Conditions: Recurrent Lymphoma Recurrent Malignant Solid Neoplasm Recurrent Primary Central Nervous System Neoplasm Refractory Lymphoma Refractory Malignant Solid Neoplasm Refractory Primary Central Nervous System Neoplasm
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of pevonedistat when given together with irinotecan hydrochloride and temozolomide in treating patients with solid tumors, central nervous system (CNS) tumors, or lymphoma that have come back after a period of improvement (recurrent) or that do not respond to treatment (refractory). Pevonedistat and irinotecan may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, 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 pevonedistat, irinotecan hydrochloride, and temozolomide may work better in treating patients with solid tumors, central nervous system (CNS) tumors, or lymphoma compared to irinotecan and temozolomide alone.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of pevonedistat administered as an intravenous infusion on days 1, 8, 10, and 12 of a 28-day cycle (cycle 1), and on days 1, 3, and 5 of a 21-day cycle (cycle 2 and beyond) in combination with irinotecan (administered as an intravenous infusion on days 8-12 of cycle 1 and days 1-5 of cycles 2+) and temozolomide (administered orally on days 8-12 in cycle 1 and days 1-5 of cycles 2+) in children with recurrent or refractory solid tumors, including central nervous system (CNS) tumors and lymphoma.

II. To define and describe the toxicities of pevonedistat administered on this schedule.

III. To characterize the pharmacokinetics of pevonedistat in children with recurrent or refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of pevonedistat within the confines of a phase 1 study.

II. To assess the biologic activity of pevonedistat.

OUTLINE: This is a dose escalation study of pevonedistat.

Patients receive pevonedistat intravenously (IV) over 60 minutes on days 1, 8, 10, and 12, temozolomide orally (PO) daily on days 8-12, and irinotecan IV over 90 minutes on days 8-12 of cycle 1. Beginning cycle 2, patients receive pevonedistat IV over 60 minutes on days 1, 3, and 5, temozolomide PO daily on days 1-5, and irinotecan IV over 90 minutes on days 1-5. Treatment repeats every 28 days for cycle 1 and 21 days for subsequent cycles for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Arms:
arm 1: Patients receive pevonedistat IV over 60 minutes on days 1, 8, 10, and 12, temozolomide PO daily on days 8-12, and irinotecan IV over 90 minutes on days 8-12 of cycle 1. Beginning cycle 2, patients receive pevonedistat IV over 60 minutes on days 1, 3, and 5, temozolomide PO daily on days 1-5, and irinotecan IV over 90 minutes on days 1-5. Treatment repeats every 28 days for cycle 1 and 21 days for subsequent cycles for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Irinotecan intervention 2: Pevonedistat intervention 3: Temozolomide
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 
ADVL1615 
Version Date: 08/27/2020 
Page 1 
Version Date: 
08/27/20 
Activated: 
11/13/17 
Closed:  03/12/2021
Amendment# : 
7 
CHILDREN’S ONCOLOGY GROUP 
ADVL1615 
A PHASE 1 STUDY OF PEVONEDISTAT (MLN4924, 
), A NEDD8 ACTIVATING 
ENZYME (NAE) INHIBITOR, IN COMBINATION WITH TEMOZOLOMIDE AND 
IRINOTECAN IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY SOLID 
TUMORS 
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. 
 
 
 
 
 
 
 
 
 
 
 
For COG PEP-CTN Operations and Data/Statistics Contacts see: http://members.childrensoncologygroup.org


                         ADVL1615 
 
 
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TABLE OF CONTENTS 
SECTION 
 
PAGE 
 
TABLE OF CONTENTS 
2 
STUDY COMMITTEE  
5 
ABSTRACT 
 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Aims 
9 
1.2 
Secondary Aims 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Preclinical Studies 
10 
2.3 
Adult Studies 
13 
2.4 
Pediatric Studies 
16 
2.5 
Overview of Proposed Pediatric Study 
16 
2.6 
Rationale for Amendment #5 (addition of dose level 4) 
17 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
18 
3.1 
Current Study Status 
18 
3.2 
IRB Approval 
19 
3.3 
Patient Registration 
19 
3.4 
Reservation and Contact Requirements 
19 
3.5 
Informed Consent/Assent 
20 
3.6 
Screening Procedures 
20 
3.7 
Eligibility Checklist 
20 
3.8 
Institutional Pathology Report 
20 
3.9 
Study Enrollment 
20 
3.10 
Dose Assignment 
20 
4.0 
PATIENT ELIGIBILITY 
21 
4.1 
Inclusion Criteria 
21 
4.2 
Exclusion Criteria 
24 
5.0 
TREATMENT PROGRAM 
27 
5.1 
Overview of Treatment Plan 
27 
5.2 
Criteria for Retreatment and Dose Delays 
29 
5.3 
Criteria for Starting Subsequent Cycles 
29 
5.4 
Dose Escalation Schema 
29 
5.5 
Grading of Adverse Events 
30 
5.6 
Definition of Dose-Limiting Toxicity (DLT) 
30 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
31 
6.1 
Dose Modifications for Hematological Toxicity (all age cohorts) 
31 
6.2 
Dose Modifications for Non-Hematological Toxicity (for patients ≥ 12 months) 
32 
6.3 
Dose Modifications for Non-Hematological Toxicity (for patients < 12 months at the time 
of the DLT) 
33 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
33 
7.1 
Concurrent Anticancer Therapy 
33 


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7.2 
Investigational Agents 
33 
7.3 
Supportive Care 
33 
7.4 
Growth Factors 
33 
7.5 
Concomitant Medications 
33 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
34 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
34 
8.2 
Radiology Studies 
35 
8.3 
Pharmacokinetics (required) 
35 
8.4 
Pharmacodynamics (optional) 
37 
9.0 
AGENT INFORMATION 
38 
9.1 
Pevonedistat 
38 
9.2 
CEFIXIME       (11/17/17) 
45 
9.3 
IRINOTECAN       (03/07/17) 
47 
9.4 
TEMOZOLOMIDE - ORAL    (06/30/14) 
50 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
53 
10.1 
Criteria for Removal from Protocol Therapy 
53 
10.2 
Off Study Criteria 
53 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
54 
11.1 
Sample Size and Study Duration 
54 
11.2 
Definitions 
54 
11.3 
Dose Escalation and Determination of MTD 
55 
11.4 
Inclusion of Children, Women and Minorities 
56 
11.5 
Pharmacokinetic and Pharmacodynamic Studies and Response Analysis 
57 
12.0 
EVALUATION CRITERIA 
57 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
57 
12.2 
Response Criteria for Patients with Solid Tumors 
57 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
63 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
63 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
65 
12.6 
Response Criteria for Patients with CNS Tumors 
66 
12.7 
Best Response 
68 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
69 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
69 
13.2 
When to Report an Event in an Expedited Manner 
72 
13.3 
Expedited Reporting Methods 
72 
13.4 
Definition of Onset and Resolution of Adverse Events 
73 
13.5 
Other Recipients of Adverse Event Reports 
73 
13.6 
Reporting Secondary AML/MDS 
74 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
74 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
76 
14.1 
Categories of Research Records 
76 
14.2 
CDUS 
76 
14.3 
Data and Safety Monitoring Plan 
76 
REFERENCES 
 
77 
APPENDIX I: 
 PERFORMANCE STATUS SCALES/SCORES 
79 


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APPENDIX II:  
CORRELATIVE STUDIES GUIDE 
80 
APPENDIX III:  
 TOXICITY-SPECIFIC GRADING 
81 
APPENDIX IV:  
 TEMOZOLOMIDE ORAL CAPSULES DOSING NOMOGRAMS 
82 
APPENDIX V: 
UNACCEPTABLE ENZYME-INDUCING AND RECOMMENDED NON-
ENZYME INDUCING ANTICONVULSANTS 
84 
APPENDIX VI:  
POTENTIAL DRUG INTERACTIONS 
85 
APPENDIX VII:  
CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
87 
APPENDIX VIII:  
 PATIENT INSTRUCTIONS FOR TREAT DIARRHEA 
89 
APPENDIX IX: 
 NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC 
DISEASE 
 
 
 
91 
APPENDIX X:  
PHARMACOKINETICS STUDY FORM 
92 
APPENDIX X-A:  
GUIDELINES FOR SHIPPING SAMPLES TO COVANCE-MADISON 
93 
APPENDIX XI:  
PHARMACODYNAMICS STUDY FORM 
95 
APPENDIX XII:  
BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT 
PERCENTILE  
96 
APPENDIX XIII-A: 
THERAPY DELIVERY MAPS (TDMS) FOR CYCLE 1 
98 
APPENDIX XIII-B: 
THERAPY DELIVERY MAPS (TDMS) FOR ALL SUBSEQUENT 
CYCLES 
 
100 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY COMMITTEE (CONTINUED) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AGENT NSC# AND IND#s 
 
 
Agent Supplied by Takeda Pharmaceuticals: 
Pevonedistat (MLN4924, NSC # 793435) 
 
 
 
Commercial Agents: 
 
Temozolomide (Temodar®, Temodal®; NSC# 362856) 
Irinotecan (Camptosar®; NSC# 616348) 
 
 
 
 
 
IND Sponsor: COG 
 
 
 
 
 
 
SEE SECTION 8.3.6 AND 8.4.6 FOR SPECIMEN SHIPPING ADDRESSES 


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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 
 
Pevonedistat is a novel first-in-class NEDD8 activating enzyme (NAE) inhibitor that blocks the degradation 
of a subset proteins which would normally be degraded by the 26S proteasome. Pevonedistat is more 
specific than previous proteasome inhibitors because it blocks the degradation of Cullin-RING ligases 
(CRL), narrowing the targets to only a handful of key regulatory proteins important in cell survival. Phase 
1 studies of pevonedistat in adults with hematologic and non-hematologic malignancies have shown 
promising results and tolerability. Pre-clinical studies demonstrate anti-tumor activity in a variety of 
pediatric tumors including neuroblastoma, Ewing sarcoma, Wilms tumor, rhabdomyosarcoma, and 
glioblastoma. In vivo experiments demonstrate additive properties of pevonedistat in combination with 
irinotecan and alkylating agents. We will use a rolling six design to conduct a phase 1 trial of pevonedistat 
in combination with irinotecan and temozolomide in pediatric patients with recurrent or refractory solid 
and brain tumors. The objectives of this study are to determine the maximum tolerated dose (MTD) and 
recommended Phase 2 dose (RP2D) of pevonedistat in combination with irinotecan and temozolomide, as 
well as to describe the toxicities, pharmacokinetic, and pharmacodynamic properties of this combination. 


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EXPERIMENTAL DESIGN SCHEMA 
 
Cycle 1 (28 days) 
 
Pevonedistat 
Irinotecan 
Temozolomide 
Cefixime* 
Evaluation 
Day 1 
X 
 
 
 
 
... 
 
Day 4 
 
 
 
 
 
… 
 
Day 6 
 
 
 
X 
 
Day 7 
 
 
 
X 
 
Day 8 
X 
X 
X 
X 
 
Day 9 
 
X 
X 
X 
 
Day 10 
X 
X 
X 
X 
 
Day 11 
 
X 
X 
X 
 
Day 12 
X 
X 
X 
X 
 
Day 13 
 
 
 
X 
 
Day 14 
 
 
 
X 
 
Day 15 
 
 
 
X 
 
… 
 
Day 27 
 
 
 
X 
 
Day 28 
 
 
 
X 
X 
 
Subsequent Cycles (21 days) 
 
Pevonedistat 
Irinotecan 
Temozolomide 
Cefixime* 
Evaluation 
Day -1 
 
 
 
X 
 
Day 0 
 
 
 
X 
 
Day 1 
X 
X 
X 
X 
 
Day 2 
 
X 
X 
X 
 
Day 3 
X 
X 
X 
X 
 
Day 4 
 
X 
X 
X 
 
Day 5 
X 
X 
X 
X 
 
Day 6 
 
 
 
X 
 
Day 7 
 
 
 
X 
 
Day 8 
 
 
 
X 
 
… 
 
Day 20 
 
 
 
X 
 
Day 21 
 
 
 
X 
X 
 
* Cefixime will be administered starting at least two days prior to the start of irinotecan, during, and 3 
days after the last dose of irinotecan of each cycle for a total of at least 10 days.  
- 
For Cycle 1, cefixime will be administered on Days 6-15 and Days 27-28. 
- 
For Cycles 2+, cefixime will be administered on Days -1 through 8 and Days 20-21.  
 
Days 27 and 28 of Cycle 1 are the same as Days -1 and 0 of Cycle 2. Days 20 and 21 of Cycles 2+ are 
the same as Days -1 and 0 of subsequent cycles. 
 
 
NOTE: Once PCP Prophylaxis begins on Cycle 1 Day 8, patient should continuously receive PCP 
prophylaxis per the prescribed schedule until the end of treatment. See Section 5.1 for more details.


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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose (RP2D) of pevonedistat administered as an intravenous infusion on Days 1, 
8, 10, and 12 of a 28-day cycle (Cycle 1), and on Days 1, 3, and 5 of a 21-day cycle 
(Cycle 2 and beyond) in combination with irinotecan (administered as an 
intravenous infusion on Days 8-12 of Cycle 1 and Days 1-5 of Cycles 2+) and 
temozolomide (administered orally on Days 8-12 in Cycle 1 and Days 1-5 of 
Cycles 2+) in children with recurrent or refractory solid tumors, including CNS 
tumors and lymphoma. 
 
1.1.2 
To define and describe the toxicities of pevonedistat administered on this schedule. 
 
1.1.3 
To characterize the pharmacokinetics of pevonedistat in children with recurrent or 
refractory cancer. 
 
1.2 
Secondary Aims 
 
1.2.1 
To preliminarily define the antitumor activity of pevonedistat within the confines 
of a phase 1 study. 
 
1.2.2 
To assess the biologic activity of pevonedistat. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
Pevonedistat (MLN4924) is a novel chemotherapy agent; it blocks the degradation of 
proteins that would normally be degraded by the 26S proteasome, the major mechanism of 
protein removal in the cell. Pevonedistat is more specific than previous proteasome 
inhibitors because it blocks the degradation of Cullin-RING ligases (CRL), narrowing the 
targets to only a handful of key regulatory proteins important in cell survival. Phase 1 
studies of pevonedistat in adults with both hematologic and non-hematologic malignancies 
have shown promising results with minimal adverse effects at the proposed dose level.1-5 
However, there is limited data with respect to pediatric malignancies. Preliminary data 
from the Pediatric Preclinical Testing Program (PPTP) showed promising results when 
tested against both the PPTP in vitro cell line panel as well as solid tumor xenografts.6   
 
Neddylation is an ATP-dependent process which is involved in the regulation of 
intracellular protein destruction. Similar to the ubiquitin system, the process of neddylation 
is controlled by a multistep process involving one activation enzyme (E1), several ubiquitin 
conjugating enzymes (E2), and many ubiquitin ligases (E3). Recent studies have shown 
that by inhibiting the E1 NEDD8 activating enzyme (NAE), pevonedistat is able to disrupt 
cancer cell proliferation by interfering with Cullin-RING ligases.7-10 Cullin-RING ligases 
are part of the ubiquitination cascade, a process that results in the timed degradation of 
many important proteins in the cell cycle progression, cell cycle checkpoint activation, and 


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cell signaling.   
 
In many malignant cell types, pevonedistat leads to re-replication of DNA in S-phase and 
resultant cell death. Inhibition of NAE results in an increase in CRL substrates Cdt1 and 
Nrf-2, both of which contribute to cell-cycle progression.11 Experiments in cancers of the 
prostate, lung, and colon, as well as glioblastoma cells have shown that Cdt1 is stabilized 
and cells continues to initiate DNA replication, resulting in multiple areas of DNA re-
replication.12 By blocking Cdt1 and Nrf-2 degradation, pevonedistat allows DNA 
replication to continue without cell division.7  This is thought to activate both apoptosis 
and senescence pathways.7,11  
 
In other cell types such as non-Hodgkin lymphoma (NHL), the induction of tumor cell 
apoptosis by pevonedistat involves inhibition of NF-κB.13 The NF-κB pathway is involved 
in multiple cellular activities, including the induction of anti-apoptotic proteins following 
chemotherapy treatment. NAE regulates the ubiquitination and degradation of IκB-α. If 
NAE is inactivated, IκB-α is stabilized and NF-κB is unable to assert its anti-apoptotic 
effects, promoting cell death in malignant lymphoma cells.13  
 
2.1.1 
Irinotecan/Temozolomide Combination 
Due to significant preclinical antitumor activity and non-overlapping toxicities, 
irinotecan and temozolomide in combination has been used in pediatric phase 1-2 
trials in patients with recurrent or refractory solid and central nervous system 
tumors, and is broadly applicable. The combination has been well-tolerated.14-22 In 
in vitro studies, irinotecan has shown to be synergistic with pevonedistat.23 In 
ADVL0414, irinotecan and temozolomide were combined along with vincristine 
in children with refractory solid tumors.22 Zero of six patients in ADVL0414 
experienced dose limiting toxicity (DLT) at the highest doses studied (irinotecan 
90 mg/m2/day on Days 1-5, temozolomide 150 mg/m2/day on Days 1-5, vincristine 
1.5 mg/m2 on Day 1). This is a similar irinotecan/temozolomide dosing schedule 
to what we propose in this study. Irinotecan and temozolomide in combination 
with temsirolimus was studied in ADVL0918.15 Irinotecan 50 mg/m2/dose and 
temozolomide 100 mg/m2/dose were combined with temsirolimus at 25 mg/m2 
intravenous (IV) infusion on Days 1 and 8. The DLT was hypercholesterolemia in 
patients who were receiving steroids, and most likely attributable to the 
temsirolimus. None of the additional 6 patients treated with irinotecan 50 
mg/m2/dose, temozolomide 100 mg/m2/dose, and temsirolimus 35 mg/m2 IV on 
Days 1 and 8 experienced Cycle 1 DLT. This is a similar irinotecan/temozolomide 
dosing schema to what we propose in this study. 
 
2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity 
 
2.2.1.1 Combination studies of pevonedistat  
 


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a. Irinotecan: In vitro combinations of pevonedistat and irinotecan (SN-38) in 4 
solid tumor cell lines show that irinotecan is synergistic in 2 of the cell lines 
(HCT-116 and U2OS), and additive in 1 cell line (A549). Among 13 agents 
tested in combination with pevonedistat, irinotecan ranked among the top 
quartile for synergy (Figure 1).24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Irinotecan was also additive with pevonedistat in in vivo models. Two 
colorectal xenograft models (HCT-116 and HT-29) exhibited an additive and 
subadditive combination effect, respectively. Balb/c nude mice were used to 
create subcutaneous xenografts of HCT-116 and HT-29. Pevonedistat was 
dosed subcutaneously (SubQ) on the following two 21-day dosing schedules: 
30 mg/kg BID for 21 days and 90 mg/kg BID twice weekly for 21 days (dosing 
on Days 1, 4, 8, 11, 15, 18). Irinotecan was concurrently dosed 
intraperitoneally (IP) at 10 mg/kg twice weekly. Both dosing schedules 
exhibited additive and subadditive combination effects for HCT-116 and HT-
29, 
respectively 
(Direct 
communication, 
Takeda 
Pharmaceuticals 
International Co.). 
 
b. Alkylating agents: In vitro combinations of pevonedistat and standard 
chemotherapeutics show that the effect of adding alkylating agents is 
synergistic (Figure 1) (Direct communication, Takeda Pharmaceuticals 
International Co.). Of all combination agents tested, as a class, alkylating 
agents show the most synergy with pevonedistat. Alkylating agents tested 
include: dacarbazine, mitomycin C, cisplatin, carboplatin, and melphalan. 
 
Both temozolomide and dacarbazine are triazine alkylating agents which are 
converted to the active alkylating metabolite (methyl-triazene-1-yl)-
imidazole-4-carboxamide (MTIC). As described above, due to both its 
tolerability and effectiveness, temozolomide, in combination with irinotecan, 
is a common chemotherapy agent used in pediatric patients with relapsed or 
refractory disease.  
Figure 1. In vitro 
combinations of 
pevonedistat + 
standard of care 
agents. 
 


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In vivo melanoma xenograft models demonstrate an additive cytotoxic effect 
when pevonedistat and dacarbazine are used together. In the in vivo studies, 
dacarbazine was dosed IP at 100 mg/kg for 5 days and pevonedistat was dosed 
BID twice weekly at either 90 mg/kg or 120 mg/kg. Additive effects were seen 
at both dose levels of pevonedistat (Figure 2) (Direct communication, Takeda 
Pharmaceuticals International Co.). 
 
2.2.1.2 Pediatric in vitro and xenograft data 
 
a. In vitro data from the Pediatric Preclinical Testing (PPTP): Pevonedistat 
showed promising results when tested against the PPTP in an in vitro cell line 
panel. The median relative IC50 (rIC50) was 0.14 μM (range, 0.015 - 0.68 μM). 
The Ewing sarcoma panel was the most sensitive to pevonedistat, with an IC50 
of 31 nM. The neuroblastoma panel had a median IC50 of 287 nM. Data from 
the PPTP shows that pevonedistat treatment resulted in significant differences 
in event free survival (EFS) in 61% of solid tumor xenografts (20/33), 
including Wilms (2 of 3 xenografts), rhabdomyosarcoma (2 of 5 xenografts), 
neuroblastoma (1 of 4 xenografts), and glioblastoma (4 of 4 xenografts). 
Twenty-nine percent (9/31) of evaluable solid tumor xenografts treated with 
pevonedistat exhibited intermediate activity, as defined by an increase in the 
ratio of the median time to event (EFS T/C values >2).  Among the solid tumor 
xenograft panel, the best response was progressive disease with growth delay. 
This was observed in glioblastoma (4 of 4), Wilms (3 of 3), neuroblastoma (3 
of 4), and rhabdomyosarcoma (2 of 5). Tumor tissue of all xenografts treated 
with pevonedistat showed a marked decrease in neddylated Cullin proteins, 
regardless of sensitivity. In our neuroblastoma xenograft experiments there 
Figure 2. Combination of pevonedistat + dacarbazine in a primary human 
melanoma xenograft model PHTX-50M. 


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was a significant decrease in tumor weight between control and pevonedistat 
treated mice. Control mice had an average tumor weight of 1.6 mg ± 0.8 mg 
versus mice treated with pevonedistat which had average tumor weights of  
0.5 mg ± 0.4 mg (p<0.05).25   
 
b. Additional in vitro data: Our preliminary data shows that neuroblastoma cell 
lines are sensitive to pevonedistat with an IC50 of 0.2-7.6 µM (Table 1). 
Treatment of the neuroblastoma cell lines LAN5, CHP212, and SHEP with 
pevonedistat resulted in a biphasic dose response curve due to increases in cell 
size with increasing drug concentrations. We are currently testing these cells 
to determine if they undergo re-replication, one of the mechanisms of 
pevonedistat-mediated cell death in carcinomas. Drug combination analysis 
with pevonedistat and doxorubicin and etoposide are ongoing in a variety of 
solid tumor cell lines. 
 
Table 1. Potency in Neuroblastoma Cell Lines 
NB Cell Line 
IC50 (μM) 
N-myc amplified 
p53 status 
IMR-32 
0.4 
Y 
WT 
LAN-5 
0.2 
Y 
WT 
SHEP 
2.6 and 4.8 
N 
WT 
CHP212 
7.6 
Y 
WT 
SK-N-AS 
0.5 and 1.7 
N 
Mutant 
 
2.2.2 
Animal Toxicology 
The dose-limiting toxicities (DLTs) of pevonedistat administered as a 30 minute 
IV infusion or SubQ injection for 2 cycles (5 days of dosing followed by 14 day 
rest) or 5 cycles (4 doses given every other day followed by 14 day rest) in rats and 
dogs were GI toxicity and bone marrow suppression. Myocardial toxicity, injection 
site necrosis, enteropathy, and sepsis were seen at doses above the maximum 
tolerated dose (MTD). Most DLTs resolved after the 14 day rest period. Other 
effects observed were decreased trabecular bone formation, serum chemistry 
changes, an acute phase response, increased developmental risk to the fetus or 
embryo, and degeneration of the seminiferous epithelium of the testes. Most 
adverse events were reversed or reversing at completion of the 14 day rest period.26  
 
2.2.3 
Preclinical Pharmacokinetic Studies 
Pevonedistat selectively inhibits the NAE with a Ki ≤ 1 nM. When tested amongst 
a panel of 11 kinases, pevonedistat was 2,000 times more selective for NAE. 
Tumor cells treated with pevonedistat showed a decrease in NEDD8 Cullin levels 
and an increase in CDL substrates, consistent with inhibition of NAE.26  
 
2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies 
Phase 1 studies of pevonedistat in adults with both hematologic and non-
hematologic malignancies have shown promising results and tolerability on an 
intermittent dosing schedule.1-5  


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In a phase 1 study of pevonedistat in adults with myelodysplastic syndrome (MDS) 
and acute myeloid leukemia (AML), when pevonedistat was administered on Days 
1, 3, and 5 (schedule A) every 21 days, the maximum tolerated dose (MTD) was 
59 mg/m2 and the DLT was hepatotoxicity. Out of 23 patients treated at or below 
the MTD, there were 2 complete responses (CRs) and 2 partial responses (PRs) for 
an overall response rate of 17%. When pevonedistat was administered on Days 1, 
4, 8, and 11 (schedule B) every 21 days, the MTD was 83 mg/m2 and the DLT was 
multi-organ failure. Out of 19 patients treated, there were 2 PRs for a response rate 
of 10%.5  
 
In a phase 1 trial of pevonedistat monotherapy in adult patients with advanced solid 
tumors, pevonedistat was well tolerated on an intermittent dosing schedule.3 In 
patients receiving pevonedistat administered on Days 1-5 (schedule A) the MTD 
was 50 mg/m2 and the DLT was grade 3 elevated transaminases (n=3). 
Additionally, two patients died during Cycle 1 of treatment-related multi-organ 
failure (including liver failure) (n=1) and disease progression (n=1). Due to the 
multi-organ failure and DLTs, the Days 1-5 continuous dosing schedule was 
deemed intolerable. In schedule B, patients received pevonedistat on Days 1, 3, 
and 5 of a 21-day cycle along with oral dexamethasone pre-treatment. The MTD 
was 50 mg/m2 and the DLTs were elevated transaminases (n=1) and 
hyperbilirubinemia (n=2). In schedule C, patients received pevonedistat without 
oral dexamethasone on Days 1, 3, and 5 of a 21-day cycle. The MTD was 67 mg/m2 
and the DLTs were hyperbilirubinemia and elevated AST (n=2). In this phase 1 
trial of pevonedistat in adults with advanced solid tumors, the majority of patients 
had colorectal cancer (n=11), melanoma (n=9), or breast cancer (n=8). Fifty-three 
percent (n=26) of patients experienced Grade ≥ 3 AEs: anemia (n=5), elevated 
ALT (n=3), and 2 patients each for the following: congestive heart failure, 
dyspnea, fatigue, elevated AST, hyperbilirubinemia, hyponatremia, hypokalemia, 
hypophosphatemia, nausea, vomiting. One patient on schedule A had a partial 
response and 80% (n=12/15) of evaluable patients on schedule B and 69% 
(n=11/16) on schedule C had stable disease with a median duration of 2 (range, 
0.5-7.4) and 2.1 (range, 0.6-3.6) months, respectively. 
 
Similar results were shown in a phase 1 trial of pevonedistat in 37 patients with 
metastatic melanoma.1 Patients received pevonedistat IV on either Days 1, 4, 8, 11 
(schedule A, 26 patients) or 1, 8, 11, 15 (schedule B, 11 patients) of a 21 day cycle. 
The MTD was determined to be 209 mg/m2, with DLTs of Grade 3 
hypophosphatemia, myocarditis, renal failure and increased creatinine. The most 
common AEs were fatigue (68%), diarrhea (49%), anemia (41%), myalgia (41%), 
nausea (35%), constipation (32%), vomiting (32%), arthralgia (30%), decreased 
appetite (30%), dizziness (27%), and peripheral neuropathy (27%). Thirty-eight 
percent of patients experienced at least one SAE, 16% of which were drug related.  
 
Pevonedistat was also tested in a phase 1 study for patients with relapsed/refractory 
multiple myeloma or lymphoma.4 In the 44 patients treated on this study, the MTD 
was found to be 110 mg/m2 (Days 1, 2, 8, 9 of a 21 day cycle) and 196 mg/m2 
(Days 1, 4, 8, 11 of a 21 day cycle). DLTs were febrile neutropenia, transaminase 
elevations, muscle cramps, and thrombocytopenia. There were no treatment related 
deaths. The most common AEs were fatigue and nausea. 
 
Among the phase 1 monotherapy studies, 1 patient had a DLT of Grade 4 cardiac 


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failure which was attributed to be related to pevonedistat and subsequently 
resolved. This patient received 147 mg/m2 of pevonedistat. Myocardial ischemia 
and atrial fibrillation occurred in 3 (1%) patients. All of the arrhythmias 
experienced by patients on the phase 1 studies were supraventricular, and all but 1 
were unrelated. The patient with related atrial fibrillation had pre-existing risk 
factors for cardiac disease. In the phase 1 study in which pevonedistat was 
combined with azacitidine in elderly patients with AML, one patient experienced 
cardiac failure which was attributed as unrelated. Tachycardia was found to be an 
expected adverse drug reaction.26  
 
There have been two phase 1 studies in adults of pevonedistat in combination with 
standard chemotherapy, one in patients with AML and another in patients with 
solid tumors. In a phase 1 study of pevonedistat in combination with azacitidine in 
elderly adults with AML who were considered unfit for conventional 
chemotherapy, the MTD of pevonedistat was 20 mg/m2 in combination with 
azacitidine.  Pevonedistat was administered on Days 1, 3, 5 of a 28-day cycle in 
combination with azacitidine 75 mg/m2 on Days 1-5 and 8-9.  Four patients 
experienced the DLT of increased transaminases. At least one adverse event (AE) 
was experienced by 64% (n=27) of patients. The most common AEs were febrile 
neutropenia (n=12), pneumonia (n=4), sepsis (n=3), pyrexia (n=2) and epistaxis 
(n=2).  In 18 response-evaluable patients, there were 6 CRs (33%) 4 PRs (22%).26 
 
The other combination study evaluated patients with advanced solid tumors treated 
with pevonedistat in combination with docetaxel (Arm 1), carboplatin lead-in and 
carboplatin + paclitaxel (Arm 2), and gemcitabine (Arm 3).  Pevonedistat was 
administered on Days 1, 3, and 5 of a 21-day cycle in Arms 1 and 2, and on Days 
1, 8, and 15 of a 28-day cycle for Arm 3. Fifty-eight patients were enrolled (Arm 
1 = 22 patients, Arm 2 = 26 patients, Arm 3 = 10 patients), corresponding to 230 
cycles of pevonedistat. The most common AEs were fatigue (48%), nausea (43%), 
AST increased (34%), anemia (34%), neutrophil count decreased (29%), 
constipation (28%), ALT increased (28%), and diarrhea (28%). Twelve patients 
experienced DLTs: 8 had increased LFTs, 3 had febrile neutropenia, and 1 had 
afebrile neutropenia. The MTDs for Arms 1 and 2 were 25 mg/m2 and 20 mg/m2 
respectively. The MTD for Arm 3 was not calculated because the treatment arm 
was closed for intolerability. There were 7 total PRs, 3 each in Arm 1 and Arm 2 
carboplatin + Paclitaxel, and 1 PR in Arm 2 lead-in with carboplatin.26  
 
2.3.2 
Phase 2 Studies 
Two studies are currently enrolling. 
 
- 
Study 2001: A Phase 2, randomized, controlled Open-Label Clinical study of 
the efficacy and safety of Pevonedistat plus Azacitidine versus single-agent 
azacitidine in patients with higher-risk myelodisplastic syndromes, chronic 
myelomococytic leukemia, and low-blast acute myelogenous leukemia. 
 
- 
Study 1012: A phase 1/1b, Open-label Study of Pevonedistat (MLN4924, 
TAK-924) as Single Agent and in Combination with Azacitidine in adult East 
Asian patients with acute myeloid leukemia or myelodisplastic syndromes. 
 
2.3.3 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
Pharmacokinetic (PK) studies of pevonedistat (25-83 mg/m2/dose) in adults with 
non-hematologic malignancies demonstrated a half-life (t½) of 5-8 hours, 


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maximum plasma concentration (Cmax) of 106-1,340 ng/mL, and an area under the 
curve (AUC0-24h) between 703 to 5,110 ng*hr/mL. PK studies in adults with 
hematologic malignancies at doses 25-147 mg/m2 demonstrated a t½ of 3-9 hours, 
Cmax of 200-2,200 ng/mL, and an AUC0-24h between 1,130-6,780 ng*hr/mL. In both 
adults with non-hematologic and hematologic malignancies, pevonedistat Cmax and 
AUC0-24hr generally increased dose dependently and there was no apparent 
accumulation following once-daily dosing.27 Following IV administration, 
pevonedistat concentrations ascended rapidly and declined in a bi-exponential 
manner by 24 hours after the end of infusion. As the dose was increased, a third 
compartment of drug disposition began to emerge in patients with quantifiable 
drug concentrations beyond 24 hours post-infusion.5  
 
Pharmacodynamic analyses of patients with hematologic and non-hematologic 
malignancies have shown that pevonedistat stabilizes IB in peripheral blood 
mononuclear cells (PBMC) as well as increases Cdt-1 and Nrf-2 in skin biopsies 
from treated patients.27  
 
2.4 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children  
None 
 
2.4.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
None 
 
2.5 
Overview of Proposed Pediatric Study 
This is a phase 1 dose escalation of pevonedistat as a single agent and in combination with 
irinotecan and temozolomide for patients with refractory or recurrent solid tumors, 
including CNS tumors and lymphoma. Pevonedistat will be administered in combination 
with IV irinotecan and PO temozolomide in a 28-day cycle for Cycle 1 and 21-day cycles 
thereafter in Part A1 (patients ≥ 12 months and ≤ 21 years). Part A2 will enroll infants  
(≥ 6 months to < 12 months) one dose level behind the dose level at which the patients in 
Part A1 are enrolling, in order to maximize the safety for infant subjects. Pharmacokinetics 
will be obtained in all patients (see Section 8.3). Pharmacodynamic studies will be obtained 
in consenting patients (see Section 8.4). 
 
A cycle of therapy is considered to be 28 days for the first cycle and 21 days for cycles 
thereafter. A cycle may be repeated 17 times, up to a total duration of therapy of 12 months. 
 
Pevonedistat will be administered IV over 1 hour on Days 1, 8, 10, and 12 of a 28-day 
cycle for Cycle 1, and on Days 1, 3, and 5 of a 21-day cycle for Cycle 2 and beyond. After 
the initial dose of pevonedistat (Cycle 1 Day 1), subsequent doses will be given in 
conjunction with irinotecan and temozolomide. The MTD in adult phase 1 studies in adults 
given in combination with standard chemotherapy with advanced solid tumors treated on 
this schedule is 20-25 mg/m2. Since in this study pevonedistat will be combined with 
irinotecan and temozolomide, a relatively well-tolerated regimen, the starting dose will be 
15 mg/m2, 75% of the adult MTD. Part A2 will open to enrollment on Dose Level 1 (15 
mg/m2) once Part A1 has escalated to Dose Level 2 (20 mg/m2). In order to obtain single 
agent PK data, pevonedistat will be given as a single dose one week prior to initiating 
combination therapy with irinotecan and temozolomide. 
 
The industry partner does not have plans to develop pevonedistat as a single agent in 


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pediatrics. Thus, this study is designed to determine the safety and pharmacokinetics of 
pevonedistat alone and in combination with irinotecan and temozolomide. 
 
2.6 
Rationale for Amendment #5 (addition of dose level 4) 
Pevonedistat, a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the 
activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation 
of key regulatory proteins important in cell survival. In adults with solid tumors, the 
maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. 28,29  
 
As a single agent in adults with MDS/AML the MTD for pevonedistat infusions on days 
1, 3, and 5 per cycle was determined to be 59 mg/m2 and for melanoma or advanced solid 
tumors, was determined to be 67 mg/m2. The recommended phase 2 dose for pevonedistat 
monotherapy for that schedule is 50mg/m2.1,30  In adults, the predominant dose limiting 
toxicity (DLT) was hepatoxicity.  
 
In our current Phase 1 Study of Pevonedistat (MLN4924) a NEDD8 Activating Enzyme 
Inhibitor, in Combination with Temozolomide (TMZ) and Irinotecan (IRN) in Pediatric 
Patients with Recurrent or Refractory Solid Tumors (ADVL1615), 18 patients have 
enrolled and all were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) 
assessment. Six patients each enrolled on pevonedistat dose levels 1 (15mg/m2), 2 
(20mg/m2), and 3 (25mg/m2).  No pediatric patients experienced a DLT, and only 1 patient 
each experienced grade 3 elevated AST and elevated ALT, which resolved and did not 
meet criteria for dose-reduction.33  
 
The pharmacokinetics (PK) of pevonedistat were similar in adult and pediatric studies. In 
our pediatric study, the mean area under the curve (AUC) at the 25 mg/m2 dose level on 
day 8 (in combination with irinotecan and temozolomide) was 1296 hr•ng/mL, half-life (T 
½) was 5-6 hours, time to maximum concentration (Tmax) was 1 hour, and average 
clearance was 20 L/hr/m2, comparable with adult trials (Figure 1).31 Both AUC and 
maximum concentration (Cmax) increased with dose level, but unlike the adult data, the 
increase appeared to be greater than dose-proportional. This was reflected in the Day 1 
clearance which showed a small decrease with dose suggesting non-linear clearance.  
 
Given that the recommended Phase 2 dose of pevonedistat as a monotherapy for the current 
schedule is 50 mg/m2 and the observed good tolerability of the combination of 
pevonedistat, irinotecan and temozolomide in pediatric patients at 25 mg/m2, we propose 
amending our trial to include a dose level 4 of 35 mg/m2. Based on our pediatric PK data, 
we expect this dose level will result in a 40% increase in AUC and Cmax, equivalent to 
approximately an adult dose of 45 mg/m2. If dose level 4 proves intolerable, we propose 
opening an expanded PK cohort at the 25 mg/m2 dose (dose level 3).  


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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 


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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. 
 
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 


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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 
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. 
 


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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. Imaging 
studies must be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging 
if necessary).  
 
 
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. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age:   
4.1.1.1 Part A1: Patients must be ≥ 12 months and  21 years of age at the time 
of study enrollment. 
 
4.1.1.2 Part A2: Patients must be ≥ 6 months and < 12 months of age at the time 
of study enrollment. Patients will enroll one dose level behind the dose 
level at which patients in Part A1 are enrolling. 
 
4.1.2 
Diagnosis: Patients with recurrent or refractory solid tumors, including CNS 
tumors and lymphoma, for which no standard therapy is available are eligible. 
Patients must have had histologic verification of malignancy at original diagnosis 
or relapse except in patients with intrinsic brain stem tumors, optic pathway 
gliomas, or patients with pineal tumors and elevations of CSF or serum tumor 
markers including alpha-fetoprotein or beta-HCG.  
 
4.1.3 
Disease Status: Patients must have either measurable or evaluable disease (see 
Section 12.2 and Section 12.3 for definitions).  
 
4.1.4 
Therapeutic Options: Patient’s current disease state must be one for which there is 
no known curative therapy or therapy proven to prolong survival with an 
acceptable quality of life. 
  
4.1.5 
Performance Level:  Karnofsky  50% for patients > 16 years of age and Lansky 
 50 for patients  16 years of age (see Appendix I).  NOTE:  Neurologic deficits 
in patients with CNS tumors must have been relatively stable for at least 7 days 
prior to study enrollment. Patients who are unable to walk because of paralysis, 
but who are up in a wheelchair, will be considered ambulatory for the purpose of 


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assessing the performance score. 
 
4.1.6 
Prior Therapy 
 
4.1.6.1 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. At least 21 days after the last dose of cytotoxic or 
myelosuppressive chemotherapy (42 days if prior nitrosourea). 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. 
 
 
 
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 
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. Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. 
 
e. 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. 
 
f. Interleukins, Interferons and Cytokines (other than Hematopoetic 
Growth Factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than Hematopoietic Growth Factors). 
 
g. 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. 
 


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h. Cellular Therapy: ≥ 42 days after the completion of any type of 
cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
 50% of the pelvis; ≥ 42 days if other substantial BM radiation. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): 
≥ 
42 
days 
after 
systemically 
administered 
radiopharmaceutical therapy. 
 
k. Patients must not have received prior exposure to pevonedistat. 
Patients with prior exposure to irinotecan or temozolomide are 
eligible. 
 
4.1.7 
Organ Function Requirements 
 
4.1.7.1 Adequate Bone Marrow Function defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC)  1000/mm3 
- 
Platelet count  100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment). 
- 
Hemoglobin ≥ 8 g/dL 
 
b. Patients with known bone marrow metastatic disease will be eligible 
for study provided they meet the blood counts in Section 4.1.7.1.a 
(may receive transfusions provided they are not known to be refractory 
to red cell or platelet transfusions). These patients will not be 
evaluable for hematologic toxicity. At least 5 of every cohort of 6 
patients on Part A1 must be evaluable for hematologic toxicity for the 
dose-escalation part of the study. If dose-limiting hematologic toxicity 
is observed, all subsequent patients enrolled must be evaluable for 
hematologic toxicity. 
 
4.1.7.2 Adequate Renal Function defined as: 
- 
Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
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. 


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4.1.7.3 Adequate Liver Function defined as: 
- 
Bilirubin (sum of conjugated + unconjugated)  upper limit of normal 
(ULN) for age  
- 
SGPT (ALT)  135 U/L.  For the purpose of this study, the ULN for 
SGPT is 45 U/L.  
- 
SGOT (AST)  150 U/L.  For the purpose of this study, the ULN for 
SGOT is 50 U/L.  
- 
Serum albumin  2.7 g/dL 
 
4.1.7.4 Adequate Cardiac Function defined as: 
- 
Shortening fraction of   27% by echocardiogram, or 
- 
Ejection fraction of ≥ 50% by gated radionuclide study. 
- 
No supraventricular arrhythmia on EKG 
- 
Prolonged rate corrected QT (QTc) interval < 500 msec 
 
4.1.7.5 Adequate Pulmonary Function defined as: 
- 
Pulse oximetry > 94% on room air if there is clinical indication for 
determination (e.g. dyspnea at rest). 
 
4.1.7.6 Adequate Neurologic Function defined as: 
- 
Patients with seizure disorder may be enrolled if on non-enzyme 
inducing anticonvulsants and well controlled. See Section 4.2.6.4 for 
further details. 
- 
Nervous system disorders (CTCAE version 5.0) resulting from prior 
therapy must be  Grade 2, with the exception of decreased tendon 
reflex (DTR). Any grade of DTR is eligible.  
 
4.1.7.7 Adequate Coagulation defined as: 
- 
INR ≤ 1.5  
 
4.1.8 
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 
 
4.2.1 
Pregnancy or Breast-Feeding 
 
4.2.1.1 Pregnant or breast-feeding women will not be entered on this study 
because there is not yet available information regarding human fetal or 
teratogenic toxicities. Pregnancy tests must be obtained in girls who are 
post-menarchal.  
 
4.2.1.2 Males or females of reproductive potential may not participate unless they 
have agreed to practice 1 highly effective and 1 additional effective 
(barrier) method of contraception at the same time during the entire study 
treatment period and through 4 months after the last dose of study drug, or 
agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal, spermicides only, 


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and lactational amenorrhea are not acceptable methods of contraception. 
 
4.2.2 
Patients with uncontrolled high blood pressure (i.e., systolic/diastolic blood 
pressure > 99th percentile) are not eligible. See Appendix XII for more details. 
 
4.2.3 
Patients with known cardiopulmonary disease are not eligible. Cardiopulmonary 
disease is defined as: 
- 
Cardiomyopathy other than chemotherapy related changes in cardiac 
function that meet the eligibility requirements in Section 4.1.7.4. 
- 
Clinically significant arrhythmia: 
1. History of polymorphic ventricular fibrillation or torsade de 
pointes, 
2. Permanent atrial fibrillation [a fib], defined as continuous a fib for 
≥ 6 months, 
3. Persistent a fib, defined as sustained a fib lasting > 7 days and/or 
requiring cardioversion in the 4 weeks before screening, 
4. Grade 3 a fib defined as symptomatic and incompletely controlled 
medically, or controlled with device (e.g. pacemaker), or ablation 
and 
5. Patients with paroxysmal a fib or < Gr 3 a fib for period of at least 
6 months are permitted to enroll provided that their rate is 
controlled on a stable regimen. 
- 
Implantable cardioverter defibrillator; 
- 
Moderate to severe aortic and/or mitral stenosis or other valvulopathy 
(ongoing); 
- 
Pulmonary hypertension 
- 
Congestive heart failure Class III or IV (See Appendix IX) 
 
4.2.4 
Patients with known hepatic cirrhosis or severe pre-existing hepatic impairment 
are not eligible. 
 
4.2.5 
Patients with uncontrolled coagulopathy or bleeding disorder are not eligible. 
 
4.2.6 
Concomitant Medications 
 
4.2.6.1 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid (See Section 4.1.6.1.d). 
 
4.2.6.2 Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.6.3 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible. 
 
4.2.6.4 Anticonvulsants:  Patients must not have received enzyme-inducing 
anticonvulsants for at least 7 days prior to enrollment (see Appendix V for 
a list of enzyme-inducing and non-enzyme-inducing anticonvulsants). 
 


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4.2.6.5 Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
4.2.6.6 Patients who are receiving any investigational agent other than 
pevonedistat, including but not limited to androgens, supraphysiologic 
doses of corticosteroids, erythropoietin, eltrombopag, or romiplostim. 
 
4.2.7 
Drug Interaction: 
Patients who have received drugs that are strong inducers of CYP3A4 within 14 
days prior to study enrollment are not eligible. See Appendix VII for more details. 
 
While on study, concomitant use of strong CYP3A4 inhibitors (see Appendix VII), 
BCRP inhibitors (cyclosporine, eltrombopag, gefitinib), and UGT1A1 inhibitors 
(diclofenac, ketoconazole, probenecid, silibinin, nilotinib, and atazanavir) should 
be avoided because of potential for increased irinotecan toxicity. 
 
4.2.8 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.9 
Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.10 Patients with known human immunodeficiency virus (HIV) seropositive are not 
eligible. 
 
4.2.11 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. 
 
4.2.12 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition as the study agents. 
 
4.2.13 Patients who in the opinion of the investigator may not be able to comply with the 
safety monitoring requirements of the study are not eligible.


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5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
Cycle 1 
Cycle Day 
1 
6 
8 
9 
10 
11 
12 
28 
 
Cefixime (Days 6 – 15, 27 – 28) -----------------------------------------------------------------------------------→ 
 
 
TEMO 
TEMO 
TEMO 
TEMO 
TEMO 
 
Eval 
 
 
IRIN 
IRIN 
IRIN 
IRIN 
IRIN 
 
Pevonedistat 
 
Pevonedistat 
 
Pevonedistat 
 
Pevonedistat 
 
 
 
PCP prophylaxis 
 
IRIN: Irinotecan; TEMO: temozolomide 
 
Cycle 2 and beyond 
Cycle Day 
-1 
0 
1 
2 
3 
4 
5 
21 
Cefixime (Days -1 to 8, 20 – 21) ------------------------------------------------------------------------------------------------------→ 
 
 
TEMO 
TEMO 
TEMO 
TEMO 
TEMO 
 
Eval 
 
 
IRIN 
IRIN 
IRIN 
IRIN 
IRIN 
 
 
Pevonedistat 
 
Pevonedistat 
 
Pevonedistat 
 
 
PCP prophylaxis 
IRIN: Irinotecan; TEMO: temozolomide 
 
See Appendix XIII for Therapy Delivery Maps for Cycle 1 and all subsequent cycles. 
 
A cycle of therapy is considered to be 28 days for Cycle 1 and 21 days for Cycle 2 and 
subsequent cycles. Therapy will be discontinued if there is evidence of progressive disease 
or drug related dose-limiting toxicity that requires removal from protocol therapy. Patients 
may continue on protocol therapy for up to 17 cycles (approximately 12 months). 
 
Pevonedistat will be administered intravenously over 60 minutes on Days 1, 8, 10, and 12 
of Cycle 1 and on Days 1, 3, and 5 of Cycles 2+ (starting dose is 15 mg/m2 [Dose Level 
1]). 
 
Cefixime will be administered starting at least two days prior to the start of irinotecan, 
during, and 3 days after the last dose of irinotecan of each cycle for a total of at least 10 
days.  
 
For Cycle 1, cefixime will be administered on Days 6-15 and Days 27-28. 
 
For Cycles 2+, cefixime will be administered on Days -1 through 8 and Days 
20 through 21.  
 
 
 Days 27 and 28 of Cycle 1 are the same as Days -1 and 0 of Cycle 2. Days 20 and 21 of 
Cycles 2+ are the same as Days -1 and 0 of subsequent cycles. 
 
Drug doses should be adjusted based on the BSA calculated from height and weight 
measured within 7 days prior to the beginning of each cycle. 
 
Method of Administration: Patients with solid tumors, including CNS tumors and 
lymphoma, will receive pevonedistat IV over one hour. In Cycle 1, pevonedistat will be 
administered as a single agent on Day 1 and in combination with oral temozolomide and 
IV irinotecan on Days 8, 10, and 12. In Cycles 2+, pevonedistat will be administered in 
combination with oral temozolomide and IV irinotecan on Days 1, 3, and 5 (see Appendix 
IV for temozolomide dosing nomogram and Section 9.4.4 for administration instructions 
for patients who cannot swallow temozolomide capsules whole). Irinotecan is administered 


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over 90 minutes one hour after temozolomide. Pevonedistat is administered over 60 
minutes at the completion of irinotecan infusion. If emesis occurs within 30 minutes of 
taking a dose of temozolomide, then the dose may be repeated once. If emesis occurs after 
30 minutes, the dose should not be repeated. 
 
CYCLE 1: 
Temozolomide: 100 mg/m2/dose (maximum dose 200 mg) PO daily x 5 on Days 8-12. 
See Appendix IV for BSA-based dosing nomograms using oral capsules. 
 
Irinotecan:  
BSA-based dosing (below), IV over 90 minutes daily x 5 on Days 8-12 
one hour after temozolomide. 
 
IRINOTECAN IV 
50 mg/m2 dose level 
BSA (m2) 
Dose (mg) 
0.25-0.29 
8 
0.3-0.34 
12 
0.35-0.39 
15 
0.4-0.44 
18 
0.45-0.49 
22 
0.5-0.54 
24 
0.55-0.59 
28 
≥ 0.6 
50 mg/m2 
 
Pevonedistat*:  IV over 60 minutes on Day 1 alone and on Days 8, 10, and 12 
immediately after irinotecan. Starting dose is 15 mg/m2 (Dose Level 1). 
See Dose Escalation Schema in Section 5.4. 
 
 
For infusion-related reactions consider premedication with 
diphenhydramine for subsequent doses and increasing infusion duration 
to 2 hours. Other supportive care measures may be used at the 
investigator’s discretion. 
 
CYCLES 2+: 
Temozolomide: 100 mg/m2/dose (maximum dose 200 mg) PO daily x 5 on Days 1-5. See 
Appendix IV for BSA-based dosing nomograms using oral capsules. 
 
Irinotecan:  
BSA-based dosing (below), IV over 90 minutes daily x 5 on Days 1-5 
one hour after temozolomide. 
 
IRINOTECAN IV 
50 mg/m2 dose level 
BSA (m2) 
Dose (mg) 
0.25-0.29 
8 
0.3-0.34 
12 
0.35-0.39 
15 
0.4-0.44 
18 
0.45-0.49 
22 
0.5-0.54 
24 
0.55-0.59 
28 
≥ 0.6 
50 mg/m2 
 
Pevonedistat*:  IV over 60 minutes on Days 1, 3, and 5 immediately after irinotecan. 
Starting dose is 15 mg/m2 (Dose Level 1). See Dose Escalation Schema 


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in Section 5.4. 
 
 
For infusion-related reactions consider premedication with 
diphenhydramine for subsequent doses and increasing infusion duration 
to 2 hours. Other supportive care measures may be used at the 
investigator’s discretion. 
 
*NOTE:  If pevonedistat dosing is delayed, a minimum of 1 full calendar day between any 
2 doses should be maintained. In Cycles 2+, a maximum of 3 doses of pevonedistat should 
not be exceeded. 
 
Diarrhea prophylaxis:  Cefixime or an available equivalent antibiotic will be used as 
diarrheal prophylaxis during all cycles. Cefixime (8 mg/kg/day as a single daily dose; 
maximum daily dose 400 mg) or Cefpodoxime (10 mg/kg/day, divided in two oral doses; 
maximum daily dose 400 mg for children < 12 years and maximum daily dose 800 mg for 
children ≥ 12 years) will be administered starting at least two days prior to the start of 
irinotecan and continuing for 3 days after the last dose of irinotecan of each cycle for a 
total of 10 days.  
 
Diarrhea treatment:  See Appendix VIII. 
 
Pneumocystis (PCP) prophylaxis: Patients must receive PCP prophylaxis starting on 
Cycle 1 Day 8, twice daily for 3 consecutive days a week (i.e., BID Friday, Saturday, and 
Sunday) every week, or per institutional practice, until the end of protocol therapy. 
 
5.2 
Criteria for Retreatment and Dose Delays 
If pevonedistat dosing is delayed, a minimum of 1 full calendar day between any 2 doses 
should be maintained. In Cycles 2+, a maximum of 3 doses of pevonedistat should not be 
exceeded. 
 
5.3 
Criteria for Starting Subsequent Cycles 
After Cycle 1 which is 28 days, a cycle may be repeated every 21 days if the patient has at 
least stable disease and has again met laboratory parameters as defined in the eligibility 
section, Section 4.0 or eligible to continue agent administration per the requirements in 
Section 6.0.   
 
5.4 
Dose Escalation Schema 
 
5.4.1 
Part A1: Inter-Patient Escalation  
The starting dose will be 15 mg/m2 (Dose Level 1) with dose levels for subsequent 
groups of patients as follows: 
 
 
Dose Level 
Pevonedistat 
Dose (mg/m2) 
Day(s) of Administration 
Cycle 1 
Day(s) of Administration 
Cycles 2+ 
-1 
10 
1, 8, 10, 12 
1, 3, 5 
1* 
15 
1, 8, 10, 12 
1, 3, 5 
2 
20 
1, 8, 10, 12 
1, 3, 5 
3 
25 
1, 8, 10, 12 
1, 3, 5 
4 
35 
1, 8, 10, 12 
1, 3, 5 
* Starting Dose Level 
 
If the MTD has been exceeded at the first dose level, then the subsequent cohort 
of patients will be treated at a dose of 10 mg/m2 (Dose Level -1). If Dose Level -1 
is not well tolerated, further de-escalation will not occur. The study will be closed 


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to accrual. 
 
5.4.2 
Part A2: Inter-Patient Escalation 
Patients enrolling on Part A2 of the study will enroll one dose level behind the 
dose level at which patients in Part A1 are enrolling. Part A2 will open to 
enrollment on Dose Level 1 once Part A1 has escalated to Dose Level 2. Once the 
MTD is determined in Part A1, patients may enroll onto the Part A1 MTD. If at 
any time 2 or more evaluable patients at a lagging dose level experience a DLT, 
Part A2 will close to further accrual. 
 
5.4.3 
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 
web 
site 
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. The DLT observation period for the 
purposes of dose-escalation will be the first cycle of therapy. Refer to Section 6.3 for 
specific criteria for patients < 12 months of age at the time of the non-hematological DLT. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
5.6.1 
Non-hematological dose-limiting toxicity for patients ≥ 12 months of age: 
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 nausea and vomiting < 3 days duration 
 Grade 3 elevation of ALT/AST/bilirubin, that returns to Grade  1 
or baseline prior to the time for the next treatment cycle.  
NOTE:  For the purposes of this study the ULN for ALT is defined 
as 45 U/L and for AST is defined as 50 UL. Adverse event grades 
will be based on increases above the upper limit of normal, 
regardless of the subject’s baseline. See section 5.6.3 and 6.2.4. See 
Appendix III for nomogram.  
 Grade 3 hypophosphatemia (See section 6.2.5), hypokalemia, 
hypocalcemia or hypomagnesemia responsive to supplementation. 
 Grade 3 arthralgia/myalgia that returns to Grade ≤ 1 prior to the start 
of the next cycle or within 14 days of optimizing oral analgesics 
(whichever is shorter). 
 
5.6.2 
Non-hematological dose-limiting toxicity for patients < 12 months of age: 
5.6.2.1 Any ≥ Grade 2 non-hematological toxicity not clearly related to the 
underlying disease and attributable to the protocol therapy will be 
considered a DLT with the specific exclusion of Grade 2 liver enzyme 


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elevation, including ALT/AST/bilirubin, that returns to Grade ≤ 1 or 
baseline prior to the time for the next treatment cycle.  
 
NOTE: For the purposes of this study the ULN for ALT is defined as 45 
U/L and for AST is defined as 50 U/L. Adverse event grades will be based 
on increases above the upper limit of normal, regardless of the subject’s 
baseline. See Appendix III for toxicity grading table. 
 
5.6.2.2 Other pevonedistat-related non-hematologic toxicities Grade 2 or greater 
that, in the opinion of the investigator, require dose reduction or 
discontinuation of therapy with pevonedistat. 
 
5.6.3 
Non-hematological toxicity that causes a delay of  14 days between treatment 
cycles. 
 
NOTE: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
5.6.4 
Hematological dose limiting toxicity 
5.6.4.1 Hematological dose limiting toxicity attributable to protocol therapy is 
defined as: 
 
 Grade 4 neutropenia for > 7 days. 
 Grade 4 anemia unexplained by underlying malignancy. 
 Platelet count < 25,000/mm3 on 2 separate days, or requiring a 
platelet transfusion on 2 separate days, within a 7 day period. 
 Myelosuppression that causes a delay of > 14 days between 
treatment cycles.  
 
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 or use of myeloid growth factor. 
 
6.1 
Dose Modifications for Hematological Toxicity (all age cohorts) 
 
6.1.1 
Patients who have dose-limiting neutropenia (Grade 4 neutropenia of > 7 days 
duration or delay in the start of the next cycle for > 14 days due to neutropenia) 
with no other dose-limiting toxicity should receive the same doses in the next cycle 
with myeloid growth factor support 24-48 hours after completion of irinotecan, 
temozolomide, and pevonedistat. Patients MUST NOT receive growth factor in 
the first cycle. If dose-limiting neutropenia recurs after myeloid growth factor is 
added, start the next cycle with a decrease in temozolomide to 75% of the original 
dose (75 mg/m2/dose) on Days 1-5. If hematologic dose limiting toxicity occurs at 
75% of the original dose of temozolomide, then pevonedistat dose level should be 
decreased to the next lower dose level.  If dose limiting neutropenia recurs after 
use of growth factor and dose reductions of temozolomide and pevonedistat the 
patient should be removed from protocol therapy. 
 
6.1.2 
For dose-limiting thrombocytopenia, after counts recover, start the next cycle with 


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a decrease in temozolomide to 75% of the original dose (75 mg/m2/dose) on Days 
1-5. Patients should continue to receive the full doses of pevonedistat and 
irinotecan. If dose limiting thrombocytopenia occurs at 75% of the original dose 
of temozolomide, then pevonedistat dose level should be decreased to the next 
lower dose level and the irinotecan should be given at full dose. 
 
6.1.3 
Patients who have a dose-limiting hematological toxicity that does not resolve to 
eligibility parameters within 21 days after the planned start of the next treatment 
cycle must be removed from protocol therapy. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity (for patients ≥ 12 months) 
 
6.2.1 
Patients who have any dose-limiting non-hematological toxicity (as defined in 
Section 5.6.1) may continue on protocol therapy upon meeting eligibility lab 
requirements or baseline but should receive subsequent doses of pevonedistat at 
the next lower dose level. Irinotecan and temozolomide should be continued at the 
same dose. 
 
6.2.2 
If the same non-hematological dose-limiting toxicity recurs after one dose 
reduction, the patient must be removed from protocol therapy. 
 
6.2.3 
Patients who have a dose-limiting non-hematological toxicity that does not resolve 
to baseline or eligibility within 21 days after the planned start of the next treatment 
cycle must be removed from protocol therapy. 
 
6.2.4 
Pevonedistat dose modification for hepatic toxicity: 
In all cycles, AST, ALT, and bilirubin should be checked prior to each dose of 
pevonedistat and then once weekly for the remaining weeks of the study. It is 
anticipated that LFTs (AST, ALT, and occasionally bilirubin) may be elevated for 
approximately 48 hours following the end of the 1st pevonedistat infusion. See 
Appendix III for toxicity grading table. 
For Grade 2 or 3 AST, ALT, or bilirubin on or after Cycle 1 Day 8, pevonedistat 
should be held. Once the elevated AST, ALT, or bilirubin returns to ≤ Grade 1 by 
the end of the current cycle, then pevonedistat dose may be resumed at the same 
dose. If a dose is delayed due to increased LFTs, pevonedistat needs to be 
administered by Day 25 of Cycle 1 or Day 18 of subsequent cycles (within a cycle 
there should be a maximum of 13 days between doses). 
For Grade 4 AST, ALT, or bilirubin on or after Cycle 1 Day 8, the pevonedistat 
dose should be held for the remainder of the cycle. If the elevated AST, ALT, or 
bilirubin return to ≤ Grade 1, then pevonedistat may be restarted at the next cycle 
at the next lower dose level. 
Interventions for Dose Modifications Secondary to Elevated AST, ALT, or bilirubin 
Grade 2 
Hold pevonedistat until resolved to < Grade 1 
Grade 3 
Hold pevonedistat until resolved to < Grade 1 
Grade 4 
Hold pevonedistat for remainder of cycle. For subsequent cycle resume 
at next lower dose level if resolved to < Grade 1 
For pevonedistat, a minimum of 1 full calendar day between any 2 doses should be maintained, 
and a maximum of 3 doses of pevonedistat within Cycles 2+ must not be exceeded. There should 
be a maximum of 13 days between doses within a given cycle. 


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6.2.5 
Pevonedistat dose modification for hypophosphatemia: 
If hypophosphatemia is ≥ Grade 3, study drug treatment should not be resumed 
until the hypophosphatemia is ≤ Grade 2. Hypophosphatemia should be evaluated 
(including severity and etiology), monitored, and treated according to institutional 
guidelines. 
6.3 
Dose Modifications for Non-Hematological Toxicity (for patients < 12 months at the 
time of the DLT) 
Patients less than 12 months of age who have a ≥ Grade 2 non-hematological toxicity 
attributable to the study drug will have pevonedistat held as per Section 6.2 and this will 
be considered a DLT with the specific exclusion of Grade 2 liver enzyme elevation, 
including ALT/AST/bilirubin, that returns to Grade ≤ 1 or baseline prior to the time for the 
next treatment cycle (see Section 6.2.4). Patients should receive subsequent cycles of the 
drug but with dose modifications according to Section 6.2. 
 
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 4.2.7 for drugs that should not be used 
concomitantly due to potential interactions with pevonedistat and irinotecan. See Section 5.1 
and Appendix VIII for diarrhea prophylaxis and treatment recommendations. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered in accordance with Section 6.1.1 or for culture proven bacteremia or invasive 
fungal infection. The Study Chair should be notified before growth factors are initiated. 
 
7.5 
Concomitant Medications 
Strong CYP3A4 inducers (see Appendix VII) are prohibited for the duration of the study. 
Strong inducers of CYP3A4 should be discontinued within 14 days prior to the first dose 
of pevonedistat.  
 
Concomitant use of strong inhibitors of CYP3A4 (see Appendix VII), UGT1A1 inhibitors 
(such as diclofenac, ketoconazole, probenecid, silibinin, tacolimus, nilotinib, and 
atazanavir), and BCRP inhibitors (cyclosporine, eltrombopag, gefitinib) also should be 
avoided because of potential for increased irinotecan toxicity. 
 
Acetaminophen may be used judiciously but should not exceed a dose of 37 mg/kg/day 
(maximum 2 g in 24 hours). 


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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. Imaging studies must 
be obtained within fourteen (14) days prior to start of protocol therapy (repeat the tumor 
imaging if necessary). See Appendix XIII for Therapy Delivery Maps for Cycle 1 and all 
subsequent cycles. 
 
Studies to be Obtained 
For all patients 
For patients ≥ 12 
months ONLY 
For patients < 12 
months ONLY 
Pre-Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
Prior to Subsequent 
Cycles^ 
History 
X 
X 
X 
X 
Physical exam with vital signs7 
X 
Weekly 
X 
X 
Height, weight, BSA 
X 
 
X 
X 
Performance status 
X 
 
X 
X 
CBC, differential, platelets 
X 
Twice weekly1 
Weekly1,2,3 
Weekly1,2,3 
Electrolytes including Ca++, 
PO4, Mg++ 
X 
Weekly 
X 
Weekly 
Creatinine 
X 
Weekly 
X 
Weekly 
ALT, AST, bilirubin 
X 
Prior to each dose of 
pevonedistat, then 
weekly* 
Prior to each dose of 
pevonedistat, then 
weekly* 
Prior to each dose of 
pevonedistat, then 
weekly* 
ECHO/EKG 
X 
 
 
 
Albumin 
X 
 
X 
X 
Pulse Oximetry 
X 
 
X 
X 
Pregnancy test4 
X 
 
X 
X 
Tumor disease evaluation  
X 
End of Cycle 1 
End of Cycle 2 then 
every other cycle x 2 
then q 3 cycles5 
End of Cycle 2 then 
every other cycle x 2 
then q 3 cycles5 
Bone Marrow Evaluation8 
X 
End of Cycle 1 
End of Cycle 2 then 
every other cycle x 2 
then q 3 cycles5 
End of Cycle 2 then 
every other cycle x 2 
then q 3 cycles5 
Pharmacokinetics6 (required) 
X 
X 
 
 
Pharmacodynamics (optional) 
X 
X 
 
 
INR 
X 
 
 
 
^ Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 Twice weekly during Cycle 1. If patients have Grade 4 neutropenia or thrombocytopenia, CBCs should be checked at least every other 
day until recovery to Grade 3 or until the criteria for dose limiting toxicity are met. 
2 If patients develop Grade 4 neutropenia, CBCs should be checked every 3 to 4 days until recovery to Grade 3. 
3 If patients remain on study for > 4 cycles and ≥ Grade 3 cytopenias are not observed, then CBCs may be obtained at the start of subsequent 
cycles and as clinically indicated. 
4 Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually active patients must use an 
acceptable method of birth control. Abstinence is an acceptable methods of birth control. All women of childbearing potential must have 
a pregnancy test done every cycle prior to initiation of a new cycle. 
5 Tumor disease evaluation should be obtained on the next consecutive cycle after initial documentation of either a PR or CR. If the 
institutional investigator determines that the patient has progressed based on clinical or laboratory evidence, he/she may opt not to confirm 
this finding radiographically. 


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6 See Section 8.3 for details. 
7 Vital signs should be checked prior to each pevonedistat infusion. Vital signs will also be assessed at the end of treatment. 
8 If a solid tumor patient is suspected to have or has a history of bone marrow involvement then a pre-study bone marrow 
biopsy and/or aspirate is required. This should then be repeated with each tumor disease evaluation if pre-study bone marrow 
was positive for metastatic disease. 
*Check prior to each dose of pevonedistat, then weekly for remaining weeks of cycle. If patients have Grade 2, 3, or 4 ALT/AST/bilirubin 
on or after Cycle 1 Day 8, AST/ALT/bilirubin should be checked at least every other day until recovery to ≤ Grade 1. See Section 6.2.4 
for more details.  
 
8.2 
Radiology Studies 
 
8.2.1 
Central Radiology Review for Response:  Patients who respond (CR, PR) to 
therapy or have long term stable disease (SD) (≥ 6 cycles) on protocol therapy will 
be centrally reviewed. COG Operations Center will notify the Imaging Center of 
any patient requiring central review. The Imaging Center will then request that the 
treating institution forward the requested images for central review. The central 
image evaluation results will be entered into RAVE for review by the COG 
Operations Center and for data analysis.  
 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the ImageInBox.   
 
COG institutions that are not connected via the ImageInBox can send the images 
on CD ROM or USB flash drive. Submitted imaging studies should be clearly 
marked with the COG patient ID, study number (ADVL1615), and date and 
shipped to Syed Aamer at the address below: 
 
 
 
  
 
 
 
 
 
  
 
8.3 
Pharmacokinetics (required) 
 
8.3.1 
Description of Studies and Assay 
Pharmacokinetics (PK) will be performed to determine the PK of pevonedistat in 
children. Pharmacokinetic analysis will be conducted at a centralized laboratory 
using a GLP-validated liquid chromatography/tandem mass spectrometry (LC-
MS/MS) assay. 
 
Individual pevonedistat plasma concentration-time data will be analyzed using 
standard noncompartmental methods. The following PK parameters of 
pevonedistat will be estimated with Cmax, Tmax, AUC0-24h, CL/F, half-life, and 
AUC0-∞ (as data permit). Individual values and descriptive statistics of 
pevonedistat plasma concentration-time data and PK parameters will be listed and 
tabulated by treatment/study day. Individual and mean pevonedistat plasma 
concentration data will also be plotted over time per treatment/study day. 
 


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8.3.2 
Sampling Schedule (see Appendix X)  
Blood samples will be obtained prior to drug administration and at the following 
time points: 
 
8.3.2.1 All patients 
 
For patients ≥ 10 kg, samples will be obtained at the following time points:  
Day 1 of Cycle 1: pre-dose, end of pevonedistat infusion, and at 1, 2, 4, 
6-8 and 24 hours post-dose infusion.  
Day 8 of Cycle 1:  pre-dose, end of pevonedistat infusion, and at 1, 2, 4, 
6-8 and 24 hours post-dose infusion.  
Day 10 of Cycle 1:  pre-dose 
 
For patients < 10 kg, samples will be obtained at the following time points: 
Day 1 of Cycle 1: pre-dose; end of infusion; and at 2, 6-8, and 24 hours 
post-dose infusion. 
Day 8 of Cycle 1: pre-dose; end of infusion; and at 2, 6-8, and 24 hours 
post-dose infusion. 
Day 10 of Cycle 1: pre-dose 
 
8.3.3 
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. 
 
8.3.4 
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 


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shipment. 
 
8.3.5 
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, which must accompany the sample(s). 
 
8.3.6 
Sample Shipping Instructions 
Samples should be batched per patient and shipped frozen on dry ice in opaque 
containers at the end of Cycle 1 as per Appendix X-A. Please send an email 
notification of shipment to the Study-Specific Research Coordinator as well as 
Matt Dodge at matthew.dodge@covance.com. 
 
8.4 
Pharmacodynamics (optional) 
 
8.4.1 
Description of Studies 
For pharmacodynamic analyses, reverse transcription-polymerase chain reaction 
(RT-PCR) will be used to analyze the expression of genes regulated following 
NAE inhibition in whole blood.1 
 
In consenting patients ≥ 12 months of age, blood samples (2 mL) will be collected 
in yellow-top citrate vacutainer tubes at a site distant from the infusion for 
pharmacodynamic evaluation. Record the exact time that the sample is drawn 
along with the exact time that the drug is administered. 
 
8.4.2 
Sampling Schedule (See Appendix XI) 
 
8.4.2.1 Samples will be collected at: 
Day 1 of Cycle 1: 
pre-dose; and at 2, 6-8, and 24 hours post-dose 
infusion. 
Day 8 of Cycle 1: 
pre-dose; and at 2, 6-8, and 24 hours post-dose 
infusion. 
Day 10 of Cycle 1: pre-dose 
 
8.4.3 
Sample Collection and Handling Instructions 
Blood samples (2 mL) will be collected in yellow-top citrate vacutainer tubes at a 
site distant from the infusion for pharmacodynamic evaluation. Record the exact 
time that the sample is drawn along with the exact time that the drug is 
administered. 
 
8.4.4 
Sample Processing 
1. 
Store at 4ºC until processed. 
2. 
Ship in thermosafe box to address provided in Section 8.4.6. 
 
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 
 


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8.4.5 
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 
PD Study Form (Appendix XI), which must accompany the sample(s). 
 
8.4.6 
Sample Shipping Instructions 
Ship samples to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
9.0 
AGENT INFORMATION 
 
9.1 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.1.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
9.1.6 
 
 


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9.1.7 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.8 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.1.9 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.10 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.1.11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.12 
 
 
 
9.1.13 
 
 
 
 
 
 


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9.1.14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2 
CEFIXIME 
 
 
 
 
 
 (11/17/17) 
(Suprax®) NSC# NA 
 
9.2.1 
Source and Pharmacology 
Cefixime is a third-generation cephalosporin antibiotic for oral administration that 
inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-
binding proteins and interfering with the final transpeptidation step of 
peptidoglycan synthesis. Its spectrum of activity is similar to other third-generation 
agents, including Enterobacteriaceae, and β-lactamase producing H. influenzae 
and N. gonorreae, and Staph. Aureus. When taken orally, it is about 40%-50% 
absorbed whether administered with or without food. The area under the time 
versus concentration curve is greater by approximately 10%-25% with the oral 
suspension than with the tablet after doses of 100 to 400 mg, when tested in normal 
adult volunteers. This increased absorption should be taken into consideration if 
the oral suspension is to be substituted for the tablet. Cefixime serum half-life is 
approximately 3-4 hours. It is excreted primarily by the kidney. There is no 
evidence of metabolism of cefixime in vivo. 
 


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9.2.2 
Toxicity 
Incidence 
Toxicities 
Common 
(>20% of patients) 
None known 
Occasional 
(4-20% of patients) 
 
Diarrhea 
 
Nausea 
 
Flatulence 
 
Loose or frequent stools 
Rare 
(≤ 3% of patients) 
 
Erythema multiforme 
 
Pruritus 
 
Rash maculo-papular 
 
Stevens-Johnson syndrome 
 
Toxic epidermal necrolysis 
 
Urticaria, angioedema 
 
Abdominal pain 
 
Pseudomembranous colitis 
 
Dyspepsia 
 
Transient white blood cell decrease 
 
Neutrophil count decreased 
 
Platelet count decreased 
 
Transient jaundice 
 
Alanine aminotransferase increased 
 
Aspartate aminotransferase increased 
 
Bilirubin increased; anaphylaxis 
 
Allergic reaction 
 
Dizziness 
 
Headache 
 
Seizure 
 
Acute kidney injury 
 
Creatinine increased 
 
Vaginal infection 
 
Vomiting 
Pregnancy & 
Lactation 
Pregnancy Category B  
Teratogenic effects were not observed in animal reproduction studies. Cefixime 
crosses the placenta and can be detected in the amniotic fluid. There are no well-
controlled studies of cefixime in pregnant women; effects of cefixime on the fetus 
are unknown. An increase in most types of birth defects was not found following 
first trimester exposure to cephalosporins. It is not known whether cefixime is 
excreted in human milk. 
 
9.2.3 
Formulation and Stability 
Cefixime is available in scored 400 mg film coated tablets, 400 mg capsules, 100 
mg chewable tablets, and 200 mg chewable tablets. The chewable tablets are tutti-
frutti flavor and contain aspartame and fd&c red #40 aluminum lake. Cefixime is 
also available in two strengths as a powder for oral suspension, which when 
reconstituted, provides either a 100 mg/5 mL or 200 mg/5 mL suspension. The 
powder for oral suspension is strawberry flavored and contains sodium benzoate, 


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sucrose, and xanthan gum. After reconstitution, suspension may be stored for 14 
days at room temperature or under refrigeration. 
 
Cefixime tablets and powder for oral suspension are stored at 20 - 25°C (68 - 77°F). 
Do not freeze. The suspension bottle should be kept tightly closed. 
 
9.2.4 
Guidelines for Administration 
See Treatment and Dose Modification sections of the protocol. 
 
Cefixime may be administered with or without food. Administration with food may 
decrease abdominal distress. Shake the suspension prior to withdrawing dose or 
administration. 
 
9.2.5 
Supplier 
Commercially available from various manufacturers. See package insert for further 
information. 
 
 
9.3 
IRINOTECAN 
 
 
 
 
 (03/07/17) 
 [CPT-11,Camptothecin-11,7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-
camptothecin), Camptosar®], NSC #616348 
 
9.3.1 
Source and Pharmacology 
Irinotecan is a semisynthetic water-soluble analog of camptothecin (a plant 
alkaloid isolated from Camptotheca acuminata). Irinotecan is a prodrug that 
requires conversion, by the carboxylesterase enzyme to the topoisomerase-I 
inhibitor, SN-38 in order to exert anti-tumor activity. SN-38 is approximately 
1000 times more potent than irinotecan. Camptothecins interact specifically with 
the enzyme topoisomerase I which relieves torsional strain in DNA by inducing 
reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to 
the topoisomerase I-DNA complex and prevent religation of these single-strand 
breaks. Current research suggests that the cytotoxicity of irinotecan is due to 
double-strand DNA damage produced during DNA synthesis when replication 
enzymes interact with the ternary complex formed by topoisomerase I, DNA, and 
either irinotecan or SN-38. Renal excretion is a minor route of elimination of 
irinotecan. The majority of the drug is metabolized in the liver. SN-38 is 
conjugated to glucuronic acid and this metabolite has no anti-tumor activity. The 
extent of conversion of SN-38 to its glucuronide has been inversely correlated with 
the risk of severe diarrhea, because the other major route of SN-38 excretion is 
biliary excretion by canalicular multispecific organic anion transporter (cMOAT) 
which presumably leads to mucosal injury. In addition, APC and NPC are 
oxidative metabolites of irinotecan dependent on the CYP3A4 isoenzyme. After 
intravenous infusion of irinotecan in humans, irinotecan plasma concentrations 
decline in a multiexponential manner, with a mean terminal elimination half-life 
of about 6 to 12 hours. The mean terminal elimination half-life of the active 
metabolite SN-38 is about 10 to 20 hours. Irinotecan is 30% to 68% bound to 
albumin and SN-38 is approximately 95% bound to albumin. 
 
 


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9.3.2 
Toxicity 
Incidence 
Toxicities 
Common 
(>20% of patients)  
 
Anemia 
 
Thrombocytopenia 
 
Neutrophil count decreased 
 
White blood cell count decreased 
 
Nausea 
 
Vomiting 
 
Constipation 
 
Anorexia 
 
Fever 
 
Asthenia 
 
Cholinergic symptoms: (rhinitis, increased salivation, miosis, lacrimation, 
diaphoresis, flushing, and intestinal hyperperistalsis that can cause 
abdominal cramping and early diarrhea) 
 
Alopecia 
 
Bilirubin increased 
 
Mucositis 
 
Dyspnea 
 
Cough 
 
Weight loss 
 
Pain 
Occasional 
(4-20% of patients)  
 
Abdominal fullness 
 
Flatulence 
 
Vasodilation 
 
Hypotension 
 
Dehydration 
 
Edema 
 
AST increased 
 
Alkaline phosphatase increased 
 
Ascites 
 
Jaundice 
 
Febrile neutropenia 
 
Infection 
 
Headache 
 
Dizziness 
 
Chills 
 
Insomnia 
 
Rash 
 
Dyspepsia 
 
Somnolence 
 
Thromboembolic events 
 
Pneumonia 
Rare 
(≤ 3% of patients)  
 
Anaphylaxis 
 
Bradycardia 
 
Disorientation/confusion 
 
Colitis 


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 
Renal failure (secondary to severe dehydration) 
 
Ileus 
 
Pancreatitis 
 
Pneumonitis (L) 
Pregnancy & 
Lactation 
Fetal toxicities and teratogenic effects of irinotecan have been noted in animals at 
doses similar or less than those used in humans. Toxicities include: decreased 
skeletal ossification, multiple anomalies, low birth weight and increased fetal 
mortality. It is not known if irinotecan is excreted into breast milk but it is 
excreted into rat milk. 
(L) Toxicity may also occur later 
 
9.3.3 
Formulation & Stability 
Each mL of irinotecan injection contains 20 mg irinotecan (on the basis of the 
trihydrate salt), 45 mg sorbitol, and 0.9 mg lactic acid. When necessary, pH has 
been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric 
acid. Irinotecan is available in single-dose amber glass vials in 40 mg (2 mL), 
100 mg (5 mL), 300 mg (15 mL), and 500 mg (25 mL). Store at controlled room 
temperature 15°-30°C (59°-86°F). Protect from light. It is recommended that the 
vial (and backing/plastic blister) should remain in the carton until the time of use.  
 
9.3.4 
Guidelines for Administration 
See Treatment and Dose Modifications sections of the protocol. 
 
IV Administration: Irinotecan must be diluted prior to infusion. Irinotecan should 
be diluted in D5W, (preferred) or NS to a final concentration range of 
0.12-2.8 mg/mL. The solution is physically and chemically stable for up to 24 
hours at room temperature (approximately 25°C) and in ambient fluorescent 
lighting. Solutions diluted in D5W and stored at refrigerated temperatures 
(approximately 2°-8°C), and protected from light are physically and chemically 
stable for 48 hours. Refrigeration of admixtures using NS is not recommended due 
to a low and sporadic incidence of visible particulates. Care should be taken to 
avoid extravasation; the use of a central line is suggested. 
 
9.3.5 
Supplier 
Commercially available from various manufacturers. See package insert for more 
detailed information. 
 


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9.4 
TEMOZOLOMIDE - ORAL  
 
 
(06/30/14) 
(Temodar, Temodal) NSC #362856 
 
 
 
9.4.1 
Source and Pharmacology 
An orally administered alkylating agent, a second generation imidazotetrazine. A 
prodrug of MTIC, temozolomide spontaneously decomposes to MTIC at 
physiologic pH. Exerts its effect by cross-linking DNA. This is likely a site-specific 
alkylation at the O6-position of guanine with some effect at the N7 position. 
Temozolomide reaches its peak concentration in 1 hour. Food reduces the rate and 
extent of absorption. It has an elimination half-life of 1.13 hr (intraperitoneally) and 
1.29 hr (orally) with an oral bioavailability of 0.98. Total apparent body clearance is 
100 mL/min/m2 and plasma elimination half-life is ~ 100 minutes.  
 
9.4.2 
Toxicity 
Incidence 
Toxicities 
Common 
(>20% of patients) 
 
Constipation 
 
Nausea 
 
Vomiting 
 
Diarrhea 
 
Anorexia 
 
Alopecia 
 
Alanine aminotransferase increased 
 
Aspartate aminotransferase increased 
 
Ataxia 
 
Anxiety 
 
Depression 
 
Insomnia 
 
Nervous system disorders – other: hemiparesis or paresis, dizziness, gait 
disturbance, amnesia, paresthesia, somnolence, headache, seizure, fatigue 
Occasional 
(4-20% of patients) 
 
Edema limbs 
 
Localized edema 
 
Rash maculopapular 
 
Dysphagia 
 
Mucositis oral 
 
Anemia 
 
Platelet count decreased 
 
White blood cell count decreased 
 
Lymphocyte count decreased 
 
Aplastic anemia 
 
Blood bilirubin increased 
 
Urinary frequency 
 
Cough 
 
Upper respiratory infection 
 
Sinusitis 
Rare 
(≤ 3% of patients) 
 
Stevens-Johnson syndrome 
 
Toxic epidermal necrolysis 
 
Erythema multiforme 
 
Hypercalcemia 


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 
Lower gastrointestinal hemorrhage 
 
Upper gastrointestinal hemorrhage 
 
Cholecystitis 
 
Alkaline phosphatase increased 
 
Myelodysplastic syndrome 
 
Leukemia secondary to oncology chemotherapy 
 
Infections and infestations – other: Pneumocystis pneumonia, pulmonary 
fibrosis, anaphylaxis, allergic reaction, hepatic failure 
Pregnancy & 
Lactation 
Pregnancy Category D 
Adequate, well-controlled studies have not been conducted in humans. Women of 
childbearing potential should be advised against becoming pregnant while taking 
temozolomide and for at least 6 months following the end of therapy. Temozolomide 
administration to rats and rabbits at 3/8 and 3/4 the human dose resulted in the 
development of malformations of the external organs, soft tissues, and skeleton. 
These animal studies also demonstrated embryolethality (increased resorptions) at 
similar doses. There is no information available regarding the transmission of 
temozolomide during lactation; women should avoid breastfeeding while receiving 
temozolomide. 
 
 
 
9.4.3 
Formulation and Stability 
Temozolomide capsules are available in six different strengths (5, 20, 100, 140, 
180, 250 mg). The capsules vary in size, color, and imprint according to strength. 
In the US, capsules are packaged in 5-count and 14-count bottles. In other countries 
temozolomide may be packaged in 5-count, 14-count or 20-count bottles. 
Temozolomide capsules are stored at controlled room temperature. 
 
9.4.4 
Guidelines for Administration 
See Treatment and Dose Modifications sections of the protocol. 
 
There is a potential for medication errors involving temozolomide capsules 
resulting in drug overdosages, which may have been caused by dispensing/taking 
the wrong number of capsules per day and/or product usage exceeding the 
prescribed dosing schedule. 
 
When dispensing, it is extremely important that prescribing and dispensing include 
clear instructions on which capsules, and how many of each capsule(s) are to be 
taken per day. Only dispense what is needed for the course, and clearly indicate 
how many days of dosing the patient will have and how many days are without 
temozolomide dosing. When counseling patients, it is important for each 
patient/parent to understand the number of capsules per day and the number of 
days that they take temozolomide. It is also important for the patient/parent to 
understand the number of days that they will be off the medication.  
 
Each strength of temozolomide must be dispensed in a separate vial or in its 
original container (e.g., bottle or sachet). Based on the dose prescribed, determine 
the number of each strength of temozolomide capsules needed for the full course 
as prescribed by the physician. For example, 275 mg/day for 5 days would be 
dispensed as five 250 mg capsules, five 20 mg capsules, and five 5 mg capsules. 
Label each container with the appropriate number of capsules to be taken each day. 
Dispense to the patient/parent, making sure each container lists the strength (mg) 


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per capsule and that he or she understands to take the appropriate number of 
capsules of temozolomide from each bottle or vial to equal the total daily dose 
prescribed by the physician. Institutions that have the capability to dispense 
temozolomide as daily doses in a blister pack may do so, taking specific 
precautions to ensure that the appropriate dose is provided and that the patient is 
educated to understand the daily dosing regimen. 
 
For children unable to swallow the capsules whole, the oral capsules may be 
formulated into a suspension. To prepare a 10 mg/mL suspension triturate the 
contents of ten 100 mg capsules (1000 mg), 500 mg povidone K-30 and 25 mg 
anhydrous citric acid dissolved in 1.5 mL purified water in a glass mortar to form a 
uniform paste. To the paste add 50 mL of Ora-Plus® by adding a small amount, 
mixing, and then adding the balance. Transfer to a glass graduated cylinder. Add 
Ora-Sweet® or Ora-Sweet® SF to a total volume of 100 mL by rinsing the mortar 
with small amounts of the syrup (Ora-Sweet® or Ora-Sweet® SF). Rinse at least 
four times. Package in an amber plastic prescription bottle. The packaged suspension 
is stable for 7 days at room temperature or 60 days in the refrigerator. The suspension 
should be shaken well before each use. Procedures for proper handling and disposal 
of cytotoxic drugs should be used when preparing the suspension.34 
 
Alternatively, the capsules can be opened and mixed with apple sauce or juice. 
 
9.4.5 
Supplier 
Commercially available. See package insert for further information.


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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12.0) 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6.0) 
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 17 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 pevonedistat (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
 
 
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) 
Death 
c) 
Lost to follow-up 
d) 
Withdrawal of consent for any required observations or data submission. 
e) 
Enrollment onto another COG therapeutic (anti-cancer) study  
f) 
Patient did not receive protocol treatment after study enrollment 


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11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
Part A1: Patients ≥ 12 months and ≤ 21 years of age: 
A minimum of 4 evaluable patients will be required to complete this dose escalation study 
if 2 subjects experience a dose limiting toxicity (DLT) at Dose Level 1 followed by 2 
subjects experiencing a DLT at Dose Level -1. The projected maximum number of 
evaluable patients is 24 which includes 6 patients at each of Dose Levels 1-3 as well as 6 
additional patients for PK analysis. Therefore, the projected maximum number of patients 
enrolled into this study allowing for 20% inevaluability is 30, and this number is expected 
to be accrued over 15-30 months. The study design includes several contingencies that may 
increase the maximum sample size if all contingencies are needed to estimate the MTD. A 
maximum of 53 patients may be possible in the unlikely scenario that dose levels 1-3 
require expansion to 12 patients plus 6 additional patients for steady state analysis and a 
20% inevaluable rate. The maximum sample size of 53 patients could accrue over 27-53 
months.  
 
Part A2: Patients ≥ 6 months and < 12 months of age: 
Patients enrolling on Part A2 of the study will enroll one dose level behind the dose level 
at which patients in Part A1 are enrolling. Up to 6 evaluable patients may enroll in each 
lagging dose level. Once the MTD is determined in Part A1, up to 6 evaluable patients may 
enroll onto the Part A1 MTD. If at any time 2 or more evaluable patients at a lagging dose 
level experience a DLT, Part A2 will close to further accrual. A maximum of 23 patients 
is anticipated for Part A2, which accounts for 20% inevaluability rate. 
 
Part A2 will open to enrollment on Dose Level 1 once Part A1 has escalated to Dose Level 
2. If the dose level assigned to patients in Part A1 is de-escalated, then patients in Part A2 
will continue on treatment at the assigned dose level and new patients will continue to be 
enrolled at this dose level as well. 
 
Amendment 5 (October 2019) 
Amendment 5 will add dose level 4 (35 mg/m2) to the dose escalation part of this study. 
This amendment will require a minimum of 2 evaluable patients and a maximum of 15 
additional patients. The maximum includes 6 patients at dose level 4, 6 additional patients 
for PK analysis, and 20% inevaluability. The current enrollment rate is approximately 1 
patient per month, and this number is expected to be accrued within 15 months. If dose 
level 4 is expanded to 12 patients due to DLTs of different classes, then the absolute 
maximum number of patients enrolled is 23. This would require up to 23 months for 
accrual. 
 
Part A2 is expected to enroll a maximum of 15 patients including 6 at dose level 3, 6 at 
dose level 4, and 20% inevaluability.  
 
As of 6/30/19, total of 18 patients have been enrolled in Part A1. No patients have enrolled 
in Part A2. Therefore, the maximum number of patients required to complete this study 
overall is expected to be 48, and the absolute maximum is 56. 
 
 
11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Events 
Any patient who receives at least one dose of the study drug(s) or who experiences 


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a dose-limiting toxicity is considered evaluable for Adverse Events. In addition, 
for the dose-escalation portion during Cycle 1, patients must receive all prescribed 
doses of pevonedistat and at least 85% of the prescribed dose of irinotecan and 
temozolomide 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. 
 
11.2.2 Maximum Tolerated Dose 
 
The MTD will be the maximum dose at which fewer than one-third of patients 
experience DLT (See Section 5.5) 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-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 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, the dose escalation can proceed. 
 
 
The DLTs observed in the pharmacokinetic (PK) expansion cohort will be 
counted towards the total number of DLTs observed at the MTD during the 
dose escalation portion of the study. If ≥ 1/3 of the cohort of patients at the 
MTD (during the dose escalation plus the PK expansion) experience DLT then 
the MTD will be exceeded.  
 
11.3 
Dose Escalation and Determination of MTD 
 
The rolling six phase 1 trial design will be used for the conduct of this study.35 Two to six 
patients can be concurrently enrolled onto a dose level, dependent upon (1) the number of 
patients enrolled at the current dose level, (2) the number of patients who have experienced 
DLT at the current dose level, and (3) the number of patients entered but with tolerability 
data pending at the current dose level. Accrual is suspended when a cohort of six has 
enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the 
cohort, the number of DLTs observed, and the number of participants at risk for developing 
a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, 
when three participants are enrolled onto a dose cohort, if toxicity data is available for all 
three when the fourth participant entered and there are no DLTs, the dose is escalated and 
the fourth participant is enrolled to the subsequent dose level. If data is not yet available 
for one or more of the first three participants and no DLT has been observed, or if one DLT 
has been observed, the new participant is entered at the same dose level. Lastly, if two or 
more DLTs have been observed, the dose level is de-escalated. This process is repeated for 
participants five and six. In place of suspending accrual after every three participants, 
accrual is only suspended when a cohort of six is filled. When participants are inevaluable 
for toxicity, they are replaced with the next available participant if escalation or de-
escalation rules have not been fulfilled at the time the next available participant is enrolled 


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onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose 
level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study 
is suspended to accrual: 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
3 
0 
3 
0 
Escalate** 
 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
 
4 
0 
4 
0 
Escalate** 
 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
 
5 
0 
5 
0 
Escalate** 
 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
the MTD has been exceeded and dose escalation will be stopped (see Section 11.2.2 for 
exception to rule). 
 
In addition to determination of the MTD, a descriptive summary of all toxicities will be 
reported. 
 
11.4 
Inclusion of Children, Women and Minorities 
 
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. 
 


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DOMESTIC 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 
3 
0 
0 
3 
Native Hawaiian 
or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
6 
3 
0 
0 
9 
White 
16 
19 
0 
0 
35 
More Than One 
Race 
0 
3 
0 
0 
3 
Unknown or not 
reported 
0 
3 
0 
3 
6 
Total 
22 
31 
0 
3 
56 
 
11.5 
Pharmacokinetic and Pharmacodynamic Studies and Response Analysis 
 
A descriptive analysis of pharmacokinetic (PK) parameters of 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 pevonedistat, patients will 
have disease evaluations performed as indicated in Section 8.1. Disease response will be 
assessed according to RECIST criteria for patients with solid tumors, and will be reported 
descriptively. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
 
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 web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
12.2 
Response Criteria for Patients with Solid Tumors  
See the table in Section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained on the next consecutive cycle 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).36  Key points are 
that 5 target lesions are identified and that changes in the largest diameter (unidimensional 
measurement) of the tumor lesions but the shortest diameter of malignant lymph nodes are 
used in the RECIST v 1.1 criteria. 
 


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12.2.1 Definitions 
 
12.2.1.1 Evaluable for objective response: Eligible patients who receive at least 
one dose of protocol therapy will be considered evaluable for response. 
Evaluable patients who demonstrate a complete or partial response 
confirmed by central review before receiving non-protocol anti-cancer 
therapy will be considered a responder. All other evaluable patients will 
be considered non-responders. 
 
12.2.1.2 Evaluable Non-Target Disease Response: Eligible patients who have 
lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease and have received at least one dose of 
protocol therapy will be considered evaluable for non-target disease. 
The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
 
12.2.2 Disease Parameters 
 
12.2.2.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 
mm with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
NOTE: Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable. If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
12.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
12.2.2.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis), are considered non-measurable 
disease. 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
NOTE: Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, 
these are preferred for selection as target lesions. 
 
12.2.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 


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organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion that can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
12.2.2.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
12.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
12.2.3.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and  10 mm diameter as assessed using calipers (e.g., skin nodules). In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
12.2.3.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable.  
 
12.2.3.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 


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12.2.3.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.2.3.5 Tumor markers: Tumor markers alone cannot be used to assess 
response. If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
12.2.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.2.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD. If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
NOTE: A ‘positive’ FDG-PET scan lesion means one that is FDG 
avid with an uptake greater than twice that of the surrounding 
tissue on the attenuation corrected image. 
 
 
12.2.4 Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.2.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 


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target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology. 
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
(Note:  the appearance of one or more new lesions 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
12.2.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, 


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not a single lesion increase.     
 
12.2.5 Overall Response Assessment 
 
Table 2. For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 28 days Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once ≥ 
28 days from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
Table 3. For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 4. Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 


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12.2.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
12.3.1 Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately measured 
in at least one dimension.  Such lesions may be evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers or other reliable 
measures.  
 
12.3.2 Complete Response 
Disappearance of all evaluable disease. 
 
12.3.3 Partial response 
Partial responses cannot be determined in patients with evaluable disease. 
 
12.3.4 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), 
or Progressive Disease. 
 
12.3.5 Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
12.3.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.4.1 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
12.4.2 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
12.4.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 


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for study endpoint. See Section 8.2.1 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 


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12.4.4 Overall Response Assessment 
 
Table 5. Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease 
Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered 
progressive disease. 
 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
12.4.5 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Table 6 in Section 12.7. 
 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
12.5.1 Bone Marrow Involvement  
Bone marrow obtained within 28 days prior to study enrollment with tumor cells 
seen on routine morphology (not by immunohistochemical staining only) of 
bilateral aspirate or biopsy on one bone marrow sample. 
 
Bone Marrow responses are determined by H&E Staining of bilateral bone marrow 
biopsies and aspirates. 
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 


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or aspirations done at least 21 days apart. 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
12.5.2 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.7. 
 
12.6 
Response Criteria for Patients with CNS Tumors 
 
12.6.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
12.6.2 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
12.6.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
12.6.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
 
Complete Response (CR): Disappearance of all target lesions. 
 
 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements. 
 
 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD. 


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 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
12.6.5 Response Criteria for Non-Target Lesions: 
 
 
Complete Response (CR): Disappearance of all non-target lesions. 
 
 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
12.6.6 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
12.6.7 Overall Response Assessment: 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 
2BTarget Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect. Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
 


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12.7 
Best Response 
 
12.7.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Table 6.  Sequences of overall response assessments with corresponding best response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
12.7.2 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements. 


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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. 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 web 
site 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 
 
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. 
 


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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 below under the 
section entitled “Additional Instructions or Exceptions.” 
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, 
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. 
 


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 
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. 
 
 Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), does 
not require expedited reporting, unless it is associated with hospitalization. 
Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
 
Grade 1 and 2 adverse events listed in the table below do not require expedited reporting via 
CTEPAERS, unless it is associated with hospitalization 
 
Category 
Adverse Events 
GASTROINTESTINAL DISORDERS 
Nausea 
GASTROINTESTINAL DISORDERS 
Vomiting 
GASTROINTESTINAL DISORDERS 
Diarrhea 
GASTROINTESTINAL DISORDERS 
Constipation 
GASTROINTESTINAL DISORDERS 
Decreased appetite 
GASTROINTESTINAL DISORDERS 
Abdominal distension 
GASTROINTESTINAL DISORDERS 
Stomatitis 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Fever 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Peripheral edema 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Fatigue 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Pain 
INFECTIONS AND INFESTATIONS 
Infection 
INVESTIGATIONS 
Alanine aminotransferase increased 
INVESTIGATIONS 
Aspartate aminotransferase increased 
INVESTIGATIONS 
Alkaline phosphatase increased 
INVESTIGATIONS 
GGT increased 
INVESTIGATIONS 
Blood bilirubin increased 
INVESTIGATIONS 
Creatinine increased 
METABOLISM AND NUTRITION 
DISODERS 
Dehydration 
METABOLISM AND NUTRITION 
Hypophosphatemia 


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DISODERS 
MUSCOLOSKELETAL AND 
CONNECTIVE TISSUE DISORDERS 
Myalgia 
MUSCOLOSKELETAL AND 
CONNECTIVE TISSUE DISORDERS 
Arthralgia 
MUSCOLOSKELETAL AND 
CONNECTIVE TISSUE DISORDERS 
Muscle Spasms 
NERVOUS SYSTEM DISORDERS 
Dizziness 
NERVOUS SYSTEM DISORDERS 
Headache 
NERVOUS SYSTEM DISORDERS 
Peripheral neuropathy 
NERVOUS SYSTEM DISORDERS 
Paresthesia 
PSYCHIATRIC DISORDERS 
Anxiety 
PSYCHIATRIC DISODERS 
Confusion 
PSYCHIATRIC DISODERS 
Insomnia 
RENAL AND URINARY DISODERS 
Dysuria 
REPIRATORY, THORACIC AND 
MEDISTINAL DISORDERS 
Cough 
REPIRATORY, THORACIC AND 
MEDISTINAL DISORDERS 
Nasal congestion 
RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS 
Dyspnea 
REPIRATORY, THORACIC AND 
MEDISTINAL DISORDERS 
Wheezing 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Night sweats 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Pruritus 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS  
Rash 
 
 
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 (email the ADVL1615 COG study assigned Research 
Coordinator 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. 
 
13.3 
Expedited Reporting Methods  


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13.3.1 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 by email to the ADVL1615 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. 
 
13.4.1 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. 
 
13.4.2 If an adverse event progresses through several grades during one course of therapy, 
only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) grade 
of the Adverse Effects.  
 
13.4.4 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."   
 
13.4.5 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 
 
13.5.1 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). 
 
13.5.2 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 industry 
sponsored trials). 
 
13.5.3 Adverse events determined to be reportable must also be reported according to the 


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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 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 
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 
ADVL1615 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. 
 
13.7.1 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 
“Pregnancy, puerperium and perinatal conditions - Other (Pregnancy) 
under the Pregnancy, puerperium and perinatal conditions SOC and 
reported as Grade 3. 
 
 
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 


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required. 
 
13.7.2 Pregnancy Loss (Fetal Death) 
 
Pregnancy loss is defined in CTCAE version 5.0 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 recognized any Grade 5 event as a patient death. 
 
13.7.3 Death Neonatal 
 
Neonatal death, defined in CTCAE version 5.0 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. 
 
 
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. 
 
 
Neonatal death should NOT be reported as “Death neonatal” under the 
General disorders and administration SOC, a Grade 5 event. If reported as 
such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
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.  


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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 by FTP burst of data.  Reports are due January 31, April 30, July 
31, and October 31.  Instructions for submitting data using the CDUS can be found on the 
CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
14.3 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.3.1 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. 
 
14.3.2 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 COG 
PEP-CTN Chair, Vice Chair, and Statistician on a weekly conference call. 


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REFERENCES 
 
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Bhatia S, Pavlick A, Boasberg P, et al: A phase I study of the investigational NEDD8-activating 
enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma. Invest 
New Drugs 34:439-49, 2016 
2. 
Erba H, Swords, R, DeAngelo, D, Bixby, D, Pickard, M, Mulligan, G, Kuan, S, Smith, P, Dezube, 
B, Giles, F, Medeiros, B: MLN4924, A Novel Investigational NEDD8-Activating Enzyme (NAE) 
Inhibitor in Adult Patients with Acute Myeloid Leukemia (AML) or High-Grade Meylodysplastic 
Syndromes (MDS): Results from a Phase I Study. European Hematology Association:abstract 
#0068, 2011 
3. 
Sarantopoulos J, Shapiro GI, Cohen RB, et al: Phase I Study of the Investigational NEDD8-
activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid 
Tumors. Clin Cancer Res, 2015 
4. 
Shah J, Jakubowiak A, O'Connor O, et al: Phase I Study of the Novel Investigational NEDD8-
Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory 
Multiple Myeloma or Lymphoma. Clin Cancer Res 22:34-43, 2016 
5. 
Swords R, Erba H, DeAngelo D, 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 
6. 
PF E, NG C, G K, et al: A Description of the Surgical Experience in Children, Adolescents and 
Young Adults with Renal Cell Carcinoma: A Report from the Children's Oncology Group Study 
AREN 03B2. BJU International 110:18, 2012 
7. 
Lin J, Milhollen M, Smith P, et al: NEDD8-targeting drug MLN4924 elicits DNA rereplication by 
stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer 
cells. Cancer Res 70:10310-20, 2010 
8. 
Milhollen M, Narayanan U, Soucy T, et al: Inhibition of NEDD8-activating enzyme induces 
rereplication and apoptosis in human tumor cells consistent with deregulating CDT1 turnover. 
Cancer Res 71:3042-51, 2011 
9. 
Soucy T, Smith P, Milhollen M, et al: An inhibitor of NEDD8-activating enzyme as a new approach 
to treat cancer. Nature 458:732-6, 209 
10. 
Swords R, Kelly K, Smith P, et al: Inhibition of NEDD8-activating enzyme: a novel approach for 
the treatment of acute myeloid leukemia. Blood 115:3796-800, 2010 May 6 
11. 
Jia L, Li H, Sun Y: Induction of p21-dependent senescence by an NAE inhibitor, MLN4924, as a 
mechanism of growth suppression. Neoplasia 13:561-9, 2011 
12. 
Liao H, Liu X, Blank J, et al: Quantitative proteomic analysis of cellular protein modulation upon 
inhibition of the NEDD8-activating enzyme by MLN4924. Mol Cell Proteomics 10, 2011 
13. 
Milhollen M, Traore T, Adams-Duffy J, et al: MLN4924, a NEDD8-activating enzyme inhibitor, 
is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-
dependent lymphoma. Blood 116:1515-23, 2010 
14. 
Bagatell R, London W, Wagner L, et al: Phase II study of irinotecan and temozolomide in children 
with relapsed or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 
29:208-13, 2011 
15. 
Bagatell R, Norris R, Ingle A, et al: Phase 1 trial of temsirolimus in combination with irinotecan 
and temozolomide in children, adolescents and young adults with relapsed or refractory solid 
tumors: a Children's Oncology Group Study. Pediatr Blood Cancer 61:833-9, 2014 
16. 
Casey D, Wexler L, Merchant M, et al: Irinotecan and temozolomide for Ewing sarcoma: the 
Memorial Sloan-Kettering experience. Pediatr Blood Cancer 53:1029-34, 2009 
17. 
Hargrave D, Geoerger B, Frappaz D, et al: A phase II single-arm study of irinotecan in combination 
with temozolomide (TEMIRI) in children with newly diagnosed high grade glioma: a joint ITCC 
and SIOPE-brain tumour study. J Neurooncol 113:127-34, 2013 
18. 
McNall-Knapp R, Williams C, Reeves E, et al: Extended phase I evaluation of vincristine, 


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irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood 
Cancer 54:909-15, 2010 
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Mixon B, Eckrich M, Lowas S, et al: Vincristine, irinotecan, and temozolomide for treatment of 
relapsed alveolar rhabdomyosarcoma. J Pediatr Hematol Oncol 35:e16306, 2013 
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Raciborsk aA, Bilska K, Drabko K, et al: Vincristine, irinotecan, and temozolomide in patients with 
relapsed and refractory Ewing sarcoma. Pediatr Blood Cancer 60:1621-5, 2013 
21. 
Wagner L, Villablanca J, Stewart C, et al: Phase I trial of oral irinotecan and temozolomide for 
children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy 
consortium study. J Clin Oncol 27:1290-6, 2009 
22. 
Wagner LM, Perentesis JP, Reid JM, et al: Phase I trial of two schedules of vincristine, oral 
irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a 
Children's Oncology Group phase I consortium study. Pediatr Blood Cancer 54:538-45, 2010 
23. 
Garcia K, Blank J, Bouck D, et al: Nedd8-activating enzyme inhibitor MLN4924 provides synergy 
with mitomycin C through interactions with ATR, BRCA1/BRCA2, and chromatin dynamics 
pathways. Mol Cancer Ther 13:1625-35, 2014 
24. 
Traore T, Mihollen M, Garnsey J, et al: Antitumor Activity of MLN4924, an investigational 
inhibitor of NEDD8-activating enzyme (NAE), in preclinical models of melanoma., ASCO. 
Chicago, IL, J Clin Oncol, 2011 
25. 
Smith M, Maris J, 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 
26. 
Massari F, Santoni M, Ciccarese C, et al: PD-1 blockade therapy in renal cell carcinoma: current 
studies and future promises. Cancer Treat Rev 41:114-21, 2015 
27. 
Kauh J, Cohen R, Clarke J, et al: Pharmacodynamic effetcs of MLN4924, a novel NAE inhibitor, 
on blood and skin. J Clin Oncol 27:suppl; abstr 2562, 2009 
28. 
Lockhart AC, Bauer TM, Aggarwal C, et al: Phase Ib study of pevonedistat, a NEDD8-activating 
enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in 
patients with advanced solid tumors. Investigational New Drugs 37:87-97, 2019 
29. 
Swords RT, Coutre S, Maris MB, et al: Pevonedistat, a first-in-class NEDD8-activating enzyme 
(NAE) inhibitor, combined with azacitidine, in patients with AML. Blood:blood-2017-09-805895, 
2018 
30. 
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 
31. 
MLN4924 Investigator's Brochure, Edition 10. 2018 
32. 
Shah JJ, Jakubowiak AJ, O'Connor OA, et al: Phase I Study of the Novel Investigational NEDD8-
Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory 
Multiple Myeloma or Lymphoma. Clinical Cancer Research 22:34-43, 2016 
33. 
Foster J, Muscal JA, Minard CG, et al: Phase 1 study of pevonedistat (MLN4924) in combination 
with temozolomide (TMZ) and irinotecan (IRN) in pediatric patients with recurrent or refractory 
solid tumors (ADVL1615). Journal of Clinical Oncology 37:e21521-e21521, 2019 
34. 
Trissel LA , Zhang Y, SE K: Temozolomide stability in extemporaneously compounded oral 
suspensions. Int J Pharm Compd 19, 2006 
35. 
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 
36. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
37. 
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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Page 79 
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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Page 80 
APPENDIX II:  
CORRELATIVE STUDIES GUIDE  
 
Correlative Study 
Appx. 
Sample Volume 
 
Tube Type 
Volume 
per 
sample 
Total Volume 
For subjects  
≥ 10 kg  
For subjects  
< 10 kg 
Pharmacokinetics (PK) 
(required) 
X 
2 - 3 mL 
30 - 45 mL 
22 - 33 mL 
Vacutainer 
tubes 
Pharmacodynamics (PD)*  
(optional) 
XI 
2 mL 
18 mL  
18 mL 
Yellow-top 
Citrate 
vacutainer 
tubes 
Total Blood Volume 
30 - 63 mL 
22 - 51 mL   
*Not applicable for patients < 12 months.


 
 
 
 
 
 
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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 ALT 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 AST 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 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN - 5.0 x ULN 
Grade 3: 
> 5.0 x ULN -20.0 x ULN 
Grade 4: 
> 20.0 x ULN 


 
 
 
 
 
 
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APPENDIX IV:  
 
TEMOZOLOMIDE ORAL CAPSULES DOSING NOMOGRAMS 
 
For the starting dose of 100 mg/m2/dose: 
 
BSA (m2) 
Total pill count 
Calculated dose (mg) 
Actual dose (mg) 
0.2-0.22* 
1 
20-22 
20 
0.23-0.27 
2 
23-27 
25 
0.28-0.32 
3 
28-32 
30 
0.33-0.37 
4 
33-37 
35 
0.38-0.42 
2 
38-42 
40 
0.43-0.47 
4 
43-47 
45 
0.48-0.52 
3 
48-52 
50 
0.53-0.57 
5 
53-57 
55 
0.58-0.62 
3 
58-62 
60 
0.63-0.67 
4 
63-67 
65 
0.68-0.72 
5 
68-72 
70 
0.73-0.77 
6 
73-77 
75 
0.78-0.82 
4 
78-82 
80 
0.83-0.87 
5 
83-87 
85 
0.88-0.92 
6 
88-92 
90 
0.93-0.97 
7 
93-97 
95 
0.98-1.02 
1 
98-102 
100 
1.03-1.07 
2 
103-107 
105 
1.08-1.12 
3 
108-112 
110 
1.13-1.17 
4 
113-117 
115 
1.18-1.23 
2 
118-123 
120 
1.24-1.28 
3 
124-128 
125 
1.29-1.33 
4 
129-133 
130 
1.34-1.37 
5 
134-137 
135 
1.38-1.42 
1 
138-142 
140 
1.43-1.47 
2 
143-147 
145 
1.48-1.52 
3 
148-152 
150 
1.53-1.57 
4 
153-157 
155 
1.58-1.62 
2 
158-162 
160 
1.63-1.67 
3 
163-167 
165 
1.68-1.72 
4 
168-172 
170 
1.73-1.77 
5 
173-177 
175 
1.78-1.82 
1 
178-182 
180 
1.83-1.87 
2 
183-187 
185 
1.88-1.92 
3 
188-192 
190 
1.93-1.97 
4 
193-197 
195 
1.98-3 
2 
198-300 
200 
 


 
 
 
 
 
 
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For the reduced dose of 75 mg/m2/dose (75% of starting dose): 
 
BSA (m2) 
Total pill count 
Calculated dose (mg) 
Actual dose (mg) 
0.2-0.23 
3 
15-17.25 
15 
0.24-0.3 
1 
18-22.5 
20 
0.31-0.36 
2 
23.25-27 
25 
0.37-0.43 
3 
27.75-32.25 
30 
0.44-0.5 
4 
33-37.5 
35 
0.51-0.56 
2 
38.25-42 
40 
0.57-0.63 
3 
42.75-47.25 
45 
0.64-0.7 
4 
48-52.5 
50 
0.71-0.76 
5 
53.25-57 
55 
0.77-0.83 
3 
57.75-62.25 
60 
0.84-0.9 
4 
63-67.5 
65 
0.91-0.96 
5 
68.25-72 
70 
0.97-1.03 
6 
72.75-77.25 
75 
1.04-1.1 
4 
78-82.5 
80 
1.11-1.17 
5 
83.25-87.75 
85 
1.18-1.23 
6 
88.5-92.25 
90 
1.24-1.3 
7 
93-97.5 
95 
1.31-1.36 
1 
98.25-102 
100 
1.37-1.43 
2 
102.75-107.25 
105 
1.44-1.5 
3 
108-112.5 
110 
1.51-1.57 
4 
113.25-117.75 
115 
1.58-1.64 
2 
118.5-123 
120 
1.65-1.7 
3 
123.75-127.5 
125 
1.71-1.77 
4 
128.25-132.75 
130 
1.78-1.83 
5 
133.5-137.25 
135 
1.84-1.9 
1 
138-142.5 
140 
1.91-1.97 
2 
143.25-147.75 
145 
1.98-3 
3 
148.5-225 
150 
 
 


 
 
 
 
 
 
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Page 84 
APPENDIX V: 
UNACCEPTABLE ENZYME-INDUCING AND RECOMMENDED NON-
ENZYME INDUCING ANTICONVULSANTS 
 
 
 
 
 
Recommended Non-enzyme inducing 
anticonvulsants 
 
Generic Name 
Clonazepam 
Diazepam 
Ethosuximide 
Ezogabine 
Gabapentin 
Lacosamide 
Lamotrigine 
Levetiracetam 
Lorazepam 
Perampanel 
Tiagabine 
Topiramate 
Valproic Acid 
Zonisamide 
 
Unacceptable Enzyme inducing 
anticonvulsants 
 
Generic Name 
Carbamazepine 
Felbamate 
Phenobarbital 
Fosphenytoin 
Phenytoin 
Primidone 
Oxcarbazepine 


 
 
 
 
 
 
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APPENDIX VI:  
POTENTIAL DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
Cefixime 
Drugs that may interact with cefixime 
 Aminoglycoside antibiotics (such as gentamicin, tobramycin) 
 Oral contraceptives (“birth control”) 
 Probenecid 
 Warfarin 
Food and supplements** that may interact with cefixime 
 
Thuja 
** Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
Irinotecan 
Drugs that may interact with irinotecan 
 Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
 Antidepressants and antipsychotics  
o Citalopram, clozapine, desipramine, nefazodone, sertraline 
 Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
 Arthritis medications  
o Leflunomide, tofacitinib 
 Anti-rejection medications 
o Cyclosporine, tacrolimus 
 Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, 
tipranavir 
 Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
 Heart medications  
o Amiodarone, dronedenarone, diltiazem, verapamil 
 Some chemotherapy (be sure to talk to your doctor about this) 
 Many other drugs, including the following: 
o Bosentan, sitaxentan, aprepitant, dexamethasone, ivacaftor, lomitapide, mifepristone, 
natalizumab, succinylcholine 
Food and supplements** that may interact with irinotecan 
 
Echinacea 
 
St. John’s Wort 
 
Some fruits and juices: grapefruit, grapefruit juice, Star fruit 
** Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 


 
 
 
 
 
 
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Temozolomide 
Drugs that may interact with temozolomide  
 
Clozapine 
 
Leflunomide 
 
Natalizumab 
 
Tofacitinib  
Food and supplements that may interact with temozolomide**  
 
Echinacea 
** Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
PEVONEDISTAT 
Drugs that may interact with pevonedistat 
 Antibiotics  
o Clarithromycin, rifabutin, rifampin, telithromycin 
 Antidepressants and antipsychotics  
o Nefazodone 
 Antifungals  
o Itraconazole, ketoconazole, posaconazole, voriconazole 
 Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, indinavir, lopinavir, nelfinavir,  ritonavir, 
saquinavir, Stribild, telaprevir 
 Anti-seizure medications  
o Carbamazepine, phenobarbital, phenytoin, primidone 
 Many other drugs, including the following: 
Enzalutamide, cyclosporine, eltrombopag, gefitinib 
Food and supplements** that may interact with pevonedistat 
 
St. John’s Wort 
 
Some fruits and juices: grapefruit, grapefruit juice, Star fruit 
** Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
 
 


 
 
 
 
 
 
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APPENDIX VII:  
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 
alfentanil4,5  
acalabrutinib5 
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 
ergotamine4 
erlotinib 
eplerenone5 
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  
telaprevir 
tamoxifen 
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 4.2.6.1 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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APPENDIX VIII:   
PATIENT INSTRUCTIONS FOR TREAT DIARRHEA 
 
Guidelines for the Treatment of Diarrhea 
 
Institutional practice may be used in place of these guidelines. 
 
You should purchase or will be given a prescription for loperamide to have available to begin treatment at 
the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent 
than normally expected for the patient. Patients will also be instructed to contact their physician if any 
diarrhea occurs. Patients will be given loperamide based on body weight.  
 
Be aware of your child's bowel movements. At the first sign they become softer than usual or if your child 
has any notable increase in the number of bowel movements over what is normal for him/her, begin taking 
loperamide.  
 
Please follow these directions carefully, using dosing guidelines below: 
 
Take _____________ at the first sign of diarrhea. 
 Continue taking __________ every __ hours until the diarrhea slows or the normal pattern of 
bowel movements returns. Repeat the same doses and frequency if the diarrhea returns. 
 Do not exceed ___________ in a 24 hour period. 
 Please call your doctor if you have any questions about taking loperamide, if your child's diarrhea 
is not under control after two days, or if he/she is feeling extremely weak, lightheaded, or dizzy. 
 Make an extra effort to give your child lots of fluids (several glasses of pedialyte, fruit juices, 
soda, soup, etc.) while your child is participating in this study. 
 Side effects may include tiredness, drowsiness or dizziness. If your child experiences these side 
effects, or if your child is urinating less frequently than usual, please contact your child's 
physician. 
 
Do not give your child any laxatives without consulting with his/her physician.


 
 
 
 
 
 
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LOPERAMIDE DOSING RECOMMENDATIONS 
(NOTE: maximum dose of loperamide for adults is 16 mg/day) 
ALL patients: discontinue loperamide when the patient is no longer experiencing significant diarrhea. 
Weight (kg) 
ACTION 
<13 kg   
Take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral solution) after 
the first loose bowel movement, followed by 0.5 mg (2.5 mL [one-half 
teaspoonful] of the 1 mg/5 mL oral solution) every 3 hours.  During the night, the 
patient may take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral 
solution) every 4 hours.  Do not exceed 4 mg (20 mL or 4 teaspoonfuls) per day. 
 
≥ 13 kg to < 20 kg 
Take 1 mg (5 mL [1 teaspoonful] of the 1 mg/5 mL oral solution or one-half tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] 
of the 1 mg/5 mL oral solution or one-half tablet) every 3 hours. During the night, 
the patient may take 1 mg (5 mL [one teaspoonful] of the 1 mg/5 mL oral solution 
or one-half tablet) every 4 hours.  Do not exceed 6 mg (30 mL or 6 teaspoonfuls) 
per day. 
 
≥ 20 kg to < 30 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] 
of the 1 mg/5 mL oral solution or one-half tablet) every 3 hours.  During the night, 
the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution 
or 1 tablet) every 4 hours. Do not exceed 8 mg (40 mL or 8 teaspoonfuls) per day. 
 
≥ 30 kg to < 43 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] 
of the 1 mg/5 mL oral solution or one-half tablet) every 2 hours.  During the night, 
the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution 
or 1 tablet) every 4 hours. Do not exceed 12 mg (60 mL or 12 teaspoonfuls) per 
day. 
 
Over 43 kg 
Take 4 mg (20 mL [4 teaspoonfuls] of the 1 mg/5 mL oral solution or 2 capsules 
or tablets) after the first loose bowel movement, followed by 2 mg (10 mL 
[2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 capsule or tablet) every 
2 hours.  During the night, the patient may take 4 mg (20 mL [4 teaspoonfuls] of 
the 1 mg/5 mL oral solution or 2 capsules or tablets) every 4 hours. Do not exceed 
16 mg (80 mL or 16 teaspoonfuls) per day. 
 
 


 
 
 
 
 
 
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APPENDIX IX:  NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC 
DISEASE  
 
The following table presents the New York Heart Association classification of cardiac disease.37 
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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APPENDIX X:  
PHARMACOKINETICS 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  
 
Pevonedistat Dose Level: ______mg/m2     
Pevonedistat Total Daily Dose: ______mg 
 
Blood samples (2-3 ml) will be collected in chilled Vacutainer tubes at the following time points (± 10 min): Day 
1 (pre-dose, end of infusion, 1 hr, 2 hrs, 4 hrs, 6-8 hrs, and 24 hrs after Day 1 dose); Day 8 (pre-dose, end of 
infusion, 1 hr, 2 hrs, 4 hrs, 6-8 hrs, and 24 hrs after Day 8 dose); and Day 10 (pre-dose) of Cycle 1. 
 
Record the exact time the sample is drawn along with the exact time pevonedistat is given on Days 1, 8, 15, and 22.  
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time Sample 
Collected 
(24-hr clock) 
1 
Day 1 
Prior to pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
Pevonedistat Dose on Day 1 
Date:___/___/___ 
Infusion Start Time: |__|__| : |__|__| 
Infusion Stop Time: |__|__| : |__|__| 
2 
Day 1 
End of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
3* 
Day 1 
1 hr after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
4 
Day 1 
2 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
5* 
Day 1 
4 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
6 
Day 1 
7 (±1) hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
7 
Day 1 
24 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
8 
Day 8 
Prior to pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
Pevonedistat Dose on Day 8 
Date:___/___/___  
Infusion Start Time: |__|__| : |__|__| 
Infusion Stop Time: |__|__| : |__|__| 
9 
Day 8 
End of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
10* 
Day 8 
1 hr after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
11 
Day 8 
2 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
12* 
Day 8 
4 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
13 
Day 8 
7 (±1) hrs after end of pevonedistat 
infusion 
___/___/___ 
|__|__| : |__|__| 
14 
Day 8 
24 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
15 
Day 10 
Prior to pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
Pevonedistat Dose on Day 10 
Date:___/___/___ 
Infusion Start Time: |__|__| : |__|__| 
Infusion Stop Time: |__|__| : |__|__| 
* Collections not required for patients < 10 kg 
NOTE: Patients who are removed from therapy during Cycle 1 after receiving the dose on Day 8 should still have 
the Day 8 sample collected. 
 
One copy of this Pharmacokinetics 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 Appendix X-A for detailed guidelines for packaging and shipping 
PK samples. 
 
Signature: _________________________________________                    Date: ___________________ 
 
 
(Site personnel responsible for collection of samples) 
 
 
 


 
 
 
 
 
 
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APPENDIX X-A:  GUIDELINES FOR SHIPPING SAMPLES TO COVANCE-MADISON 
 
Regulatory Information 
 
Specific Federal and International Regulations define classes of “Hazardous Materials” 0F and “Dangerous Goods”1F.  Specimens 
transported to the Covance Madison - 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 2F 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. 
 
Guidelines for Packaging Samples 
 
Please organize samples by subject where possible (i.e. box all of subject 001 together, with dividers  
all of subject 002 together with dividers, etc ) 
 
1. Sample container caps should be securely fastened. 
a. Samples should not be transported in glass vials.  Samples should be transferred to plastic 
tubes for transport. 
(If glass must be used, containers must be immobilized.  Note: the use of glass greatly 
increases the risk of breakage and sample loss).  
b. Use labels that will not smear or fall off under cold or moist conditions.   
 
2. Samples should be placed in a primary receptacle (insulated cooler), then into a secondary 
receptacle (sturdy cardboard box).  These primary and secondary containers are available 
commercially as combination packaging. The package contents are placed in this order: 
a. Wrap the samples in enough absorbent material to absorb at least three times the contents 
should leakage occur. 
b. Place the wrapped samples in a plastic bag and seal (heat seal or zip lock) 
c. Place the sealed bag in the bottom of the primary receptacle. 
d. Add styrofoam peanuts or equivalent (barrier to dry ice and shock stabilizer) 
e. Add a sheet of cardboard onto the top of the primary receptacle. 
f. If samples are to be frozen, adequate dry ice should be included in the container to last 
the duration of the journey.  (48-72 hrs, at least 7 Kg or 15 pounds, approximately 4 
pounds per day of transit).   
g. If there is room remaining, add filler material to avoid content movement during 
transport.   
h. The primary Styrofoam container should be taped shut and placed in the secondary 
cardboard container. 
 
3. Complete a sample inventory form.  A copy of an example form is attached.  If possible please 
send this electronically (i.e. Excel file) and include all information that would be required in final 
data tables.  Please indicate sample storage conditions on inventory form.   
 
                                                     
  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 
 


 
 
 
 
 
 
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4. Seal the sample inventory form(s) into a protected plastic bag.  Place the plastic bag containing 
the sample inventory form(s) on top of the secured styrofoam primary container lid so that it is 
immediately accessible upon opening the box. 
 
5. Tape the shipping box securely closed.  Use tape that is resistant to moisture and cold. 
 
6. Place Biohazard warnings on outside of box (if applicable). 
 
7. Label the box exterior in accordance with the applicable DOT CFR / IATA Regulations. 
 
8. Complete an address label and attach it to the outside of the box.   
 
****************************************************************************** 
Guidelines for Shipping Samples 
 
Send samples to: 
 
For Shipments: 
Mohammad Koupaei, PhD 
Covance Bioanalytical Laboratory Services Inc. 
3301 Kinsman Boulevard 
Madison, WI 53704-2523 
Attn:  Sample Management—Bioanalytical (Rm131D 1S) 
 
1. Samples should be shipped least 2 days prior to a USA National Holiday. 
 
2. Frozen samples should not be shipped after Wednesday (samples should arrive at Covance by 
Friday, not on Saturday or Sunday) 
 
3. Call the Covance Bioanalytical Services Sample Management department on the day prior to 
shipment  (1-888-541-7377 Ext 2540,  Ext 2187,  or Ext 2327), as notification of the intended 
shipment, OR e-mail Madison.SA@Covance.com with shipment information (tracking numbers 
and number of boxes sent).  
 
4. Samples to be shipped to the United States from outside the U.S.A., should be shipped using 
an International carrier.  The name of the carrier, shipping date, expected date of arrival, and 
tracking numbers should be e-mailed to Madison.SA@Covance.com and 
mohammad.koupaei@covance.com and matthew.dodge@covance.com with a copy to the study-
specific Research Coordinator, prior to shipment. 
 
5. Any questions regarding shipping instructions may be directed to the Sample Management Group 
at 1-888-541-7377 Ext 2540,  Ext 2187,  or Ext 2327, or via   
Fax 608-245-7082.  International phone code is 001. 
 
 


 
 
 
 
 
 
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APPENDIX XI:  
PHARMACODYNAMICS 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  
 
Pevonedistat Dose Level: ______mg/m2     
Pevonedistat Total Daily Dose: ______mg 
 
Blood samples (2-3 ml) will be collected in yellow-top Citrate vacutainer  tubes at the following time points (± 
10 min): Day 1 (pre-dose, 2 hrs, 4 hrs, 6-8 hrs, and 24 hrs after Day 1 dose); Day 8 (pre-dose,, 2 hrs, 4 hrs, 6-8 hrs, 
and 24 hrs after Day 8 dose); and Day 10 (pre-dose) of Cycle 1. 
 
Record the exact time the sample is drawn along with the exact time pevonedistat is given on Days 1, 8, 15, and 
22. 
 
 
 
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time Sample 
Collected 
(24-hr clock) 
1 
Day 1 
Prior to pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
Pevonedistat Dose on Day 1 
Date:___/___/___ 
Infusion Start Time: |__|__| : |__|__| 
Infusion Start Time: |__|__| : |__|__| 
2 
Day 1 
2 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
3 
Day 1 
7 (±1) hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
4 
Day 1 
24 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
5 
Day 8 
Prior to pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
Pevonedistat Dose on Day 8 
Date:___/___/___  
Infusion  Start Time: |__|__| : |__|__| 
Infusion Stop Time: |__|__| : |__|__| 
6 
Day 8 
2 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
7 
Day 8 
7 (±1) hrs after end of pevonedistat 
infusion 
___/___/___ 
|__|__| : |__|__| 
8 
Day 8 
24 hrs after end of pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
9 
Day 10 
Prior to pevonedistat infusion 
___/___/___ 
|__|__| : |__|__| 
Pevonedistat Dose on Day 10 
Date:___/___/___  
Infusion  Start Time: |__|__| : |__|__| 
Infusion Stop Time: |__|__| : |__|__| 
* Collections not required for patients < 10 kg 
NOTE: Patients who are removed from therapy during Cycle 1 after receiving the dose on Day 8 should still have 
the Day 8 sample collected. 
 
One copy of this Pharmacodynamics 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 samples. 
 
Signature: _________________________________________                    Date: ___________________ 
 
(Site personnel responsible for collection of samples) 


 
 
 
 
 
 
                          
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APPENDIX XII:  BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT PERCENTILE 
 
Blood pressure (BP) levels for BOYS  
 
 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) 
Percentile 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
99th 
105 
106 
108 
110 
112 
113 
114 
61 
62 
63 
64 
65 
66 
66 
2 
99th 
109 
110 
111 
113 
115 
117 
117 
66 
67 
68 
69 
70 
71 
71 
3 
99th 
111 
112 
114 
116 
118 
119 
120 
71 
71 
72 
73 
74 
75 
75 
4 
99th 
113 
114 
116 
118 
120 
121 
122 
74 
75 
76 
77 
78 
78 
79 
5 
99th 
115 
116 
118 
120 
121 
123 
123 
77 
78 
79 
80 
81 
81 
82 
6 
99th 
116 
117 
119 
121 
123 
124 
125 
80 
80 
81 
82 
83 
84 
84 
7 
99th 
117 
118 
120 
122 
124 
125 
126 
82 
82 
83 
84 
85 
86 
86 
8 
99th 
119 
120 
122 
123 
125 
127 
127 
83 
84 
85 
86 
87 
87 
88 
9 
99th 
120 
121 
123 
125 
127 
128 
129 
84 
85 
86 
87 
88 
88 
89 
10 
99th 
122 
123 
125 
127 
128 
130 
130 
85 
86 
86 
88 
88 
89 
90 
11 
99th 
124 
125 
127 
129 
130 
132 
132 
86 
86 
87 
88 
89 
90 
90 
12 
99th 
126 
127 
129 
131 
133 
134 
135 
86 
87 
88 
89 
90 
90 
91 
13 
99th 
128 
130 
131 
133 
135 
136 
137 
87 
87 
88 
89 
90 
91 
91 
14 
99th 
131 
132 
134 
136 
138 
139 
140 
87 
88 
89 
90 
91 
92 
92 
15 
99th 
134 
135 
136 
138 
140 
142 
142 
88 
89 
90 
91 
92 
93 
93 
16 
99th 
136 
137 
139 
141 
143 
144 
145 
90 
90 
91 
92 
93 
94 
94 
≥17 
99th 
139 
140 
141 
143 
145 
146 
147 
92 
93 
93 
94 
95 
96 
97 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” PEDIATRICS Vol. 114 No. 2 August 
2004, pp. 555-576.


 
 
 
 
 
 
                          
ADVL1615 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
Version Date: 08/27/2020 
 
Page 97 
 
Blood pressure (BP) levels for GIRLS  
 
 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) 
Percentile 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
99th 
108 
108 
109 
111 
112 
113 
114 
64 
64 
65 
65 
66 
67 
67 
2 
99th 
109 
110 
111 
112 
114 
115 
116 
69 
69 
70 
70 
71 
72 
72 
3 
99th 
111 
111 
113 
114 
115 
116 
117 
73 
73 
74 
74 
75 
76 
76 
4 
99th 
112 
113 
114 
115 
117 
118 
119 
76 
76 
76 
77 
78 
79 
79 
5 
99th 
114 
114 
116 
117 
118 
120 
120 
78 
78 
79 
79 
80 
81 
81 
6 
99th 
115 
116 
117 
119 
120 
121 
122 
80 
80 
80 
81 
82 
83 
83 
7 
99th 
117 
118 
119 
120 
122 
123 
124 
81 
81 
82 
82 
83 
84 
84 
8 
99th 
119 
120 
121 
122 
123 
125 
125 
82 
82 
83 
83 
84 
85 
86 
9 
99th 
121 
121 
123 
124 
125 
127 
127 
83 
83 
84 
84 
85 
86 
87 
10 
99th 
123 
123 
125 
126 
127 
129 
129 
84 
84 
85 
86 
86 
87 
88 
11 
99th 
125 
125 
126 
128 
129 
130 
131 
85 
85 
86 
87 
87 
88 
89 
12 
99th 
127 
127 
128 
130 
131 
132 
133 
86 
86 
87 
88 
88 
89 
90 
13 
99th 
128 
129 
130 
132 
133 
134 
135 
87 
87 
88 
89 
89 
90 
91 
14 
99th 
130 
131 
132 
133 
135 
136 
136 
88 
88 
89 
90 
90 
91 
92 
15 
99th 
131 
132 
133 
134 
136 
137 
138 
89 
89 
90 
91 
91 
92 
93 
16 
99th 
132 
133 
134 
135 
137 
138 
139 
90 
90 
90 
91 
92 
93 
93 
≥17 
99th 
133 
133 
134 
136 
137 
138 
139 
90 
90 
91 
91 
92 
93 
93 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” PEDIATRICS Vol. 114 No. 2 
August 2004, pp. 555-576. 


  
 
ADVL1615 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
                                                                                                                         
Version Date: 08/27/2020 
 
Page 98 
Cycle 1  
APPENDIX XIII-A: 
THERAPY DELIVERY MAPS (TDMS) FOR CYCLE 1 
 
0BTherapy Delivery Map – Cycle 1 
This Therapy Delivery Map (TDM) relates to Cycle 1. Cycle 1 lasts 28 days. This TDM can be used 
for all dose levels of pevonedistat. Please record the dose level below. This TDM is intended to serve 
as a tool to assist in scheduling the required observations for the study; the schedule indicated in the 
chart below should be considered an example. The actual schedule must comply with the timing of 
required observations per Section 8 of the protocol.  
This form is to be completed and uploaded into RAVE at the end of every cycle. 
____________________________ 
Accession # 
____________________________ 
Patient COG ID number 
_______________________ 
Institution 
Criteria to start each cycle are listed in Section 5.3. Extensive treatment details are in Section 5.1. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Pevonedistat  
IND # 136078 
IV over 60 
minutes 
Dose Level -1: 10 mg/m2 
Dose Level 1: 
15 mg/m2 
Dose Level 2: 
20 mg/m2 
Dose Level 3: 
25 mg/m2 
Dose Level 4:    35 mg/m2 
1, 8, 10, 12 
Administer alone on Day 1. Administer 
immediately after irinotecan on Days 8, 
10, and 12. The dose level will be assigned 
via OPEN at the time of study enrollment. 
Cefixime 
PO 
8 mg/kg/dose daily 
6-15, 27-28 
Maximum dose is 400 mg/day. 
Temozolomide (TEMO) 
PO 
100 mg/m2/dose daily 
8-12 
Maximum dose is 200 mg/day. 
See Appendix IV for oral capsules dosing 
nomogram. 
Irinotecan (IRIN) 
IV over 90 
minutes 
- If BSA < 0.6 m2: BSA-based dosing 
(See Section 5.1 dosing table) 
- If BSA ≥ 0.6 m2: 50 mg/m2/dose 
daily 
8-12 
Administer one hour after temozolomide. 
 
NOTE: PCP prophylaxis should start on Cycle 1 Day 8, given twice daily for 3 consecutive days a week (i.e., BID Friday, Saturday, Sunday), 
every week or per institutional practice, until the end of protocol therapy. See Section 5.1 for details. 
 
Assigned Dose Level ______ 
Ht _________cm 
Wt _________kg 
 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Pevonedistat 
________ mg 
TEMO 
______ mg 
IRIN 
______ mg 
Cefixime 
______ mg 
Studies 
 
 
 
PRE 
 
 
 
 
a - m, n*, o, p 
 
 
1 
________ mg 
 
 
 
h, m, n* 
 
 
… 
 
 
 
 
 
 
 
4 
 
 
 
 
e 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
________ mg 
 
 
 
7 
 
 
 
________ mg 
 
 
 
8 
________ mg 
______ mg 
______ mg 
________ mg 
b, e - h, m, n* 
 
 
9 
 
______ mg 
______ mg 
________ mg 
 
 
 
10 
________ mg 
______ mg 
______ mg 
________ mg 
h, m, n* 
 
 
11 
 
______ mg 
______ mg 
________ mg 
 
 
 
12 
________ mg 
______ mg 
______ mg 
________ mg 
e, h 
 
 
13 
 
 
 
________ mg 
 
 
 
14 
 
 
 
________ mg 
 
 
 
15 
 
 
 
________ mg 
b, e - h 
 
 
… 
 
 
 
 
 
 
 
19 
 
 
 
 
e 
 
 
… 
 
 
 
 
 
 
 
22 
 
 
 
 
b, e - h 
 
 
… 
 
 
 
 
 
 
 
26/-1 
 
 
 
 
e 
 
 
27/0 
 
 
 
______ mg 
 
 
 
28/1 
 
 
 
______ mg 
a - h, j - k, l^, p 
 
 
 
Following completion of Cycle 1, Cycle 2 starts on Day 28 or when starting 
criteria are met (see Section 5.3), whichever occurs later. 
 
* For consenting patients only. 
^ Study may be obtained within 72 hours prior to the start of the subsequent cycle. 
See Section 6.0 for Dose Modifications for Adverse Events and Section 7.0 and the COG Member website for 
Supportive Care Guidelines.


  
 
ADVL1615 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
                                                                                                                      
Version Date: 08/27/2020 
 
Page 99 
Cycle 1  
 
Required Observations in Cycle 1  
All baseline studies must be performed within 7 days prior to enrollment 
unless otherwise indicated below. See Section 8.0 for schedule of assessments. 
 
a. 
History 
b. Physical exam with vital signs: Vital signs should be checked prior to each 
pevonedistat infusion. Vital signs will be also be assessed at the end of treatment. 
c. 
Height, weight, BSA 
d. Performance status 
e. 
CBC, differential, platelets: Twice weekly during Cycle 1. If patients have Grade 4 
neutropenia or thrombocytopenia, CBCs should be checked at least every other day 
until recovery to Grade 3 or until the criteria for dose limiting toxicity are met. 
f. 
Electrolytes including Ca++, PO4, MG++ 
g. Creatinine 
h. ALT, AST, bilirubin: Check prior to each dose of pevonedistat, then weekly for 
remaining weeks of cycle. If patients have Grade 2, 3, or 4 ALT/AST/bilirubin on or 
after Cycle 1 Day 8, AST/ALT/bilirubin should be checked at least every other day 
until recovery to ≤ Grade 1. See Section 6.2.4 for more details. 
i. 
ECHO/EKG 
j. 
Albumin, Pulse Oximetry 
k. Pregnancy test: Women of childbearing potential require a negative pregnancy test 
prior to starting treatment; sexually active patients must use an acceptable method of 
birth control. Abstinence is an acceptable methods of birth control. All women of 
childbearing potential must have a pregnancy test done every cycle prior to initiation 
of a new cycle. 
l. 
Tumor disease evaluation: Tumor disease evaluation should be obtained on the next 
consecutive cycle after initial documentation of either a PR or CR. If the institutional 
investigator determines that the patient has progressed based on clinical or 
laboratory evidence, he/she may opt not to confirm this finding radiographically. 
m. Pharmacokinetics (required): See Section 8.3 for details. 
n. Pharmacodynamics (optional): See Section 8.4 for details. 
o. INR 
p. Bone marrow evaluation. If a solid tumor patient is suspected to have or has a history 
of bone marrow involvement then a pre-study bone marrow biopsy and/or aspirate is 
required. This should then be repeated with each tumor disease evaluation if pre-study 
bone marrow was positive for metastatic disease. 
^ Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
 
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) 
 
 
 


  
 
ADVL1615 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
                                                                                                                         
Version Date: 08/27/2020 
 
Page 100 
All Subsequent Cycles  
APPENDIX XIII-B: 
THERAPY DELIVERY MAPS (TDMS) FOR ALL SUBSEQUENT CYCLES 
 
 
1BTherapy Delivery Map – All Subsequent Cycles 
This Therapy Delivery Map (TDM) relates to all subsequent cycles (Cycles 2+). Each cycle 
lasts 21 days. This TDM can be used for all dose levels of pevonedistat. Please record the 
dose level in the chart below. Treatment may continue in the absence of disease progression 
or unacceptable toxicity. A cycle may be repeated 17 times, up to a total duration of therapy 
of 12 months. Use a copy of this page once for each cycle (please note cycle number below).  
This form is to be completed and uploaded into RAVE at the end of every cycle. 
____________________________ 
Accession # 
____________________________ 
Patient COG ID number 
_______________________ 
Institution 
 
Criteria to start each cycle are listed in Section 5.3. Extensive treatment details are in Section 5.1. 
This TDM is on 3 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Cefixime 
PO 
8 mg/kg/dose daily 
-1 to 8,  
20-21 
Maximum dose is 400 mg/day. 
Temozolomide (TEMO) 
PO 
100 mg/m2/dose daily  
1-5 
Maximum dose is 200 mg/day. 
See Appendix IV for oral capsules 
dosing nomogram. 
Irinotecan (IRIN) 
IV over 90 
minutes 
- If BSA < 0.6 m2: BSA-based dosing 
(See Section 5.1 dosing table) 
- If BSA ≥ 0.6 m2: 50 mg/m2/dose 
daily  
1-5 
Administer one hour after 
temozolomide. 
Pevonedistat  
IND # 136078 
IV over 60 
minutes 
Dose Level -1: 10 mg/m2 
Dose Level 1: 
15 mg/m2 
Dose Level 2: 
20 mg/m2 
Dose Level 3: 
25 mg/m2 
Dose Level 4:    35 mg/m2 
1, 3, 5 
Administer immediately after 
irinotecan. If pevonedistat is delayed, a 
minimum of 1 calendar day between 
any 2 doses should be maintained. A 
maximum of 3 doses of pevonedistat per 
Cycles 2+ should not be exceeded. 
 
NOTE: PCP prophylaxis should start on Cycle 1 Day 8, given twice daily for 3 consecutive days a week (i.e., BID Friday, Saturday, Sunday), 
every week or per institutional practice, until the end of protocol therapy. See Section 5.1 for details. 
 
Cycle # _____  Assigned Dose Level ______   Ht ________cm      Wt _________kg   BSA _________m2 
 
Date Due 
Date 
Given 
Day 
Pevonedistat 
________ mg 
TEMO 
______ mg 
IRIN 
______ mg 
Cefixime 
______ mg 
Studies 
Enter calculated dose above and actual dose administered below 
 
 
 
-1* 
 
 
 
________ mg* 
 
 
 
0* 
 
 
 
________ mg* 
a - d, h, j - k 
 
 
1 
________ mg 
______ mg 
______ mg 
________ mg 
 
 
 
2 
 
______ mg 
______ mg 
________ mg 
 
 
 
3 
________ mg 
______ mg 
______ mg 
________ mg 
h 
 
 
4 
 
______ mg 
______ mg 
________ mg 
 
 
 
5 
________ mg 
______ mg 
______ mg 
________ mg 
h 
 
 
6 
 
 
 
________ mg 
 
 
 
7 
 
 
 
________ mg 
 
 
 
8 
 
 
 
________ mg 
e – g, h 
 
 
… 
 
 
 
 
 
 
 
15 
 
 
 
 
e – g, h 
 
 
… 
 
 
 
 
 
 
 
19/-1 
 
 
 
 
 
 
 
20/0 
 
 
 
______ mg 
 
 
 
21/1 
 
 
 
______ mg 
a - d, h, j - k, l#, p 
 
 
 
Following completion of this cycle, the next cycle will start on Day 21 or when 
starting criteria are met (see Section 5.3), whichever occurs later. 
 
# End of Cycle 2, then every other cycle x 2 then q 3 cycles  
*Cefixime on these days should be reported as the last two days of the 
previous cycle. 
 
See Section 5.0 for Dose Modifications for Adverse Events and Section 7.0 and the COG Member website for 
Supportive Care Guidelines. 
 


  
 
ADVL1615 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
                                                                                                                      
Version Date: 08/27/2020 
 
Page 101 
All Subsequent Cycles  
Required Observations in All Subsequent Cycles 
All baseline studies must be performed within 7 days prior to enrollment 
unless otherwise indicated below. See Section 8.0 for schedule of assessments. 
 
a. 
History^ 
b. Physical exam with vital signs^: Vital signs should be checked prior to each 
pevonedistat infusion. Vital signs will also be assessed at the end of treatment. 
c. 
Height, weight, BSA^ 
d. Performance status^ 
e. 
CBC, differential, platelets: If patients develop Grade 4 neutropenia, CBCs should 
be checked every 3 to 4 days until recovery to Grade 3. If patients remain on study 
for > 4 cycles and ≥ 4 cycles and ≥ Grade 3 cytopenias are not observed, then CBCs 
may be obtained at the start of subsequent cycles and as clinically indicated. 
f. 
Electrolytes including Ca++, PO4, MG++^ 
g. Creatinine^ 
h. ALT, AST, bilirubin*: Check prior to each dose of pevonedistat, then weekly for 
remaining weeks of cycle. If patients have Grade 2, 3, or 4 ALT/AST/bilirubin on or 
after Cycle 1 Day 8, AST/ALT/bilirubin should be checked at least every other day 
until recovery to ≤ Grade 1. See Section 6.2.4 for more details.  
i. 
ECHO/EKG 
j. 
Albumin^ ; Pulse Oximetry 
k. Pregnancy test^: Women of childbearing potential require a negative pregnancy test 
prior to starting treatment; sexually active patients must use an acceptable method of 
birth control. Abstinence is an acceptable methods of birth control. All women of 
childbearing potential must have a pregnancy test done every cycle prior to initiation 
of a new cycle. 
l. 
Tumor disease evaluation5: Tumor disease evaluation should be obtained on the next 
consecutive cycle after initial documentation of either a PR or CR. If the institutional 
investigator determines that the patient has progressed based on clinical or laboratory 
evidence, he/she may opt not to confirm this finding radiographically. 
m. Pharmacokinetics (required): See Section 8.3 for details. 
n. Pharmacodynamics (optional): See Section 8.4 for details. 
o. INR 
p. Bone marrow evaluation. With tumor disease evaluation; end of cycle 2, then every 
other cycle x2, then every 3 cycles. If a solid tumor patient is suspected to have or 
has a history of bone marrow involvement then a pre-study bone marrow biopsy 
and/or aspirate is required. This should then be repeated with each tumor disease 
evaluation if pre-study bone marrow was positive for metastatic disease. 
^ Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
 
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)