o
NOTE: Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity
6.0
DOSE MODIFICATIONS FOR ADVERSE EVENTS
The Study Chair must be notified of any dosage modification. Patients may receive up to 2 
cycles of chemotherapy.
6.1
Dose Modifications for Hematological Toxicity
Patients who experience a hematologic dose limiting toxicity (see Section 5.6.2), 
defined as failure to recover peripheral ANC > 500/uL and non-transfusion 
dependent platelet count > 20,000/uL due to documented bone marrow 
aplasia/hypoplasia (not due to malignant infiltration or Grade 3 infection) for 
greater than or equal to 50 days from the start of fludarabine and cytarabine 
administration, will be allowed to proceed at the discretion of the treating 
physician and study chair with cycle 2 at MLN4924 (pevonedistat) dose level -1.
The patient’s dose for azacitidine, fludarabine, and cytarabine will remain 
unchanged. 
6.2
Dose Modifications for Non-Hematological Toxicity
Patients will have ALT/AST/bilirubin evaluated prior to each planned dose of 
MLN4924 (pevonedistat) in order to determine whether the scheduled dose 


                    
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should be administered. It is anticipated that ALT and AST may be elevated for 
approximately 48 hours following the end of the 1st MLN4924 (pevonedistat)
infusion. 
NOTE: See Appendix III for toxicity grading table.
If a patient experiences > Grade 3 elevation of ALT/AST on or after Cycle 1, Day 
1 then the Cycle 1, Day 3 MLN4924 (pevonedistat) dose should not be given. If 
ALT/AST returns to < Grade 1 or baseline values by Day 5 then the patient should 
receive their Day 5 MLN4924 (pevonedistat) dose and this will not be considered 
a DLT. If ALT/AST does not return to < Grade 1 or baseline values by Day 5 then
MLN4924 (pevonedistat) should be held and this will be considered a DLT. 
Persistent elevations of ALT/AST > Grade 2 beyond 2 days between any other 
doses after Cycle 1, Day 1 will be considered a DLT.    
Patients who experience a dose limiting toxicity during cycle 1 that resolves to 
baseline or < Grade 1 at the time of next cycle can proceed with the next cycle at 
dose level -1.
6.3
Modifications and Supportive Care Recommendations for Toxicity Related to 
Protocol Therapy (Cycle 1 and Cycle 2) 
Neurological Toxicity
The most common neurotoxicity related to fludarabine or cytarabine 
administration is an acute cerebellar syndrome that may manifest itself as ataxia, 
nystagmus, or dysarthria. However, seizures and encephalopathy have also 
occurred following therapy with high dose cytarabine. Patients experiencing Grade 
3 or 4 cerebellar toxicity should be removed from protocol therapy.
Ara-C Syndrome including Fever, Rash, or Conjunctivitis
Do not withhold cytarabine for fever if it is likely to have been caused by the 
cytarabine. However, blood cultures should be obtained even if fever is thought to 
be likely due to cytarabine. Institution of antibiotics for fever associated with 
cytarabine infusion is at the discretion of the treating physician (see fever 
management recommendations in the COG Supportive Care Guidelines).
For rash or conjunctivitis, withhold cytarabine for Grade 3-4 toxicity until resolved 
to ≤Grade 1. Make up missed doses and consider concurrent treatment with 
hydrocortisone or dexamethasone, and/or with dexamethasone ophthalmic drops 
for conjunctivitis only.
Renal Toxicity
6.3.3.1 Cytarabine 
Patients with nephrotoxicity secondary to antibiotics, or antifungals, may 
have prolonged excretion of cytarabine leading to more severe marrow and 
extramedullary toxicity. 
•
Patients with a serum creatinine > 2 mg/dL or > 2x normal for age 
should be hydrated orally or intravenously. Following hydration, the 
patient must have a creatinine clearance ≥60 mL/min/1.73m² as 
measured preferably by a nuclear GFR scan, timed urine collection for 


                    
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creatinine clearance, or calculated by the Schwartz formula before 
proceeding with cytarabine therapy.
•
If the creatinine clearance is abnormal (< 60 mL/min/1.73m2) then 
Cycle 2 high dose cytarabine should be reduced by 50% for each daily 
dose. With this approach, previous research has shown the prevention 
of subsequent neurotoxicity in recipients of high dose cytarabine in 
the face of renal insufficiency.25
6.3.3.2 Fludarabine 
Renal clearance accounts for about 40% of the total body clearance of 
fludarabine and clearance of the primary active metabolite is decreased in 
patients with renal impairment. Renal elimination appears to become more 
important at high dosages of the drug. The dose of fludarabine needs to be 
adjusted in patients with moderate renal impairment. The following are 
suggested guidelines for dose adjustment of fludarabine in renal 
impairment:
GFR > 50 mL/minute/1.73m2: no adjustment required
GFR 30-50 mL/minute/1.73m2: administer 80% of the dose
GFR < 30 mL/minute/1.73m2: not recommended
Hemodialysis: administer 25% of the dose
Continuous ambulatory peritoneal dialysis (CAPD): not recommended
Continuous renal replacement therapy (CRRT): Administer 80% of dose26
Hand-Foot Syndrome 
Hand-foot syndrome has been reported in patients treated with high-dose 
cytarabine. Patients who develop hand-foot syndrome may receive topical 
emollients (such as Aquaphor) as well as topical or systemic steroids or 
antihistamines if appropriate. Oral administration of vitamin B6 (pyridoxine) can 
also be used for these patients- BSA < 0.5 m2: 50 mg per day; BSA 0.5-1.0 m2: 
100 mg per day; BSA 1.1-1.5 m2: 200 mg per day, and BSA > 1.5 m2: 300 mg per 
day.
MLN4924 (pevonedistat) dose modification for hepatic toxicity:
AST, ALT, and bilirubin should be checked and read prior to each dose of 
MLN4924 (pevonedistat) and then weekly.
If a patient experiences > Grade 3 elevation of ALT/AST/bilirubin that does not 
return to < Grade 1 or baseline prior to the next dose of MLN4924 (pevonedistat), 
the dose will be held and this will be considered a DLT. However, patients can still 
receive azacitidine as scheduled and can receive subsequent fludarabine and 
cytarabine if ALT > Grade 3 after discussion with study chair. NOTE: See 
Appendix III for values that represent thresholds between CTCAE grades.
Patients who experience a dose limiting toxicity during cycle 1 that resolves to 
baseline or < Grade 1 at the time of next cycle can proceed with the next cycle at 
dose level -1. 


                     
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7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See Section 7.5 for drugs that should not be used 
concomitantly due to potential interactions with MLN4924 (pevonedistat). For COG 
Supportive Care Guidelines see: https://childrensoncologygroup.org/index.php/cog-
supportive-care-guidelines under Standard Sections for Protocols. 
 
The use of GCSF is not required on this protocol, however filgrastim or biosimilar can be 
initiated per discretion of the treating physician in the setting of serious confirmed (culture 
proven) or suspicious infection. The use of filgrastim (G-CSF) or biosimilar is allowed at 
the treating physician’s discretion to enhance neutrophil recovery when clinically 
indicated. If the treating physician determines that filgrastim use is indicated in Cycle 1, 
the pegylated formulation (pegfilgrastim) should not be used.  
 
Pneumocystis Jirovecii pneumonia (PJP) prophylaxis: Patients should receive PJP 
prophylaxis with trimethoprim/sulfamethoxazole 5 mg/kg/day divided BID (max: 160 mg 
PO BID) for 2-3 consecutive days a week, or per institutional practice, until the end of 
protocol therapy. 
 
Antifungal prophylaxis 
Antifungal agents per institutional guidelines should be administered when ANC falls 
below 200/µL and continued until count recovery. See Section 7.4.2 on CYP3A4 inducers 
and inhibitors for guidelines regarding concurrent administration with MLN4924 
(pevonedistat).  
 
Hospitalization/Hospital Environment 
Hospitalization following each cycle of chemotherapy is strongly recommended until the 
absolute phagocyte count (sum of the neutrophils, bands and monocytes) rises for 2 
successive days, and the patient is afebrile and clinically stable. An additional discharge 
criterion of an absolute neutrophil count (ANC) of at least 200/µL is also suggested. 
 
It is recommended that patients should be assigned to rooms with special air filtration 
systems such as high efficiency particulate air filters (HEPA) or clean-air rooms with 
constant positive pressure airflow if at all possible. 
 
Tumor Lysis Syndrome 
Prophylaxis for tumor lysis syndrome (TLS) should be considered for patients at risk of 
developing rapid tumor lysis (e.g., patients with a high tumor burden or a higher number 
of circulating malignant cells). These patients should be followed closely and appropriate 
laboratory monitoring performed. Appropriate medical therapy should be provided for 


                    
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patients who develop signs and symptoms consistent with rapid tumor lysis. 
7.4
Concomitant Medications
Corticosteroids should not be used as anti-emetic therapy. Corticosteroid 
therapy is not permissible except for the following indications: 
•
As treatment or prophylaxis for anaphylactic reactions
•
As a treatment for symptoms of ARA-C syndrome including fever, rash, 
or conjunctivitis (see Section 6.3.2)
•
Suspected or confirmed adrenal insufficiency
In vitro, MLN4924 (pevonedistat) is metabolized predominantly by CYP3A4 
with a small contribution from CYP2D6. Based on drug-drug interaction study 
results, administration of MLN4924 (pevonedistat) with moderate and strong 
CYP3A inhibitors and P-gp inhibitors is permitted, while use of strong CYP3A 
inducers should be avoided. Strong inducers of CYP3A4 should be discontinued 
within 14 days prior to the first dose of MLN4924 (pevonedistat) and are 
prohibited for the duration of the study (see Appendix IX).
Concomitant administration of BCRP inhibitors (e.g., cyclosporine, eltrombopag) 
should be avoided, however, limited use is permitted if clinically necessary and 
no suitable alternative exists. In this case, a patient may receive the BCRP 
inhibitor from 24 hours after the last MLN4924 (pevonedistat) dose until 72 
hours before the next MLN4924 (pevonedistat) dose. 
Acetaminophen and acetaminophen-containing products may be used judiciously 
but should not exceed a dose of 37 mg/kg/day (maximum 2 g in 24 hours) on 
days MLN4924 (pevonedistat) is administered. 
8.0
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED
8.1
Required Clinical, Laboratory and Disease Evaluation
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility.  If a post-enrollment lab value is outside the limits of eligibility, or laboratory
values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum  creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Bone marrow aspirate 
and/or biopsy, must be obtained within 14 days prior to start of protocol therapy. See 
Appendix VIII for Therapy Delivery Maps for each cycle. 


                    
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STUDIES TO BE OBTAINED
Pre-
Study
During Cycle 1
During Cycle 2
History
X
Weekly
X^
Physical Exam  with vital signs7
X
Weekly
X^
Height, weight, BSA
X
Weekly
X^
Performance Status
X
CBC, differential, platelets
X
Twice Weekly 
X^
Pharmacokinetics1
X
X
Electrolytes including Ca++, PO4, Mg++
X
Weekly6
X^
Creatinine
X
Weekly
X^
ALT, AST, bilirubin (fractionated)8
X
Prior to each dose 
of MLN4924 
(pevonedistat), then 
weekly
Prior to each dose of 
MLN4924 
(pevonedistat), then 
weekly 
Albumin
X
X^
Pregnancy Test2
X
X^
ECHO or gated radionuclide study
X
X5
X5
EKG
X
X5
X5
Bone Marrow Aspirate and/or biopsy
X
End of Cycle 1
End of Cycle 2
CSF for cell count, cytospin
X
End of Cycle 1
End of Cycle 2
PD (mRNA Transcript Levels)3
X
PD (NEDDylated Protein Analysis)4
X
^ 
Studies may be obtained within 72 hours prior to the start of the subsequent cycle.
1
See Section 8.2 for timing of PK studies.
2
Women of childbearing potential require a negative pregnancy test prior to starting Cycle 1 treatment
and prior to Cycle 2; sexually active patients must use an acceptable method of birth control.  Abstinence 
is an acceptable method of birth control.
3
See Section 8.3 for timing of optional PD – mRNA Transcript Level studies. 
4
See Section 8.4 for timing of optional PD – NEDDylated Protein Analysis studies. 
5      Echo and EKG performed prior to Cycle 2 therapy (echo and EKG done at the end of Cycle 1 can count 
as long as it is done within 2 weeks prior to the start of Cycle 2 and before any subsequent therapy). An 
additional echo and EKG are to be obtained at the end of Cycle 2. 
6
Monitor as clinically indicated for tumor lysis. 
7
Vital signs should be checked prior to each MLN4924 (pevonedistat) infusion as well as at the end of 
treatment.
8
ALT, AST, and bilirubin tests must be performed and read prior to each dose of MLN4924 
(pevonedistat). 
8.2
Pharmacology (Required)
Description of Studies and Assay 
Pharmacokinetics (PK) will be performed to determine the PK of MLN4924 
(pevonedistat) in children. Serum will be collected and MLN4924 (pevonedistat)
concentration will be determined by a validated liquid chromatography/tandem 
mass spectrometry (LC/MS/MS) assay. Samples will be analyzed by Covance 
Madison BioA.
Sampling Schedule (See Appendix IV-A and Appendix IV-B)
8.2.2.1 For patients < 10 kg, blood samples will be obtained at the following time 
points during Cycle 1: 


                    
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-
Day 1: pre-dose, at the end of infusion, and at 4 – 6, and 24 hours 
after the end of infusion
-
Day 5: pre-dose, at the end of infusion, and at 4 – 6, and 24 hours 
after the end of infusion
8.2.2.2 For patients > 10 kg, blood samples will be obtained at the following time 
points during Cycle 1: 
-
Day 1: pre-dose, at the end of infusion, and at 1, 2, 4, 6 – 8, and
24 hours after the end of infusion
-
Day 3: pre-dose
-
Day 5: pre-dose, at the end of infusion, and at 1, 2, 4, 6 – 8, 24, 
and 48 OR 72 hours after the end of infusion
Sample Collection and Handling Instructions 
Blood samples (3 mL) will be collected into a chilled Becton-Dickinson 
Vacutainer K2 EDTA tube at a site distant from the infusion for pharmacokinetic 
evaluation. Samples cannot be drawn from the 2nd lumen of a multi-lumen catheter 
through which drug is being administered. Record the exact time that the sample 
is drawn along with the exact time that the drug infusion begins and ends.
Sample Processing
•
Collect 3.0 mL of venous blood into a chilled K2EDTA lavender top Becton-
Dickinson Vacutainer.
•
Gently invert the Vacutainer 8 to 10 times to mix the additive with the 
collected blood prior to centrifugation and place immediately on ice.
•
Centrifuge the Vacutainers for 10 minutes at approximately 1100 to 1300 x g 
(RCF) at approximately 4°C in a refrigerated centrifuge. Note: if using a 
collection device other than Becton-Dickinson, refer to manufacturer’s 
instruction for proper centrifugation force and time.
•
Immediately following centrifugation, gently remove plasma from the 
packed cells and transfer into 2 appropriately labeled 2.0 mL cryogenic vials. 
To ensure a more homogeneous sample, transfer all plasma into one cryovial. 
From there, split the plasma evenly between the 2 aliquots. A minimum of 
0.6 mL needs to be obtained for each aliquot.
•
Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -70°C or lower. If a -70°C freezer is not available, freeze and 
store samples at -20°C. No more than 45 minutes will elapse between blood 
collection and freezing the plasma sample.
•
Store samples frozen at approximately -70°C or lower until shipment.
Note: If a -70°C freezer is not available, the samples may be stored at 
approximately -20°C in a commercial grade freezer with no auto-defrost until 
shipment.
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on the 
Pharmacokinetic Study Form (Appendix IV-A; Appendix IV-B), which must 
accompany the sample(s).


                    
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Sample Shipping Instructions 
See Appendix XIII. 
8.3
Pharmacodynamics - mRNA Transcript Levels (Optional)
Description of Studies and Assay 
Peripheral blood will be collected from consenting patients to evaluate the effects 
of MLN4924 (pevonedistat) on mRNA transcript levels of genes that have been 
shown to be induced by MLN4924 (pevonedistat) mediated NAE inhibition. 
Samples will be analyzed by reverse transcription-polymerase chain reaction (RT-
PCR) by Takeda Pharmaceuticals.  
Sampling Schedule (See Appendix V)
Blood samples will be collected from consenting patients at the following time 
points during Cycle 1: 
-
Day 1: pre-dose
-
Day 3 OR Day 5: 3 hours and 6 hours after the end of MLN4924 
(pevonedistat) infusion (which is given after azacitidine)
Sample Collection and Handling Instructions 
Blood samples (2 ml) will be collected in citrate vacutainer tubes at a site distant 
from the infusion in consenting patients. Record the exact time that the sample is 
drawn along with the exact time that the drug infusion begins and ends.
Sample Processing
1.
Store at 4ºC until processed.
2.
Ship in thermosafe box to address provided in Section 8.3.6.
•
Box should be of thick Styrofoam (NO CLINI-PACS) inside a 
cardboard box.
•
Pack sample in primary container using soft packing material
•
Place 2 ice packs outside primary container (one ice pack is 
sufficient Nov-April).
•
Ship overnight mail on Mon-Thurs
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on the 
Correlative Study Form (Appendix V), which must accompany the sample(s).
Sample Shipping Instructions 
Samples should be batched per patient and shipped frozen on dry ice in opaque 
containers at the end of Cycle 1 according to the lab manual.
8.4
Pharmacodynamics - NEDDylated Protein Analysis (Optional)
Description of Studies and Assay 
Bone marrow and/or peripheral blood will be collected from consenting patients 
to examine NEDDylated protein degradation and to correlate it with MLN4924


                    
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(pevonedistat) response. Peripheral blood samples will only be collected from 
consenting patients with an initial absolute blast count > 1000 blasts/µL (see 
Appendix VI-A for details). Bone marrow samples will be collected from 
consenting patients regardless of initial absolute blast count. Samples will be 
analyzed by reverse protein lysate array and immune-capillary electrophoresis.  
Sampling Schedule (See Appendix VI-B and Appendix VII)
For questions about the sample delivery process, please contact Gaye Jenkins
(gnjenkin@txch.org) or Dr. Terzah Horton (tmhorton@txch.org). Blood samples 
will only be collected from consenting patients with an initial absolute blast count 
> 1000 blasts/µL (see Appendix VI-A for details). Blood samples will be collected 
from consenting patients at the following time points during Cycle 1: 
-
Day 1: prior to IV azacitidine and MLN4924 (pevonedistat) dose, 10 
hours after the end of MLN4924 (pevonedistat) infusion, and 24 
hours after the end of MLN4924 (pevonedistat) infusion
•
NOTE: The Day 1, Hour 0 sample can be obtained after the 
IT cytarabine dose.  
-
At the end of Cycle 1 on the same day as bone marrow evaluation.
Bone marrow aspirate will be collected from consenting patients at the following 
time points, regardless of initial absolute blast count:
-
Pre-study on the same day as bone marrow evaluation
-
At the end of Cycle 1 on the same day as bone marrow evaluation
Sample Collection and Handling Instructions 
Blood samples will be collected in Cell Save tubes (3 ml) and heparinized tubes (2 
ml). Samples may be collected from a central line. Either lithium heparin or sodium 
heparin is acceptable. Do NOT use lithium PST (plasma separator tubes). Record 
the exact time that the sample is drawn along with the exact time that the drug 
infusion begins. For end of Cycle 1 samples, drug infusion timing is not needed.
See Appendix VI-A for detailed instructions. 
Bone marrow samples (3 ml) will be collected in heparinized tubes or in COG 
shipping media. Record the exact time that the sample is drawn and whether the 
sample is a pre-study or end of Cycle 1 sample. 
Sample Processing
Store samples in refrigerator until shipment. 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
number (ADVL1712), accession number, and the date and time the sample was 
drawn.  Data should be recorded on the Correlative Study Forms (Appendix VI-B; 
Appendix VII), which must accompany the sample(s).
Please note the WBC and % blasts on the specimen transmittal form.
Sample Shipping Instructions 
Ship the sample by Federal Express Priority Overnight delivery to: 


                    
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Dr. Terzah Horton c/o Gaye Jenkins
Feigin Center, Suite 760.01
1102 Bates St. 
Baylor College of Medicine
Houston, TX 77030
(832) 824-4676
Please email the Fed-Ex tracking number to the email addresses above and 
copy the ADVL1712 Research Coordinator on the email.
See Appendix VI-A for detailed shipping instructions. 
9.0
AGENT INFORMATION
9.1
MLN4924 (Pevonedistat)
      
       (08/15/20)
(TAK924, MLN4924-003 (hydrochloride salt), MLN4924-001 (free base), ML644507, 
ML00644807) NSC#793435
Structure and molecular weight
Molecular formula: 
C21H26ClN5O4S
Molecular weight: 
443.52 (free base)
479.98 (hydrochloride salt)
Mode of Action:  MLN4924 (pevonedistat) is an inhibitor of neural precursor cell 
expressed development down-regulated 8 (NEDD8)-activating enzyme or NAE.  
NAE is essential in the NEDD8-conjugation pathway to control the activity of a 
subset of multiprotein complexes that transfer NEDD8 molecules to protein 
substrates by E3 ligases.  NAE inhibitors stop the degradation of a subset of proteins 
that are regulated by the proteasomes.
Supplied by:
MLN4924 (pevonedistat) is supplied by Takeda Pharmaceuticals and distributed 


                    
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by the Division of Cancer Treatment and Diagnosis (DCTD), NCI.
Formulation
The agent is supplied as a single-use 50 mg or 44 mg vial containing 10 mg/mL
MLN4924 (pevonedistat) (free base, equivalent to 10.8 mg/mL MLN4924 
[pevonedistat HCl]) in an aqueous solution of citric acid (anhydrous), trisodium 
citrate dihydrate, and Betadex Sulfobutyl Ether Sodium (Captisol) at pH 3.3. 
Each USP Type I glass vial nominally contains 5 mL or 4.4 mL of compounded 
sterile solution, sealed with a fluoropolymer-coated butyl rubber stopper and 
oversealed with an aluminum seal and a plastic cap.
Storage
Vials of MLN4924 (pevonedistat) are to be kept dry and refrigerated at 2°-8°C 
(36° – 46° F) until dilution and use. Pevonedistat vials should be kept in their 
original carton until time of use. If original carton is not available, wrap vials in 
aluminum foil or similar light protective cover to protect from light. MLN4924 
(pevonedistat) injection is stable at ambient temperature for 6 hours before 
dilution. Return vials to refrigerator if vial(s) are not to be used within 6 hours after 
removing from the refrigerator. All investigational supplies are to be kept in a secure 
area with controlled access.
If a storage temperature excursion is identified, promptly return MLN4924 
(pevonedistat) to 2°-8°C (36° – 46° F) and quarantine the supplies.  Provide a 
detailed report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability.
Solution Preparation
To prepare the agent for administration dilute MLN4924 (pevonedistat) injection
in 5% dextrose or 0.9% sodium chloride. The vial must not be shaken at any time 
during dose preparation. Before use, bring MLN4924 (pevonedistat) vials to ambient 
room temperature (15° – 30° C / 59° – 86° F).  Do not use a water bath to warm up 
the vials. 
MLN4924 (pevonedistat) is a cytotoxic anticancer drug. As with other potentially 
toxic compounds, caution should be exercised when handling MLN4924 
(pevonedistat) injection. Refer to institutional guidelines regarding the proper 
handling and disposal of cytotoxic agents.
•
The specified number of MLN4924 (pevonedistat) 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.
For the pevonedistat packaged 10 vials per carton, two recommendations 
to protect the vial(s) from light (1 or 2 dispensed per cycle day) are: 
o
Use a spare carton in the pharmacy and put the vial(s) in it 
o
Wrap vial(s) in aluminum foil
•
Using aseptic technique, the appropriate volume of drug should be 
withdrawn from vial(s), then injected into an IV bag containing 5% 
dextrose solution or 0.9% sodium chloride (QS to a final volume of 100 
mL), and then gently inverted repeatedly to mix. 


                    
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•
For volume-restricted infants, a 20-fold dilution in 5% dextrose or 0.9% 
sodium chloride can be used to achieve the smallest possible volume. For 
example, to deliver 20 mg/m2 dose of MLN4924 (pevonedistat) to an 
infant with a BSA of 0.5 m2, withdraw 1 mL (10 mg) of MLN4924 
(pevonedistat) solution from the vial and further dilute in 20 mL of 
5% dextrose or 0.9% sodium chloride for administration.
•
Inspect the prepared solution to ensure it is clear and free of visible 
particles. 
•
The MLN4924 (pevonedistat) prepared IV bag must be used within 6 
hours (time to the end of an infusion) if stored at ambient temperature. 
•
The bag, needle, and syringe must be disposed of in a proper biohazard 
container.
•
Use of non-DEHP IV bags, non-DEHP tubing with Teflon or polyurethane 
catheter and stainless steel needle, and non-DEHP solution set is preferred.
Stability
Stability studies are ongoing. 
•
The prepared IV solution is stable when stored at ambient room 
temperature up to 6 hours and must be administered within that time frame. 
Discard the IV bag if > 6 hours from the time of preparation.
•
The prepared IV solution is stable when stored at 20 – 80 C (360 – 460 F) 
up to 18 hours. The IV solution can be brought to ambient room 
temperature before administering to patient, but must be used within 3 
hours from the time it is removed from the refrigerator to completion of 
the IV infusion. Discard the IV bag if > 3 hours. 
Administration
See Treatment and Dose Modification sections of the protocol.
MLN4924 (pevonedistat) will be administered intravenously over 60 minutes. 
MLN4924 (pevonedistat) should be administered through central or peripheral 
venous access. The use of in-line filter is NOT necessary for administration. 
Protecting IV bag from light during infusion is not required. The infusion may be 
slowed or stopped for any associated infusion-related reactions per institutional 
standards. All infusion times must be recorded. The total time from drug 
reconstitution to end of infusion must not exceed 6 hours. Doses of MLN4924 
(pevonedistat) must be separated by at least 1 full calendar day. Infusion line 
should be flushed with 5% Dextrose or 0.9% sodium chloride immediately after 
IV administration is complete.
Potential drug interactions
Acetaminophen may be used judiciously but should not exceed a dose of 
37 mg/kg/day (maximum 2 g in 24 hours) on days MLN4924 (pevonedistat) is 
administered.
In vitro, MLN4924 (pevonedistat) is metabolized via hydroxylation and 
oxidation, predominantly by CYP3A4 with a small contribution from CYP2D6 
(approximately 3%). Based on drug-drug interaction study results, the 
administration of MLN4924 (pevonedistat) with moderate and strong CYP3A 
inhibitors and P-gp inhibitors is permitted, while the use of strong CYP3A 


                    
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inducers should be avoided.
In vitro, MLN4924 (pevonedistat) does not inhibit the activities of CYP1A2, 
2C9, 2C19, 2D6, and 3A4/5, but weakly and reversibly inhibits both CYP2B6 
and 2C8; it does not induce CYP1A2, 2B6, and 3A4/5. Thus, MLN4924 
(pevonedistat) is unlikely to affect the PK of drugs that are metabolized by these 
CYP450 isoforms.
MLN4924 (pevonedistat) is also a substrate for the drug efflux transporters, P-gp 
and BCRP, and a weak inhibitor of P-gp and BCRP-mediated transport. Additional 
in vitro transport studies showed that MLN4924 (pevonedistat) is not a substrate 
of the hepatic OATP, but it can inhibit OATP-mediated uptake of E3S and 
simvastatin and lovastatin. On the basis of these data and the recommended clinical 
dose range, MLN4924 (pevonedistat) is unlikely to affect the PK of other drugs 
that are known P-gp, BCRP, or OATP substrates, while the potential exists, albeit 
low, for drug interactions with BCRP inhibitors. Exclusion of P-gp inhibitors is 
not deemed warranted in clinical studies of MLN4924 (pevonedistat). However, 
the concomitant administration of BCRP inhibitors (e.g., cyclosporine, eltrombopag) 
should be avoided, however, limited use is permitted if clinically necessary and no 
suitable alternative exists. In this case, a patient may receive the BCRP inhibitor from 
24 hours after the last MLN4924 (pevonedistat) dose until 72 hours before the next 
MLN4924 (pevonedistat) dose. 
Patient Care Considerations
No dose adjustment is recommended for patients with mild or moderate renal 
impairment (estimated glomerular filtration rate [eGFR] of 30 mL/min/1.73 m2 or 
higher) based on the results of a population PK analysis. The effect of severe 
renal impairment (eGFR less than 30 mL/min/1.73 m2) on MLN4924 
(pevonedistat) PK has not been studied. Avoid use of MLN4924 (pevonedistat)
in patients with severe renal impairment or end-stage renal disease. 
The effect of hepatic impairment on MLN4924 (pevonedistat) PK has not been 
studied. 
Toxicities
Comprehensive Adverse Events and Potential Risks list (CAEPR)
for 
MLN4924 (Pevonedistat HCl, NSC 793435)
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except 
as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf
for 
further 
clarification. Frequency is provided based on 474 patients. Below is the CAEPR for MLN4924 (Pevonedistat 
HCl).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 


                     
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41 
investigational agents and has an AE listed on different SPEERs, use the lower of the 
grades to determine if expedited reporting is required. 
 
 Version 2.3, July 10, 202027 
 
 Adverse Events with Possible  
 Relationship to MLN4924 (Pevonedistat HCl) 
 (CTCAE 5.0 Term) 
[n= 474] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Sinus tachycardia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
Fever 
 
 
 Fever (Gr 2) 
 
Pain 
 
 Pain (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Lung infection 
 
 Lung infection (Gr 2) 
 
Upper respiratory infection 
 
  
 
Urinary tract infection 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
 Bruising (Gr 2) 
INVESTIGATIONS 
  
Alanine 
aminotransferase 
increased 
 
 
 Alanine 
aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase increased  
 Alkaline 
phosphatase 
increased (Gr 2) 
Aspartate 
aminotransferase 
increased 
 
 
 Aspartate 
aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Creatinine increased 
 
  
 
GGT increased 
 
  
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
 
Hypercalcemia 
 
  
 
Hyperglycemia 
 
  
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 


                     
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 Adverse Events with Possible  
 Relationship to MLN4924 (Pevonedistat HCl) 
 (CTCAE 5.0 Term) 
[n= 474] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
 Hypokalemia (Gr 2) 
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
  
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
Myalgia 
 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
Nervous system disorders - 
Other (neuropathy peripheral, 
peripheral neuropathy) 
 
  
 
Paresthesia 
 
  
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Confusion 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
  
 
Hypoxia 
 
  
 
Pleural effusion 
 
  
 
Productive cough 
 
  
 
Respiratory, 
thoracic 
and 
mediastinal disorders - Other 
(rales) 
 
  
 
Wheezing 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
Pruritus 
 
  
 
Purpura 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
 Hypotension (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 


                    
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Adverse events reported on MLN4924 (Pevonedistat HCl) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that MLN4924 
(Pevonedistat HCl) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Leukocytosis
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocarditis
EYE DISORDERS - Blurred vision
GASTROINTESTINAL DISORDERS
-
Ascites; Dyspepsia; Gastrointestinal disorders -
Other 
(gastrointestinal necrosis); Gastrointestinal disorders - Other (gastrointestinal hemorrhage); Ileus; Small 
intestinal obstruction
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Generalized edema; Multi-organ 
failure; Non-cardiac chest pain
HEPATOBILIARY DISORDERS - Hepatic failure
INFECTIONS AND INFESTATIONS - Bacteremia; Sepsis; Sinusitis; Skin infection
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall
INVESTIGATIONS - Investigations - Other (brain natriuretic peptide increased); Neutrophil count 
decreased; Weight loss; White blood cell decreased
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hyperuricemia
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Treatment related secondary malignancy
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Spinal cord compression
PSYCHIATRIC DISORDERS - Psychiatric disorders - Other (mental status changes)
RENAL AND URINARY DISORDERS - Dysuria; Renal and urinary disorders - Other (renal impairment); 
Urinary retention
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Nasal 
congestion; Oropharyngeal pain; Respiratory failure; Rhinorrhea
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Rash maculo-papular
VASCULAR DISORDERS - Hypertension; Phlebitis; Thromboembolic event
Note: MLN4924 (Pevonedistat HCl) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent.
Agent Ordering and Agent Accountability
NCI supplied agent may be requested by the eligible participating investigator (or their 
authorized designee) at each participating institution. The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible 
investigator at each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF). If there are several participating 
investigators at one institution, CTEP supplied investigational agents for the study should be 
ordered under the name of one lead participating investigator at that institution.
Clinical Drug Request
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a “current” 
password, and active person registration status. For questions about drug orders, transfers, 


                    
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returns, or accountability call or email PMB any time. Refer to the PMB’s website for 
specific policies and guidelines related to agent management.
Agent Inventory Records
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol.
Investigator Brochure Availability
The current version(s) of the IB for the agent will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status, a “current” password 
and active person registration status. Questions about IB access may be directed to the 
PMB IB coordinator via email.
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:
http://ctep.cancer.gov/forms/
• NCI CTEP Investigator Registration:
RCRHelpDesk@nih.gov
• PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm
• PMB Online Agent Order Processing (OAOP) application:
https://ctepcore.nci.nih.gov/OAOP
• CTEP Identity and Access Management (IAM) account:
https://ctepcore.nci.nih.gov/iam/
• CTEP IAM account help:
ctepreghelp@ctep.nci.nih.gov
• PMB email:
PMBAfterHours@mail.nih.gov
• IB Coordinator:
IBCoordinator@mail.nih.gov
• PMB phone and hours of service:
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm 
(ET)
9.2
Azacitidine – Injection
(Vidaza®, 5-azacitidine) NSC# 102816
(09/09/19)
Source and Pharmacology
Azacitidine (4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one) is an analog of the 
naturally occurring pyrimidine nucleoside, cytidine. It differs from cytidine in 
having nitrogen in the 5-position of the heterocyclic ring. This substitution renders 
the ring chemically unstable and leads to rapid decomposition of the compound in 


                    
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neutral or alkaline solution. Therefore, for SC or IV administration, the drug is
supplied as a lyophilized powder to be reconstituted immediately prior to use.
Azacitidine was developed based on its strong in vitro and in vivo antileukemic 
activity at cytotoxic concentrations, and its differentiation-inducing potential at 
lower concentrations in hematopoietic and non-hematopoietic cell lines. The 
cytotoxic effects of azacitidine may be due to inhibition of protein synthesis and 
activation of DNA damage pathways, through incorporation into ribonucleic acid 
(RNA) and DNA, respectively. The ability of azacitidine to cause differentiation 
is attributed to its activity as a hypomethylating agent. Similar to cancer cells, the 
disturbed maturation of morphologically dysplastic hematopoietic cells in MDS is 
thought to reflect a block in their differentiation, resulting in accumulation of these 
precursors in the bone marrow in spite of low peripheral blood counts. This block 
in maturation (differentiation), with proliferation of preleukemic myeloblasts, 
provides a rationale for clinical trials of DNA methylation inhibitors (eg, 
azacitidine) in the treatment of MDS.
Pharmacokinetic studies using 14C-radiolabeled azacitidine to evaluate drug 
disposition demonstrated that azacitidine undergoes rapid and complete absorption 
following SC administration, with SC bioavailability greater than 70% and 
maximum concentration (Cmax) achieved 0.5 to 2 hours after dosing. The volume 
of distribution of azacitidine is 76 ± 26 L following IV administration. Its protein 
binding in human serum is low (< 10% bound). Azacitidine and/or its metabolites 
are cleared by the kidneys. The plasma elimination half-life (t1/2) is 3.4 to 6.2 
hours and amount of radioactivity recovered in urine (50% to 98% of administered 
dose) were similar after IV and SC dosing.
In vitro and in vivo studies have demonstrated that spontaneous hydrolysis of 
azacitidine is the major pathway in different species, regardless of the route of 
administration. Azacitidine is not metabolized by cytochrome P450 isozymes 
(CYPs) and it will not produce clinically relevant PK drug-drug interactions due 
to CYP enzyme inhibition or induction when coadministered with CYP substrates, 
inducers, or inhibitors. Azacitidine is not a substrate for P-glycoprotein (P-gp) and 
is unlikely to produce any clinically relevant interactions as a P-gp substrate or an 
inhibitor.
Toxicity 
Comprehensive Adverse Events and Potential Risks list (CAEPR)
for 
Azacitidine (NSC 102816)
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf
for further 
clarification. Frequency is provided based on 1800 patients. Below is the CAEPR for Azacitidine.
Version 2.7, July 30, 201928


                     
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 Adverse Events with Possible  
 Relationship to Azacitidine 
 (CTCAE 5.0 Term) 
[n= 1800] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
 
 
Febrile neutropenia 
 
 
CARDIAC DISORDERS 
 
 
Heart failure 
 
 
 
Pericardial effusion 
 
 
 
Sinus tachycardia 
 
 
 
Supraventricular tachycardia 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
 
Colitis 
 
 
Constipation 
 
 
 
Diarrhea 
 
 
 
 
Esophagitis 
 
 
 
Gastrointestinal hemorrhage29 
 
 
 
Mucositis oral 
 
 
Nausea 
 
 
 
Vomiting 
 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Chills 
 
 
 
Edema limbs 
 
 
Fatigue 
 
 
 
Fever 
 
 
 
Injection site reaction 
 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
Allergic reaction 
 
 
 
Anaphylaxis 
 
INFECTIONS AND INFESTATIONS 
 
Infection30 
 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Bruising 
 
 
INVESTIGATIONS 
 
 
Alanine aminotransferase increased  
 
 
Alkaline phosphatase increased 
 
 
 
Aspartate 
aminotransferase 
increased 
 
 
 
Blood bilirubin increased 
 
 
 
GGT increased 
 
 
 
Lymphocyte count decreased 
 
 
Neutrophil count decreased 
 
 
 
Platelet count decreased 
 
 
 
 
Weight loss 
 
 
 
White blood cell decreased 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Acidosis 
 
 
 
Anorexia 
 
 


                     
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 Adverse Events with Possible  
 Relationship to Azacitidine 
 (CTCAE 5.0 Term) 
[n= 1800] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Hypokalemia 
 
 
 
 
Tumor lysis syndrome 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
Back pain 
 
 
 
Generalized muscle weakness 
 
 
 
Myalgia 
 
 
 
Pain in extremity 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
 
Headache 
 
 
 
Peripheral motor neuropathy 
 
 
 
Somnolence 
 
 
PSYCHIATRIC DISORDERS 
 
 
Anxiety 
 
 
 
Confusion 
 
 
 
Insomnia 
 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
 
Bronchopulmonary hemorrhage  
 
Cough 
 
 
 
Dyspnea 
 
 
 
Epistaxis 
 
 
 
Pharyngolaryngeal pain 
 
 
 
Postnasal drip 
 
 
 
Respiratory, 
thoracic 
and 
mediastinal 
disorders 
- 
Other 
(abnormal breath sound)31 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
 
Pruritus 
 
 
 
Purpura 
 
 
 
Rash maculo-papular 
 
 
VASCULAR DISORDERS 
 
 
Hematoma 
 
 
 
Hypotension 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 


                     
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hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
3Infection may include any of the 75 infection sites under the INFECTIONS AND 
INFESTATIONS SOC. 
4Abnormal breath sounds include rales and rhonchi. 
 
Adverse events reported on azacitidine trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that azacitidine caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(agranulocytosis); Blood and lymphatic system disorders - Other (lymphadenopathy); Blood and lymphatic 
system disorders - Other (pancytopenia); Blood and lymphatic system disorders - Other (splenomegaly); 
Blood and lymphatic system disorders - Other (transfusion: platelets); Bone marrow hypocellular; 
Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Atrioventricular block complete; Cardiac 
arrest; Cardiac disorders - Other (cardiac valve vegetation); Cardiac disorders - Other (Wolff-Parkinson-
White syndrome); Chest pain - cardiac; Myocardial infarction; Palpitations; Pericarditis; Restrictive 
cardiomyopathy; Sinus bradycardia; Ventricular fibrillation 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
EYE DISORDERS - Eye disorders - Other (eye/conjunctival hemorrhage); Eye disorders - Other (retina 
hemorrhage); Papilledema; Uveitis 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Duodenal ulcer; Dyspepsia; 
Dysphagia; Enterocolitis; Esophageal pain; Esophageal ulcer; Flatulence; Gastritis; Gastrointestinal 
disorders - Other (enteritis); Gastrointestinal disorders - Other (inguinal hernia, obstructive); 
Gastrointestinal disorders - Other (intestinal ischemia); Gastrointestinal disorders - Other (intussusception); 
Gastrointestinal pain; Hemorrhoids; Pancreatitis; Periodontal disease; Small intestinal obstruction; Visceral 
arterial ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; 
Flu like symptoms; Gait disturbance; General disorders and administration site conditions - Other (systemic 
inflammatory response syndrome); Generalized edema; Malaise; Multi-organ failure; Non-cardiac chest 
pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (bile 
duct stone); Hepatobiliary disorders - Other (hepatic cirrhosis) 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder; Immune system disorders - Other (GVHD) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Burn; Fall; Fracture; Hip fracture; 
Injury, poisoning and procedural complications - Other (excoriation); Injury, poisoning and procedural 
complications - Other (transfusion reaction); Postoperative hemorrhage; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood lactate dehydrogenase 
increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; INR increased; 
Investigations - Other (blood urea increased); Investigations - Other (cardiac murmur); Investigations - 
Other (coagulopathy); Investigations - Other (protein total decreased); Investigations - Other 
(thrombocytosis); Lipase increased; Lymphocyte count increased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; 
Hyperuricemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypomagnesemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (gout exacerbation); 
Metabolism and nutrition disorders - Other (hypovolemia); Metabolism and nutrition disorders - Other (low 
carbon dioxide) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Bone pain; Chest 
wall pain; Flank pain; Muscle cramp; Muscle weakness lower limb; Musculoskeletal and connective tissue 
disorder - Other (chondritis); Musculoskeletal and connective tissue disorder - Other (intervertebral disc 
protrusion); Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness); Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 


                    
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Myelodysplastic syndrome; Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(colonic polyp, vaginal polyp); Neoplasms benign, malignant and unspecified (incl cysts and polyps) -
Other (metastases to central nervous system); Treatment related secondary malignancy
NERVOUS SYSTEM DISORDERS - Dysesthesia; Dysgeusia; Hydrocephalus; Intracranial hemorrhage; 
Lethargy; Memory impairment; Nervous system disorders - Other (head injury); Paresthesia; Peripheral 
sensory neuropathy; Seizure; Stroke; Syncope
PSYCHIATRIC DISORDERS - Delirium; Depression; Hallucinations; Psychiatric disorders - Other 
(mental status changes)
RENAL AND URINARY DISORDERS - Chronic kidney disease; Dysuria; Hematuria; Proteinuria; 
Renal and urinary disorders - Other (bladder distention); Renal and urinary disorders - Other (calculus 
urinary); Renal calculi; Urinary frequency; Urinary retention
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Reproductive system 
and breast disorders - Other (benign prostatic hyperplasia); Uterine hemorrhage; Vaginal hemorrhage
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Hypoxia; Laryngeal 
hemorrhage; Nasal congestion; Oropharyngeal pain; Pleural effusion; Pleuritic pain; Pneumonitis; 
Pneumothorax; Productive cough; Pulmonary edema; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (chronic obstructive pulmonary disease); Respiratory, thoracic and 
mediastinal disorders - Other (pharyngeal erythema); Rhinorrhea; Sinus pain; Wheezing
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Palmar-plantar 
erythrodysesthesia syndrome; Skin and subcutaneous tissue disorders - Other (skin laceration); Skin and 
subcutaneous tissue disorders - Other (skin lesion); Skin and subcutaneous tissue disorders - Other (skin 
nodule); Skin and subcutaneous tissue disorders - Other (Sweet's Syndrome); Skin induration; Urticaria
VASCULAR DISORDERS - Flushing; Hypertension; Thromboembolic event; Vascular disorders - Other 
(pallor); Vascular disorders - Other (poor venous access); Vasculitis
Note: Azacitidine in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated.
Formulation and Stability
Azacitidine is supplied as lyophilized powder in 100 mg single-use vials without 
antibacterial preservatives. Store unreconstituted vials at 25° C (77° F); excursions 
permitted to 15°-30° C (59°-86° F).
For IV administration: Reconstitute vial with 10 mL SWFI to form a 10 mg/mL 
solution; vigorously shake or roll vial until solution is dissolved and clear. Mix in 
50 to 100 mL of NS or lactated Ringer's injection for infusion. For infants and 
small children, azacitidine can be diluted in volumes less than 50 mL to a final 
concentration between 0.9 mg/mL and 4 mg/mL. The reconstituted product may 
be stored at 25° C (77° F), but the administration of the intravenous solution must 
be completed within 1 hour of reconstitution. Solutions for IV administration 
have very limited stability and must be prepared immediately prior to each 
dose.
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. 
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See Treatment and Dose Modification sections of the protocol.
IV: Infuse over 10 to 40 minutes. Infusion must be completed within 1 hour of vial 
reconstitution.
Supplier: 
Commercially available from various manufacturers. See package insert for further 
information.
9.3
Cytarabine
(07/13/15)
(Cytosine arabinoside, Ara-C, Cytosar®) NSC #63878
Source and Pharmacology 
Cytarabine appears to act through the inhibition of DNA polymerase. A limited, 
but significant, incorporation of cytarabine into both DNA and RNA has also been 
reported. It exhibits cell phase specificity, primarily killing cells undergoing DNA 
synthesis (S-phase) and under certain conditions blocking the progression of cells 
from the G1 phase to the S-phase. Cytarabine is metabolized by deoxycytidine 
kinase and other nucleotide kinases to the nucleotide triphosphate (Ara-CTP), an 
effective inhibitor of DNA polymerase. Ara-CTP is inactivated by a pyrimidine 
nucleoside deaminase, which converts it to the nontoxic uracil derivative (Ara-U). 
It appears that the balance of kinase and deaminase levels may be an important 
factor in determining sensitivity or resistance of the cell to cytarabine. It has an 
initial distributive phase t½ of about 10 minutes, with a secondary elimination 
phase t½ of about 1 to 3 hours. Peak levels after intramuscular or subcutaneous 
administration of cytarabine occur about 20 to 60 minutes after injection and are 
lower than IV administration. Intrathecally administered doses are metabolized 
and eliminated more slowly with a t½ of about 2 hours.
Toxicity 
Toxicity: (Intravenous, SubQ, IM)
Common
Happens to 21-100 children 
out of every 100
Occasional
Happens to 5-20 children 
out of every 100
Rare
Happens to < 5 children out of 
every 100
Immediate:
Within 1-2 days of 
receiving drug
Nausea, vomiting, anorexia
With 
High 
Dose: 
conjunctivitis 
Flu-like 
symptoms 
with 
fever, rash 
Ara-C syndrome (fever, myalgia, 
bone pain, occasionally chest 
pain, 
maculopapular 
rash, 
malaise, 
conjunctivitis), 
anaphylaxis, swelling, pain and 
redness at the site of the 
medication injection (SubQ or IM 
injection)
With 
High 
Dose:
cardiomyopathies (vasculitis, and 
pericarditis), 
cerebral 
and 
cerebellar dysfunction including: 
encephalopathy, 
aseptic 
meningitis, 
ataxia, 
dysphasia, 


                    
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nystagmus, a decreased level of 
consciousness, 
personality 
changes, somnolence, seizures
Prompt:
Within 
2-3 
weeks, 
prior to the next course
Myelosuppression (anemia, 
thrombocytopenia, 
leukopenia, megaloblastosis, 
reticulocytopenia), 
stomatitis, alopecia
Diarrhea, 
hypokalemia, 
hypocalcemia, 
hyperuricemia
With High Dose: capillary
pulmonary leak syndrome 
(RDS, pulmonary edema)
Hepatotoxicity, 
sinusoidal 
obstruction 
syndrome 
(SOS, 
formerly VOD), urinary retention, 
renal 
dysfunction,
pain 
and 
erythema of the palms and soles
Delayed:
Any time later during 
therapy, excluding the 
above conditions
Asymptomatic 
nonoliguric 
rhabdomyolysis
Unknown Frequency 
and Timing:
Fetal toxicities and teratogenic effects of cytarabine have been noted in humans. It is unknown 
whether the drug is excreted in breast milk.
Toxicity: (Intrathecal)
Common
Happens to 21-100 children 
out of every 100
Occasional
Happens to 5-20 children 
out of every 100
Rare
Happens to < 5 children out of
every 100
Immediate:
Within 1-2 days of
receiving drug
Nausea, 
vomiting, 
fever, 
headache
Arachnoiditis
Rash, 
somnolence, 
meningismus, 
convulsions, 
paresis
Prompt:
Within 2-3 weeks, 
prior to the next 
course
Myelosuppression, ataxia
Delayed:
Any time later during 
therapy, excluding the 
above condition
Necrotizing 
leukoencephalopathy, paraplegia, 
blindness (in combination with 
XRT & systemic therapy)
Formulation 
Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, and 2 g 
containing a sterile powder for reconstitution. It is also available at a 20 mg/mL 
concentration with benzyl alcohol (25 mL per vial) or as a preservative free 
solution (5 mL, 50 mL per vial), and at a 100 mg/mL concentration with benzyl 
alcohol (20 mL vial) or as preservative free solution (20 mL vial). Hydrochloric 
acid and/or sodium hydroxide may be added to adjust the pH. Store at 25°C (77°F); 
excursions permitted to 15°-30°C (59° 86°F). Cytarabine solutions should be 
protected from light.
Guidelines for Administration 
See Treatment and Dose Modification sections of the protocol.
IV Infusion:
Reconstitute the lyophilized powder with Bacteriostatic Water for Injection or NS
injection. Solution containing bacteriostatic agent should not be used for the 
preparation of doses > 200 mg/m2. May be further diluted with dextrose or sodium 
chloride containing solutions. May give by IV push injection, by IV infusion, or 
by continuous infusion. 


                    
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High Dose (≥1000 mg/m²/dose): Administer steroid eye drops (dexamethasone 
or prednisolone), 2 drops each eye q6h beginning immediately before the first dose 
and continuing 24 hours after the last dose. If patient does not tolerate steroid eye 
drops, administer artificial tears on a q2-4 hour schedule.
Stability: When reconstituted with Bacteriostatic Water for Injection, cytarabine is 
stable for 48 hours at room temperature. Solutions reconstituted without a 
preservative should be used immediately. Discard if solution appears hazy. Diluted 
solutions in D5W or NS are stable for 8 days at room temperature; however, the 
diluted cytarabine should be used within 24 hours for sterility concerns. 
Intrathecal:
For intrathecal administration, dilute with 5-10 mL (or volume per institutional
practice) preservative free 0.9% sodium chloride injection, lactated Ringer’s
injection, Elliot’s B solution. The volume of CSF removed should be equal to at 
least ½ the volume delivered.
Patient 
Age 
(years)
Recommended 
volume
10% CSF volume
CSF Volume *
1 – 1.99
5 – 10 mL
5 mL
50 + 10 mL (babies)
2 – 2.99
5 – 10 mL
8 mL
80 + 20 mL (younger children)
3 – 8.99
5 – 10 mL
10 mL
100 + 20 mL (older children)
9 or greater
5 – 10 mL
13 mL
130 + 30 mL (adults)
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 20; 
267:1273-8
Of Note: Larger volumes approximating at least 10% of the CSF volume, 
isovolumetric delivery, with the patient remaining prone after the procedure may 
facilitate drug distribution. These procedures have not been validated in clinical 
trials. They are allowed but not mandated for patients on COG studies.
Intrathecal cytarabine mixed in NS, lactated Ringer’s injection, or Elliot’s B 
solution is stable for 24 hours at 25ºC but contains no preservative and should be 
administered as soon as possible after preparation.
Supplier: 
Commercially available from various manufacturers. See package insert for further 
information.
9.4
Fludarabine 
(01/10/18)
(Fludara®, fludarabine phosphate, 2-fluoro-ara-AMP) NSC# 312887
Source and Pharmacology: 
Fludarabine phosphate is a synthetic purine nucleoside. It differs from the 
physiologic nucleosides, adenosine, in that the sugar moiety is arabinose instead 
of ribose, and by the addition of a fluorine atom to the purine base adenine. 
Fludarabine is also a fluorinated nucleotide analog the antiviral agent vidarabine, 
(ara-A). The addition of fluorine results in increased aqueous solubility and 
resistance to enzymatic degradation by adenosine deaminase. Fludarabine 


                     
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(2-fluoro-ara-A) is commercially available as the monophosphate salt (2-fluoro-
ara-AMP). The monophosphorylation increases the drug's aqueous solubility while 
maintaining pharmacologic activity. The chemical name for fludarabine phosphate 
is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono β-D-arabino-furanosyl) (2-
fluoro-ara-AMP) and the molecular weight is 365.2. 
 
Fludarabine is a purine antagonist antimetabolite. In vivo, fludarabine phosphate is 
rapidly dephosphorylated to 2-fluoro-ara-A and then it is phosphorylated 
intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-
ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, 
ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The 
mechanism of action of this antimetabolite is not completely characterized and 
may be multi-faceted. 
 
Phase I studies in humans have demonstrated that within several minutes after 
intravenous infusion, fludarabine phosphate is converted to the active metabolite, 
2-fluoro-ara-A and becomes undetectable. Therefore, pharmacokinetics studies 
have focused on 2-fluoro-ara-A. Fludarabine phosphate 25 mg/m2 
infused 
intravenously over 30 minutes to adult cancer patients, showed a moderate 
accumulation of 2-fluoro-ara-A. During a 5-day treatment schedule, 2-fluoro-ara-
A plasma trough levels increased by a factor of about 2. 
 
Fludarabine is widely distributed. The volume of distribution at steady state (Vss) 
reported after daily administration of 25 mg/m2 for 5 days to adults averaged at 96-
98 L/m2. Tissue distribution studies in animals indicate that the highest 
concentrations of the drug are in liver, kidney, and spleen. Although the extent to 
which fludarabine and/or its metabolites distribute into the CNS in humans has not 
been determined to date, severe neurologic toxicity (e.g., blindness, coma) has 
been reported in patients receiving the drug, particularly in high dosages. There is 
evidence from animal studies that fludarabine distributes into the CNS and that a 
toxic metabolite (2-fluoroadenine, possibly formed by bacteria in the GI tract), can 
be absorbed systematically via enterohepatic circulation and distributed into CSF. 
According to in vitro data, about 19-29% of fludarabine is bound to plasma 
proteins. 
 
Following IV administration, fludarabine phosphate is dephosphorylated rapidly 
to fludarabine. Plasma concentrations of fludarabine decline in a linear, dose-
independent manner. The elimination profile of fludarabine also has been reported 
to be either biphasic or triphasic; however, reported terminal elimination half-lives 
have been similar. In adult cancer patients receiving fludarabine 25 mg/m2 as a 
30-minute IV infusion daily for 5 days, a terminal half-life of about 20 hours was 
reported. In a limited number of pediatric patients, the plasma concentration profile 
of fludarabine exhibited both monoexponential and biexponential decay, with a 
mean t1/2 of 10.5 hours in patients with monoexponential elimination and a t1/2 of 
1.2-1.4 and 12.4-19 hours, respectively, in patients with biexponential elimination. 
 
Renal clearance accounts for about 40% of the total body clearance of fludarabine. 
Renal elimination appears to become more important at high dosages of the drug. 
The dose of fludarabine needs to be adjusted in patients with moderate renal 
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The use of fludarabine in combination with pentostatin is not recommended due to 
the risk of severe pulmonary toxicity.
Toxicity: 
Common
Happens to 21-100 
subjects out of every 100
Occasional
Happens to 5-20 subjects 
out of every 100
Rare
Happens to < 5 subjects out of every 100
Immediate:
Within 1-2 days 
of receiving drug
Fever, fatigue, weakness, 
pain, nausea, vomiting, 
anorexia, cough, dyspnea
Edema including 
peripheral edema, chills, 
rash, diarrhea, rhinitis, 
diaphoresis, malaise, 
abdominal pain, 
headache, back pain, 
myalgia, stomatitis, 
flu-like syndrome
Anaphylaxis, tumor lysis syndrome, 
dehydration*
Prompt:
Within 2-3 
weeks, prior to 
next course
Myelosuppression 
(anemia, neutropenia, 
thrombocytopenia), 
infection (urinary tract 
infection, herpes simplex 
infection, pneumonia, 
upper respiratory)
Weight loss, 
gastrointestinal bleeding, 
hemoptysis, paresthesia, 
allergic pneumonitis, 
bronchitis, pharyngitis, 
visual disturbance, 
hearing loss, 
hyperglycemia 
Sinusitis, dysuria, opportunistic infections 
and reactivation of latent viral infections like 
Epstein-Barr virus (EBV), herpes zoster and 
John Cunningham (JC) virus (progressive 
multifocal leukoencephalopathy [PML])L, 
EBV associated lymphoproliferative 
disorder, panycytopenia (can be prolonged), 
pulmonary hypersensitivitya (dyspnea, 
cough, hypoxia, interstitial pulmonary 
infiltrate), pulmonary toxicity (acute 
respiratory distress syndrome [ARDS], 
pulmonary fibrosis, pulmonary hemorrhage, 
respiratory distress, respiratory failure), 
pericardial effusion, skin toxicity (erythema 
multiforme, Stevens-Johnson syndrome, 
toxic epidermal necrolysis, pemphigus), liver 
failure, renal failure, hemorrhage, 
transfusion-associated graft-versus-host 
disease has occurred following transfusion of 
nonirradiated blood products, phlebitis*, 
sleep disorder*, cerebellar syndrome*, 
depression*, mentation impaired*, alopecia*, 
pruritus*, seborrhea*, esophagitis*, 
constipation*, mucositis*, dysphagia*, 
hesitancy*, cholelithiasis*, abnormal liver 
function tests*, osteoporosis*, arthralgia*, 
abnormal renal function test*, proteinuria*, 
epistaxis*, hemorrhagic cystitis*, 
eosinophilia* 
Delayed:
Any time later 
during therapy, 
excluding the 
above conditions
Neurotoxicity (increased with high doses): 
seizures, agitation, confusion, weakness, 
visual disturbances, optic neuritis, optic 
neuropathy, photophobia, blindness, 
paralysis, coma, death, peripheral 
neuropathya; autoimmune phenomena: 
thrombocytopenia/thrombocytopenic purpura 


                    
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(ITP), Evans syndrome, hemolytic anemia, 
acquired hemophilia
Late:
Any time after 
completion of 
treatment
Myelodysplastic syndrome/acute myeloid 
leukemia (mainly associated with prior or 
concomitant or subsequent treatment with 
other anticancer treatments), skin cancer (new 
onset or exacerbation)
Unknown 
Frequency and 
Timing:
Pregnancy Category D 
Based on its mechanism of action, fludarabine phosphate can cause fetal harm when administered 
to a pregnant woman. Fludarabine phosphate was embryolethal and teratogenic in both rats and 
rabbits.
(L) Toxicity may also occur later.
* Reported in ≤ 3% of subjects. Since these are not considered life threatening they are not included in the consent.
a These effects were not reported in children.
Formulation and Stability 
Fludarabine phosphate injection is available as sterile lyophilized powder and in 
solution. Each single-dose vial of powder contains 50 mg of the active ingredient 
fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust the pH 
to 7.7. After reconstitution, the pH range for the final product is 7.2-8.2. The 
single-dose solution vial contains 25 mg/mL, 2 mL of fludarabine phosphate. It 
may contain mannitol and is preservative-free. 
Fludarabine phosphate vials should be stored refrigerated at 2-8ºC (36-46ºF).
Guidelines for Administration
See Treatment and Dose Modification sections of the protocol.
Fludarabine phosphate powder should be reconstituted with 2 mL of Sterile Water 
for Injection. The solid cake should fully dissolve in 15 seconds or less. The 
resulting concentration is 25 mg/mL. When reconstituted to a final concentration 
of 25 mg/mL, the drug is stable for at least 16 days at room temperature and normal 
light conditions. The manufacturer recommends that the solution be used within 
8 hours after reconstitution.
Prior to administration, fludarabine 25 mg/mL solution or the reconstituted 
25 mg/mL solution should be further diluted in 100 mL or 125 mL of D5W or NS. 
Concentrations of 0.25 to 1 mg/mL have been used in clinical trials. When diluted 
to a final concentration of 1 mg/mL, fludarabine is stable for at least 16 days at 
room temperature and normal light conditions. The manufacturer recommends that 
the diluted solution be used within 8 hours after preparation. Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior 
to administration.
Supplier: 
Commercially available from various manufacturers. See package insert for further 
information.
9.5
Intrathecal Triples (Methotrexate/Hydrocortisone/Cytarabine, IT-3)            (05/08/12)


                    
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Source and Pharmacology
The intrathecal route of administration of a drug produces more consistent CSF 
drug concentrations at relatively smaller doses because of the volume difference 
between the CSF and blood compartments (140 mL vs. 3500 mL in an adult). (The 
CSF volume of children after the first 3 years is equivalent to that of an adult). 
Drug half-lives are longer as well because clearance is related to flow rather than 
metabolism or protein binding. Intrathecal methotrexate has a biphasic elimination 
curve from the CSF with a t½ of 4.5 and 14 hours respectively. Following IT 
injection of cytarabine the elimination of the drug from the CSF is biphasic with a 
t½ of 1 and 3.4 hours respectively which is 8-fold longer than the clearance from 
plasma. The elimination of hydrocortisone is similarly prolonged.
Toxicity 
Intrathecal Triple Therapy (Methotrexate/Hydrocortisone/Cytarabine) Toxicity: 
Common
Happens to 21-100 
children out of every 100
Occasional
Happens to 5-20 
children out of every 
100
Rare
Happens to < 5 children out of 
every 100
Immediate:
Within 1-2 days of
receiving drug
Nausea, vomiting, fever, 
headache
Arachnoditis: 
(headache, fever, 
vomiting, meningismus 
and pleocytosis) 
Rash, anaphylaxis (L), paresis, 
bleeding into subarachnoid or 
subdural space (risk > with 
platelet counts <20,000), 
confusion, fatigue, 
disorientation, seizures
Prompt:
Within 2-3 weeks, prior 
to the next course
Myelosuppression, somnolence, 
ataxia, cranial nerve palsy, 
transient and rarely permanent 
paraplegia (L), speech disorders
Delayed:
Any time later during 
therapy, excluding the 
above condition
Cognitive 
disturbances (L), learning 
disabilities (L)
Demyelating 
leukoencephalopathy1 (L), 
blindness1
Late:
Any time after the 
completion of treatment
Progressive CNS deterioration1
1 May be enhanced by systemic therapy such as high dose methotrexate or cytarabine and/or cranial irradiation.
(L) Toxicity may also occur later.
Formulation and Stability 
Methotrexate 25 mg/mL preservative free 2 mL vial or methotrexate 20 mg 
preservative free sterile powder for injection vial. Cytarabine 100 mg preservative 
free sterile powder for injection. Hydrocortisone sodium succinate 100 mg vial 
sterile powder for injection.
Guidelines for Administration
See Treatment and Dose Modification sections of the protocol.
For intrathecal administration, dilute each agent with 5-10 mL preservative free 
NS, lactated ringers or Elliot’s B solution or as per institutional standard of 


                    
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practice. The volume of CSF removed should be equal to at least half the volume 
delivered.
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection. N Engl J Med 1962 Dec 20; 
267:1273-8
Of note: Larger volumes approximating at least 10% of the CSF volume, 
isovolumetric delivery, with the patient remaining prone after the procedure may 
facilitate drug distribution. These procedures have not been validated in clinical trials. 
They are allowed but not mandated for patients on COG studies.
Intrathecal triples are stable in NS for 24 hours at 25ºC but contain no preservative 
and should be administered as soon as possible after preparation.
Supplier 
Commercially available from various manufacturers. See package insert for further 
information.
10.0
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
10.1
Criteria for Removal from Protocol Therapy 
a)
Evidence of treatment failure (See Section 12.2.5).
b)
Adverse Events requiring removal from protocol therapy (See Section 6).
c)
Refusal of protocol therapy by patient/parent/guardian
d)
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation.
e)
Completion of 2 cycles of therapy.
f)
Physician determines it is not in the patient’s best interest.
g)
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of MLN4924 (pevonedistat) (See Section 8.1).
h)
Study is terminated by Sponsor.
i)
Pregnancy
Patient Age 
(years)
Doses 
(MTX/Hydrocortisone/Ara-C)
Recommended 
volume
10% CSF 
volume
CSF Volume *
0 – 0.99
7.5 mg / 7.5 mg / 15 mg
5-10 mL
5 mL
50 + 10 mL 
(babies)
1 – 1.99
8 mg / 8 mg / 16 mg
5-10 mL
5 mL
50 + 10 mL 
(babies)
2 – 2.99
10 mg / 10 mg / 20 mg
5-10 mL
8 mL
80 + 20 mL 
(younger children)
3 – 8.99
12 mg / 12 mg / 24 mg
5-10 mL
10 mL
100 + 20 mL 
(older children)
9 or greater
15 mg / 15 mg / 30 mg
5-10 mL
13 mL
130 + 30 mL 
(adults)


                     
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Patients who are removed from protocol therapy during Cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent. Patients who are removed from protocol therapy in subsequent cycles should 
have the necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Ongoing adverse events, or adverse events that emerge after the patient 
is removed from protocol therapy, but within 30 days of the last dose of investigational 
agent, must be followed and reported via RAVE and CTEP-AERS (if applicable).  Follow-
up data will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
 
a) 
Thirty days after the last dose of the investigational agent. 
b) 
The patient does not receive protocol treatment after study enrollment. 
c) 
Death 
d) 
Lost to follow-up 
e) 
Withdrawal of consent for any required observations or data submission. 
f) 
Enrollment onto another COG therapeutic (anti-cancer) study  
 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
A minimum of 4 and a maximum of 18 evaluable patients will be required to complete the 
dose confirmation part of the study using a rolling 6 design. Once the MTD or 
recommended Phase 2 dose has been defined, up to 6 additional patients may be enrolled 
to acquire PK data in a representative number of young patients (i.e. patients < 12 years 
old).  Therefore, a maximum of 23 patients are anticipated to be enrolled in this study 
allowing for two dose levels, PK expansion, and 20% inevaluability. Review of the 
enrollment rate into previous COG new agent studies indicates that 1-2 patients per month 
are available, which will permit completion of the study within 12-23 months.   
 
In the unlikely event that two DLTs of different classes occur, then expansion to 12 patients 
at that dose level may be considered if ALL of the following conditions are met: 1) one of 
the DLTs does not appear to be dose and/or drug-related, 2) the Adverse Effects are readily 
reversible, 3) the study chair, DVL statistician, DVL committee chair or vice chair, and 
IND sponsor all agree that expansion of the cohort is acceptable (see Section 11.2.2). In 
this case, the absolute maximum number of patients would be 38 patients allowing for 12 
patients at each of two dose levels, 6 patients for PK expansion, and 20% inevaluability. 
This would be completed within 19-38 months.  
 
Given the novelty of this regimen, enhanced monitoring for DLTs will be performed in the 
first 3 patients. If 2 DLTs are observed then the dose will be de-escalated to DL-1. If 1 
DLT is observed in the first 2 patients then a period of 30 days must have elapsed between 
the first dose of MLN4924 (pevonedistat) in the 3rd patient prior to enrolling the 4th patient.  
 


                    
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11.2
Definitions
Evaluable For Adverse Events
Any patient who receives at least 2/3 doses of MLN4924 (pevonedistat) during 
Cycle 1 or who experiences a dose-limiting toxicity is considered evaluable for 
Adverse Events. In addition, for the dose-confirmation portion during Cycle 1, 
patients must receive at least 85% of the prescribed dose per protocol guidelines 
and must have the appropriate toxicity monitoring studies performed to be 
considered evaluable for dose limiting toxicity. Patients who do not have DLT and 
are not considered evaluable for toxicity will be replaced.
Maximum Tolerated Dose
•
The MTD will be the maximum dose at which fewer than one-third of 
patients experience DLT (See Section 5.6) during Cycle 1 of therapy. 
•
In the unlikely event that two DLTs observed out of 6 evaluable patients are 
different classes of Adverse Effects (e.g. hepatotoxicity and 
myelosuppression), AND all of the following conditions are met, expansion 
of the cohort to 12 patients will be considered: 
•    One of the DLTs does not appear to be dose and/or drug-related
• The Adverse Effects are readily reversible
• The study chair, DVL statistician, DVL committee chair or vice chair, 
and IND sponsor all agree that expansion of the cohort is acceptable
•
The DLTs observed in the pharmacokinetic (PK) expansion cohort will be 
counted towards the total number of DLTs observed at the RP2D/MTD 
during the dose confirmation portion of the study. If ≥ 1/3 of the cohort of 
patients at the RP2D/MTD (during the dose confirmation plus the PK 
expansion) experience DLT then the MTD will be exceeded. 
11.3
Dose Confirmation and Determination of MTD/RP2D
The rolling six phase 1 trial design will be used for the conduct of this study.32 There is no 
dose escalation beyond DL1 (20 mg/m2); but the R6 logic will be used to determine the 
MTD/RP2D. DL1 will be defined as the RP2D if there are less than or equal to 1 patient(s) 
with a DLT among up to six evaluable patients. Otherwise, DL-1 will open to accrual of 
up to six evaluable patients. DL-1 will be defined as the MTD/RP2D if there are less than 
or equal to 1 patient(s) with a DLT among six evaluable patients. Otherwise, DL-1 will 
have exceeded the MTD and the study will close to accrual without having defined an 
MTD/RP2D. 
In addition to determination of the RP2D/MTD, a descriptive summary of all toxicities will 
be reported.


                     
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11.4 
Inclusion of Children, Women and Minorities 
 
 
PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ 
Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native 
Hawaiian 
or 
Other 
Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
3 
3 
0 
0 
6 
White 
11 
17 
2 
2 
32 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
14 
20 
2 
2 
38 
 
 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual 
to past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase 1 trial which will accrue a limited number of 
patients, a balance must be struck between patient safety considerations and limitations on 
the number of individuals exposed to potentially toxic or ineffective treatments on the one 
hand and the need to explore gender, racial, and ethnic aspects of clinical research on the 
other. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, 
accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
 
11.5 
Pharmacokinetic and Response Analysis 
 
A descriptive analysis of pharmacokinetic (PK) parameters of MLN4924 (pevonedistat) 
will be performed to define systemic exposure, drug clearance, and other pharmacokinetic 
parameters. The PK parameters will be summarized with simple summary statistics, 
including means, medians, ranges, and standard deviations (if numbers and distribution 
permit).   
 
While the primary aim of this study is to evaluate the toxicity of MLN4924 (pevonedistat), 
patients will have disease evaluations performed as indicated in Section 8.1.  Disease 
response will be assessed according to criteria for patients with AML, and will be reported 
descriptively. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
 


                    
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12.0
EVALUATION CRITERIA
12.1
Common Terminology Criteria for Adverse Events (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
12.2
Response Criteria for Patients with Leukemia
Complete Remission (CR)
Attainment of an M1 bone marrow (< 5% blasts and adequate marrow cellularity) 
with no evidence of circulating blasts or extramedullary disease and with recovery 
of peripheral blood counts (ANC > 1000/uL and platelet count > 100,000/uL). 
Flow cytometry may be useful to distinguish between leukemia and a regenerating 
bone marrow. There is no requirement for bone marrow cellularity. 
Complete Remission with Partial Recovery of Platelet Count (CRp)
Attainment of an M1 bone marrow (< 5% blasts) and no evidence of circulating 
blasts or extramedullary disease and with recovery of ANC > 1000/uL and platelet 
transfusion independence (defined as no platelet transfusions x 1 week).  
Complete Remission with Incomplete Blood Count Recovery (CRi): 
Attainment of an M1 bone marrow (<5% blasts) and no evidence of circulating 
blasts or extramedullary disease and with ANC < 1000/uL or platelet count < 
100,000/uL without platelet transfusion independence (defined as no platelet 
transfusions x 1 week). 
Partial Response
Attainment of M2 marrow status (> 5% or < 25% blasts cells and adequate 
cellularity) and at least 50% decrease in bone marrow blast percent from baseline. 
Bone marrow must have adequate cellularity (e.g. > 10% if a biopsy is performed) 
to determine response. PR status will not be included in the calculation of response 
to the regimen. A repeat bone marrow aspiration within 14 days may be required 
to distinguish between a PR and increased blasts caused by bone marrow 
regeneration, and is left to the discretion of the investigator. 
Treatment Failure 
The definition of treatment failure includes: 
A.
An increase in the extent of bone marrow infiltration by leukemic cells 
(absolute increase of > 20% blasts) OR
B.
Development of extramedullary disease (EMD) OR
C. 
M2 marrow that does not qualify for PR status OR
D. 
An M1 marrow with circulating blasts OR
E. 
> 25% blasts in the bone marrow after Cycle 1 of therapy 
F.
Subjects who have persistent CNS disease despite 6 doses of IT cytarabine 
or IT triples


                    
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Relapse 
Morphologic relapse after CR/CRp/CRi is defined as a reappearance of leukemic 
blasts in the peripheral blood or > 5% blasts in the bone marrow not attributable to 
any other cause (e.g. bone marrow regeneration after therapy). In the setting of 
recent treatment, if there are no circulating blasts and the bone marrow contains 5-
20% blasts, a repeat bone marrow performed at least a week later is necessary to 
distinguish relapse from bone marrow regeneration. Should flow cytometric or 
molecular analyses suggest relapse (by reappearance of similar immunophenotype 
or mutation to the original leukemia) in the presence of < 5% blasts or > 5% blasts 
in a regenerating marrow, a repeat bone marrow performed at least a week later is 
necessary to confirm relapse by morphologic methods. In such instances, the date 
of recurrence is defined as the first date that more than 5% blasts were observed in 
the bone marrow. The reappearance or development of cytogenetically proven 
extramedullary disease also indicates relapse. Molecular and/or genetic relapse is 
characterized by reappearance of a cytogenetic or molecular abnormality. 
Unevaluable: 
Aplastic or severely hypocellular marrow. In this instance, marrow evaluation 
should be repeated weekly until response determination can be made through at 
least Day 60. 
Bone Marrow Classification: 
M1 is < 5% blasts
M2 is 5-25% blasts
M3 is > 25% blasts 
12.3
CNS Leukemia at Diagnosis 
CNS 1:
In cerebral spinal fluid (CSF), absence of blasts on cytospin 
preparation, regardless of the number of WBCs.
CNS 2:
In CSF, presence < 5/L WBCs and cytospin positive for blasts, or 
≥ 5/L WBCs but negative by Steinherz/Bleyer algorithm:
CNS 2a:
< 10/L RBCs; < 5/L WBCs and cytospin positive for blasts;
CNS 2b:
≥ 10/L RBCs; < 5/L WBCs and cytospin positive for blasts;
CNS 2c: ≥ 10/L RBCs; ≥ 5/L WBCs and cytospin positive for blasts but 
negative by Steinherz/Bleyer algorithm (see below).
CNS 3:
In CSF, presence of ≥ 5/µL WBCs and cytospin positive for blasts 
and/or clinical signs of CNS leukemia:
CNS 3a:
< 10/L RBCs; ≥ 5/µL WBCs and cytospin positive for blasts;
CNS 3b:
≥ 10/µL RBCs, ≥ 5/µL WBCs and positive by Steinherz/Bleyer 
algorithm (see below);
CNS 3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye 
involvement or hypothalamic syndrome).
Method of Evaluating Initial Traumatic Lumbar Punctures:
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and contains 5 WBC/L and blasts, the following algorithm should be used to 
distinguish between CNS 2 and CNS 3 disease:


                     
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CSF WBC   > 2X   Blood WBC 
CSF RBC               Blood RBC 
A patient with CSF WBC  5/L blasts, whose CSF WBC/RBC is 2X greater than the blood 
WBC/RBC ratio, has CNS disease at diagnosis. Example: CSF WBC = 60/L; CSF RBC = 
1500/L; blood WBC = 46000/L; blood RBC = 3.0 X 106/L: 
  60    = 0.04  >  2X     46,000      = 0.015 
1,500                          3.0 X 106 
 
 
 
 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the Case Report Forms 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source.  The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 5.0.  The 
descriptions and grading scales found in the revised CTCAE version 5.0 will be 
used for AE reporting. All appropriate treatment areas should have access to a copy 
of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded 
from 
the 
CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 


                     
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• 
there are any protocol-specific exceptions to the reporting requirements.  
 
NOTE: This includes all events that occur within 30 days of the last dose of 
protocol treatment.  Any event that occurs more than 30 days after the 
last dose of treatment and is attributed (possibly, probably, or definitely) 
to the agent(s) must also be reported according to the instructions in the 
table below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via CTEP-AERS within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 


                     
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rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 
Trials Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not clearly due 
to progressive disease must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP 
IND agent per the timelines outlined in the table above. 
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.9 of the 
protocol.   
• Grade 1-4 myelosuppression (anemia, thrombocytopenia, neutropenia) do not require expedited 
reporting 
• Grade 1-2 AST/ALT elevations do not require expedited reporting  
 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that resolves and then recurs 
during a subsequent cycle does not require CTEP-AERS reporting unless (1) the Grade increases; or (2) 
hospitalization is associated with the recurring AE. 
 
13.2 
When to Report an Event in an Expedited Manner  
 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable) and by telephone call to the Study Chair. Once internet 
connectivity is restored, a 24-hour notification phoned in must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page https://eapps-
ctep.nci.nih.gov/ctepaers. 
 


                    
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13.3
Expedited Reporting Methods 
CTEP-AERS Reporting
To report adverse events in an expedited fashion use the NCI’s Adverse Event 
Expedited 
Reporting 
System 
(CTEP-AERS) 
that 
can 
be 
found 
at 
http://ctep.cancer.gov.
A CTEP-AERS report must be submitted electronically via the CTEP-AERS Web-
based application located at https://eapps-ctep.nci.nih.gov/ctepaers/. If prompted 
to 
enter 
a 
sponsor 
email 
address, 
please 
type 
in: 
PEPCTNAERS@childrensoncologygroup.org.
Send supporting documentation to the NCI by fax (fax# 301-897-7404) and by 
email to the ADVL1712 COG Study Assigned Research Coordinator.  ALWAYS 
include the ticket number on all faxed and emailed documents.
13.4
Definition of Onset and Resolution of Adverse Events
Note:
These guidelines below are for reporting adverse events on the COG case report
forms and do not alter the guidelines for CTEP-AERS reporting.
If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported.
If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported.
The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects. 
The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than or equal to Grade 1, whichever level is higher (note that the 
resolution date may therefore be different from the date at which the grade of the 
AE decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."  
An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs. 
13.5
Other Recipients of Adverse Event Reports
Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the CRF
packet (See Section 14.1).
COG will forward reports and supporting documentation to the Study Chair, to 
the FDA (when COG holds the IND) and to the pharmaceutical company (for 
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Adverse events determined to be reportable must also be reported according to 
the local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient.
13.6
Reporting Secondary AML/MDS
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients following their chemotherapy for cancer must be reported to the 
Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation Program 
(CTEP) via CTEP-AERS and included as part of the second malignant neoplasm reporting 
requirements for this protocol (see data submission packet).  Submit the completed CTEP-
AERS report within 14 days of an AML/MDS diagnosis occurring after protocol treatment 
for cancer.
Secondary Malignancy: 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
1)
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])
2)
Myelodysplastic syndrome (MDS)
3)
Treatment-related secondary malignancy.
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.
Second Malignancy: 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified.
13.7
Data and Safety Monitoring Plan
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee.
Data and Safety Monitoring Committee
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the developmental therapy 
scientific committee; and a member from the NCI. The DSMC meets at least every 
6 months to review current study results, as well as data available to the DSMC 
from other related studies. Approximately 6 weeks before each meeting of the 
Phase 1 and 2 DSMC, study chairs will be responsible for working with the study 


                    
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statistician to prepare study reports for review by the DSMC. The DSMC will 
provide recommendations to the COG Developmental Therapeutics Chair and the 
Group Chair for each study reviewed to change the study or to continue the study 
unchanged. Data and Safety Committee reports for institutional review boards can 
be prepared using the public data monitoring report as posted on the COG Web 
site.
Monitoring by the Study Chair and Developmental Therapeutics Leadership 
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the 
Developmental Therapeutics Chair, Vice Chair and Statistician on a weekly 
conference call.
13.8
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and emailed to the 
ADVL1712 COG Study Assigned Research Coordinator along with any additional medical 
information along with any additional medical information. The potential risk of exposure 
of the fetus to the investigational agent should be documented in the “Description of Event” 
section of the CTEP-AERS report.
Pregnancy
•
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should be reported in an expedited manner via CTEP-AERS as
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 
(Pregnancy)”
under the “Pregnancy, puerperium and perinatal 
conditions” SOC.
•
Pregnancy should be followed until the outcome is known. If the baby is 
born with a birth defect or anomaly, then a second CTEP-AERS report is 
required. 
Pregnancy Loss (Fetal Death)
•
Pregnancy loss is defined in CTCAE as “Death in utero.”
•
Any pregnancy loss should be reported expeditiously as Grade 4
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
Death Neonatal
•
Neonatal death, defined in CTCAE as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least 
possibly due to the investigational agent/intervention, should be reported 
expeditiously.


                     
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• 
A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the General disorders and administration SOC when the 
death is the result of a patient pregnancy or pregnancy in partners of 
men on study.  
 
• 
Do NOT report a  neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
Pregnancy should be followed up until the outcome of the pregnancy is known at intervals 
deemed appropriate by her physicians. The “Pregnancy Information Form” should be used 
for 
all 
necessary 
follow-ups. 
This 
form 
is 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyRepo
rtForm.pdf. If the baby is born with a birth defect or other anomaly, then a second CTEP-
AERS report is required. 
 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Therapy Delivery Maps, Pathology Reports, 
Surgical Reports. These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the case report form (CRF) 
packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis.  Reports are due January 31, April 30, July 31 and October 31.  
This is not a responsibility of institutions participating in this trial. Instructions for submitting 
data 
using 
the 
CDUS 
can 
be 
found 
on 
the 
CTEP 
web 
site: 
http://ctep.cancer.gov/reporting/cdus.html 
 
14.3 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 


                     
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NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected , used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 


                    
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sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them.
5.
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial.
6.
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP for immediate delivery to Collaborator(s) for advisory review and comment 
prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies 
of any manuscript, abstract and/or press release/ media presentation should be sent 
to:
Email: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information.
14.4
Data and Safety Monitoring Plan
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee.
Data and Safety Monitoring Committee
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the PEP-CTN scientific 
committee; and a member from the NCI. The DSMC meets at least every 6 months 
to review current study results, as well as data available to the DSMC from other 
related studies. Approximately 6 weeks before each meeting of the Phase 1 and 2 
DSMC, study chairs will be responsible for working with the study statistician to 
prepare study reports for review by the DSMC. The DSMC will provide 
recommendations to the COG PEP-CTN Chair and the Group Chair for each study 
reviewed to change the study or to continue the study unchanged. Data and Safety 
Committee reports for institutional review boards can be prepared using the public 
data monitoring report as posted on the COG Web site.
Monitoring by the Study Chair and Developmental Therapeutics Leadership 


                     
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The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the COG 
PEP-CTN Chair, Vice Chair and Statistician on a weekly conference call. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                     
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Sarantopoulos J, Shapiro GI, Cohen RB, et al: Phase I Study of the Investigational NEDD8-
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2. 
Soucy TA, Smith PG, Milhollen MA, et al: An inhibitor of NEDD8-activating enzyme as a new 
approach to treat cancer. Nature 458:732-6, 2009 
3. 
Lin JJ, Milhollen MA, Smith PG, et al: NEDD8-targeting drug MLN4924 elicits DNA rereplication 
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Erba HP, Maris MB, Swords RT, et al: MLN4924, a Novel Investigational Inhibitor Of NEDD8-
Activating Enzyme (NAE), In Adult Patients With Acute Myeloid Leukemia (AML) and 
Myelodysplastic Syndrome (MDS): Results From Multiple Dosing Schedules In a Phase 1 Study. 
Blood 122:1443-1443, 2013 
5. 
Smith MA, Maris JM, Gorlick R, et al: Initial testing of the investigational NEDD8-activating 
enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer 
59:246-53, 2012 
6. 
Swords RT, Coutre S, Maris MB, et al: Results of a Clinical Study of Pevonedistat (Pev), a First-
in-Class NEDD8-Activating Enzyme (NAE) Inhibitor, Combined with Azacitidine (Aza) in Older 
Patients (Pts) with Acute Myeloid Leukemia (AML). Blood 128:98-98, 2016 
7. 
Swords RT, Erba HP, DeAngelo DJ, et al: Pevonedistat (MLN4924), a First-in-Class NEDD8-
activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic 
syndromes: a phase 1 study. Br J Haematol 169:534-43, 2015 
8. 
Kaspers GJ, Zimmermann M, Reinhardt D, et al: Improved outcome in pediatric relapsed acute 
myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International 
BFM Study Group. J Clin Oncol 31:599-607, 2013 
9. 
Bhatla T, Wang J, Morrison DJ, et al: Epigenetic reprogramming reverses the relapse-specific gene 
expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood 
119:5201-10, 2012 
10. 
Bullinger L, Ehrich M, Dohner K, et al: Quantitative DNA methylation predicts survival in adult 
acute myeloid leukemia. Blood 115:636-42, 2010 
11. 
Khan R, Schmidt-Mende J, Karimi M, et al: Hypomethylation and apoptosis in 5-azacytidine-
treated myeloid cells. Exp Hematol 36:149-57, 2008 
12. 
Murakami T, Li X, Gong J, et al: Induction of apoptosis by 5-azacytidine: drug concentration-
dependent differences in cell cycle specificity. Cancer Res 55:3093-8, 1995 
13. 
Yang X, Han H, De Carvalho DD, et al: Gene body methylation can alter gene expression and is a 
therapeutic target in cancer. Cancer Cell 26:577-590, 2014 
14. 
Avramis VI, Mecum RA, Nyce J, et al: Pharmacodynamic and DNA methylation studies of high-
dose 1-beta-D-arabinofuranosyl cytosine before and after in vivo 5-azacytidine treatment in 
pediatric patients with refractory acute lymphocytic leukemia. Cancer Chemother Pharmacol 
24:203-10, 1989 
15. 
Sun W, Triche T, Jr., Malvar J, et al: A phase 1 study of azacitidine combined with chemotherapy 
in childhood leukemia: a report from the TACL consortium. Blood 131:1145-1148, 2018 
16. 
Czuczman NM, Barth MJ, Gu J, et al: Pevonedistat, a NEDD8-activating enzyme inhibitor, is active 
in mantle cell lymphoma and enhances rituximab activity in vivo. Blood 127:1128-37, 2016 
17. 
Swords RT, Kelly KR, Smith PG, et al: Inhibition of NEDD8-activating enzyme: a novel approach 
for the treatment of acute myeloid leukemia. Blood 115:3796-800, 2010 
18. 
Nawrocki ST, Kelly KR, Smith PG, et al: The NEDD8-activating enzyme inhibitor MLN4924 
disrupts nucleotide metabolism and augments the efficacy of cytarabine. Clin Cancer Res 21:439-
47, 2015 
19. 
Visconte V, Nawrocki ST, Espitia CM, et al: Comprehensive quantitative proteomic profiling of 


                     
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74 
the pharmacodynamic changes induced by MLN4924 in acute myeloid leukemia cells establishes 
rationale for its combination with azacitidine. Leukemia 30:1190-4, 2016 
20. 
Investigator's Brochure Pevonedistat (TAK-924/MLN4924),  (ed 9), Millennium Pharmaceuticals, 
Inc., 2017 
21. 
Swords RT, Watts J, Erba HP, et al: Expanded safety analysis of pevonedistat, a first-in-class 
NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic 
syndromes. Blood Cancer J 7:e520, 2017 
22. 
Iuvone L, Mariotti P, Colosimo C, et al: Long-term cognitive outcome, brain computed tomography 
scan, and magnetic resonance imaging in children cured for acute lymphoblastic leukemia.   . 
Cancer 95(12):2562-70, 2002 
23. 
Swords RT, Coutre S, Maris MB, et al: Pevonedistat, a first-in-class NEDD8-activating enzyme 
inhibitor, combined with azacitidine in patients with AML. Blood 131:1415-1424, 2018 
24. 
Swords RT, Savona MR, Maris MB, et al: Pevonedistat (MLN4924), an Investigational, First-in-
Class NAE Inhibitor, in Combination with Azacitidine in Elderly Patients with Acute Myeloid 
Leukemia (AML) Considered Unfit for Conventional Chemotherapy: Updated Results from the 
Phase 1 C15009 Trial. Blood 124:2313-2313, 2014 
25. 
Smith GA, Damon LE, Rugo HS, et al: High-dose cytarabine dose modification reduces the 
incidence of neurotoxicity in patients with renal insufficiency. J Clin Oncol 15:833-9, 1997 
26. 
Bennett WM, Aronoff GR, Morrison G, et al: Drug prescribing in renal failure: dosing guidelines 
for adults. Am J Kidney Dis 3:155-93, 1983 
27. 
This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and 
the agent should be included in the e-mail.,  
28. 
Soldi R, Horrigan SK, Cholody MW, et al: Design, Synthesis, and Biological Evaluation of a Series 
of Anthracene-9,10-dione Dioxime beta-Catenin Pathway Inhibitors. J Med Chem 58:5854-62, 
2015 
29. 
Savvidou I, Khong T, Cuddihy A, et al: beta-Catenin Inhibitor BC2059 Is Efficacious as 
Monotherapy or in Combination with Proteasome Inhibitor Bortezomib in Multiple Myeloma. Mol 
Cancer Ther 16:1765-1778, 2017 
30. 
Nomura M, Rainusso N, Lee YC, et al: Tegavivint and the beta-catenin/ALDH Axis in 
Chemotherapy-Resistant and Metastatic Osteosarcoma. J Natl Cancer Inst, 2019 
31. 
Varghese S, Braggio DA, Gillespie J, et al: TGF-beta and CTGF are Mitogenic Output Mediators 
of Wnt/beta-Catenin Signaling in Desmoid Fibromatosis. Appl Immunohistochem Mol Morphol 
25:559-565, 2017 
32. 
Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the timeline of pediatric phase I trials: the 
rolling six design. J Clin Oncol 26:190-5, 2008 
33. 
The Criteria Committee of New York Heart Association: Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels (ed 9). Boston, MA, Little, Brown & Co, 1994 pp. 253-
256 
  
 
 


                     
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75 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 
 
 


                     
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76 
APPENDIX II: CORRELATIVE STUDIES GUIDE 
 
FOR PATIENTS < 10 KG:  
 
Correlative Study 
Appx. 
Volume per 
Sample 
Total Volume 
Tube Type 
Pharmacokinetics Study 
IV-A 
3 ml 
24 ml 
Vacutainer 
Tubes 
Pharmacodynamics 
(mRNA Transcript 
Levels) 
V 
2 ml 
6 ml 
Citrate 
Vacutainer 
Tubes 
Pharmacodynamics 
(NEDDylated 
Protein Analysis) – 
Blood Samples 
      VI 
 
 
5 ml 
 
20 ml 
 Cell Save 
Tubes and 
Heparinized 
Tubes 
Pharmacodynamics 
(NEDDylated 
Protein Analysis) – 
Bone Marrow 
Samples 
VII 
3 ml 
6 ml 
Heparinized 
Tubes 
Total Blood + Bone 
Marrow Volume 
56 ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                     
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FOR PATIENTS > 10 KG:  
 
Correlative Study 
Appx. 
Volume per 
Sample 
Total Volume 
Tube Type 
Pharmacokinetics Study 
IV-B 
3 ml 
48 ml 
Vacutainer 
Tubes 
Pharmacodynamics 
(mRNA Transcript 
Levels) 
V 
2 ml 
6 ml 
Citrate 
Vacutainer 
Tubes 
Pharmacodynamics 
(NEDDylated 
Protein Analysis) – 
Blood Samples 
      VI 
 
 
5 ml 
 
20 ml 
 Cell Save 
Tubes and 
Heparinized 
Tubes 
Pharmacodynamics 
(NEDDylated 
Protein Analysis) – 
Bone Marrow 
Samples 
VII 
3 ml 
6 ml 
Heparinized 
Tubes 
Total Blood + Bone 
Marrow Volume 
80 ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                     
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78 
APPENDIX III: TOXICITY-SPECIFIC GRADING  
 
Bilirubin 
 
Grade 1: 
> ULN - ≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN – 3.0 x ULN 
Grade 3: 
> 3.0 x ULN – 10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
ALT: For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
> 45 U/L - ≤ 135 U/L 
Grade 2: 
136 U/L – 225 U/L 
Grade 3: 
226 U/L – 900 U/L 
Grade 4: 
> 900 U/L 
 
 
AST: For the purpose of this study, the ULN for SGOT is 50 U/L regardless of baseline. 
 
Grade 1: 
> 50 U/L - ≤ 150 U/L 
Grade 2: 
151 U/L – 250 U/L  
Grade 3: 
251 U/L – 1000 U/L 
Grade 4: 
> 1000 U/L  


                     
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APPENDIX IV-A: PHARMACOKINETIC STUDY FORM FOR PATIENTS < 10 KG 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg  
 
Body Surface Area: ______m2  
 
MLN4924 (Pevonedistat) Dose Level: ______mg/m2   MLN4924 (Pevonedistat) Total Daily Dose: ______mg 
 
Blood samples (3 ml) will be collected in chilled Becton-Dickinson Vacutainer K2 EDTA tubes at the following 
time points during Cycle 1 (± 10 min): Day 1 (pre-dose, at the end of MLN4924 [pevonedistat] infusion, and at 4 
– 6 hrs, and 24 hrs after the end of MLN4924 [pevonedistat] infusion), and Day 5 (pre-dose, at the end of MLN4924 
[pevonedistat] infusion, and at 4 – 6 hrs, and 24 hrs after the end of MLN4924 [pevonedistat] infusion).  
 
Record the exact time the sample is drawn along with the exact time MLN4924 [pevonedistat] infusion begins and 
ends on Days 1 and 5.  
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1 
Day 1 
Prior to MLN4924 infusion 
___/___/___ 
|__|__| : |__|__| 
MLN4924 Dose on Day 1       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
                                                                                          Infusion Stop Time: |__|__| : |__|__| 
2 
Day 1 
At the end of MLN4924 infusion 
___/___/___ 
|__|__| : |__|__| 
3 
Day 1 
4 – 6  hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
4 
Day 1 
24 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
5 
Day 5 
Prior to MLN4924 infusion 
___/___/___ 
|__|__| : |__|__| 
MLN4924 Dose on Day 5       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
                                                                                          Infusion Stop Time: |__|__| : |__|__| 
6 
Day 5 
At the end of MLN4924 infusion  
___/___/___ 
|__|__| : |__|__| 
7 
Day 5 
4 – 6 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
8 
Day 5 
24 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
   
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with 
the samples to the address listed in Section 8.2.6.  See Section 8.2 for detailed guidelines for packaging and shipping 
PK samples. 
 
Signature: _________________________________________                    Date:___________________ 
 
(site personnel who collected samples) 
 
 


                     
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80 
APPENDIX IV-B: PHARMACOKINETIC STUDY FORM FOR PATIENTS > 10 KG 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg  
 
Body Surface Area: ______m2  
 
MLN4924 (Pevonedistat) Dose Level: ______mg/m2  MLN4924 (Pevonedistat) Total Daily Dose: ______mg 
Blood samples (3 ml) will be collected in chilled Becton-Dickinson Vacutainer K2 EDTA tubes at the following 
time points during Cycle 1 (± 10 min): Day 1 (pre-dose, at the end of MLN4924 [pevonedistat] infusion, and at 1 
hr, 2 hrs, 4 hrs, 6 – 8 hrs, and 24 hrs after the end of MLN4924 [pevonedistat] infusion), Day 3 (pre-dose), and 
Day 5 (pre-dose, at the end of MLN4924 [pevonedistat] infusion, and at 1 hr, 2 hrs, 4 hrs, 6 – 8 hrs, and 24 hrs 
after the end of MLN4924 [pevonedistat] infusion, as well as at 48 OR 72 hours after the end of MLN4924 
[pevonedistat] infusion).  
 
Record the exact time the sample is drawn along with the exact time MLN4924 (pevonedistat) infusion begins and 
ends on Days 1, 3, and 5.  
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1 
Day 1 
Prior to MLN4924 infusion 
___/___/___ 
|__|__| : |__|__| 
MLN4924 Dose on Day 1       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
                                                                                          Infusion Stop Time: |__|__| : |__|__| 
2 
Day 1 
At the end of MLN4924 infusion 
___/___/___ 
|__|__| : |__|__| 
3 
Day 1 
1 hr after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
4 
Day 1 
2 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
5 
Day 1 
4 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
6 
Day 1 
6 – 8 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
7 
Day 1 
24 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
8 
Day 3 
Prior to MLN4924 infusion 
___/___/___ 
|__|__| : |__|__| 
MLN4924 Dose on Day 3       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
                                                                                          Infusion Stop Time: |__|__| : |__|__| 
9 
Day 5 
Prior to MLN4924 infusion 
___/___/___ 
|__|__| : |__|__| 
MLN4924 Dose on Day 5       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
                                                                                          Infusion Stop Time: |__|__| : |__|__| 
10 
Day 5 
At the end of MLN4924 infusion  
___/___/___ 
|__|__| : |__|__| 
11 
Day 5 
1 hr after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
12 
Day 5 
2 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
13 
Day 5 
4 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
14 
Day 5 
6 – 8 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
15 
Day 5 
24 hrs after MLN4924 infusion end time 
___/___/___ 
|__|__| : |__|__| 
16 
Day 5 
48 hrs after MLN4924 infusion end time* 
___/___/___ 
|__|__| : |__|__| 
17 
Day 5 
72 hrs after MLN4924 infusion end time* 
___/___/___ 
|__|__| : |__|__| 
*Blood samples are to be drawn 48 hours OR 72 hours after the Day 5 MLN4924 (pevonedistat) infusion end time. 
Do not collect blood for both timepoints.   
 


                     
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One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with 
the samples to the address listed in Section 8.2.6.  See Section 8.2 for detailed guidelines for packaging and shipping 
PK samples. 
 
Signature: _________________________________________                    Date:___________________ 
 
(site personnel who collected samples) 
 
 


                     
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82 
APPENDIX V: PHARMACODYNAMICS (MRNA TRANSCRIPT LEVELS) STUDY FORM 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg  
 
Body Surface Area: ______m2  
 
MLN4924 (Pevonedistat) Dose Level: ______mg/m2  MLN4924 (Pevonedistat) Total Daily Dose: ______mg 
 
In consenting patients, blood samples (2 ml) will be collected in citrate vacutainer tubes at the following time 
points during Cycle 1 (± 10 min): Day 1 (pre-dose) and Day 3 OR Day 5 (3 hrs and 6 hrs after the end of MLN4924 
[pevonedistat] infusion).  
 
Record the exact time the sample is drawn along with the exact time MLN4924 (pevonedistat) infusion begins and 
ends on Day 1 and Day 3 OR 5.  
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1 
Day 1 
Prior to MLN4924 dose 
___/___/__ 
|__|__| : |__|__| 
MLN4924 Dose on Day 1       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
                                                                                          Infusion Stop Time: |__|__| : |__|__| 
MLN4924 Dose on Day 3*       Date:___/___/___      Infusion Start Time: |__|__| : |__|__| 
                                                                                          Infusion Stop Time: |__|__| : |__|__| 
2 
Day 3* 
3 hrs after MLN4924 infusion end time 
___/___/__ 
|__|__| : |__|__| 
3 
Day 3* 
6 hrs after MLN4924 infusion end time 
___/___/__ 
|__|__| : |__|__| 
MLN4924 Dose on Day 5*       Date:___/___/___      Infusion Start Time: |__|__| : |__|__| 
                                                                                          Infusion Stop Time: |__|__| : |__|__| 
2 
Day 5* 
3 hrs after MLN4924 infusion end time 
___/___/__ 
|__|__| : |__|__| 
3 
Day 5* 
6 hrs after MLN4924 infusion end time 
___/___/__ 
|__|__| : |__|__| 
 
*Blood samples are to be drawn on Day 3 OR Day 5, not on both days.  
 
 
 
 
 
One copy of this Pharmacodynamic Study Form should be uploaded into RAVE. A second copy should be sent with 
the samples to the address listed in Section 8.3.6.  See Section 8.3 for detailed guidelines for packaging and shipping 
PD – mRNA Transcript Level samples. 
 
Signature: _________________________________________                    Date:___________________ 
 
(site personnel who collected samples) 
 
 


                     
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83 
APPENDIX VI-A: PHARMACODYNAMICS (NEDDYLATED PROTEIN ANALYSIS) STUDY 
BLOOD SAMPLE INSTRUCTIONS 
 
Eligible samples: 
 
Samples should be sent to the Horton lab only if the patient samples meet the following criteria: 
 
1) Eligible patients must have an initial absolute blast count of at least 1000 blasts/µL. To  
 calculate the absolute blast percentage, multiply the total WBC by the % peripheral blasts: 
 
(WBC)(% blast)(1000) = absolute blast count/µL 
 
As an example, if the patient has a WBC of 10 and 50% blasts, the absolute blast count is: 
 
 
 
 
 
 
 
 
 
(10)(.5)(1000) = 5000/µL 
 
If the initial % blasts is unknown, send samples only if the total WBC is more than 10 and notify the Horton 
lab of the % blast as soon as available (contact info provided below). Sample can be batched, but must be 
received by the Horton lab no later than 72h after collection.   
 
Note: Do not collect NEDDylated Protein Analysis samples if minimal residual disease is < 1%. 
 
Sample collection time points: 
 
 
Day 1, Hour 0 
Day 1, Hour 10 
Day 1, Hour 24 
End of Cycle 1 
Peripheral 
Blood 
 
5 mL total* 
(before start of IV 
azacitidine and 
MLN4924 
[pevonedistat] 
infusion)** 
• 3 mL Cell Save 
• 2 mL heparin 
 
 
5 mL total*  
(10h following 
completion of 
MLN4924 
[pevonedistat] 
infusion) 
• 3 
mL 
Cell 
Save 
• 2 mL heparin 
 
5 mL total* 
(24h following 
completion of 
MLN4924 
[pevonedistat] 
infusion) 
• 3 mL Cell Save 
• 2 mL heparin 
 
5 mL total*  
(same day as bone 
marrow 
evaluation) 
• 3 mL Cell Save 
2 mL heparin 
 
*Sample Collection: Collect sample in syringe and send samples in Cell Save tubes (3 mL) and heparin 
tubes (2 mL). Either lithium heparin or sodium heparin is acceptable. Do NOT use lithium PST (plasma 
separator tubes). Cell Save tubes should have been received upon study activation by the lead CRA at 
your site. If Cell Save tubes are not available, the 5 mL can be sent in Heparin collection tubes. Do NOT 
send only Cell Save tubes as the proteasome and NF-kB analyses can be done only in heparin tubes.   
**It is permissible to collect the Day 1, Hour 0 sample after the intrathecal cytarabine dose.  
 
Shipping Note: Samples collected on Friday, Saturday and Sunday can be shipped Monday for Tuesday 
arrival.  
 
Specimen Requirements: 
• 
Store samples in refrigerator until shipment. 
• 
Cell Save tubes will be provided by the Horton lab to each institution upon IRB approval.   


                     
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• 
To obtain more Cell Save tubes, contact the Horton lab at the numbers provided below. 
• 
If the Cell Save tubes are not available, submit entire 5 mL sample in heparin tubes. Note that the 
sample integrity is greatly enhanced by the use of Cell Save tubes for 3 mL of the 5 mL 
material collected.  
• 
Each sample should be clearly labeled to include the study number (ADVL1712) as well as the 
treatment ID number and the accession number; along with date and time sample was drawn.  
• 
Please note the WBC and % blasts on the specimen transmittal form below. 
• 
The institutional immunophenotype report should be FAXed to 832-825-1206 (or e-mailed) and 
sent attn.: Gaye Jenkins c/o Horton laboratory.  This is a secure FAX and is used only by laboratory 
personnel.  NOTE: it is acceptable for blood to be collected from a central line. 
 
Shipping Requirements:  
Prior to sample collection, please contact Dr. Horton at (832) 824-4269 or Gaye Jenkins/Horton lab at (832) 
824-4676 for instructions on shipping. Samples should be shipped in a box with a thick styrofoam container 
(NO clinic-packs).  These containers can be found in your pathology department and are frequently received 
when your department receives antibody shipments.  If you do not have access to these storage containers, 
a Thermo-safe box can be mailed to your site by regular mail.  Please contact us before a patient is ready 
to enroll if you require a box for sample shipment. Shipment of boxes/tubes takes 5-7 business days and 
will be sent by USPS.     
 
If Thermo-Safe shipping container is not available: 
• 
Place collection tubes in a primary container. Wrap each collection tube separately to protect from 
breakage during shipment. Place the container in a thick Styrofoam box.  
• 
Please place an ice pack around the primary container. During the non-winter months (year round 
except Christmas Day in Texas) (other parts of the country: April-October) add additional ice 
packs to the Styrofoam box to assure the samples stays cold during shipment.  
• 
Package sample as appropriate for biologic material. 
 
For all samples, including those in ThermoSafe containers: 
• 
Include ice packs in the ThermoSafe container in the space provided. 
• 
Include a copy of the Specimen Transmittal Form with each shipment. 
• 
If possible, please FAX the bone marrow immunophenotype report with the first peripheral 
blood sample. If this is not possible, please send the report that day via fax (832 825-1206) or 
email to Dr. Horton at tmhorton@txch.org and Gaye Jenkins at gnjenkin@txch.org (Please strip 
HPI identifiers) 
• 
Ship the sample by Federal Express Priority Overnight delivery to: 
 
Dr. Terzah Horton c/o Gaye Jenkins 
Feigin Center, Suite 760.01 
1102 Bates St. 
Baylor College of Medicine 
Houston, TX  77030 
832-824-4676 
 
Courier information:  
• 
Notify Gaye Jenkins or Horton lab representative prior to shipment of the sample. Phone: (832) 
824-4676. Please email the Fed-Ex tracking number to the email addresses above.  
If possible, do not ship samples for delivery on a weekend or holiday. Weekend samples can be 
mailed Monday for Tuesday delivery. 


                     
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85 
APPENDIX VI-B: PHARMACODYNAMICS (NEDDYLATED PROTEIN ANALYSIS) STUDY 
FORM – BLOOD SAMPLES 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg  
 
Body Surface Area: ______m2  
 
MLN4924 (Pevonedistat) Dose Level: ______mg/m2   MLN4924 (Pevonedistat) Total Daily Dose: ______mg 
 
 
WBC: ___________ /L  
 
% Blasts: __________ % 
 
In consenting patients, blood samples (5 ml) will be collected in Cell Save tubes (3 ml) and heparinized tubes (2 
ml) at the following time points during Cycle 1 (± 10 min): Day 1 (prior to IV azacitidine and MLN4924 
[pevonedistat] dose, 10 hrs after the end of MLN4924 [pevonedistat] infusion, and 24 hrs  after the end of 
MLN4924 [pevonedistat] infusion), and at the end of Cycle 1 on the same day as bone marrow evaluation.  
 
Record the exact time the sample is drawn along with the exact time MLN4924 (pevonedistat) infusion begins and 
ends on Day 1.  
 
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1 
Day 1 
Prior to MLN4924 dose 
___/___/__ 
|__|__| : |__|__| 
MLN4924 Dose on Day 1       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
                                                                                          Infusion Stop Time: |__|__| : |__|__| 
2 
Day 1 
10 hrs after MLN4924 infusion end time 
___/___/__ 
|__|__| : |__|__| 
3 
Day 1 
24 hrs after MLN4924 infusion end time 
___/___/__ 
|__|__| : |__|__| 
4 
End of 
Cycle 1 
Same day as bone marrow evaluation 
___/___/__ 
|__|__| : |__|__| 
 
 
 
 
 
 
 
 
One copy of this Pharmacodynamic Study Form should be uploaded into RAVE. A second copy should be sent with 
the samples to the address listed in Section 8.4.6.  See Section 8.4 for detailed guidelines for packaging and shipping 
PD – mRNA Transcript Level samples. 
 
Signature: _________________________________________                    Date:___________________ 
 
(site personnel who collected samples) 
 


                     
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86 
APPENDIX VII: PHARMACODYNAMICS (NEDDYLATED PROTEIN ANALYSIS) STUDY 
FORM – BONE MARROW SAMPLES 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg  
 
Body Surface Area: ______m2  
 
MLN4924 (Pevonedistat) Dose Level: ______mg/m2  MLN4924 (Pevonedistat) Total Daily Dose: ______mg 
 
WBC: ___________ /L  
 
% Blasts: __________ % 
 
In consenting patients, bone marrow samples (2-3 ml) will be collected in heparinized tubes at the following time 
points: pre-study, and at the end of Cycle 1 on the same day as bone marrow evaluation.   
 
 
Record the exact time the sample is drawn. 
 
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual 
Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1 
Pre-study 
Pre-study 
___/___/__ 
|__|__| : |__|__| 
2 
End of 
Cycle 1 
Same day as bone marrow evaluation 
___/___/__ 
|__|__| : |__|__| 
 
 
 
 
 
 
 
 
 
One copy of this Pharmacodynamic Study Form should be uploaded into RAVE. A second copy should be sent with 
the samples to the address listed in Section 8.4.6.  See Section 8.4 for detailed guidelines for packaging and shipping 
PD – mRNA Transcript Level samples. 
 
Signature: _________________________________________                    Date:___________________ 
 
(site personnel who collected samples)


                     
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87 
APPENDIX VIII-A: THERAPY DELIVERY MAP FOR CYCLE 1  
Therapy Delivery Map – Cycle 1 
This Therapy Delivery Map (TDM) relates to Cycle 1. Each cycle lasts 35 days. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Criteria to start each cycle are in Section 5.3. Extensive treatment details are in Section 5.2.  
This TDM is on 4 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
IT Cytarabine 
(ARAC) 
(all patients) 
Intrathecal (IT) 
Age-based dosing: 
Age (yrs) Dose 
< 1 
20 mg 
1-1.99 
30 mg 
2-2.99 
50 mg 
> 3 
70 mg 
 
0 
Given at the time of diagnostic lumbar 
puncture OR Day 0. 
IT Cytarabine 
(CNS 2 or 3 
patients)* 
IT 
Age-based dosing: 
Age (yrs) Dose 
< 1 
20 mg 
1-1.99  
30 mg 
2-2.99  
50 mg 
> 3 
70 mg 
Twice 
weekly  
A minimum of 4 and a maximum of 6 
(count includes day 0 IT) intrathecal 
treatments may be given. 
 
The choice between IT Cytarabine OR IT 
Triples for patients with CNS 2 or 3 is up 
to the treating physician’s discretion. 
IT Triples 
(Methotrexate/
Hydrocortisone
/Cytarabine) 
(CNS 2 or 3 
patients)* 
IT 
Age-based dosing: 
Age (yrs)             Dose 
< 1                   MTX: 7.5 mg, HC: 7.5 mg, ARAC: 15 mg 
1-1.99              MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2-2.99              MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3-8.99              MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
> 9                   MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
Twice 
weekly 
A minimum of 4 and a maximum of 6 
(count includes day 0 IT) intrathecal 
treatments may be given. 
 
The choice between IT Cytarabine OR IT 
Triples for patients with CNS 2 or 3 is up 
to the treating physician’s discretion. 
Azacitidine 
(AZA) 
IV over 15 
minutes 
Age-based dosing: 
Age (yrs) Dose 
< 1 
2.5 mg/kg/dose 
> 1  
75 mg/m2/dose 
 
1-5  
On days 1, 3, and 5, administer before 
MLN4924 (pevonedistat) infusion. See 
below for timing.  
MLN4924 
Intravenous (IV) 
Patients < 1 year of age:  
1, 3, 5 
Administer 30-60 minutes after completion 
Cycle 1 
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88 
(Pevonedistat)  
  
over 1 hour 
Dose Level -1: 10 mg/m2 
Dose Level 1: 15 mg/m2 
 
Patients > 1 year of age:  
Dose Level -1: 15 mg/m2 
Dose Level 1: 20 mg/m2 
of azacitidine. 
Fludarabine 
(FLU) 
IV over 30 
minutes 
Age-based dosing: 
Age (yrs) Dose 
< 1 
1 mg/kg/dose 
> 1  
30 mg/m2/dose 
 
6-10 
 
Cytarabine 
(ARAC) 
IV over 1-3 
hours 
Age-based dosing: 
Age (yrs) Dose 
< 1 
67 mg/kg/dose 
> 1  
2000 mg/m2/dose 
 
6-10 
Use eye drops as described in Section 5.2.  
 
To begin 4 hours after the start of the 
fludarabine infusion.  
*CNS2 and CNS 3 patients will receive additional IT cytarabine OR IT triples 2x/weekly until the CNS is clear of blasts on 2 consecutive LPs, with a minimum of 
4 IT cytarabine OR IT Triples doses administered. Days of therapy may vary depending on scheduling.  
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Dose Level _________mg/m2 
 
 
 
Date Due 
Date 
Given 
Day 
IT* ARAC 
_________ mg 
IT* Triples 
_________ mg 
AZA 
_________ mg 
MLN4924 
(Pevonedistat) 
_________ mg 
FLU 
_________ mg 
ARAC 
_________ mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
Pre- 
_________ mg 
 
 
 
 
 
a – m, p 
 
 
1 
 
 
_________ mg 
_________ mg 
 
 
e, n, o, p, q 
a, 
b, 
d, 
f, 
g 
 
 
2 
 
 
_________ mg 
 
 
 
 
 
 
3 
 
 
_________ mg 
_________ mg 
 
 
e, n, p, q 
 
 
4 
 
 
_________ mg 
 
 
 
 
 
 
5 
 
 
_________ mg 
_________ mg 
 
 
e, n, p, q 
 
 
6 
 
 
 
 
_________ mg 
_________ mg 
 
 
 
7 
 
 
 
 
_________ mg 
_________ mg 
 
Cycle 1 
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8 
_________ mg* 
 
 
 
_________ mg* 
_________ mg* 
 
 
 
_________ mg* 
 
 
_________ mg 
_________ mg 
 
a, 
b, 
d, 
f, 
g, 
p 
 
 
9 
 
 
_________ mg 
_________ mg 
 
 
 
10 
 
 
_________ mg 
_________ mg 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
_________ mg* 
 
 
 
_________ mg* 
_________ mg* 
 
 
 
_________ mg* 
 
 
 
 
 
a, 
b, 
d, 
f, 
g, 
p 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
_________ mg* 
 
 
 
 
 
 
 
_________ mg* 
 
 
 
 
 
 
 
 
 
a, 
b, 
d, 
f, 
g, 
p 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
 
a, 
b, 
d, 
f, 
g, 
p 
 
 
30 
 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
 
34 
 
 
 
 
 
 
 
 
 
35 
 
 
 
 
 
 
l, m, o 
*CNS2 and CNS 3 patients will receive additional IT cytarabine OR IT triples 2x/weekly until the CNS is clear of blasts on 2 consecutive LPs, with a minimum of 
4 IT cytarabine OR IT triples doses administered. Days of therapy may vary depending on scheduling.  
 
 
 
Cycle 1 
Cycle 1 
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90 
Required Observations in Cycle 1 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below.  
 
a.    Hx/Wt /Ht/BSA. Prior to Cycle 1 and every week during Cycle 1.  
b. Physical exam (including VS). Prior to Cycle 1 and every week during Cycle 1. 
c. 
Performance Status. Prior to Cycle 1.  
d. CBC/diff/platelets. Prior to Cycle 1 and twice weekly during Cycle 1.  
e. 
Pharmacokinetics. In patients < 10 kg, samples to be collected on Day 1 and Day 5 
pre-MLN4924 (pevonedistat) dose, at the end of MLN4924 (pevonedistat) infusion, 
and at 4 – 6 hours, and 24 hours after the end of MLN4924 (pevonedistat) infusion. 
In patients > 10 kg, samples to be collected on Day 1 pre-MLN4924 (pevonedistat) 
dose, at the end of MLN4924 (pevonedistat) infusion, and at 1, 2, 4, 6 – 8, and 24 
hours after the end of MLN4924 (pevonedistat) infusion; on Day 3 pre-MLN4924 
(pevonedistat); and on Day 5 pre-MLN4924 (pevonedistat) dose, at the end of 
MLN4924 (pevonedistat) infusion, and at 1, 2, 4, 6 – 8, 24, and 48 OR 72 hours 
after the end of MLN4924 (pevonedistat) infusion. See Section 8.2 for details. 
f. 
Electrolytes including Ca++, Mg++, PO4. Prior to Cycle 1 and weekly during Cycle 1.   
g. Creatinine. Prior to Cycle 1 and weekly during Cycle 1. 
h.    Albumin. Prior to Cycle 1.  
i. 
Pregnancy test. Prior to Cycle 1.  
j. 
ECHO or gated radionuclide study. Prior to Cycle 1.   
k.    EKG. Prior to Cycle 1. 
l.     Bone marrow aspirate and/or biopsy. Prior to Cycle 1 and at the end of Cycle 1. 
m.   CSF for cell count, cytospin. Prior to Cycle 1 and at the end of Cycle 1.  
n.    Pharmacodynamics (mRNA Transcript Levels). Optional samples to be collected on 
day 1 pre-MLN4924 (pevonedistat) dose and on day 3 OR day 5 at 3 hours and 6 
hours after the end of MLN4924 (pevonedistat) infusion. See Section 8.3 for details. 
o.    Pharmacodynamics (NEDDylated Protein Analysis). Optional samples to be 
collected on day 1 pre-MLN4924 (pevonedistat) dose, and at 10 hours and 24 hours 
after the end of MLN4924 (pevonedistat) infusion. An additional sample is to be 
collected at the end of Cycle 1 on the same day as bone marrow evaluation. See 
Section 8.4 for details.  
p.    ALT, AST, Bilirubin. Prior to Cycle 1, prior to each dose of MLN4924 
(pevonedistat), and then weekly.  
Cycle 1 
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91 
q.    Vital signs. Prior to each dose of MLN4924 (pevonedistat).  
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD CLINICAL CARE.  
 
 
 
Comments 
(Include any held doses, or dose modifications) 
 
 
Page 4 of 5 
Cycle 1 
Cycle 1 
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92 
APPENDIX VIII-B: THERAPY DELIVERY MAP FOR CYCLE 2  
 
Therapy Delivery Map – Cycle 2 
This Therapy Delivery Map (TDM) relates to Cycle 2. Each cycle lasts 35 days. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Criteria to start each cycle are listed in Section 5.3. Extensive treatment details are in Section 5.2.  
This TDM is on 3 pages.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
IT Cytarabine 
(ARAC) 
(all patients) 
Intrathecal (IT) 
Age-based dosing: 
Age (yrs) Dose 
< 1 
20 mg 
1-1.99  
30 mg 
2-2.99  
50 mg 
>  3 
70 mg 
 
0 
Given at the time of bone marrow 
aspirate/biopsy at the end of Cycle 1 OR on 
Day 0 of Cycle 2. See Section 5.2 and Section 
5.3 for full details.  
Azacitidine 
(AZA) 
IV over 15 
minutes 
Age-based dosing: 
Age (yrs) Dose 
< 1 
2.5 mg/kg/dose 
> 1  
75 mg/m2/dose 
 
1-5  
On days 1, 3, and 5, administer before 
MLN4924 (pevonedistat) infusion. See timing 
below.   
MLN4924 
(Pevonedistat) 
 
 
Intravenous (IV) 
over 1 hour 
Patients < 1 year of age: 
Dose Level -1: 10 mg/m2 
Dose Level 1: 15 mg/m2 
 
Patients > 1 year of age: 
Dose Level -1: 15 mg/m2 
Dose Level 1: 20 mg/m2 
1, 3, 5 
Administer 30-60 minutes after completion of 
azacitidine.  
Fludarabine 
(FLU) 
IV over 30 
minutes 
Age-based dosing: 
Age (yrs) Dose 
< 1 
1 mg/kg/dose 
> 1  
30 mg/m2/dose 
 
6-10 
 
Cytarabine 
IV over 1-3 
Age-based dosing: 
6-10 
Use eye drops as described in Section 5.2.  
Cycle 2 
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93 
(ARAC) 
hours 
Age (yrs) Dose 
< 1 
67 mg/kg/dose 
> 1  
2000 mg/m2/dose 
 
 
To begin 4 hours after the start of the 
fludarabine infusion.  
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Dose Level _________mg/m2 
 
Date Due 
Date 
Given 
Day 
IT ARAC 
_________ mg 
AZA 
_________ mg 
MLN4924 
(Pevonedistat) 
_________ mg 
FLU 
_________ mg 
ARAC 
_________ mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
Pre- 
_________ mg 
 
 
 
 
a – f , h, i, 
k 
 
 
 
1 
 
_________ mg 
_________ mg 
 
 
g, l 
 
 
2 
 
_________ mg 
 
 
 
 
 
 
3 
 
_________ mg 
_________ mg 
 
 
g, l 
 
 
4 
 
_________ mg 
 
 
 
 
 
 
5 
 
_________ mg 
_________ mg 
 
 
g, l 
 
 
6 
 
 
 
_________ mg 
_________ mg 
 
 
 
7 
 
 
 
_________ mg 
_________ mg 
 
 
 
8 
 
 
 
_________ mg 
_________ mg 
 
g 
 
 
9 
 
 
 
_________ mg 
_________ mg 
 
 
 
10 
 
 
 
_________ mg 
_________ mg 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
g 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
g 
Cycle 2 
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23 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
g 
 
 
30 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
34 
 
 
 
 
 
 
 
 
35 
 
 
 
 
 
h – k   
 
Required Observations in Cycle 2 
 
a.    Hx/Wt /Ht/BSA. Prior to Cycle 2.  
b. Physical exam (including VS). Prior to Cycle 2.  
c. 
CBC/diff/platelets. Prior to Cycle 2.  
d.  Electrolytes including Ca++, Mg++, PO4. Prior to Cycle 2.  
e. 
Creatinine. Prior to Cycle 2.  
f. 
Albumin. Prior to Cycle 2.  
g.    ALT, AST, Bilirubin. Prior to each dose of MLN4924 (pevonedistat), then weekly.  
h.    ECHO or gated radionuclide study. Prior to Cycle 2 and at the end of Cycle 2. 
i.     EKG. Prior to Cycle 2 and at the end of Cycle 2.  
j.     Bone marrow aspirate and/or biopsy. At the end of Cycle 2. 
k.    CSF for cell count, cytospin. With day 0 IT and at the end of Cycle 2. 
l.     Vital signs. Prior to each dose of MLN4924 (pevonedistat). 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD CLINICAL CARE.  
Cycle 2 
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Comments 
(Include any held doses, or dose modifications) 
 
 
Page 4 of 4 
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96 
APPENDIX IX: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is 
important to regularly consult frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong Inducers 
Moderate 
Inducers 
acalabrutinib5 
alfentanil4,5  
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 
 
 


                     
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ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 7.4.1 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent.  
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors) 


                     
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98 
APPENDIX X:  PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions 
with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
      
Study 
Doctor: 
      
Study Doctor 
Phone #:  
      
Study 
Drug(s): 
MLN4924 
(Pevonedistat) 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse practitioners, 
pharmacists), and tell them you are taking part in a clinical trial sponsored by the National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
MLN4924 (pevonedistat) interacts with certain specific enzyme in your liver or other tissue like the gut and 
certain transport proteins that help move drugs in and out of cell. 
 
 
Explanation 
CYP 
isoenzymes 
The enzymes in question are CYP3A4/5.  MLN4924 (pevonedistat) is broken down by 
CYP3A4/5 and may be affected by drugs that are moderate or strong inducers of 
CYP3A4/5.  Use of CYP3A4 inducers (e.g., St. John’s Wort, rifampin, phenytoin) is 
not allowed while taking MLN4924. 
 
Transport 
proteins 
The transporter enzymes and proteins in question are P-glycoprotein (P-gp), OATP and 
BCRP.  MLN4924 is moved in and out of cells/organs by P-gp and BCRP.  Use caution 
with concomitant drugs that are inhibitors of P-gp.  Concurrent use of drugs that are 
BCRP inhibitors (e.g., cyclosporine) is not allowed.   MLN4924 may affect the ability 
of other drugs to be moved in and out of cells by inhibiting P-gp, OATP and BCRP.  
Use substrates of these transport proteins with caution. 
 
These are the things that you need to know: 
The study drug MLN4924 (pevonedistat), may interact with other drugs which can cause side effects. For 
this reason, it is very important to tell your doctors about all your medicines, including: (a) medicines you 
are taking before this clinical trial, (b) medicines you start or stop taking during this study, (c) medicines 
you buy without a prescription (over-the-counter remedy), (d) herbals or supplements (e.g. St. John’s Wort). 
It is helpful to bring your medication bottles or an updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers 
to review any medicines and herbal supplements that are considered moderate or strong inhibitors or 
inducers of CYP3A4/5, P-gp, OATP and BCRP. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects. Avoid ingesting grapefruit and grapefruit juice. 
• Make sure your doctor knows to avoid certain prescription medications.  
• Your regular health care provider should check a frequently updated medical reference or call your 
study doctor before prescribing any new medicine or discontinuing any medicine.   
Version JAN/2019 
 
 


                    
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PATIENT DRUG INTERACTION WALLET CARD
EMERGENCY 
INFORMATION
DRUG INTERACTIONS 
Show this card to all of your 
healthcare providers. Keep it 
with you in case you go to the 
emergency room.
Tell your doctors before you start or 
stop any medicines.
Check with your doctor or 
pharmacist if you need to use an 
over-the-counter medicine or herbal 
supplement!
Carry this card with you at all times  
MLN4924 (pevonedistat) interacts with enzymes in your liver or other tissue 
like the gut, transport proteins that help move drugs in and out of cells and 
must be used very carefully with other medicines.
Patient Name:
Use caution and avoid the 
following drugs if possible:
St. John’s Wort, grapefruit or grapefruit 
juice
Your healthcare providers should be aware of any medicines that are strong 
inhibitors/inducers of CYP3A4/5, P-gp and OATP.  Drugs that are CYP3A4/5 
inducers (e.g., rifampin, St. John’s Wort), or BCRP inhibitors (e.g., 
cyclosporine) ae not allowed. 
Diagnosis:
Study Doctor:
Study Doctor Phone #:
NCI Trial #:
Before prescribing new medicines, your health care provider should check a 
frequently-updated medical reference for a list of drugs to avoid or contact 
your study doctor.
Study Drug(S): MLN4924 (pevonedistat)
             Version JAN/2019
For more information: 1-800-4-CANCER
For more information: 1-800-4-CANCER
For more information: 1-800-4-
CANCER
For more information: 1-800-4-CANCER
cancer.gov | clinicaltrials.gov
cancer.gov | clinicaltrials.gov
cancer.gov | clinicaltrials.gov
cancer.gov | clinicaltrials.gov


                     
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100 
APPENDIX XI: NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC 
DISEASE  
 
The following table presents the New York Heart Association classification of cardiac disease.33 
Class 
Functional Capacity 
Objective Assessment 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease 
 
 
 


                     
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101 
APPENDIX XII: CTEP AND CTSU REGISTRATION PROCEDURES  
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually.  To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type 
of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined in the table 
below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI 
Biosketch 
(education, 
training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list all 
clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the RCR Help 
Desk by email at < RCRHelpDesk@nih.gov >. 
 
 


                     
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102 
 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and 
submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory criteria 
including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not required 
to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the CIRB, IRB 
approval information is received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via IRBManager 
to indicate their intent to open the study locally.  The CIRB’s approval of the SSW is then communicated 
to the CTSU Regulatory Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the Signatory Institution are 
participating in the study. 
 
Requirements For ADVL1712 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-signed 
CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
For applicable studies with a radiation and/or imaging (RTI) component, the enrolling site must be 
aligned to a RTI provider.  To manage provider associations access the Provider Association tab on 
the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove 
associated providers.  Sites must be linked to at least one IROC credentialed provider to participate on 
trials with an RT component. Enrolling sites are responsible for ensuring that the appropriate 
agreements are in place with their RTI provider, and that appropriate IRB approvals are in place.   
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab →Regulatory 


                     
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Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
      1818 Market Street, Suite 3000 
      Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
 
 


                     
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104 
APPENIX XIII: GUIDELINES FOR SHIPPING SAMPLES TO COVANCE – MADISON  
 
Packing Instructions 
1. Place samples into a divided specimen box in the exact order of the pharmacokinetic study form 
(Appendix IV-A and/or Appendix IV-B). 
2. Place enough absorbent material to absorb at least three times the contents. 
3. Secure the lid on the specimen box and seal the box inside a biohazard sample transport bag. 
4. Place the specimen boxes in the center of an insulated shipping container. 
5. Surround and cover the contents with at least enough dry ice to last the duration of the journey. 
• 
Dry ice recommendations: 
o Large Styrofoam cooler, between 12 to 14 kg of pellet dry ice.  
o Medium Styrofoam cooler, between 10 to 12 kg of pellet dry ice.  
o Small Styrofoam cooler, between 7 to 10 kg of pellet dry ice (amount dependent on 
actual box size). 
Note: Block dry ice or ice packs should never be used to ship bioanalytical samples. 
6. Include a hard copy of the pharmacokinetic study form (Appendix IV-A and/or Appendix IV-B) 
in a water proof bag. 
7. Add packing material to prevent contents from shifting during transport and secure the lid. 
8. Place the shipping container in a shipping box and securely close the box.  Use tape that is 
resistant to moisture and cold. 
9. Place Biohazard warnings on outside of box (if applicable). 
10. Label the box exterior in accordance with the applicable DOT CFR / IATA Regulations. 
 
Shipping Instructions  
Unless otherwise directed, address the shipment to: 
 
Attention: Melanie Ivancic, PhD 
Sample Management—Bioanalytical (Rm 1S 160)  
Covance Laboratory Inc.  
3301 Kinsman Boulevard  
Madison, WI 53704-2523  
 
The pharmacokinetic study form should be attached to an e-mail sent to both the study-specific Research 
Coordinator as well as Madison.SA@covance.com on the day of shipping as notification of the intended 
shipment.  
 
When possible, shipments should be made Monday through Wednesday.  Specify a Priority A.M. delivery 
to Covance.  Sample shipments should be made at least 2 days prior to a United States National Holiday.  
For shipments that may result in a weekend or holiday delivery, please contact the Bioanalytical Principal 
Investigator and Madison.SA@covance.com to discuss delivery details. 
 
Any questions regarding shipping instructions may be directed to phone number (608) 395-3750 or via 
email at SampleInformationCoordination@covance.com.   


                     
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105 
Regulatory Information 
Specific Federal and International Regulations define classes of “Hazardous Materials” and “Dangerous 
Goods”.  Specimens transported to the Covance- Bioanalytical Chemistry Department should be evaluated 
for their Hazardous Material Class and categorized, packaged, labeled, documented, and transported in 
accordance with the applicable regulations.  Facilities shipping Hazardous Materials are required to 
maintain designated personnel trained in accordance with part 49 CFR-Subpart H within the last 36 months 
and International Air Transportation Association (IATA) regulations (if shipping by air) within the last 24 
months.  The IATA regulation manual also lists additional regulations imposed individually by a variety of 
Commercial Carriers and Airlines.   
 
The information provided here are Covance Labs guidelines to assist in the proper and safe transport of 
samples for assay in this facility.  They are not to be construed as a replacement or complete summary of 
applicable DOT (CFR) or IATA regulations. 
 
 
  Term used by Department of Transportation (DOT) in the Code of Federal Regulations (CFR) 
  Similar term used by the International Air Transportation Association (IATA), will use the term Hazardous 
Material in this document  
  Part 49 is “Hazardous Materials in Commerce” in the CFR 

ICF_001.pdf: 
 
 
Pediatric Early Phase Clinical Trial 
Network (PEP-CTN) and  
Developmental Therapeutics (DVL) 
Chair 
Brenda J. Weigel, M.D. 
weige007@umn.edu 
 
PEP-CTN and  
Developmental Therapeutics (DVL) 
Vice Chair  
Elizabeth Fox, M.D. 
elizabeth.fox@stjude.org 
 
PEP-CTN Operations  
Data & Statistics Center Director 
Thalia Beeles, MPH 
tbeeles@childrensoncologygroup.org 
 
PEP-CTN Statistician  
Charles G. Minard, Ph.D. 
minard@bcm.edu 
 
 
PEP-CTN and  
DVL Chair’s Office 
University of Minnesota/ 
Masonic Cancer Center 
Masonic Children’s Hospital 
420 Delaware Street, SE 
MMC 366 
Minneapolis, MN  55455 
 
P 612 626 5501 
F 612 624 3913 
 
 
Children’s Oncology Group 
Group Chair 
Douglas S. Hawkins, MD 
Seattle Children’s Research 
Institute  
Mailstop: JMB 9 
1900 9th Avenue 
Seattle, WA 98101 
P 206 884 1107 
doug.hawkins@seattlechildrens       
.org  
 
 
 
PEP-CTN Operations Data & 
Statistics Center 
800 Royal Oaks Drive 
Suite 210  
Monrovia, CA 91016 
 
P 626 241 1500 
F 626 445 4334 
 
 
A National Cancer Institute-  
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
 
 
 
 
 
 
i 
 
August 27, 2020 
 
 
Martha Kruhm, M.S., RAC  
Head, Protocol and Information Office (PIO) 
National Institutes of Health/NCI/DCTD/CTEP/OIB/PIO 
9609 Medical Center Drive, OIB MSC 9742, Room #5W246 
Bethesda, MD 20892-9742 
 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #3A to ADVL1712, A Feasibility Trial of 
MLN4924 (pevonedistat, TAK 924, IND#) given in Combination with 
Azacitidine, Fludarabine, and Cytarabine, in Children, Adolescents, and Young 
Adults 
with 
Relapsed 
or 
Refractory 
Acute 
Myeloid 
Leukemia 
or 
Myelodysplastic Syndrome. 
 
This amendment is being submitted in response to a Request for Rapid 
Amendment (RRA) from Dr. John J. Wright (wrightj@ctep.nci.nih.gov), dated 
August 7, 2020. In this amendment, the revised CAEPR for MLN4924 
(Pevonedistat HCl) (Version 2.3, July 10, 2020) has been inserted in the 
protocol, and the associated risk information in the informed consent document 
has been revised. All revisions are detailed in the summary of changes below. 
 
Please let me know if you have any questions or need additional information. 
 
Sincerely,  
Jennifer Knothe, Protocol Coordinator (for) 
Katherine Tarlock, M.D., ADVL1712 Study Chair, and 
Brenda Weigel, M.D., PI, PEP-CTN 


 
ii 
 
SUMMARY OF CHANGES: INFORMED CONSENT 
In accordance with the above discussion, the following specific revisions have been made to the informed 
consent. Additions are in boldfaced font and deletions in strikethrough font. 
 
# 
Section 
Page(s) 
Change 
1. 
General 
Throughout 
Updated protocol version date in the footer.  
2. 
Risks and side effects 
related to MLN4924 
(pevonedistat) 
8-9 
In response to a Request for Rapid Amendment (RRA) from Dr. 
John J. Wright, dated August 7, 2020, the MLN4924 
(Pevonedistat HCl) risk insert has been updated as follows: 
 
• 
Decrease in Risk Attribution:  
• 
Changed to Occasional from Common: 
Constipation; Dizziness 
• 
Changed to Also Reported on MLN4924 Trials 
But With Insufficient Evidence for Attribution 
from Occasional (i.e., removed from the Risk 
Profile): Rash 
 
• 
Provided Further Clarification:  
• 
Infection, especially when white blood cell 
count is low (under Occasional) is now 
reported as Infection, especially when white 
blood cell count is low which may cause 
painful and frequent urination (under 
Occasional). 
 
 


 
 
                                                                                                                                  
 
                                                                      
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Version Date: 08/27/2020 
 
Page 1 
 
 
 
This model informed consent form has been reviewed by the DCT/NCI and is the official consent document 
for this study. Local IRB changes to this document are allowed. (Institutions should attempt to use sections 
of this document which are in bold type in their entirety.) Editorial changes to these sections may be made 
as long as they do not change information or intent. If the institutional IRB insists on making deletions or 
more substantive modifications to the risks or alternatives sections, they must be justified in writing by the 
investigator and approved by the IRB.  
 
SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM 
 
ADVL1712, A Feasibility Trial of MLN4924 (Pevonedistat, TAK 924, 
IND#) Given in Combination with Azacitidine, Fludarabine, and 
Cytarabine, in Children, Adolescents, and Young Adults with 
Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic 
Syndrome 
 
If you are a parent or legal guardian of a child who may take part in this study, permission from 
you is required. The assent (agreement) of your child may also be required. When we say “you” 
in this consent form, we mean you or your child; “we” means the doctors and other staff. 
 
Overview 
 
You are being asked to take part in this research study because you have been diagnosed with 
leukemia or myelodysplastic syndrome that has either come back (“relapsed”) or does not 
respond to therapy (“is refractory”). 
 
Taking part in this study is voluntary. You may choose not to be in this study. If you decide not to 
be in this study, you will not be penalized and you will not lose any benefits to which you are 
entitled. You will still receive medical care.  
 
The overall goal of this study is to find the highest dose of MLN4924 (pevonedistat) that can be 
given safely in combination with the commercial drugs azacitidine, fludarabine, and cytarabine. 
 
If the exams, tests and procedures show that you can be in the study, and you choose to take 
part, MLN4924 (pevonedistat) will be given by vein on Days 1, 3, and 5 over a 35 day cycle. 
This entire 35 day period is called a cycle. You will also receive the commercial drugs 
azacitidine, cytarabine, and fludarabine. Cytarabine will be given into the spinal fluid prior to 
each cycle, azacitidine will be given by vein on Days 1-5, fludarabine will be given by vein on 
Days 6-10, and cytarabine will be given by vein on Days 6-10. You may continue to receive 
MLN4924 (pevonedistat) for up to 2 cycles unless you develop serious side effects or your 
cancer worsens. 
 
Certain patients will also receive the commercial drugs cytarabine or intrathecal triples 
(methotrexate + hydrocortisone + cytarabine) through the spinal cord twice weekly between Days 
8 and 34 of Cycle 1. This will happen to patients whose leukemia has affected their spinal fluid. 
Your doctor will let you know if you are one of these patients.    
 


 
 
                                                                                                                                  
 
                                                                      
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Page 2 
 
 
There will be two different amounts (doses) of MLN4924 (pevonedistat) given to children on this 
study – a higher dose, which is the dose given to adults, and a lower dose. Up to 6 children will 
be given each dose. Your dose will not increase but might be decreased depending on side 
effects. Dosing is done this way because we do not yet know the best dose to use in children.  
 
All people who receive cancer treatment are at risk of having side effects. In addition to killing 
tumor cells, cancer chemotherapy can damage normal tissue and produce side effects. 
 
This study uses the investigational drug, MLN4924 (pevonedistat). Common side effects of this 
drug are anemia, diarrhea, nausea, vomiting, chills, tiredness, fever, loss of appetite, pain, 
dizziness, headache, and shortness of breath. Some less common but notable side effects are 
liver injury, kidney injury, lung dysfunction, and infection. The full list of risks for MLN4924 
(pevonedistat) is available in the section What side effects or risks can I expect from being in the 
study? 
 
You can ask your study doctor questions about side effects at any time.  
 
We hope that this study will help you personally, but we do not know if it will. The potential benefits 
to you associated with participation in this study are described in the section Are there benefits to 
taking part in the study? 
 
You have a choice between another treatment for leukemia or myelodysplastic syndrome and this 
clinical trial.  
 
The rest of this form provides detailed information about the study and what to expect should you 
decide to participate. 
 
Why am I being invited to take part in this study? 
 
You are being asked to take part in this research study because you have been diagnosed with 
leukemia or myelodysplastic syndrome that has either come back (“relapsed”) or that has not 
responded to standard therapy (is “refractory”). 
 
This study is called a clinical trial. A clinical trial is a research study involving treatment of a 
disease in human patients. This study is being carried out by the Children’s Oncology Group 
(COG) Pediatric Early Phase Clinical Trial Network (PEP-CTN). COG is an international research 
group that consists of more than 200 hospitals that treat children with cancer in the United States, 
Canada, Australia, New Zealand, and Switzerland. The PEP-CTN is the group within COG that 
consists of 21 hospitals based in the United States and Canada, and participation in this study 
will be limited to these hospitals.  
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to improve 
cancer treatment over time. Clinical trials include only people who choose to take part. You have 
a choice between another treatment for leukemia or myelodysplastic syndrome and this clinical 
trial. 
 
Please take your time to make your decision. You may want to discuss it with your friends and 
family. We encourage parents to include their child in the discussion and decision to the extent 
that the child is able to understand and take part. 
 


 
 
                                                                                                                                  
 
                                                                      
ADVL1712 
Version Date: 08/27/2020 
 
Page 3 
 
 
 
What is the current standard of treatment for this disease? 
 
We are asking if you want to participate in this study because there is not a standard treatment 
for your cancer at this point. 
 
Why is this study being done? 
 
This is a Phase 1 study of a drug called MLN4924 (pevonedistat). We are testing new 
experimental drugs such as MLN4924 (pevonedistat) in the hopes of finding a treatment that 
may be effective against leukemia or myelodysplastic syndrome that has come back or that has 
not responded to standard therapy. This study looks at how well MLN4924 (pevonedistat) works 
in children and young adults with relapsed or refractory leukemia or myelodysplastic syndrome 
in combination with the commercial drugs azacitidine, fludarabine, and cytarabine. We are using 
MLN4924 (pevonedistat) because it seems to work against cancer in test tubes and animals. 
MLN4924 (pevonedistat) has been used in adults and there is a lot that we do not know about it 
yet. This is called a Phase 1 study because the goal is to find the highest dose of MLN4924 
(pevonedistat) that we can give safely in combination with the commercial drugs azacitidine, 
fludarabine, and cytarabine. 
 
The overall goals of this study are: 
• 
To find the highest dose of MLN4924 (pevonedistat) that can be given safely in 
combination with the commercial drugs azacitidine, fludarabine, and cytarabine; 
• 
To learn what kind of side effects MLN4924 (pevonedistat) can cause when given in 
combination with the commercial drugs azacitidine, fludarabine, and cytarabine; 
• 
To learn more about the pharmacology (how your body handles the drug) of 
MLN4924 (pevonedistat); 
• 
To determine whether MLN4924 (pevonedistat) in combination with the commercial 
drugs azacitidine, fludarabine, and cytarabine is a beneficial treatment for your 
cancer. 
  
What will happen on this study that is research?   
 
If the exams, tests and procedures show that you can be in the study, and you choose to take 
part, MLN4924 (pevonedistat) will be given by vein on Days 1, 3, and 5 of each 35 day cycle. This 
entire 35 day period is called a cycle. You will also receive the commercial drugs azacitidine, 
cytarabine, and fludarabine. Cytarabine will be given into the spinal fluid prior to each cycle, 
azacitidine will be given by vein on Days 1-5, fludarabine will be given by vein on Days 6-10, and 
cytarabine will be given by vein on Days 6-10. You may continue to receive MLN4924 
(pevonedistat) for up to 2 cycles unless you develop serious side effects or your tumor worsens.   
 
Certain patients will also receive cytarabine or intrathecal triples (methotrexate + hydrocortisone 
+ cytarabine) through the spinal cord twice weekly between Days 8 and 34 of Cycle 1. This will 
happen to patients whose leukemia has affected their spinal fluid. Your doctor will let you know if 
you are one of these patients.     
 


 
 
                                                                                                                                  
 
                                                                      
ADVL1712 
Version Date: 08/27/2020 
 
Page 4 
 
 
Dose Confirmation  
There will be two different amounts (doses) of MLN4924 (pevonedistat) given to children on this 
study – a higher dose, which is the dose given to adults, and a lower dose. Up to 6 children will 
be given each dose. Your dose will not increase but might be decreased depending on side 
effects. Dosing is done this way because we do not yet know the best dose to use in children.  
 
Diagram of Treatment 
An overview of a treatment cycle is below: 
 
      Intrathecal Cytarabine  
 MLN4924 (pevonedistat) 
 Azacitidine 
 Cytarabine 
 
 Fludarabine 
  Intrathecal Cytarabine OR Intrathecal Triples*  
 
  
 
 
 
  
 
 
 
 
*Twice weekly during the first cycle of therapy. Only for patients whose leukemia has affected their spinal 
fluid. Your doctor will let you know if you are one of these patients.  
 
The table below describes one cycle of therapy:  
 
Drug 
How the drug will be given  
Days 
Cytarabine 
Into the spinal fluid (intrathecal) 
Before each cycle 
Azacitidine 
By vein 
1 – 5 
MLN4924 (Pevonedistat) 
By vein 
1, 3, 5 
Fludarabine 
By vein 
6 – 10 
Cytarabine 
By vein 
6 – 10 
Cytarabine OR Intrathecal 
Triples 
(Methotrexate/Hydrocortisone/
Cytarabine)* 
Into the spinal fluid (intrathecal)* 
Twice weekly 
between Days 8 
and 34* 
*These drugs will only be given to patients whose leukemia has affected their spinal fluid. These 
drugs will be given twice weekly during the first cycle of therapy. Your doctor will let you know if 
you are one of these patients.  
 
For more details regarding what drugs and tests will be given on each day of therapy, please 
see Attachment 2.  
 
Research Study Tests and Procedures 
During the study you will have tests and procedures to check for side effects and see how your 
cancer is doing. These tests are part of regular cancer care, but you may have them more often 
because you are on the study:  
• 
Physical exam 
• 
Vital signs (blood pressure, pulse, temperature) 
• 
Blood tests 
Day 


 
 
                                                                                                                                  
 
                                                                      
ADVL1712 
Version Date: 08/27/2020 
 
Page 5 
 
 
• 
Pregnancy test 
• 
MRI, X-rays, CT scans, or other tests that are needed to check your cancer 
• 
Bone marrow tests 
• 
Heart function test (EKG) 
 
Copies of the scans used to diagnose your cancer and some of the tissue already taken may be 
sent to a central review center. COG does this to double check the hospitals’ results and central 
review is performed for research purposes. 
 
Research Study Tests 
We would also like to do some extra tests called pharmacokinetic studies and biologic studies. 
Pharmacokinetic studies help us determine how much of the MLN4924 (pevonedistat) is in your 
blood. Biologic studies help us evaluate the effect of MLN4924 (pevonedistat) on your body. These 
tests will help us learn more about MLN4924 (pevonedistat) and may help children who receive this 
drug in the future. The information learned would not change the way you are treated, and the results 
of these tests will not be given to you. Some of these tests are required but others are optional (you 
can decide whether you want to do them or not). If you weigh 10 kg or less (22 pounds or less), a 
total of 50 mL of blood (approximately 10 teaspoons) and 6 mL of bone marrow sample 
(approximately 1 teaspoon) will be drawn  for all the pharmacokinetic and biology study tests in this 
study. If you weigh over 10 kg (over 22 pounds), a total of 74 mL of blood (approximately 15 
teaspoons) and 6 mL of bone marrow sample (approximately 1 teaspoon) will be drawn for all the 
pharmacokinetic and biology study tests in this study. This amount of blood and bone marrow is safe 
to draw even from small children. You can still be a part of the main study even if you say “No” to 
taking part in any of the optional research studies. 
 
Pharmacokinetic Studies (Required) 
 
For patients that weigh 10 kg or less (22 pounds or less): 
During the study, a total of 8 blood samples will be collected (about 3 mL or about ½ teaspoon 
each sample) for the pharmacokinetic tests. These samples will be taken before the drug begins, 
at the end of MLN4924 (pevonedistat) infusion, between 4 – 6 hours after MLN4924 
(pevonedistat) infusion (1 sample only between these time points) and 24 hours after MLN4924 
(pevonedistat) infusion. These blood draws will occur on Day 1 and Day 5 of Cycle 1. These 
samples will be required from all participants in the study. Because we cannot draw the samples 
from the same IV or central line we give the drug through, we will start a separate IV to get the 
samples. 
 
A total volume of 24 mL (about 5 teaspoons) will be drawn for pharmacokinetic tests in this study. 
This amount of blood is safe to draw even from small children. 
 
You may be reimbursed up to $100 for inconveniences you experience as a result of your 
participation.  Your doctor will explain to you what qualifies for reimbursement (e.g. costs of 
parking). 
 
Please see Attachment 2 for more details on what days blood draws for pharmacokinetic studies 
will occur.  
 
For patients that weigh over 10 kg (over 22 pounds):  
During the study, a total of 16 blood samples will be collected (about 3 mL or about ½ teaspoon 
each sample) for the pharmacokinetic tests. These samples will be taken before the drug begins, 


 
 
                                                                                                                                  
 
                                                                      
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at the end of MLN4924 (pevonedistat) infusion and at 1 hour after MLN4924 (pevonedistat) 
infusion, 2 hours after MLN4924 (pevonedistat) infusion, 4 hours after MLN4924 (pevonedistat) 
infusion, between 6 – 8 hours after MLN4924 (pevonedistat) infusion (1 sample only between 
these time points), 24 hours after MLN4924 (pevonedistat) infusion, and 48 hours after MLN4924 
(pevonedistat) infusion. These blood draws will occur on Day 1 and Day 5 of Cycle 1. A sample 
72 hours after MLN4924 (pevonedistat) is given on Day 5 can be substituted for the sample taken 
48 hours after MLN4924 (pevonedistat) is given on Day 5 instead. These samples will be required 
from all participants in the study. Because we cannot draw the samples from the same IV or 
central line we give the drug through, we will start a separate IV to get the samples. 
 
A total volume of 48 mL (about 10 teaspoons) will be drawn for pharmacokinetic tests in this study. 
This amount of blood is safe to draw even from small children. 
 
You may be reimbursed up to $100 for inconveniences you experience as a result of your 
participation.  Your doctor will explain to you what qualifies for reimbursement (e.g. costs of 
parking). 
 
Please see Attachment 2 for more details on what days blood draws for pharmacokinetic studies 
will occur.  
 
Optional Research Study Tests 
During the study we would like to collect additional blood and bone marrow samples to evaluate 
the effect of MLN4924 (pevonedistat) on your body. There are 2 different studies we would like 
your blood and/or bone marrow samples for, and you can participate in either, both, or neither.  
 
The first study will help us evaluate the effect of MLN4924 (pevonedistat) on gene expression. 
The blood samples, 2 mL (½ teaspoon) each, will be obtained prior to treatment on Day 1, and 3 
hours and 6 hours after treatment on Day 3 OR Day 5.  
 
A total blood volume of 6 mL (about 1½ teaspoons) will be drawn for this gene expression study. 
This amount of blood is safe to draw even from small children.  
 
The second study will help us evaluate the effect of MLN4924 (pevonedistat) on your proteins. 
The blood samples, 5 mL (1 teaspoon) each, will be obtained prior to treatment on Day 1, 10 
hours after Day 1 treatment, 24 hours after Day 1 treatment, and at the end of Cycle 1 on the 
same day as bone marrow evaluation.  
 
Bone marrow samples, 3 mL (½ teaspoon) each, will be obtained prior to treatment with MLN4924 
(pevonedistat) on the same day as bone marrow evaluation and at the end of Cycle 1. 
 
A total blood volume of 20 mL (about 4 teaspoons) and a total bone marrow volume of 6 mL 
(about 1 teaspoon) will be drawn for this protein study. This amount of blood and bone marrow is 
safe to draw even from small children. 
 
Please see Attachment 2 for more details on what days blood draws for biology studies will occur.  
 
The table below summarizes the blood volume and bone marrow volume required if you 
participate in all of the above studies: 
 
 


 
 
                                                                                                                                  
 
                                                                      
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Patients that weigh 10 kg or less (22 pounds or less): 
 
Correlative Study 
Blood 
Volume per 
Sample 
Total Volume 
 
Pharmacokinetics 
3 mL (½ 
teaspoon) 
24 mL (5 
teaspoons) 
Pharmacodynamics 
(mRNA Transcript 
Levels) 
2 mL (½ 
teaspoon) 
6 mL (1 teaspoon) 
Pharmacodynamics 
(NEDDylated Protein 
Analysis) – Blood 
Samples 
5 mL (1 
teaspoon) 
20 mL (4 
teaspoons) 
Pharmacodynamics 
(NEDDylated Protein 
Analysis) – Bone 
Marrow Samples 
3 mL (½ 
teaspoon) 
6 mL (1 teaspoon) 
Total Volume for All 
Studies 
 
56 mL (11 
teaspoons) 
 
Patients that weigh over 10 kg (over 22 pounds): 
 
Correlative Study 
Blood 
Volume per 
Sample 
Total Volume 
 
Pharmacokinetics 
3 mL (½ 
teaspoon) 
48 mL (10 
teaspoons) 
Pharmacodynamics 
(mRNA Transcript 
Levels) 
2 mL (½ 
teaspoon) 
6 mL (1 teaspoon) 
Pharmacodynamics 
(NEDDylated Protein 
Analysis) – Blood 
Samples 
5 mL (1 
teaspoon) 
 20 mL (4 
teaspoons) 
Pharmacodynamics 
(NEDDylated Protein 
Analysis) – Bone 
Marrow Samples 
3 mL (½ 
teaspoon) 
6 mL (1 teaspoon) 


 
 
                                                                                                                                  
 
                                                                      
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Total Volume for All 
Studies 
 
80 mL (16 
teaspoons) 
What side effects or risks can I expect from being in the study? 
 
If you choose to take part in this study, there is a risk that the MLN4924 (pevonedistat) may not 
be as good as the usual approach for your cancer or condition at shrinking or stabilizing your 
cancer. 
 
You also may have the following discomforts: 
• 
Spend more time in the hospital or doctor’s office. 
• 
Be asked sensitive or private questions about things you normally do not discuss. 
• 
May not be able to take part in future studies. 
 
The MLN4924 (pevonedistat) used in this study may affect how different parts of your body work 
such as your liver, kidneys, heart, and blood.  The study doctor will test your blood and will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important things to know about side effects: 
• 
The study doctors do not know who will or will not have side effects. 
• 
Some side effects may go away soon, some may last a long time, and some may never 
go away. 
• 
Some side effects may make it hard for you to have children. 
• 
Some side effects may be mild.  Other side effects may be very serious and even result 
in death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
• 
If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• 
Your study doctor will work with you to treat your side effects. 
• 
Your study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
 
Risks and side effects related to MLN4924 (pevonedistat): 
  
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving MLN4924 (pevonedistat HCl), more than 20 and up to 100 may 
have: 
• 
Diarrhea, nausea, vomiting 


 
 
                                                                                                                                  
 
                                                                      
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• 
Tiredness, fever 
• 
Loss of appetite 
• 
Pain 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving MLN4924 (pevonedistat HCl), from 4 to 20 may have: 
• 
Anemia which may require blood transfusion 
• 
Infection, especially when white blood cell count is low which may cause 
painful and frequent urination 
• 
Bloating, constipation  
• 
Sores in the mouth which may cause difficulty swallowing 
• 
Chills 
• 
Swelling of arms, legs 
• 
Cold symptoms such as stuffy nose, sneezing, sore throat 
• 
Bruising, bleeding 
• 
Dehydration 
• 
Dizziness, headache 
• 
Muscle weakness          
• 
Numbness, tingling or pain of the arms and legs 
• 
Feeling of "pins and needles" in arms and legs 
• 
Worry, confusion 
• 
Difficulty sleeping 
• 
Cough, shortness of breath, wheezing 
• 
Nose bleed 
• 
Fluid around lungs 
• 
Increased sweating 
• 
Itching 
• 
Low blood pressure which may cause feeling faint 
 
RARE, AND SERIOUS 
In 100 people receiving MLN4924 (pevonedistat HCl), 3 or fewer may have: 
• 
Abnormal heartbeat 
• 
Kidney damage which may cause swelling, may require dialysis 
 
 
Risks and side effects related to azacitidine: 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving azacitidine, more than 20 and up to 100 may have: 
• 
Anemia which may require blood transfusion 
• 
Constipation, diarrhea, nausea, vomiting 
• 
Tiredness, fever 
• 
Swelling and redness at the site of the medication injection 
• 
Infection, especially when white blood cell count is low 
• 
Bruising, bleeding 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving azacitidine, from 4 to 20 may have: 


 
 
                                                                                                                                  
 
                                                                      
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• 
Heart failure which may cause shortness of breath, swelling of ankles, and 
tiredness 
• 
Fluid around heart 
• 
Abnormal heartbeat 
• 
Pain 
• 
Difficulty swallowing or sleeping 
• 
Bleeding from multiple sites including nose 
• 
Internal bleeding which may cause black tarry stool, blood in vomit or 
coughing up blood 
• 
Sores in the mouth 
• 
Chills 
• 
Swelling of arms, legs 
• 
Weight loss, loss of appetite 
• 
Muscle weakness 
• 
Dizziness, headache 
• 
Worry, confusion 
• 
Cough, shortness of breath, postnasal drip 
• 
Hair loss, itching, rash 
• 
Low blood pressure which may cause feeling faint 
 
RARE, AND SERIOUS 
In 100 people receiving azacitidine, 3 or fewer may have: 
• 
Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat 
• 
Kidney damage which may cause swelling, may require dialysis 
 
 
Risks and side effects related to cytarabine when given into the spinal fluid (intrathecal): 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving cytarabine (ara-c) when given into the spinal fluid, more than 20 
and up to 100 may have: 
• Nausea, vomiting 
• Fever 
• Headache 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving cytarabine (ara-c) when given into the spinal fluid, from 4 to 20 
may have: 
• Anemia which may cause tiredness, or may require blood transfusions 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Tiredness, dizziness, loss of coordination 
• Numbness and tingling of the arms and legs  
• Inflammation of the lining of the brain that can lead to headache, numbness and 
tingling 
 


 
 
                                                                                                                                  
 
                                                                      
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RARE, AND SERIOUS 
In 100 people receiving cytarabine (ara-c) when given into the spinal fluid, 3 or fewer may 
have: 
• Seizure 
• Paralysis  
• Blurred vision with a chance of blindness 
• Damage to the brain that may result in a decrease in the ability to learn  
 
 
Risks and side effects related to cytarabine when given by vein: 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving cytarabine, more than 20 and up to 100 may have: 
• Blood clot 
• Rash 
• Swelling in the rectum which may cause rectal pain 
• Diarrhea, loss of appetite, nausea, vomiting 
• Sores in mouth and GI tract which may cause difficulty swallowing or pain  
• Fever 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving cytarabine, from 4 to 20 may have: 
• Heart failure which may cause shortness of breath, swelling of ankles, cough or 
tiredness 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat 
• Damage to the lungs which may cause shortness of breath 
• Anemia which may cause tiredness, or may require blood transfusions 
• Numbness and tingling of the arms and legs 
• Severe blood infection 
• Kidney damage which may cause swelling, may require dialysis 
• Muscle pain 
• Headache 
• Dizziness 
• Flu-like syndrome with fever, bone pain, rash, redness of eyes, or chest pain 
• Chest pain 
• Hair loss 
• Liver damage which may cause yellowing of skin or eyes 
• Swelling and redness of the eye 
 
RARE, AND SERIOUS 
In 100 people receiving cytarabine, 3 or fewer may have: 
• Brain damage, Posterior Reversible Encephalopathy syndrome, which may cause 
headache, seizure, blindness 
• Difficulty speaking, trouble standing or walking  
 


 
 
                                                                                                                                  
 
                                                                      
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Risks and side effects related to fludarabine: 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving fludarabine, more than 20 and up to 100 may have: 
• Infection, especially when white blood cell count is low 
• Vomiting, loss of appetite 
• Tiredness, fever 
• Pain 
• Bruising, bleeding 
• Cough 
• Increased risk of unusual infections lasting more than 6 months 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving fludarabine, from 4 to 20 may have: 
• Anemia, kidney problems which may cause tiredness, bruising, or swelling 
• Nausea, chills 
• Feeling of "pins and needles" in arms and legs 
• Damage to organs (brain, lungs, others) which may cause tiredness, changes in 
thinking or shortness of breath 
• Confusion 
 
RARE, AND SERIOUS 
In 100 people receiving fludarabine, 3 or fewer may have: 
• Kidney damage which may require dialysis 
Rarely, fludarabine has also been associated with damage to or inflammation of the optic nerve 
(the nerve from the brain to the eye) which can cause blurred vision with a chance of blindness, 
decreased vision, other visual disturbances, or pain with eye movements. 
 
 
Risk and Side Effects of Intrathecal Triples (cytarabine, methotrexate, and 
hydrocortisone) when given into the spinal fluid:  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving intrathecal triples, more than 20 and up to 100 may have: 
• 
Nausea, vomiting 
• 
Fever 
• 
Headache 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving intrathecal triples, from 4 to 20 may have: 
• 
Inflammation of the lining of the brain that can lead to headache, stiff neck, 
numbness and tingling 
• 
Bruising, bleeding  
• 
Pain 
• 
Numbness and tingling of the arms and legs 
• 
Tiredness, sleepiness, dizziness, loss of coordination, confusion 
• 
Rash 


 
 
                                                                                                                                  
 
                                                                      
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RARE, AND SERIOUS 
In 100 people receiving intrathecal triples, 3 or fewer may have: 
• 
Seizure  
• 
Damage to the brain which could lead to coma 
• 
Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat 
• 
Bleeding into the space of the spine at the site of the injection  
• 
Paralysis, weakness 
• 
Blurred vision with a chance of blindness 
 
You will be provided a patient drug handout and wallet card for the study drug MLN4924 
(pevonedistat). MLN4924 (pevonedistat) may interact with other drugs. Talk to your doctor, 
pharmacist, or study team before starting any new prescription or over-the-counter drugs, 
herbals, 
or 
supplements 
and 
before 
making 
a 
significant 
change 
in 
your 
diet.  Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided. 
 
If you have a drop in the red blood cell count, the cells that carry oxygen around the body, you 
may feel tired. If your red blood cell count drops very low you may need a blood transfusion. 
 
If you have a decrease in the white blood cell count, the cells that fight infection, you may be 
more likely to get an infection, including a serious infection that spreads through the blood 
stream (sepsis).  If this happens, you will have to come to the hospital to be treated with 
antibiotics.  If your white blood cell count is very low and you get a fever, you may have to come 
to the hospital to get treated with antibiotics. 
 
If you have a low platelet count, particles in the blood that help with clotting, you may have easy 
bruising or bleeding.  If the count is very low and there is bleeding, you might need platelet 
transfusions to help stop the bleeding. 
 
Transfusions may be accompanied by or followed by fever and/or reactions that can cause 
kidney failure, heart failure, anemia, hepatitis, A.I.D.S (acquired immune deficiency syndrome) 
and other infections. 
 
In addition to the risks described above, there may be unknown risks, or risks that we did not 
anticipate, associated with being in this study. 
Reproductive risks   
Women should not become pregnant and men should not father a baby while on this study 
because the drug(s) in this study can be bad for an unborn baby. If you or your partner can 
get pregnant, it is important for you to use birth control or not have sex while on this study 
and for 4 months after the completion of MLN4924 (pevonedistat) administration. Check 
with your study doctor about what kind of birth control methods to use and how long to 
use them. Some birth control methods might not be approved for use in this study. If you 
are a woman and become pregnant or suspect you are pregnant while participating in this 
study, please inform your treating physician immediately. Women should not breastfeed a 
baby while on this study. Also check with your doctor about how long you should not 
breastfeed after you stop the study treatment(s).  


 
 
                                                                                                                                  
 
                                                                      
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Risks of blood drawing or placing an intravenous catheter for blood drawing: 
Risks associated with drawing blood are slight, but some risks include: pain, excessive 
bleeding, fainting or feeling lightheaded, bruising, infection (a slight risk any time the skin 
is broken), and multiple punctures to locate veins. 
 
Bone Marrow Examination Risks: 
You will be required to take a bone marrow test for diagnostic purposes. You will be 
informed of the risks associated with the procedure and your study doctor will obtain a 
separate consent form. 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
 
We hope that this study will help you personally, but we do not know if it will.  
 
Potential benefits to you could include:  
• 
your cancer may stop growing or shrink for a period of time   
• 
you may have lessened symptoms, such as pain, that are caused by the cancer 
 
It is extremely unlikely that this treatment will cure your cancer. With any cancer treatment, 
sometimes treatment does not make the cancer go away. Or, sometimes treatment makes the 
cancer go away for a while but the cancer comes back later.  
 
We expect that the information learned from this study will benefit other patients in the future. 
 
What other options are there? 
 
Instead of being in this study, you have these options:  
 
• 
Getting treatment for your cancer without being in a study 
 
• 
Taking part in another study 
 
• 
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat 
the cancer directly. Instead it tries to improve how you feel. Comfort care tries to keep 
you as active and comfortable as possible. 
 
Please talk to your doctor about these and other options. 
 
How many people will take part in the study? 
 
The total number of people enrolled on this study is expected to be between 4 and 38. 
 
How long is the study? 
 


 
 
                                                                                                                                  
 
                                                                      
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People in this clinical trial are expected to receive treatment on this study for about 4 months (2 
cycles of therapy). After treatment, you will have follow-up examinations and medical tests. 
 
We would like to continue to find out about your health for about 30 days after you finish study 
treatment. By keeping in touch with you for a while after you complete treatment, we can better 
understand the long-term effects of the study treatments. 
 
You can stop taking part in the study at any time. However, if you decide to stop participating in 
the study, we encourage you to talk to the study doctor and your regular doctor first. They will 
help you stop safely.  
 
Your doctor or the study doctor may decide to take you off this study if any of the following occur: 
• Your cancer gets worse 
• The side effects of MLN4924 (pevonedistat) are too harmful for you 
• You need a treatment that is not allowed on this study 
• You are not able to follow study-related treatment instructions 
• New information becomes available 
• The study is not in your best interest 
• The study is stopped 
• You get pregnant 
 
 
What about privacy? 
  
We will do our best to make sure that the personal information in your medical record will be 
kept private. If information from this study is published or presented at scientific meetings, your 
name and other personal information will not be used. The Children’s Oncology Group has a 
privacy permit to help protect your records if there is a court case. However, some of your 
medical information may be given out if required by law. If this should happen, the Children’s 
Oncology Group will do their best to make sure that any information that goes out to others will 
not identify who you are. Information about this Certificate of Confidentiality is included in 
Attachment 1. 
 
Organizations that may look at and/or copy your research or medical records for research, 
quality assurance and data analysis include groups such as: 
 
• 
Children’s Oncology Group and research partners 
• 
Representatives of the National Cancer Institute (NCI), Food and Drug 
Administration (FDA), and other U.S. and international governmental regulatory 
agencies involved in overseeing research  
• 
The Institutional Review Board (IRB) of this hospital 
• 
Pediatric Central Institutional Review Board (CIRB) of the National Cancer Institute  
• 
The study sponsor and any drug company supporting the study or their 
designated reviewers  
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy. The goal of this data 
sharing is to make more research possible that may improve people’s health. Your study 


 
 
                                                                                                                                  
 
                                                                      
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records may be stored and shared for future use in public databases. However, your name and 
other personal information will not be used.   
 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data 
with older study data. However, right now we don’t know what research may be done in the 
future using your information. This means that:  
 
• 
You will not be asked if you agree to take part in the specific future research studies 
using your health information. 
• 
You and your study doctor will not be told when or what type of research will be done. 
• 
You will not get reports or other information about any research that is done using your 
information.  
 
What are the costs? 
 
Taking part in this study may lead to added costs to you or your insurance company. There are 
no plans for the study to pay for medical treatment. Please ask about any expected added costs 
or insurance problems. Staff will be able to assist you with this. 
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to compensate 
you in the event of injury. However by signing this form, you are not giving up any legal rights to 
seek to obtain compensation for injury. 
 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
You will not be charged for the costs of the special blood studies and bone marrow studies that 
are being done for research purposes only, such as the pharmacokinetic and biology studies. The 
NCI will be covering the costs of the EKGs that are being performed for research purposes before 
the study treatment begins. 
 
The NCI will supply the MLN4924 (pevonedistat) at no charge while you take part in this study. 
The NCI does not cover the cost of getting the MLN4924 (pevonedistat) ready and giving it to 
you, so you or your insurance company may have to pay for this.  
 
Even though it probably won’t happen, it is possible that the manufacturer may not continue to 
provide the MLN4924 (pevonedistat) to the NCI for some reason. If this does happen, other 
possible options are:  
 
• 
You might be able to get the MLN4924 (pevonedistat) from the manufacturer or 
your pharmacy but you or your insurance company may have to pay for it. 
 
• 
If there is no MLN4924 (pevonedistat) available at all, no one will be able to get 
more and the study would close. 
 
If a problem with getting MLN4924 (pevonedistat) occurs, your study doctor will talk to you 
about these options.  


 
 
                                                                                                                                  
 
                                                                      
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Funding support 
 
If you choose to enroll on this study, this institution will receive some money from the Children’s 
Oncology Group to do the research. There are no plans to pay you for taking part in this study. 
 
The drug company that makes MLN4924 (pevonedistat) is providing money to the Children’s 
Oncology Group to do the research. 
 
This study includes providing specimens to the researcher, there are no plans for you to profit 
from any new product developed from research done on your specimens.  
 
What are my rights as a participant? 
 
Taking part in this study is voluntary. You may choose not to be in this study. If you decide not to 
be in this study, you will not be penalized and you will not lose any benefits to which you are 
entitled. You will still receive medical care.   
 
You can decide to stop being in the study at any time. Leaving the study will not result in any 
penalty or loss of benefits to which you are entitled. Your doctor will still take care of you. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay 
in this study. A committee outside of COG closely monitors study reports and notifies COG if 
changes must be made to the study. Members of COG meet twice a year to discuss results of 
treatment and to plan new treatments.  
 
Whom do I call if I have questions or problems? 
 
For questions about the study or if you have a research related problem or if you think you have 
been injured in this study, you may contact Dr. XXXX or your doctor at XXXX. 
 
If you have any questions about your rights as a research participant or any problems that you 
feel you cannot discuss with the investigators, you may call XXXX Institutional Review Board 
(IRB) Administrator at XXXX.  
 
If you have any questions or concerns that you feel you would like to discuss with someone who 
is not on the research team, you may also call the Patient Advocate at XXXX. 
 
 
Where can I get more information? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources. Your 
doctor can get you this Handbook, or you can get it at 
https://www.childrensoncologygroup.org/index.php/cog-family-handbook. 
 
Visit the NCI’s Web site at http://cancer.gov. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at:  


 
 
                                                                                                                                  
 
                                                                      
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1-800-4-CANCER (1-800-422-6237). 
 
Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at 
any time. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
Specimens for optional research tests 
 
The choice to let us use specimens for research is up to you. No matter what you decide to do, 
it will not affect your care. You can still be a part of the main study even if you say ‘No’ to taking 
part in any of these optional research studies. 
 
If you decide that your specimens can be used for research, some of your health information 
may be placed in central databases for researchers to use.  The databases will not include your 
name or contact information.   
 
If you decide now that your specimens can be used for research, you can change your mind at 
any time. Just contact us and let us know that you do not want us to use your specimens. Then, 
any specimens that we have will be destroyed.  
 
If you want to learn more about tissue research with specimens, the NCI website has an 
information sheet called "Providing Your Tissue For Research: What You Need To Know.” This 
sheet can be found at: https://www.cancer.gov/publications/patient-education/providing-
tissue.pdf.  
 
Please read the information below and think about your choices. After making your decisions, 
check “Yes” or “No”, then add your initials and the date after your answer. If you have any 
questions, please talk to your doctor or nurse, or call our research review board at the IRB’s 
phone number included in this consent. 
 
 
1.) Please indicate by initialing below whether you choose to participate in the 
gene expression study. 
 
Yes_____  
No_____  
________ / _______ 
 Initials  
Date 
 
2.) Please indicate by initialing below whether you choose to participate in the 
protein study. 
 
Yes_____  
No_____  
________ / _______ 
 Initials  
Date 
 


 
 
                                                                                                                                  
 
                                                                      
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Signature 
 
I have been given a copy of all ____ pages of this form. The form includes 2 attachments. 
 
I have reviewed the information and have had my questions answered.   
I agree to take part in this study. 
 
 
Participant 
Date  
 
 
Parent/Guardian 
Date  
 
 
Parent/Guardian 
Date  
 
 
Physician/PNP obtaining consent 
Date  
  
 
 
 


 
 
                                                                                                                                  
 
                                                                      
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Attachment 1 
 
Certificate of Confidentiality 
 
This trial is covered by a Certificate of Confidentiality from the federal government, which will 
help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered 
studies. The researchers involved in the studies cannot be forced to disclose the identity or 
any information collected in the study in any legal proceedings at the federal, state, or local 
level, regardless of whether they are criminal, administrative, or legislative proceedings. 
However, the subject or the researcher may choose to voluntarily disclose the protected 
information under certain circumstances. For example, if the subject or his/her guardian 
requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited 
circumstances, such as a DHHS request for information for an audit or program evaluation 
or an FDA request under the Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against the required reporting by hospital 
staff of information on suspected child abuse, reportable communicable diseases, and/or 
possible threat of harm to self or others. 
 
 
 
 
 


 
 
                                                                                                                                  
 
                                                                      
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Attachment 2 
 
STUDY CHART 
You will receive MLN4924 (pevonedistat) by vein once a day on days 1, 3, and 5 every 35 days. This 
entire 35-day period is called a cycle.  The chart below shows what will happen to you during Cycle 
1 and Cycle 2.  
Cycle 1 
Cycle 2 
DAY 
WHAT YOU DO 
DAY 
WHAT YOU DO 
Before 
Starting 
Study 
Come into the hospital and do the following: 
• 
Get routine blood tests 
• 
Get urine tests 
• 
Get a physical exam by your doctor 
• 
Get a pregnancy test (if you are a woman) 
• 
EKG 
• 
Get a bone marrow test  
• 
Get a disease evaluation that will be done 
by your doctor. Depending on the results 
of this evaluation, your doctor will tell you 
whether or not you may begin treatment 
on this study. 
• 
Get the commercial drug cytarabine into 
the spinal fluid 
Before 
Cycle 2 
Come into the hospital and do the following: 
• 
Get routine blood tests 
• 
Get urine tests 
• 
Get a physical exam by your doctor 
• 
EKG 
• 
Get the commercial drug cytarabine into the 
spinal fluid 
Day 1 
Come into the hospital and do the following: 
• 
Get the study drug MLN4924 
(pevonedistat) as well as the commercial 
drug azacitidine 
• 
Get optional blood tests for biology 
studies  
• 
Get routine blood tests and blood tests for 
Pharmacokinetic (PK) studies  
 
Day 1 
Come into the hospital and do the following: 
• 
Get routine blood tests  
• 
Get the study drug MLN4924 (pevonedistat) 
as well as the commercial drug azacitidine 
 
 
Day 2 
Come into the hospital and do the following:  
• 
Get the commercial drug azacitidine 
 
Day 2 
Come into the hospital and do the following:  
• 
Get the commercial drug azacitidine 
 
Day 3 
Come into the hospital and do the following:  
• 
Get routine blood tests and blood tests for 
Pharmacokinetic (PK) studies 
• 
Get the study drug MLN4924 
(pevonedistat) as well as the commercial 
drug azacitidine 
• 
Get optional blood tests for biology 
studies 
 
 
Day 3 
Come into the hospital and do the following:  
• 
Get routine blood tests  
• 
Get the study drug MLN4924 (pevonedistat) 
as well as the commercial drug azacitidine 
 
Day 4 
Come into the hospital and do the following:  
• 
Get the commercial drug azacitidine 
 
Day 4 
Come into the hospital and do the following:  
• 
Get the commercial drug azacitidine 
 
Day 5 
Come into the hospital and do the following:  
• 
Get the study drug MLN4924 
(pevonedistat) as well as the commercial 
drug azacitidine 
• 
Get routine blood tests and blood tests for 
Pharmacokinetic (PK) studies 
• 
Get optional blood tests for biology 
Day 5 
Come into the hospital and do the following:  
• 
Get routine blood tests 
• 
Get the study drug MLN4924 (pevonedistat) 
as well as the commercial drug azacitidine 
 


 
 
                                                                                                                                  
 
                                                                      
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studies 
Days 6 
to 10  
Come into the hospital and do the following:  
• 
Get the commercial drugs fludarabine and 
cytarabine 
 
Days 6 
to 10 
Come into the hospital and do the following:  
• 
Get the commercial drugs fludarabine and 
cytarabine 
 
Days  
2 to 34 
Come into the hospital and do the following: 
• 
Get a physical exam weekly 
• 
Get routine blood tests twice weekly 
• 
Get urine tests weekly 
Days 2 
to 34 
 
 
 
Come into the hospital and do the following: 
• 
Get routine blood tests weekly 
 
Day 35 
Come into the clinic and do the following: 
• 
Get a bone marrow test  
• 
Get optional blood tests for biology 
studies 
• 
Your doctor will tell you whether or not 
you may continue to the next cycle and 
continue to receive MLN4924 
(pevonedistat). If you continue, please 
follow the schedule listed under “Cycle 
2”. 
Day 35 
 
 
 
 
 
Come into the clinic and do the following: 
• 
Get a bone marrow test  
• 
ECHO or MUGA 
• 
EKG