Clinical trial NCT04800627
Conditions: Locally Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm Unresectable Malignant Solid Neoplasm
Sponsor: M.D. Anderson Cancer Center
Start date: 2021-03-29; Completion date: 2022-11-03
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial identifies the side effects and best dose of pevonedistat when given together with pembrolizumab in treating mismatch repair deficiency (dMMR)/high-frequency microsatellite instability (MSI-H) solid tumor that has spread to other places in the body (metastatic) or has spread to nearby tissue or lymph nodes (locally advanced) and cannot removed by surgery (unresectable). Pevonedistat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pevonedistat and pembrolizumab may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine safety and phase II dose of pevonedistat in combination with pembrolizumab. (Phase I) II. To assess the efficacy of pevonedistat in combination with pembrolizumab in patients with dMMR/MSI-H cancers.

SECONDARY OBJECTIVES:

I. To assess additional efficacy endpoints of the combination of pevonedistat and pembrolizumab in dMMR/MSI-H cancers.

II. To assess the safety of pevonedistat and pembrolizumab in the dMMR/MSI-H patient cohort.

III. To assess the pharmacodynamics impact of pevonedistat and pembrolizumab on tumor and immune-related components.

EXPLORATORY OBJECTIVES:

I. Immune context evaluation of tumor microenvironment. II. Determine clinical benefit. III. Evaluate pevonedistat pharmacokinetics and resistance mechanisms in combination therapy.

OUTLINE: This is a phase I, dose escalation study of pevonedistat followed by a phase II study.

Patients receive pevonedistat intravenously (IV) over 60 minutes on days 1, 3, and 5, and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months.

Arms: arm 1: Patients receive pevonedistat IV over 60 minutes on days 1, 3, and 5, and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Pembrolizumab intervention 2: Pevonedistat
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL  
A Phase I/II Trial of Pevonedistat in Combination with Pembrolizumab in Patients 
with dMMR/MSI-H Cancers  
 
 
 
 
 
Indication: 
PD-1 progressive dMMR/MSI-H cancers  
Phase: 
I/II 
 
 
 
Protocol History 
Original 
 
4 September 2020 
 
 
Investigator and Study Center: 
 Michael Overman, MD  
University of Texas, M. D. Anderson Cancer Center 
1515 Holcombe Blvd  
 Unit 0426 
Houston, TX 77030 
713-792-2828 
 
 
Collaborators 
Ying Yuan (statistician) 
Shiaw-Yih Lin 
Scott Kopetz, Ryan Huey, Bryan Kee, Van Morris, Mairela Blum, Milind Javle, Christine 
Parseghian, Arvind Dasari, Benny Johnson, Kanwal Raghav, JP Shen, Eduardo Vilar-
Sanchez, Robert Wolff, Sunyoung Lee 
 
 
This is an investigator-initiated study.  The principal investigator is Michael Overman, MD,  


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TABLE OF CONTENTS 
PROTOCOL SUMMARY .................................. ERROR! BOOKMARK NOT DEFINED. 
STUDY OVERVIEW DIAGRAM ..................... ERROR! BOOKMARK NOT DEFINED. 
SCHEDULE OF EVENTS ................................. ERROR! BOOKMARK NOT DEFINED. 
LIST OF TABLES AND FIGURES ........................................................................................5 
TABLES ...................................................................................................................................5 
FIGURES ..................................................................................................................................5 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..............................................7 
1. BACKGROUND AND STUDY RATIONALE ................................................................10 
1.1 Scientific Background ..................................................................................................10 
1.1.1 Disease Under Treatment.......................................................................................10 
1.1.2 Study Drug .............................................................................................................14 
1.2 Preclinical Experience with Pevonedistat .....................................................................15 
1.3 Clinical Experience with Pevonedistat .........................................................................17 
1.3.1 Clinical Pharmacokinetics .....................................................................................20 
1.3.2 Pharmacodynamics ................................................................................................22 
1.3.3 Summary of Safety and Efficacy Data Findings Available on Takeda 
Sponsored Trials .............................................................................................22 
1.4 Additional Safety Considerations .................................................................................27 
1.4.1 Cycle 1, Day 1 Toxicity/Multi Organ Failure........................................................27 
1.4.2 Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise ....................................................................................................28 
1.4.3 Increases in Serum Creatinine ...............................................................................29 
1.4.4 Increases in Liver Enzymes and Biochemical Tests ..............................................29 
1.4.5 Drug Drug Interactions (DDIs) ..............................................................................30 
2. STUDY OBJECTIVES ......................................................................................................30 
2.1 Primary Objectives .......................................................................................................30 
2.2 Secondary Objectives: ..................................................................................................30 
3. STUDY ENDPOINTS ........................................................................................................31 
3.1 Primary Endpoints ........................................................................................................31 
3.2 Secondary Endpoints ....................................................................................................31 
3.3 Exploratory Endpoints ..................................................................................................31 
4. STUDY DESIGN ...............................................................................................................32 
4.1 Overview of Study Design ...........................................................................................32 
4.2 Number of Patients .......................................................................................................34 
4.3 Duration of Study .........................................................................................................34 
5. STUDY POPULATION .....................................................................................................34 
5.1 Inclusion Criteria ..........................................................................................................34 
5.2 Exclusion Criteria .........................................................................................................36 
6. STUDY DRUG ...................................................................................................................39 
6.1 Study Drug Administration ..........................................................................................39 
6.2 Definitions of Dose Limiting Toxicity .........................................................................40 
6.3 Dose-Modification Guidelines .....................................................................................41 
6.3.1 Criteria for Retreatment and Dose Delays .............................................................42 
6.3.2 Pevonedistat Dose Modifications for Hematologic Toxicities ..............................43 


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6.3.3 Pevonedistat dose Modifications for Nonhematologic Toxicities .........................43 
6.3.4 Pembrolizumab Dose Modifications for Management of Immune-Related 
Toxicities ........................................................................................................44 
6.3.5 Pembrolizumab Dose Modifications for Management of Infusion-Reactions ......47 
6.4 Excluded Concomitant Medications and Procedures ...................................................50 
6.5 Permitted Concomitant Medications and Procedures ...................................................51 
6.6 Precautions and Restrictions .........................................................................................51 
6.7 Management of Clinical Events ...................................................................................53 
6.8 Description of Investigational Agents ..........................................................................53 
6.8.1 Pevonedistat ...........................................................................................................53 
6.8.2 Preparation, Reconstitution, and Dispensing .........................................................54 
6.8.3 Packaging and Labeling .........................................................................................54 
6.8.4 Storage, Handling, and Accountability ..................................................................55 
6.9 Study Compliance .........................................................................................................55 
6.10 Termination of Treatment and/or Study Participation ................................................55 
7. STATISTICAL AND QUANTITATIVE ANALYSES .....................................................56 
7.1.1 Determination of Sample Size ...............................................................................56 
7.1.2 Safety Analysis ......................................................................................................56 
7.1.3 Pharmacokinetics ...................................................................................................59 
7.1.4 Translational Studies..............................................................................................59 
8. ADVERSE EVENTS..........................................................................................................61 
8.1 Definitions ....................................................................................................................61 
8.1.1 Adverse Event Definition ......................................................................................61 
8.1.2 Serious Adverse Event Definition .........................................................................63 
8.2 Procedures for Reporting Serious Adverse Events .......................................................66 
8.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........68 
9.    
ADMINISTRATIVE REQUIREMENTS ..................................................................68 
9.1       Product Complaints ..............................................................................................68 
10.    REFERENCES ...........................................................................................................70 
11. 
72 
Appendix 1:    
Eastern Cooperative Oncology Group (ECOG) Scale for 
Performance Status ...............................................................................................72 
Appendix 2:    
Body Surface Area ..................................................................................73 
Appendix 3:    
New York Heart Association Classification of Cardiac Disease ............74 
Appendix 4:    
Definition of Postmenopausal .................................................................75 
Appendix 5:    
Methods of Contraception Considered Effective ...................................76 
Appendix 6:    
Schedule of Events .................................................................................78 
Appendix 7:    
Laboratory Manual .................................................................................82 
 


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LIST OF TABLES and FIGURES  
Tables 
Table 1. Pevonedistat Dose Levels .........................................................................................33 
Table 2. 
Dose modification and toxicity management guidelines for immune-
related AEs associated with pembrolizumab .............................................44 
Table 3.  Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines ......................................................................................................48 
Table 4. Concomitant Medications Excluded During the Study ............................................50 
Table 5.  Concomitant Medications and Procedures Permitted During the Study .................51 
Table 6.  Optimized Stopping Boundaries ..............................................................................58 
Table 7.  Operating Characteristics for Toxicity Monitoring .................................................58 
Table 8. ECOG Scale for Performance Status ........................................................................72 
Table 9. NYHA Classification of Cardiac Disease ................................................................74 
Table 10. Schedule of Events .................................................................................................78 
Table 11. PK sampling timepoints..........................................................................................81 
 
 
Figures 
Figure 1. Thermodynamic modeling of mutations in MSI HCT-116 and MSS SW948 cells. 
A higher ΔΔG represents more destabilization. Shaded region depicts 
mutations that are significantly destabilizing. Rank-sum test. .......................10 
 Figure 2. Immunoprecipitation with anti-Nedd8 shows neddylation of mutant, but not WT 
and P87S-mutant PTS that is blocked by a 24 hour treatment with 1 μM 
Pevonedistat. ...................................................................................................11 
Figure 3. Comparison of HSPA8 gene expression in MSS and MSI colorectal (COAD) and 
endometrial  (UCEC) cancers. White dot indicated median, box indicates 
interquartile range. Rank-sum test ..................................................................11 
Figure 4. Change in chaperone binding between wild-type and mutant genes based on if a 
mutation has no effect on stability or is destabilizing. Rank-sum test ...........11 
Figure 5. a)Percentage of cells positive for cell surface calreticulin following 24 hours 
ofspecified drug treatments. Mean±s.e.m. b) Media ATP concentration 
following a 24 hour treatment with the specified drugs. Mean±s.e.m. 21b = 
murine endometrial dMMR cancer cell line, HCT-116 = human colon cancer 
cell line ............................................................................................................12 
Figure 6. a) Detection of antibody production against 21B tumor cells (murine endometrial 
dMMR cancer cell line) in serum from mice (left and right membranes were 


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developed simultaneously for equal exposure).  b) Antibody production was 
quantified from band intensities in 4a ............................................................12 
Figure 7. Tumor growth curves for the dMMR 21B mouse cell line treated with 
PEVONEDISTAT, anti-PD1, or a combination thereof. Mean±s.e.m.; Holm-
Sidak correction ..............................................................................................13 
Figure 8. CD8 immunostaining in tumors treated with drug combinations that were 
quantified as the CD8 staining area normalized to DAPI (nuclei) for total 
tumor area. Kruskal-Wallis test ......................................................................13 
Figure 9. Phase 1b 3+3 Design ............................................... Error! Bookmark not defined. 
Figure 10. Study Schema ........................................................................................................33 
 
 
 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Common abbreviations used in oncology protocols are provided below.  Program-specific 
or protocol-specific abbreviations must be added to this list, and unnecessary abbreviations 
removed, as applicable.  Abbreviations that are retained should not be changed.  
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC24 hr 
area under the plasma concentration versus time curve from zero to 24 hours 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CL 
clearance, IV dosing 
Cmax 
single-dose maximum (peak) concentration   
CNS 
central nervous system 
CR 
complete response     
CT 
computed tomography 
CV 
coefficient of variation  
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
dMMR 
deficient DNA mismatch repair 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment (visit) 
FDA 
United States Food and Drug Administration 
G-CSF 
granulocyte colony stimulating factor 
GM-CSF 
 
granulocyte macrophage colony-stimulating factor.   
 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 


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Abbreviation 
Term 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
IRB 
institutional review board 
IV 
intravenous; intravenously 
Ki 
inhibition constant 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MRI 
magnetic resonance imaging 
MSI-H 
Microsatellite instability high 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
PCR 
polymerase chain reaction 
PD 
progressive disease (disease progression) 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial response  
QD 
quaque die; each day; once daily 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RBC 
red blood cell 
RECIST 
RP2D 
Response Evaluation Criteria in Solid Tumors 
Recommended Phase 2 Dose 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
t1/2 
terminal disposition half-life 
TGI 
tumor growth inhibition 


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Abbreviation 
Term 
ULN 
upper limit of the normal range 
WBC 
white blood cell 
 


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1.    
BACKGROUND AND STUDY RATIONALE 
1.1    Scientific Background 
1.1.1    
Disease Under Treatment 
Deficient DNA mismatch repair (dMMR) propagates a phenotype of hypermutability 
known as microsatellite instability (MSI) [1]. This dysfunction is responsible for a 
number of MSI high (MSI-H) malignancies, among which endometrial, gastric and 
colorectal cancers are well known [2-4]. Although these are considered ideally suited for 
immunotherapy due to immunogenic neoantigen production, in reality, only a fraction 
are responsive. In the case of dMMR/MSI-H colorectal cancer (CRC), among the 15% 
that responds to immune blockade therapy there is still the risk of developing resistance 
to this mode of therapy [5].  
 
Several mechanisms exist to enable dMMR/MSI-H tumor survival. One of these is 
facilitated through the Nedd8-mediated misfolded protein clearance pathway. 
Neddylation is responsible for the activity of cullin-RING ubiquitin ligases (CRLs), 
most of which manage crucial cell cycle proteins and may be induced by external 
stressors including heat shock or proteasome inhibition [6, 7]. Data from MD Anderson 
Cancer Center[8] supports the notion that the use of Nedd8-activating enzyme inhibitors 
in combination with immunotherapy would be an effective treatment strategy for 
dMMR/MSI-H cancers.  
 
To start, analysis of dMMR/MSI-H cell lines with thermal stability profiling 
demonstrated the presence of more destabilizing mutations compared to microsatellite 
stable (MSS) cell lines (Fig. 1). Further experimentation performing 
immunoprecipitation with anti-Nedd8 antibody on transfected FLAG-tagged wild-type 
or P87S-mutant PTS (a highly destabilizing mutation) support the hypothesis that 
aggregation of these misfolded proteins can imitate conditions promoting stress-induced 
neddylation (Fig. 2). Thus dMMR/MSI-H cancers are dependent on the Nedd8-mediated 
misfolded protein clearance pathway to maintain proteome functionality.   
 
Figure 1. Thermodynamic modeling of mutations in MSI 
        
HCT-116 and MSS SW948 cells. A higher ΔΔG represents 
more destabilization. Shaded region depicts mutations that are 
significantly destabilizing. Rank-sum test. 
 
 
 


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 Figure 2. Immunoprecipitation with anti-Nedd8 
shows neddylation of mutant, but not WT and 
P87S-mutant PTS that is blocked by a 24 hour 
treatment with 1 μM Pevonedistat.  
 
 
Furthermore, findings from earlier studies inform us that tumors tend to upregulate 
expression of chaperone proteins to offset the effects of destabilizing mutations [9]. 
Hsc70 is one such protein folding chaperone, encoded by the HSPA8 gene that is 
overexpressed in dMMR/MSI-H tumors (Fig. 3). This chaperone selectively binds 
destabilizing mutations (Fig. 4). Studies have noted their ability to mitigate toxicity from 
proteins that tend to cluster [10]. In the event of inadequate functioning chaperone 
proteins, the cell undergoes the endoplasmic reticulum (ER) stress or an unfolded protein 
response that culminates in immunogenic cell death (ICD) [11].  
 
Figure 3. Comparison of HSPA8 gene expression in 
MSS and MSI colorectal (COAD) and endometrial  
(UCEC) cancers. White dot indicated median, box 
indicates interquartile range. Rank-sum test  
 
 
 
 
 
Figure 4. Change in chaperone 
binding between wild-type and 
mutant genes based on if a mutation 
has no effect on stability or is 
destabilizing. Rank-sum test 
 
 
 
 
 
 
Pevonedistat is a Nedd8-activating enzyme inhibitor that interferes with dMMR/MSI-H 
cancer cell ability to survive by influencing neddylation and overwhelming the 
chaperone system ability to clear misfolded proteins. Testing murine endometrial dMMR 
cancer cell line (designated “21B”) and human colon cancer cell line (denoted “HCT-
116”) after pevonedistat administration revealed the following: markers of ER stress, 
calreticulin expression and ATP secretion denoting ICD (Fig 5), and rise in cytokines 
reflecting cytotoxic T-cell recruitment. Likewise, injection of Pevonedistat treated 21B 


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cells as an anti-tumor vaccine into immunocompetent mice produced more circulating 
tumor antibodies compared to mice treated with cisplatin or sham PBS (Fig 6).  
 
a. 
                  b.  
 
Figure 5. a) Percentage of cells positive for cell surface calreticulin following 24 hours of 
specified drug treatments. Mean±s.e.m. b) Media ATP concentration 
following a 24 hour treatment with the specified drugs. Mean±s.e.m. 21b = 
murine endometrial dMMR cancer cell line, HCT-116 = human colon cancer 
cell line  
 
 
a.
    b.
 
Figure 6. a) Detection of antibody production against 21B tumor cells (murine endometrial 
dMMR cancer cell line) in serum from mice (left and right membranes were 
developed simultaneously for equal exposure).  b) Antibody production was 
quantified from band intensities in 4a  
 
Finally, the ability to enhance immune checkpoint therapy was characterized through 
treatment of Msh2-null 21B tumors treated with monotherapy of anti-PD1 or 
pevonedistat or a combination of both. While tumor growth was acceptably inhibited by 
monotherapy, the combination therapy group exhibited markedly decreased tumor 
growth (Fig 7) and increased CD8 immunostaining compared to pevonedistat 
monotherapy alone (Fig 8).  
 
 


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Figure 7. Tumor growth curves for the 
dMMR 21B mouse cell line treated with 
PEVONEDISTAT, anti-PD1, or a 
combination thereof. Mean±s.e.m.; Holm-
Sidak correction 
 
 
 
 
 
 
Figure 8. CD8 immunostaining 
in tumors treated with drug 
combinations that were quantified 
as the CD8 staining area 
normalized to DAPI (nuclei) for 
total tumor area. Kruskal-Wallis 
test 
 
 
 
 
In light of all these findings, we propose a clinical trial of Nedd8-activating enzyme 
inhibitor Pevonedistat in combination with the PD-1 inhibitor, Pembrolizumab, in patients 
with dMMR/MSI-H cancers. 
Combination therapy with pembrolizumab and pevonedistat 
The mechanism of action for the two study agents is non-overlaping. However, Pevonedistat 
is noted to cause AST/ALT elevations or increased bilirubin [12], which is also seen in 
pembrolizumab. However, it should be noted that the mechanisms of action  causing 
transaminitis or elevation of bilirubin differ between these two agents.  However, given this 
common toxicity this study plans to utilize a 3+3 design to determine RP2D of pevonedistat 
to use in combination with pembrolizumab.  
 


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1.1.2    
Study Drug 
Pevonedistat (also known as TAK 924 and MLN4924; hereinafter referred to as 
pevonedistat) is a first-in-class, small molecule inhibitor of neural precursor cell expressed, 
developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) under development 
for the treatment of malignancies. The NEDD8 conjugation (neddylation) pathway is 
responsible for much of the regulated protein turnover in the cell [13, 14], which is similar 
to the ubiquitin-proteasome system (UPS). However, UPS is known to regulate a myriad of 
processes in eukaryotic cells, whereas only a limited number of neddylation substrates have 
been described to date. VELCADE® (bortezomib) for Injection, a drug that acts by 
inhibiting the 26S proteasome, has proven utility in the treatment of multiple myeloma and 
mantle cell lymphoma [15]. Therefore, it is anticipated that other compounds directed 
against different components of the UPS and/or the NEDD8 conjugation pathway may prove 
useful in the treatment of malignancies. 
NAE, E1 ligase, is an essential component of the NEDD8 conjugation pathway, which 
initiates the neddylation to protein substrates. Specifically, NEDD8 conjugation to cullin 
dependent ubiquitin E3 ligases (CDLs) is necessary for their activity. The ligases in the 
NEDD8 conjugation pathway control the timely neddylation of many substrate proteins with 
important roles in cell cycle progression and signal transduction. The 
ubiquitination/neddylation of proteins targets them for proteasomal degradation. These 
cellular processes are relevant to tumor cell growth, proliferation, and survival; as such, 
inhibitors of NAE activity may be of therapeutic value in the treatment of various cancers by 
inhibiting the degradation of a subset of proteins that are regulated by the proteasome. In 
nonclinical studies, treatment of cells with pevonedistat results in the accumulation of CDL 
substrates, followed by a deoxyribonucleic acid (DNA) damage response and cell death. 
Pevonedistat treatment results in tumor growth inhibition (TGI) in mouse tumor xenograft 
models of solid tumors, lymphoma, and acute myeloid leukemia (AML). 
PD-1 inhibitors, especially pembrolizumab, have been extensively studied in the context of 
dMMR/MSI-H cancers. At present, pembrolizumab has been approved by the FDA for use 
in metastatic or unresectable, dMMR/MSI-H CRC with progressive disease following 
fluoropyrimidine, oxaliplatin and irinotecan treatment as well as for dMMR/MSI-H solid 
tumors which progressed on prior treatment and do not have satisfactory alternative therapy 
options.[16] Additional information regarding the agent is available through its current 
package insert. 


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1.2    Preclinical Experience with Pevonedistat 
Target pharmacology 
Pevonedistat is a potent and selective inhibitor of NAE activity (pevonedistat was at least 
300- and 1800- fold more selective for NAE than for the closely related ubiquitin activating 
enzyme and sumo activating enzyme, respectively). Pevonedistat treatment of cultured 
tumor cells resulted in growth inhibition of a wide variety of cell lines derived from acute 
leukemias, lymphomas, multiple myeloma, and a range of solid tumor types. Changes in 
protein levels observed in cultured cells treated with pevonedistat were consistent with the 
inhibition of NAE, in particular a decrease in NEDD8-cullin levels and a reciprocal increase 
in the levels of known CDL substrates, including NFE2-related factor 2 (Nrf2) and 
chromatin-licensing and DNA-replication factor-1 (Cdt-1). In most cell lines evaluated, 
NAE inhibition by pevonedistat led to DNA re-replication and accumulation of cells in the S 
phase of the cell cycle; this resulted in DNA damage and subsequent cell death through 
apoptosis [17-19]. When administered in combination with hypomethylating agents 
azacitidine and decitabine demonstrated synergistic activity in AML cell lines. 
Pevonedistat demonstrated pharmacodynamic and antitumor activity in solid tumor (HCT-
116 colon and Calu-6 lung), lymphoma (OCI-Ly10, OCI-Ly19, and PHTX-22L), and AML 
(HL-60) xenograft models when administered to immunocompromised mice by the 
subcutaneous (SC) route. Antitumor activity of pevonedistat in mice bearing HL-60 and 
THP-1 tumor xenografts was enhanced by combination treatment with azacitidine. 
Combination treatment with pevonedistat and docetaxel significantly inhibited tumor growth 
in the PHTX-02B primary human breast cancer model and the LU1143 primary human 
squamous non-small cell lung cancer (sqNSCLC) xenograft model. Combination treatment 
with pevonedistat and carboplatin in both NCI-H69 human small cell lung cancer (SCLC) 
xenografts and LU1143 primary sqNSCLC xenografts resulted in significant antitumor 
activity. 
Safety pharmacology 
In vitro assay results indicated a low risk for human ether-à-go-go related gene (hERG) 
channel inhibition by pevonedistat  (Ki=17.3 μM) or its 3 major circulating metabolites. 
A non-GLP-compliant PO toxicity study was performed in Sprague Dawley rats dosed with 
150 mg/kg pevonedistat on Days 1, 3, and 5. Minimal to mild pulmonary artery adventitial 


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hyperplasia and correlative increases in pulmonary artery pressure were observed at 24 
hours postdose. However, there was no correlation observed between severity of the 
microscopic lesions and increases in pulmonary artery pressure. This finding was not 
observed in rats dosed IV or SC in studies up to 3 months in duration, so the relevance of 
this finding to clinical safety is not known. 
In a Good Laboratory Practices (GLP)-compliant cardiovascular safety pharmacology 
assessment in male beagle dogs dosed via intravenous (IV) infusion at 15, 30, or 40 mg/kg 
(300, 600, or 800mg/m2, respectively), pevonedistat was not well tolerated at doses ≥30 
mg/kg (≥600mg/m2). Mortality and/or moribundity were observed within 24 hours postdose 
as a result of gastrointestinal injury at 40 mg/kg. Increased heart rate was observed at all 
doses. In a separate GLP-compliant, 2-cycle, repeat-dose toxicology study in dogs, no test 
article-related effects were noted in the electrocardiogram (ECG) data. 
Toxicology 
The systemic toxicity of pevonedistat was assessed in GLP-compliant repeat-dose studies in 
rats and dogs. Pevonedistat was administered via a 30-minute IV infusion or by SC injection 
for 2 cycles (5 days of dosing followed by a 14-day nondosing period) or for 5 cycles (4 
doses administered every other day followed by a 14-day nondosing period). The DLTs in 
the 2-cycle studies for both species were GI toxicity and bone marrow and lymphoid tissue 
depletion. In tolerated doses in both species, adverse effects included GI tract injury with 
emesis (dogs only) and abnormal excreta, hematologic alterations, and an acute phase 
response (increased fibrinogen and decreased albumin). Increased new trabecular bone 
formation was observed in the 2 cycle study, while decreased trabecular bone formation was 
observed in the 5-cycle study and was considered an adverse finding. Microscopic 
observations in both species included karyomegaly, apoptosis, and increased mitotic figures 
occurring in rapidly dividing tissues, including the intestinal tract and bone marrow. Most 
adverse effects were resolving or had resolved after a 2 week recovery period. 
Pevonedistat did not result in lethality in either of the 5-cycle studies. The primary adverse 
test article related effects in IV dosed dogs included an acute phase response (increased 
body temperature, decreased albumin, increased globulin, increased monocytes and 
neutrophils, and increased fibrinogen levels); neutrophilic infiltrates in multiple tissues 
(liver, intestines, spleen, trachea, Peyer patches, and gallbladder); and in males, vacuolation 
and degeneration of the seminiferous epithelium of the testes. Most adverse effects were 
reversing or had reversed after a 2-week recovery period in both rats and dogs. 


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Pevonedistat did not induce any local tissue response when administered by IV infusion to 
rats or dogs.  
Pevonedistat was not mutagenic in the bacterial reverse mutation assay (Ames assay). 
Microscopic changes were observed in male and female reproductive organs in the GLP 
compliant repeat-dose toxicology studies in both dogs and rats, therefore pevonedistat likely 
represents a substantial reproductive and developmental hazard. 
Non clinical pharmacokinetics 
Pevonedistat was extensively partitioned into RBCs in mice, rats, dogs, monkeys, and 
humans, most likely as a result of the binding to carbonic anhydrase (CA) in the RBCs. The 
partitioning was species dependent and concentration dependent and was saturable. 
Pevonedistat was highly bound in whole blood and plasma of mice, rats, dogs, monkeys and 
humans. No metabolite unique to humans was observed in vitro. In vitro, pevonedistat is 
predominantly metabolized by the cytochrome P450 (CYP) isozyme 3A4. There is potential 
for drug drug interactions (DDIs) if pevonedistat is coadministered with drugs that are 
CYP3A inhibitors or inducers. Pevonedistat is neither an inhibitor of CYP1A2, 2C9, 2C19, 
2D6, or 3A4/5 (IC50 > 100 μM and Ki > 50 μM) nor an inducer of CYP1A2, 2B6, or 3A4/5 
(at concentrations up to 30 μM), but is a weak inhibitor of CYP2B6 and 2C8 (IC50 = 97.6 
and 23.1 μM, respectively). The major elimination pathway of pevonedistat in animals is 
through the hepatic route. Pevonedistat is a substrate of P-glycoprotein (P-gp), breast cancer 
resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) in Caco 2 cells. 
Pevonedistat is also a weak inhibitor of P-gp (IC50 = 41.2 to 56.0 μM) and BCRP (IC50 = 6.3 
μM), but not of MRP2 (IC50 > 200 μM). Additionally, pevonedistat is not a substrate for 
organic anion-transporting proteins (OATPs). 
Detailed information regarding the nonclinical pharmacology and toxicology of pevonedistat 
is provided in the Investigator’s Brochure (IB). 
1.3    
Clinical Experience with Pevonedistat 
To date, the pevonedistat clinical development program consists of 14 clinical studies in 
patients with advanced malignancies. 
The clinical development program of pevonedistat began with 4 phase 1 studies of single 
agent pevonedistat at doses ranging from 25 to 278 mg/m2: 


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x Study C15001 in patients with solid tumors [6]. 
x Study C15002 in patients with lymphoma or multiple myeloma [20].  
x Study C15003 in patients with AML, high-grade myelodysplastic syndrome (MDS), 
or acute lymphoblastic leukemia (ALL) [21]. 
x Study C15005 in patients with melanoma [22]. 
In these studies, toxicity involving multi-organ failure on Cycle 1 Day 1, including serious 
adverse events (SAEs) of renal, hepatic, and cardiac failure, some with a fatal outcome, was 
identified at doses equal to or above 110 mg/m2. On the basis of a comprehensive review of 
the available phase 1 clinical safety data at the time, a revised risk mitigation strategy, 
including limiting the dose to no higher than 100 mg/m2 for single agent administration, was 
implemented across the pevonedistat program in October 2012. The current understanding 
of the renal toxicity observed with pevonedistat suggests that it is not a primary event but is 
likely secondary to hemodynamic changes occurring in the setting of a type of acute phase 
response. Results from an investigational toxicity study performed to model the Cycle 1 Day 
1 findings in rats suggested that an existing pro-inflammatory state in rats driven by 
administration of a single dose of TNFD followed by a single dose of pevonedistat was 
associated with a more robust sepsis-like response. These rats exhibited a robust toxicity that 
was evidenced by the exacerbation of TNFD- or pevonedistat induced- microscopic changes 
in the liver, kidney, heart, and intestine (large and small). Rats dosed with the combination 
also displayed a profound increase in circulating cytokines and chemokines that correlated 
with microscopic changes. Overall, this investigational study suggests a potential synergy 
between inflammatory state and administration of pevonedistat. 
The schedule for pevonedistat infusion of Days 1, 3, and 5 was chosen for further studies. 
The maximum tolerated dose (MTD) for that schedule for patients with AML in Study 
C15003 was determined to be 59 mg/m2, and the MTD for patients with solid tumors in 
Study C15001 was determined to be 67 mg/m2.   
Current development is focused on pevonedistat in combination with standard clinically 
available therapies in hematologic malignancies and solid tumors. 
x Study C15009 (phase 1b) evaluated the maximum tolerated dose (MTD) of 
pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2 azacitidine 


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(administered on a 5-on/2-off [weekend]/2-on schedule) in a 28 day treatment cycle 
in elderly patients with treatment-naïve AML and is completed [23]. 
x Study C15010 (phase 1b) is complete; combination therapy also included 
pevonedistat + gemcitabine [24, 25]. 
x Study C15011 (phase 1) evaluated  the effects of CYP3A mediated inhibition of 
pevonedistat in patients with solid tumors (DDI assessment; Part A) is complete. 
After completion of the DDI assessment portion of the study, patients had the 
opportunity to continue in the study by participating in Part B (pevonedistat plus 
docetaxel or the combination of carboplatin and paclitaxel). 
x Pevonedistat-2001 (phase 2) evaluated the efficacy and safety of pevonedistat 20 
mg/m2 on Days 1, 3, and 5 in combination with 75 mg/m2 azacitadine (administered 
on a 5-on/2-off [weekend]/2-on schedule) in a 28 day versus single-agent azacitidine 
in patients with higher-risk MDS (HR MDS), higher-risk chronic myelomonocytic 
leukemia (CMML), and low-blast AML. The study is completed, and the final results 
have been reported. The combination of pevonedistat and azacitidine had a 
comparable safety profile to azacitidine alone [26]. 
 Pevonedistat-3001 (phase 3) is evaluating the efficacy and safety of Pevonedistat 20 
mg/m2 on Days 1, 3, and 5 in combination with 75 mg/m2 azacitidine (administered 
on a 5-on/2-off [weekend]/2-on schedule) in a 28 day  versus single-agent azacitidine 
in patients with higher-risk MDS (HR MDS), higher-risk chronic myelomonocytic 
leukemia (CMML), and low-blast AML. The study is currently is fully enrolled. 
x Pevonedistat-1012 (phase 1) is investigating pevonedistat as a single agent and in 
combination with azacitidine in adult East Asian patients with AML or MDS is 
complete and ongoing.  
x Study Pevonedistat 1013 (phase 1) (Part A: Absorption, distribution, metabolism, 
and excretion [ADME] is complete). Part B, combination therapy, completed 
enrollment and is ongoing. 
x Study Pevonedistat-1014 (phase 1) Part A, QTc, and Part B, combination therapy, 
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x Study Pevonedistat-1015 (phase 1) Part A, DDI, and Part B, combination therapy, 
completed enrollment and is ongoing 
x Study Pevonedistat-1016 (phase 1) in patients with higher risk (HR) MDS, chronic 
myelomonocytic leukemia (CMML), and AML who have renal or hepatic 
impairment is ongoing. 
In addition, supportive studies investigating pevonedistat in patients with organ 
impairement, Drug-drug interaction effect, QTc interval effect and Mass Balance, 
Pharmacokinatics and metabolism of pevonedistat have been completed and reported. 
As of 22 January 2019, an estimated 647 patients received active treatment with 
pevonedistat based upon exposure data from completed and ongoing studies, including 99 
patients from Study P3001. Notably, Study P3001 is an open-label study; however, Takeda 
staff or its designee that are directly involved in the study are blinded to the treatment 
assignments. As such, the current number of patients randomized to pevonedistat plus 
azacitidine versus azacitidine alone is unknown; however, it is estimated that 99 of the total 
198 patients currently enrolled received pevonedistat based on the randomization scheme 
(1:1) described in the protocol. An estimated 372 patients with hematologic indications and 
275 patients with solid tumor indications have received pevonedistat. 
 
1.3.1    
Clinical Pharmacokinetics 
Plasma concentrations of pevonedistat declined in a bi-exponential manner at the end of IV 
infusion, with little or no drug accumulation following intermittent dosing or once-daily 
dosing for 5 consecutive days of a 21 day cycle. Mean terminal disposition t1/2z was 
estimated to be approximately 10 hours (range 7.7-15.2) across doses and schedules. 
Consistent with in vitro data, pevonedistat is extensively partitioned in human blood (mean 
blood-to-plasma concentration ratio of approximately 65) with whole blood and plasma 
kinetics declining in parallel over time. Pevonedistat generally exhibited linear PK over the 
dose range studied. Observed interindividual variability (IIV) was generally moderate with 
18% to 41% coefficient of variation (CV) for maximum concentration (Cmax), 12% to 56% 
CV for area under the plasma concentration-time curve from time zero to 24 hours postdose 
(AUC24), and 15% to 33% CV for the area under the plasma concentration-time curve from 
time zero to the end of the dosing interval when pevonedistat was administered on Days 1, 
3, and 5. Body size influences pevonedistat systemic clearance and volume of distribution, 


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thus supporting body surface area (BSA)-normalized dosing to reduce variation in systemic 
exposure of pevonedistat in cancer patients. Pevonedistat clearance tended to gradually 
decrease in elderly patients (by approximately 25% over the 30-90 age range). There was 
also no apparent effect of renal function status (as assessed by estimated creatinine clearance 
≥ 30 mL/min) on pevonedistat PK.  
Population pharmacokinetic (PK) analysis was conducted using data from pevonedistat 
single-agent studies (C15001, C15002, C15003, and C15005) and pevonedistat in 
combination with SOC chemotherapy (C15009 and C15010) in patients with solid tumor or 
hematologic malignancies. The database contained 335 subjects contributing 3768 PK 
observations over the pevonedistat dose range of 15 - 278 mg/m2. Pevonedistat plasma 
concentration-time profiles were well described by a 2-compartment model with linear 
elimination. Coadministration with azacitidine did not appear to affect the CL of 
pevonedistat. Race, sex, age, tumor type (hematologic vs solid), mild or moderate renal 
impairment (creatinine clearance [CrCL] ≥30 mL/minutes), and mildly impaired liver 
function, to the extent represented in this dataset, had no impact on pevonedistat PK. An 
open-label drug-drug interaction (DDI) Study C15011 evaluated the CYP3A-mediated 
inhibitory effects of fluconazole and itraconazole on pevonedistat PK in patients with 
advanced solid tumors. The results indicated that itraconazole, a strong CYP3A/P-gp 
inhibitor, and fluconazole, a moderate CYP3A inhibitor, had no clinically meaningful 
effects on pevonedistat PK. On the basis of these findings, use of CYP3A/P-gp inhibitors in 
patients receiving pevonedistat is permitted.Study Pevonedistat-1012 is a phase 1/1b, open-
label study of pevonedistat as single agent and in combination with azacitidine in adult East 
Asian patients with AML or MDS enrolled in Japan, South Korea, and Taiwan. Pevonedistat 
20 mg/m2 in combination with 75 mg/m2 azacitidine was determined to be the 
MTD/recommended phase 2 dose in Asian patients. The preliminary analysis indicated that 
the systemic exposure of pevonedistat was similar among major East Asian races, ie, 
Japanese, Korean, Chinese. Furthermore, the systemic exposures of pevonedistat was 
comparable between East Asian and Western patients. These results support the same 
RP2/3D of pevonedistat in combination with azacitidine in global patient population. 
Additional data from 11 patients who completed protocol-specified dosing and PK 
evaluations indicated that pevonedistat systemic exposures following IV administration at 
20 mg/m2 in the presence of itraconazole were similar to those in the absence of 
itraconazole. On the basis of these results, moderate and strong CYP3A inhibitors and P-gp 
inhibitors can be used in patients receiving pevonedistat. For individual studies in the 


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pevonedistat clinical program, reference should be made to the respective protocols for 
specific information relating to excluded and permitted medications. 
For detailed information please consult the current IB. 
1.3.2    
Pharmacodynamics 
Preliminary data provide evidence of pathway inhibition downstream of NAE and biological 
activity of pevonedistat in skin and tumor tissue (solid tumor or AML bone marrow derived 
blasts) at all doses tested in pharmacodynamic assays. These doses range from 15 to 261 
mg/m2 across various studies (single-agent, phase 1 pevonedistat trials and DDI Study 
C15011). 
For detailed information please consult the current IB. 
1.3.3   Summary of Safety and Efficacy Data Findings Available on Takeda Sponsored 
Trials 
For detailed information please consult the current IB. 
1.3.3.1    Phase 1 Monotherapy Studies 
Overall, 99 patients with advanced solid tumors or melanoma in Study C15001 and Study 
C15005 were treated with single-agent pevonedistat at doses ranging from 25 to 278 mg/m2. 
Common AEs (reported by ≥ 25% of patients) were fatigue, nausea, anemia, decreased 
appetite, vomiting, diarrhea, myalgia, constipation, arthralgia, dizziness, and peripheral 
neuropathy. DLTs included increased LFTs, increased creatinine, acute renal failure and 
acute hepatic failure, hypophosphatemia, and myocarditis. Acute renal failure occurred in 3 
patients: 2 patients on Study C15001 at 196 mg/m2 (1 patient also reported acute hepatic 
failure); and 1 patient on Study C15005 at 157 mg/m2, who also reported myocarditis and 
hyperbilirubinemia. Deaths on study that were considered related to study treatment 
included multi-organ failure (at 61 mg/m2 QD × 5 consecutive days and 196 mg/m2 in Study 
C15001), disease progression (at 83 mg/m2 in Study C15001), and renal failure acute (at 209 
mg/m2 in Study C15005). 
A total of 128 patients with hematologic malignancies (lymphoma, multiple myeloma, 
AML, MDS, or ALL) in Study C15002 and Study C15003 were treated with single-agent 
pevonedistat at doses ranging from 25 to 261 mg/m2. Common AEs (reported by ≥ 25% of 
patients in either study) were ALT increased, anemia, AST increased, chills, constipation, 
decreased appetite, diarrhea, dizziness, dyspnea, fatigue, febrile neutropenia, headache, 


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muscle spasms, myalgia, nausea, peripheral edema, pyrexia, and vomiting. DLTs included 
increased LFTs, febrile neutropenia, muscle spasms, thrombocytopenia, acute renal failure, 
orthostatic hypotension, cardiac failure, rash morbilliform, GI necrosis, hypotension, lactic 
acidosis, and myocardial ischemia. Deaths on study that were considered related to study 
treatment (all in Study C15003) included 2 deaths from multi organ failure (at 110 and 147 
mg/m2), 1 from sepsis (at 78 mg/m2), and 1 from cardiopulmonary failure (at 45 mg/m2).  
The primary aims of the phase 1 monotherapy studies were to establish the safety profile and 
to determine the MTDs of pevonedistat administered by several different dose schedules in 
both hematologic and solid tumor settings. While safety, PK, and pharmacodynamic 
objectives were the primary focus of these studies, disease response was also assessed. A 
total of 12 patients experienced PRs or better in the phase 1 monotherapy studies. 
In Study C15003, responses (CRs and PRs) were observed in a variety of patient settings, 
including postallogeneic transplant, therapy-related AML, and primary refractory AML 
[27]. Although some of the responses were of relatively short duration, 1 patient each in the 
44 mg/m2 cohort of Schedule A, the 83 mg/m2 MTD cohort of Schedule B, and the 25 mg/m2 
cohort of Schedule A achieved a remission for 12.3, 10.1, and 5.1 months, respectively. 
Another patient had stable disease (SD) for 8 cycles, then a PR, followed by a CR for a total 
of 2.7 months. All 13 patients who received treatment for 5 or more cycles achieved SD or 
better, ranging from 2.56 to 13.44 months. The duration of SD or better was considered 
clinically meaningful if the patient had SD or better at Cycle 4 Day 21 and proceeded to 
Cycle 5. 
1.3.3.2    Phase 1 Combination Studies 
1.3.3.2.1   C15009 
Study C15009 was a phase 1b study evaluating the MTD of pevonedistat on Days 1, 3, and 5 
in combination with 75 mg/m2 azacitidine (administered on a 5-on/2-off [weekend]/2-on 
schedule) in a 28-day treatment cycle in patients 60 years of age or older with treatment 
naïve AML who are unlikely to benefit from standard induction therapy. As of 22 January 
2017, enrollment had completed and as of January 2019 no patients remain on study. Data 
are available in CSR addendum 1 for 64 patients enrolled in the study who received at least 
1 dose of pevonedistat in combination with azacitidine; the median number of treatment 
cycles overall for the MTD pevonedistat dose cohort (20 mg/m2) was 4.0 (range 1-33 
cycles). The most common events (reported by ≥ 25% of patients) were constipation (48%), 
nausea (42%), fatigue (42%), anemia (41%), febrile neutropenia and thrombocytopenia 


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(both 31%), decreased appetite (30%)and pyrexia  (27%). A total of 46 (72%) patients 
experienced at least 1 SAE including: febrile neutropenia (27%); pneumonia (14%); AML 
(11%).  A total of 22 patients (34%)  overall experienced at least 1 TEAE resulting in 
discontinuation. Eleven patients died during treatment or within 30 days of the last dose of 
study drug); none assessed as related to study treatment. Five of the deaths were due to PD, 
2 were due to multiple organ dysfunction syndrome (multi-organ failure), and 1 was due to 
sepsis. Six patients were assessed as having died from PD or AML.PEVO PK was not 
altered by the addition of AZA.  
Overall, responses of CR, CRi, and PR were observed in 31 out of 61 (51%) of patients 
treated at the MTD of the safety population and 31 out of 52 patients (60%) of patients in 
the MTD response-evaluable population. These responses were seen regardless of low or 
high myeloblast count at baseline or disease characteristics, de novo or secondary AML, and 
cytogenetic risk category. 
1.3.3.2.2   C15010 
Study C15010 was a  phase 1b study evaluating the MTD of pevonedistat plus standard 
chemotherapy, in patients with solid tumors. As of 22 January 2016, enrollment was 
completed; 2 patients remain on study as of January 2018. The treatment arms are:  
x Arm 1: pevonedistat dosing on Days 1, 3, and 5 with 75 mg/m2 docetaxel dosing on 
Day 1 in a 21-day cycle. 
x Arm 2 Lead-in: pevonedistat dosing on Days 1, 3, and 5 with AUC6 carboplatin 
dosing on Day 1 in a 21-day cycle. 
x Arm 2: pevonedistat dosing on Days 1, 3, and 5 with paclitaxel dosing on Day 1 and 
carboplatin dosing on Day 1 in a 21-day cycle. Per protocol, the dose levels for 
paclitaxel and carboplatin were to be based on the DLTs in the Arm 2 Lead-in 
cohort; because there were 2 DLTs in the Arm 2 Lead-in cohort doses were set at 
175 mg/m2 paclitaxel and AUC5 for carboplatin.  
x Arm 3: pevonedistat dosing on Days 1, 8, and 15 with 1000 mg/m2 gemcitabine 
dosing on Day 1, 8, and 15 in a 28-day cycle. 
Patients received pevonedistat with docetaxel (22 in arm 1), carboplatin+paclitaxel (26 in 
arm 2), or gemcitabine (10 in arm 3), in 21-day (arms 1 and 2) or 28-day (arm 3) cycles. A 
lead-in cohort (arm 2a, n = 6) determined the arm 2 carboplatin dose. Dose escalation 


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proceeded via continual modified reassessment. The MTD for pevonedistat was 25 mg/m2 
(arm 1) or 20 mg/m2 (arm 2); arm 3 was discontinued due to poor tolerability. Fifteen (23%) 
patients experienced dose limiting toxicities during cycle 1 (grade ≥3 liver enzyme 
elevations, febrile neutropenia, and thrombocytopenia), managed with dose holds or 
reductions. Drug related adverse events (AEs) occurred in 95% of patients. Most common 
AEs included fatigue (58%), followed by nausea (50%), anemia (41%), constipation and 
diarrhoea (each 34%), aspartate aminotransferase increased (31%), vomiting (30%), alanine 
aminotransferase increased (28%), alopecia (27%).. One drug-related death occurred in arm 
3 (febrile neutropenia). Pevonedistat exposure increased when co-administered with 
carboplatin+paclitaxel; no obvious changes were observed when co-administered with 
docetaxel or gemcitabine. Among 54 response-evaluable patients, two had complete 
responses (arm 2) and 10 had partial responses (three in arm 1, one in arm 2a, six in arm 2); 
overall response rates were 16% (arm 1) and 35% (arm 2). High ERCC1 expression 
correlated with clinical benefit of pevonedista-t+carboplatin+paclitaxel. [28] 
1.3.3.2.3   C15011 
In Part A of Study C15011, patients receive a single dose of pevonedistat given as an IV 
infusion on Day 1 and Day 8, and either concomitant oral fluconazole or itraconazole on 
Day 4 through Day 10. After completion of the drug-drug interactions (DDI) assessments 
(including a washout period of at least 2 weeks from the last dose of fluconazole or 
itraconazole), patients could continue treatment with pevonedistat in combination with 
standard-of-care agents (either docetaxel or the combination of carboplatin and paclitaxel; 
Part B).  As of 22 January 2017 enrollement was completed, 36 of the 51 patients enrolled in 
Study C15011 continued into Part B of the study In Part B, the most common TEAE overall 
in the pevonedistat + docetaxel arm was dehydration (48%), followed by fatigue and 
decreased appetite (43% each); stomatitis, neutropenia, and oedema peripheral (35% each); 
nausea, diarrhoea, and hypotension (30% each). The most common TEAEs in the 
pevonedistat + carboplatin/paclitaxel arm were nausea and vomiting (54% each), followed 
by fatigue, diarrhoea, and constipation (38% each); anaemia and neuropathy peripheral 
(31% each).  
None of the SAEs reported during Part A was assessed as related to treatment. In Part B, the 
only SAEs reported in more than 1 patient were nausea and vomiting (2 patients each) in the 
pevonedistat+ carboplatin/paclitaxel arm and pneumonia and hypotension (2 patients each) 
in the pevonedistat + docetaxel arm. A total of 7 patients (14%) overall experienced at least 
1 TEAE resulting in study drug discontinuation during Part A and 8 (22%) patients in Part 


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B. In Part B, 1fatal AE was considered to be treatment-related (respiratory failure); 15 
patients were assessed as having died from causes related to the disease under study or 
associated complications. 
The ORR in Response evaluable patients was 10.5% for pevonedistat+docetaxel and 22.2% 
for pevonedistat + carboplatin/paclitaxel (2 patients in each treatment arm). The overall 
median duration of response was 6.26 months, with a longer duration in the pevonedistat + 
carboplatin/paclitaxel arm (8.46 months) compared with the pevonedistat+docetaxel arm 
(4.07 months). Clinical benefit (defined as PR/SD ≥5 cycles) was observed in 10 patients. A 
broad variety of tumor types were represented, and clinical benefit was observed despite 
prior exposure to a platin or a taxane. 
   Pevonedistat-1012  
In the phase 1 Study Pevonedistat-1012, patients are enrolled in 1 of 4 treatment arms: 
x Cohort S1 (pevonedistat 25 mg/m2). 
x Cohort S2 (pevonedistat 44 mg/m2). 
x Cohort C1 (pevonedistat 10 mg/m2+azacitidine 75 mg/m2). 
x Cohort C2 (pevonedistat 20 mg/m2+azacitidine 75 mg/m2). 
Patients in Cohorts S1 and S2 received pevonedistat on Days 1, 3, and 5 in a 21-day cycle. 
In the combination treatment cohorts, C1 and C2, patients received pevonedistat on Days 1, 
3, and 5 with 75 mg/m2 azacitidine dosing on Days 1 through 5, 8, and 9 in a 28-day cycle. 
Twenty three patients received therapy (mean, 15.2 doses; median, 8.0 doses) for a total of 
118treatment cycles (mean, 5.1 cycles; median, 3.0 cycles). 
Overall, the most common AEs (occurring in at least 30% of patients [7 patients overall]) 
were constipation (57%), nausea and vomiting and pneumonia (each 39%), febrile 
neutropenia and stomatitis (each 35%), and diarrhea (30%). Fifteen (65%) patients reported 
an SAE during the study. Except for febrile neutropenia (single-agent pevonedist, 3 patients) 
and pneumonia (single agent pevonedistat, 6 patients; combination treatment, 1 patient), no 
other SAE was reported by more than 1 patient. Three deaths occurred during treatment of 
within 30 days of receiving last dose of study drug and were assessed as not related to the 
study treatment.  Final efficacy data are not available at this time. 
1.3.3.2.4   Pevonedistat-2001  


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This ongoing, phase 2 study is evaluating the efficacy and safety of pevonedistat+azacitidine 
versus single-agent azacitidine in patients (aged 18 years and older) with HR MDS, CMML, 
and low blast AML. With a 28-day treatment cycle, pevonedistat is administered on Days 1, 
3, and 5 at a starting dose of 20 mg/m2, with azacitidine at a starting dose of 75 mg/m2 
administered on Days 1 through 5, 8, and 9. As of January 2019, 58 patients were treated 
with the combination of pevonedistat+azacitidine, and 62 patients received azacitidine 
alone. 
As of 22 January 2019, a total of 58 patients were ongoing in the study in the combination 
arm [26]. The most common AEs ≥ grade 3 reported in the combination group were 
neutropenia (33%), febrile neutropenia (26%), anemia (19%), and thrombocytopenia (19%).. 
On-study deaths occurred in 9% of patients in the combination arm, compared to 16% of 
patients receiving only azacitidine (n=53). Among the 39 evaluable patients receiving both 
pevonedistat and azacitidine, ORR was 71% with CR or 45%.  
1.3.3.2.5    Pevonedistat-3001 
As of 22 January 2020, 443 patients were enrolled and 433 (98%) patients reported at least 1 
TEAE. The most common AEs reported were constipation (159 patients [36%]), anemia 
(135 patients [30%]), neutropenia (132 patients [30%]), nausea (125 patients [28%]), and 
thrombocytopenia (120 patients [27%]). The most frequently reported SAEs were febrile 
neutropenia (64 patients [14%]), pneumonia (46 patients [10%]), pyrexia (19 patients [4%]), 
and anemia (18 patients [4%]). The most frequently reported TEAEs leading to study drug 
discontinuation were pneumonia (10 patients [2%]), septic shock (9 patients [2%]), febrile 
neutropenia and thrombocytopenia (each, 6 patients [1%]). Five on-study deaths occurred 
that were considered related to treatment, 2 patients with septic shock, 1 patient each for the 
following: bronchopulmonary aspergillosis, abdominal sepsis, and soft 
tissue necrosis.  
Efficacy data are not available at this time. 
 
1.4   Additional Safety Considerations 
1.4.1    
Cycle 1, Day 1 Toxicity/Multi Organ Failure 
A comprehensive review of the clinical trial safety data has shown that C1D1 toxicity 
involving multi-organ failure, including SAEs of renal, hepatic, and cardiac failure, some 
with a fatal outcome, has been observed in phase 1, single agent pevonedistat studies at 
doses equal to or above 110 mg/m2. Based on the observation that these events are 


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associated with higher pevonedistat doses, Millennium Pharmaceuticals, Inc. determined 
that all newly enrolling patients would receive pevonedistat at doses equal to or below 100 
mg/m2.  
The current understanding of the renal toxicity observed with pevonedistat suggests that it is 
not a primary event but is likely secondary to hemodynamic changes occurring in the setting 
of a type of acute phase response. 
Nonclinical investigative activities were undertaken to better understand the potential 
physiology behind the C1D1 events observed with pevonedistat dosing. As summarized in 
the latest IB, a model in which a minimally toxic, single dose of pevonedistat was 
administered with TNFα had several hallmarks associated with septic and/or cytokine-
induced shock. The overall time course and target organs affected in this nonclinical model 
also appeared to closely mimic those observed in clinical C1D1 events at single agent doses 
ranging from 110 to 278 mg/m2. 
In October 2012, a revised risk mitigation strategy limiting the dose to no higher than 50 
mg/m2 for dosing on Days 1, 3, and 5 and no higher than 100 mg/m2 for dosing on Days 1, 
4, 8, and 11 or 1, 8, and 15 for all studies for single agent administration was implemented 
across the pevonedistat program. As of January 2019, approximately 436 additional patients 
have been treated in single agent and combination studies, and no C1D1 SAEs as described 
above have been observed. These patients received pevonedistat at a dose of 50 to 100 
mg/m2 as a single agent, a dose of 15 to 30 mg/m2 in combination with different standard of 
care therapies, or a dose of 8 mg/m2 to 20 mg/m2 in combination with a CYP3A inhibitor. 
The Days 1, 3, and 5 schedule for pevonedistat infusion was chosen for further studies. The 
MTD for that schedule for patients with AML in Study C15003 was determined to be 
59 mg/m2, and the MTD for patients with solid tumors in Study C15001 was determined to 
be 67 mg/m2. 
1.4.2    
Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise 
Because of the underlying conditions of patients with advanced malignancies, patients must 
be carefully evaluated at screening and before each pevonedistat dose for early symptoms 
and signs of hemodynamic compromise and active infection. Particular attention should be 
paid to unexplained fever, tachycardia, hypotension, orthostasis, tachypnea, recent nausea 
and vomiting, and clinical evidence of dehydration. For those patients for whom there is a 


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concern of dehydration, the following guidance for rehydration before pevonedistat dosing 
may be considered: 500 mL/hour of 0.5 N saline given over 2 to 4 hours for a total of 1 to 2 
L of fluid as clinically appropriate. For all patients with anemia, and especially for patients 
with hemoglobin values  8 g/dL at screening or during the conduct of the study, RBC 
transfusions should be considered before pevonedistat dosing based on the patient’s risk of 
inadequate oxygenation, underlying cardiopulmonary status, clinical judgment, and/or 
hospital guidelines. Patients who experience signs and symptoms of hemodynamic 
compromise after pevonedistat dosing (eg, tachycardia, hypotension, orthostasis, and 
changes in mental status, syncope, and dizziness) should be followed closely and managed 
with supportive care, including hospitalization as clinically indicated. 
1.4.3    
Increases in Serum Creatinine 
At current doses equal to or below 100 mg/m2 on a Day 1, 3, and 5 or a Day 1, 4, 8, and 11 
schedules, there have been reports of changes in serum creatinine from baseline levels of 
Grade 0 to Grade 1, and from baseline levels of Grade 1 to Grade 2. 
1.4.4    
Increases in Liver Enzymes and Biochemical Tests 
Grade 1 to Grade 4 increases in adverse events related to liver function analyses (such as for 
liver transaminases [up to Grade 4], bilirubin [up to Grade 3], and alkaline phosphatase [up 
to Grade 3]), have been noted following administration of pevonedistat in patients with 
advanced malignancies receiving pevonedistat as a single agent and in combination with 
standard of care cytotoxic therapies. Among the single-agent studies, one patient in Study 
C15001 with metastatic colon cancer experienced a Grade 4 adverse event related to liver 
function analyses (alanine aminotransferase increased). In Study C15009, in patients with 
AML treated with pevonedistat in combination with azacitidine, Grade 4 increases for 
adverse events related to liver function analyses occurred in 2 patients as DLTs (alanine 
aminotransferase increased, aspartate aminotransferase increased). A third patient in Study 
C15009 experienced a Grade 4 adverse event (aspartate aminotransferase increased) that 
was not assessed as a DLT. In Study C15010 in patients with solid tumors treated with 
pevonedistat in combination with docetaxel, gemcitabine, or carboplatin plus paclitaxel, and 
also in Study C15011, a drug-drug interaction study, adverse events related to liver function 
analyses up to Grade 3 were observed.  
Patients experiencing these increases in laboratory values have been asymptomatic. The 
elevations in laboratory values have been reversible with dose modification including dose 


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delay and reduction. One patient was discontinued from study C15010 because of LFT 
elevations. 
1.4.5    
Drug Drug Interactions (DDIs) 
Because the metabolic and excretion pathways of pevonedistat remain to be characterized in 
humans, the risk of DDIs between pevonedistat and concomitantly administered drugs is 
currently informed by available nonclinical and clinical data. On the basis of completed DDI 
studies, administration of pevonedistat with CYP3A inhibitors and P-gp and BCRP 
inhibitors is permitted. 
As a general precaution, patients receiving concomitant medications, particularly those with 
narrow therapeutic indices, should be carefully monitored as the DDI potential between 
pevonedistat and other drugs has not been formally studied in humans. Patients should also 
be instructed to consult with the investigator before taking any new medications, including 
over-the-counter products and herbal supplements. 
For detailed information please consult the current IB. 
 
2.    
STUDY OBJECTIVES 
2.1    Primary Objectives 
x For Phase I: determine safety and phase II dose of pevonedistat in combination 
with pembrolizumab 
x To assess the efficacy of Pevonedistat in combination with Pembrolizumab in 
patients with dMMR/MSI-H cancers. 
2.2    Secondary Objectives: 
x To assess additional efficacy endpoints of the combination of Pevonedistat and 
pembrolizumab in dMMR/MSI-H cancers 
x To assess the safety of Pevonedistat and pembrolizumab in the dMMR/MSI-H 
patient cohort. 
x To assess the pharmacodynamics impact of Pevonedistat and pembrolizumab on 


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tumor and immune-related components. 
2.3    Exploratory Objectives: 
x Immune context evaluation of tumor microenvironment 
x Determine clinical benefit 
x Evaluate pevonedistat pharmacokinetics and resistance mechanisms in 
combination therapy  
 
3.    
STUDY ENDPOINTS 
3.1    Primary Endpoints  
x 
Phase I: To identify the RP2D of pevonedistat when combined with pembrolizumab 
x 
Phase II: Objective response (PR or CR) as measured with iRECIST v1.1  
3.2    Secondary Endpoints 
a. To analyze the pharmacodynamics impact of pevonedistat by evaluating changes in 
protein misfolding between pre-treatment and on-treatment tumor biopsies 
b. PFS (by iRECIST v1.1) 
c. Duration of response 
d. OS  
e. Safety 
3.3    Exploratory Endpoints 
a. To evaluate immune context of the tumor microenvironment at various time 
points in treatment course  
b. clinical benefit rate (CR+PR+SD by iRECIST v1.1)  
c. To evaluate pharmacokintetics of pevonedistat in combination with 
pembrolizumab 
d. To analyze potential mechanisms of anti-PD1/pevonedistat combination therapy 
resistance/sensitivity by evaluating such markers as neoantigen burden, 
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from pre-treatment tumor biopsies and changes from pre-treatment and on-
treamtent tumor biopsies. 
e. To analyze potential mechanisms of anti-PD1/pevonedistat combination therapy 
resistance/sensitivity by evaluating immunological changes in peripheral blood 
and microbiome diversity and immune-conducive signatures. 
f. To evaluate RNA signatures of gene expression and correlate them with patient 
response on study 
 
4.    
STUDY DESIGN  
4.1    Overview of Study Design 
 This clinical trial will be a single-arm, non-randomized, open-label two stage phase I/II 
study of pembrolizumab and pevonedistat in dMMR/MSI-H cancers. All patients are 
required to have prior progressive disease on prior anti-PD1 therapy.  
This study will follow a 3+3 dose escalation design for the phase I portion of the study (fig 
9) to determine RP2D. Therefore, a minimum of 3 subjects will be enrolled in each dose 
cohort: 
• If 0 out of the 3 subjects in a dose cohort experience a DLT during the DLT 
evaluation period, dose escalation may proceed to the next planned level. 
• If 1 of the 3 subjects in any dose cohort experiences a DLT during the DLT 
evaluation period, that dose cohort will be expanded to a total of 6 subjects. If no 
more than 1 of 6 subjects in the dose cohort experiences a DLT, dose escalation may 
proceed to the next planned dose level.  
• If 2 or more subjects in a dose cohort experience a DLT during the DLT evaluation 
period, the MTD will have been exceeded and no further subjects will be enrolled 
into that dose cohort. A previous lower dose cohort or an intermediate dose cohort 
may be explored. 
x If 0/3 patients experience DLTs at the highest dose level, this will be declared 
RP2D 
 
No intra-patient dose escalation will occur. Dose levels for pevonedistat are described in the 
Table 1. General schema for the study is outlined in figure 10. Determination of MTD and 
R2PD is outlined in figure 9. The MTD is defined as the highest dose with the DLT rate 
d1/6. The RP2D will represent the highest dose level at which the MTD is not exceeded. 
Once R2PD is determined, phase 2 portion of the study may proceed according to the study 
schema.  Patients included at the R2PD in the phase I portion of the study will be included 
as part of the planned enrollment in the phase II portion of the study for enrollment 
purposes.
 


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Table 1. Pevonedistat Dose Levels 
 
Level -2 
10 mg/m2 
Level -1 
15 mg/m2 
Level 1 (starting dose level) 
20 mg/m2 
Level 2 
25 mg/m2 
 
Study agents will be dosed as follows:  
x Pevonedistat starting at 20 mg/m2 IV on days 1, 3, and 5 of a 21 day cycle. Dose 
escalation will proceed based on criteria described above to determine RP2D.  
x Pembrolizumab 200 mg flat dose IV every 3 weeks  
 
 
Figure 9. Phase 1b 3+3 Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 10. Study Schema 
 
 
 
 
 
3 patients 
started at 
Pevonedistat 
20 mg/m2 
0/3 DLT 
1/3 DLT 
≥ 2/3 
DLT 
Escalate 
Dose 
Add 3 
patients 
on dose 
level 
1/6 DLT 
≥ 2/6 DLT 
Accrue 3 pts 
at lower dose 
≤ 1/6 
DLT 
RP2D 
≥ 2/6 
DLT 
Lower 
Dose 
Level - 
RP2D 
Baseline biopsy 
Week 3 biopsy 
Pevonedistat + 
Pembrolizumab 
Primary endpoint:  
Efficacy of 
Pevonedistat + 
Pembrolizumab  
 
Patients with 
Progressive 
disease of  
MSI-H tumors 
on or after anti-
PD1 therapy 
≤ 1/6 
DLT 
RP2D 


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Study specific procedures for each visit are outline in the Schedule of Events (Appendix 6). 
4.2    Number of Patients 
 In order to provide RP2D, we plan to enroll on a 3+3 design with approximately 3-6 
patients per cohort followed by a phase II two stage design in which 11 to 21 patients will be 
enrolled. Approximately 14-39 patients will be enrolled overall in  the study to evaluate 
initial efficacy estimate of the proposed drug combination 
4.3    Duration of Study 
Anticipated enrollment will be 1 to 1.5 patients per month and thus full enrollment will take 
22 months with an additional 6 months for further followup following the last enrolled 
patient. 
 
5.    
STUDY POPULATION 
5.1    Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female patients 18 years or older.  
2. Patients must have metastatic or locally advanced unresectable solid tumor 
3. Tumor that is deficient in mismatch repair (dMMR) or microsatellite instability high (MSI-H) 
as determined by one of three methods: 
x 
 Immunohistochemistry determined dMMR by complete loss of MLH1, PMS2, 
MSH2 or MSH6 
x 
PCR determined microsatellite instability at >30% of tested microsatellites 
x 
Next-generation determined MSI-H based upon instability at multiple 
microsatellites as determined by the specific next generation sequencing panel 
4. Eastern Cooperative Oncology Group (ECOG) performance status  0 or 1. 
5. Clinical laboratory values within the following parameters: 
a. Hemoglobin ≥8 g/dL (may transfuse to achieve this threshold) 
b. ANC ≥ 1,500/mm3  


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c. Platelet count ≥ 100,000/mm3  
d. Albumin > 2.7 g/dL 
 
e. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except in patients with 
Gilbert’s syndrome. Patients with Gilbert’s syndrome may enroll if direct 
bilirubin ≤ 3 x ULN of the direct bilirubin.  
f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 
× ULN  
g. Creatinine clearance ≥ 30 mL/min according to MD Anderson standard, 
automated laboratory calculation. 
6. HIV patients may be considered as long as they meet the following criteria: 
x CD4 count > 350 cells/mm3 
x Undetectable viral load 
x No history of AIDS-defining opportunistic infections 
7. Female patients who: 
x Are postmenopausal (see Appendix 4 for definition) for at least 1 year before the 
screening visit, OR 
x Are surgically sterile, OR 
If they are of childbearing potential: 
x Agree to practice 1 highly effective method and 1 additional effective (barrier) 
method of contraception (see Appendix 5), at the same time, from the time of 
signing the informed consent through 4 months after the last dose of study drug 
(female and male condoms should not be used together), or 
x Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception.)  
Male patients, even if surgically sterilized (ie, status postvasectomy), who: 


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x Agree to practice effective barrier contraception during the entire study treatment  
period and through 4 months after the last dose of study drug (female and male 
condoms should not be used together), or 
x Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods for the female partner] withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception.) 
8. Voluntary written consent must be given before performance of any study related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care. 
9. Demonstrated prior progression on or after anti-PD1/L1 based therapy by radiographic 
progression.  The potential for psuedoprogression should be excluded by concurrent tumor 
marker (for example carcinoembryonic antigen) or ctDNA elevation, or clinical symptom 
progression, or short interval repeat imaging confirming progression. (if uncertain if patient 
meets eligibility please discuss with study PI) 
x 
Must have received at least 2 doses of a PD1/PD-L1 inhibitor 
x 
Progressive disease either during therapy or within 2 months of last dose of therapy. 
10. Measureable disease by iRECIST v1.1 by treating investigator or study PI. 
11.  Tumor that is accessible to biopsy and patient is willing to undergone mandatory 
tumor biopsies at pre-treatment and on-treatment (unless exception granted by study 
PI) 
12. Life expectancy ≥12 weeks as judged by treating physician 
5.2    Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Treatment with any investigational products within 4 weeks before the first dose of 
any study drug. 
2. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of study procedures. 


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3. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, 
meningitis, or septicemia. 
4. Major surgery within 14 days before the first dose of any study drug or a scheduled 
surgery during study period. 
5. Patients with a prior or concurrent malignancy whose natural history or treatment 
does not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
6. Life-threatening illness unrelated to cancer. 
7. Patients with uncontrolled coagulopathy or bleeding disorder. 
8. Known hepatitis B surface antigen seropositive or known or suspected active 
hepatitis C infection 
Note:  Patients who have isolated positive hepatitis B core antibody (ie, in the setting 
of negative hepatitis B surface antigen and negative hepatitis B surface antibody) 
must have an undetectable hepatitis B viral load.  Patients who have positive 
hepatitis C antibody may be included if they have an undetectable hepatitis C viral 
load. 
9. Known hepatic cirrhosis or severe pre-existing hepatic impairment 
10. Known cardiopulmonary disease defined as: 
x Unstable angina;  
x Congestive heart failure (New York Heart Association [NYHA] Class III or 
IV; see appendix 3); 
x Myocardial infarction (MI) within 6 months prior to first dose (patients who 
had ischemic heart disease such as a (ACS), MI, and/or revascularization 
greater than 6 months before screening and who are without cardiac 
symptoms may enroll); 
x Symptomatic Cardiomyopathy; 
x Clinically significant arrhythmia: 
1. History of polymorphic ventricular fibrillation or torsade de pointes, 


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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, within 6 months of starting protocol therapy, defined as  
symptomatic and incompletely controlled medically, 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. 
x Clinically significant pulmonary hypertension requiring pharmacologic 
therapy. 
11. Uncontrolled high blood pressure (ie, systolic blood pressure ≥ 160 mm Hg, diastolic 
blood pressure ≥ 100 mm Hg). 
12. Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to 
institutional guidelines. 
13. Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or 
radionuclide angiography. 
14. Known moderate to severe chronic obstructive pulmonary disease, interstitial lung 
disease, and pulmonary fibrosis. 
15. Known central nervous system (CNS) involvement unless controlled with surgery or 
radiation therapy and has demonstrated no progression over 3 months from last local 
modality therapy. 
16. Systemic antineoplastic therapy or radiotherapy for other malignant conditions 
within 14 days before the first dose of any study drug. 
17. Female patients who are both lactating and breastfeeding or have a positive serum 
pregnancy test during the screening period or a positive urine pregnancy test on Day 
1 before first dose of study drug. 
18. Female patients who intend to donate eggs (ova) during the course of this study or 4 
months after receiving their last dose of study drug(s). 


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19. Male patients who intend to donate sperm during the course of this study or 4 months 
after receiving their last dose of study drug(s). 
20.  Known hypersensitivity to a study agent(s).  
21. Residual adverse events from prior therapy (other than endocrinopathies or alopecia 
or neuropathy due to chemotherapy) that have not resolved to Grade 0-1  
22. Serious adverse immune related adverse events (grade 3 or 4) with previous immune 
checkpoint therapy, that were symptomatic and required prolong immunosuppression 
(>6weeks). 
 
6.    
STUDY DRUG 
6.1    Study Drug Administration 
All protocol-specific criteria for administration of study drug must be met and documented 
prior to drug administration. Study drug will be administered only to eligible patients 
underthe supervision of the investigator or identified subinvestigator(s). 
If pevonedistat dosing is delayed, a minimum of 1 full calendar day between any 2 doses 
should be maintained. In each cycle, a maximum of 3 doses of pevonedistat should not be 
exceeded.  
The amount of study drug to be administered will be based on BSA. BSA will be calculated 
using a standard formula (see example in Appendix 2) on Cycle 1 Day 1, and on Day 1 of 
subsequent cycles. If the patient experiences a >5% change in body weight from the weight 
used for the most recent BSA calculation than the dose should be adjusted according to this 
new body weight. 
Pevonedistat  will be administered roughly over 60-minute via IV infuision on Days 1, 3 and 
5 of a 21 day cycle. Dose administered will be determined by patient’s assigned dose 
escalation level, as outlined in the study design. Detailed instructions on drug preparation, 
handling and administration are outlined in section 6.8.  
On Day 1 of each cycle, when the patient receives both agents, pembrolizumab will be 
administered following pevonedistat infusion. Patient should be monitored for adverse 
reactions roughly 30 minutes prior to infusion of the second agent.  


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Pembrolizumab 200 mg will be administered as an IV infusion over roughly 30 minutes on 
Day 1 of each cycle. The current label for pembrolizumab contains specific instructions for 
the preparation of the pembrolizumab infusion fluid and administration of infusion solution. 
6.2    Definitions of Dose Limiting Toxicity 
DLT will be defined as any of the following events that are considered by the investigator to 
be related (possible, probably or definitely related) to therapy with pevonedistat and or 
pembrolizumab, and occur during the first 21 days of study therapy: 
x Grade 3 or greater PT or aPTT elevation in the absence of anticoagulation therapy.  
x Grade 2 or greater elevation of the PT or aPTT that is associated with clinically 
significant bleeding (CNS, GI, etc).  
x Grade 3 or greater nausea and/or emesis despite use of optimal anti-emetic 
prophylaxis. Optimal anti-emetic prophylaxis is defined as an anti-emetic regimen 
that employs a 5-hydroxytryptamine 3 serotonin receptor antagonist given in 
standard doses and according to standard schedules.  
x Grade 3 or greater diarrhea that occurs despite maximal supportive therapy 
x Grade 3 arthralgia/myalgia despite the use of optimal analgesia  
x Any other Grade 3 or greater non-hematologic toxicity with the following 
exceptions: 
x Brief ( 1 week) Grade 3 fatigue 
x Grade 3 hypophosphatemia  
x Grade 3 or greater elevation in transaminases concurrent with Grade 2 or greater 
bilirubin 
x Other pevonedistat-related non-hematologic toxicities Grade 2 or greater that, in the 
opinion of the investigator, require a dose reduction or discontinuation of therapy 
with pevonedistat.  
x A delay in the initiation of Cycle 2 due to a lack of adequate recovery from 
treatment-related toxicity (recovery to ≤Grade 1 or to patient’s baseline values): 
 Of more than 4 weeks due to hematologic toxicity  
 Of more than 2 weeks due to nonhematologic toxicities. 
x Grade 4 neutropenia (ANC  500 cells/mm3) lasting more than 7 consecutive days 
x Grade 3 neutropenia with fever and/or infection, where fever is defined as an oral 
temperature t 38.5qC 
x Grade 4 thrombocytopenia (platelets  25,000/mm3 but ! 10,000/mm3) lasting more 
than 7 consecutive days 
x Grade 3 thrombocytopenia with bleeding 
x
A platelet count  10,000/mm3 at any time
x Grade ≥ 3 immune colitis 
x Grade ≥3 immune pneumonitis 


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x Grade ≥ 3 immune hypophysitis 
x Grade ≥ 3 Type I Diabetes Mellitus 
x Grade ≥ 3 immune nephritis 
x Grade 4 immune skin rashes (including, but not limited to SJS; TEN) 
x Grade ≥3 of any other clinically significant immune mediated dose limitingtoxicities, 
including but not limited to: Guillain Barrè syndrome, myasthenia gravis, vasculitis, 
pancreatitis,encephalitis, myelitis and myocarditis. 
x Grade 5 toxicity. 
 
Although DLTs may occur at any point during treatment, only DLTs occurring during 
Cycle 1 of treatment will necessarily influence decisions regarding dose escalation, 
expansion of a dose level, or evaluation of intermediate dose levels.  Patients will be 
monitored through all cycles of therapy for treatment related toxicities. 
 
The incidence of DLTs occurring during Cycle 1 will represent the 21-day DLT period.  
This will be used to define the dose escalation and the RP2D. Study adverse events (AEs) 
will be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  
6.3Dose-Modification Guidelines  
Pevonedistat dose may be reduced by one or two dose levels based on type and grade of 
toxicity experienced. Guidelines for dose-modification to manage various toxicities are 
specified in sections 6.3.2 and 6.3.3.  
Dose levels will not be reduced for pembrolizumab. Dose-modifications to manage immune-
related toxicities and infusion related reactions attributed to pembrolizumab are detailed in 
sections 6.3.4 and 6.3.5, respectively  
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE version 5.0).  
Immunological AEs are expected to be related to pembrolizumab and should be managed as 
listed for pembrolizumab dose-modification, while non-immunologic toxicities are expected 
to be related to pevonedistat and should be managed as listed for pevonedistat.  If a clinician 
is uncertain the attribution than dose modification of both agents for a toxicity can be done. 
If one drug is discontinued due to toxicity the patient may continue on study with the other 
study drug. 


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6.3.1   Criteria for Retreatment and Dose Delays 
6.3.1.1   Retreatment within a Cycle 
If dosing of either drug is delayed for safety reasons, retreatment may be resumed upon 
resolution of the safety condition. For pevonedistat, a minimum of 1 full calendar day 
between any 2 doses should be maintained. A maximum of 3 doses of pevonedistat should 
not be exceeded. 
If dosing is interrupted within a cycle because of drug-related toxicity, and if the  Principal 
investigator agrees that it is in the patient’s interest to continue therapy with the study 
drug(s), then after recovery of the toxicity or toxicities in question to ≤Grade 1 or to the 
patient’s baseline values, the dose of study drug may be reduced in the next cycle. For 
toxicity not related to drug (eg, disease-related toxicity), although a similar dose reduction is 
permitted, in general it is discouraged. If the reduced dose is well tolerated and the toxicity 
leading to dose reduction was ≤Grade 3, has resolved, and does not reoccur, the dose may 
resume at the original dose level in the next cycle after endorsement by the  Principal 
investigator (or designee). 
6.3.1.2   Initiation of a New Cycle 
Treatment with study drugs will be repeated each cycle. For therapy to resume, toxicity 
considered related to treatment with study drugs must have resolved to dGrade 1, to the 
patient’s baseline values, or to a level considered acceptable by the sponsor Principal 
investigator. The maximum delay from end of a cycle to the initiation of a new cycle is 
6weeks. Patients requiring a delay of longer, should be removed from the study unless there 
is a clear clinical benefit and this can be discussed with the principal investigator. 
If a patient fails to meet the criteria for retreatment, initiation of the next cycle of treatment 
may be delayed for up to 2 weeks. At the end of that time, the patient should be reevaluated 
to determine whether the criteria for retreatment have been met. A dose reduction would be 
triggered if treatment is delayed for >2 weeks because of incomplete recovery from 
treatment related non-hematologic toxicity. An exception to this treatment plan is for a 
patient who experiences an immune related toxicity to pembrolizumab and pembrolizumab 
is held while that toxicity is managed. In this situation the patient may continue on cycle 
with pevonedistat alone until it is safe to treat with pembrolizumab again. 
For hematologic toxicity a delay in the initiation of a cycle by 4 weeks or greater because of 
lack of recovery from treatment-related hematologic toxicity (resolved to dGrade 1, to 


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patient’s baseline values, or to a level considered acceptable by the Principal investigator) 
will trigger a dose reduction if treatment resumes. The pevonedistat dose should be reduced 
by at least 1 dose level. 
6.3.2   Pevonedistat Dose Modifications for Hematologic Toxicities 
It is not anticipated that pevonedistat dose modifications would be necessary due to 
myelosuppression. However, if clinically indicated in the opinion of the investigator, the 
pevonedistat dose may be reduced one dose level. The pevonedistat dose may be re-
escalated at the next cycle, if the toxicity has recovered to ≤Grade 1 or the patient’s baseline.  
6.3.3   Pevonedistat dose Modifications for Nonhematologic Toxicities 
Pevonedistat Dose Adjustment Based on Serum Transminases and Total Bilirubin 
ALT, AST and bilirubin grading will be determined by CTCAE version 5.0 in times per 
ULN irrespective of baseline levels. 
It is anticipated that LFTs (AST, ALT, and occasionally bilirubin) may be elevated for 
approximately 48 hours following the end of pevonedistat infusion on Cycle 1 Day 1.  
For elevated LFTs of Grade 2 or 3 that occur on or after Cycle 1 Day 3, pevonedistat should 
be held; once the elevated AST or ALT returns to ≤Grade 1, and/or elevated bilirubin 
returns to ≤1.5×ULN or the patient’s baseline level, pevonedistat dose may be resumed. For 
pevonedistat, a minimum of 1 full calendar day between any 2 doses should be maintained, 
and a maximum of 3 doses of pevonedistat within the cycle must not be exceeded.  
For elevated LFTs of Grade 4 that occur on or after Cycle 1 Day 3, the pevonedistat dose 
should be held for the remainder of the cycle; if the elevated AST or ALT returns to ≤Grade 
1, and/or elevated bilirubin returns to ≤1.5×ULN or the patient’s baseline level, then 
pevonedistat may be restarted at the next cycle at a reduced dose. If the toxicity returns to 
≤Grade 1 or the patient’s baseline status, pevonedistat may be re-escalated. 
Pevonedistat Dose Adjustment Based on Hypophosphatemia 
If hypophosphatemia is ≥Grade 3, study drug treatment should not be resumed until the 
hypophosphatemia is ≤Grade 2. Hypophosphatemia should be evaluated (including severity 
and etiology), monitored, and treated according to institutional guidelines. 
Pevonedistat Dose Adjustment for Other Toxicities 


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For other ≥Grade 2 nonhematologic toxicities potentially related to pevonedistat, the 
pevonedistat dose may be reduced at the discretion of the  Principal investigator as clinically 
indicated. If the toxicity returns to ≤Grade 1 or the patient’s baseline status, pevonedistat 
may be re-escalated at the next cycle. 
6.3.4   Pembrolizumab Dose Modifications for Management of Immune-Related 
Toxicities 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology 
or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, 
skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab 
are provided in Table 1. 
Table 2. 
Dose modification and toxicity management guidelines for immune-
related AEs associated with pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids. 
 
Immune-
related AEs 
Toxicity 
grade or 
conditions 
(CTCAEv
5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
x Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper 
 
x 
Monitor participants for 
signs and symptoms of 
pneumonitis 
x 
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
Grade 3 or 
4, or 
recurrent 
Permanently 
discontinue 


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Grade 2 
and initiate 
corticosteroid treatment 
x 
Add prophylactic 
antibiotics for 
opportunistic infections 
Diarrhea / 
Colitis  
Grade 2 or 
3 
Withhold 
x Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper 
 
x 
Monitor participants for 
signs and symptoms of 
enterocolitis (i.e., 
diarrhea, abdominal pain, 
blood or mucus in stool 
with or without fever) 
and of bowel perforation 
(i.e., peritoneal signs and 
ileus). 
x 
Participants with ≥ Grade 
2 diarrhea suspecting 
colitis should consider 
GI consultation and 
performing endoscopy to 
rule out colitis.  
x 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  
If sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted via 
IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
x Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
prednisone or 
equivalent) followed by 
taper 
x 
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned to 
baseline or is stable 
Grade 3 or 
4  
Permanently 
discontinue 
x Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper 


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Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglyce
mia 
 
Newly 
onset 
T1DM or  
Grade 3 or 
4 
hyperglyce
mia 
associated 
with 
evidence of 
E-cell 
failure 
Withhold 
x Initiate insulin 
replacement therapy for 
participants with T1DM  
x Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
x 
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophysiti
s 
Grade 2 
Withhold 
x Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.   
 
x 
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 
4  
Withhold or 
permanently 
discontinue1  
Hyperthyroi
dism  
Grade 2 
Continue  
x Treat with non-selective 
beta-blockers (e.g., 
propranolol) or 
thionamides as 
appropriate  
x 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 or 
4  
Withhold or  
permanently 
discontinue1 
Hypothyroid
ism 
Grade 2-4 
Continue  
x Initiate thyroid 
replacement hormones 
(e.g., levothyroxine or 
liothyroinine) per 
standard of care 
x 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Nephritis 
and Renal 
dysfunction 
Grade 2 
Withhold  
x Administer 
corticosteroids 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper. 
x 
Monitor changes of renal 
function 
 
Grade 3 or 
4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 
2 
Withhold 
x Based on severity of 
AE administer 
corticosteroids 
x 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 or 
4 
Permanently 
discontinue 
All other 
immune-
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
x Based on type and 
severity of AE 
administer 
corticosteroids  
x 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the type 
of event.  Events 
that require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Permanently 
discontinue 


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Grade 3  
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with 
hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
6.3.5   Pembrolizumab Dose Modifications for Management of Infusion-Reactions  
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 2. 


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Table 3.  Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 


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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the participant 
should be premedicated for the next scheduled 
dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment 
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should 
be used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 


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6.4    Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study: 
 
Table 4. Concomitant Medications Excluded During the Study 


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Therapy 
Comment/Exceptions 
Acetaminophen and acetaminophen-containing 
products 
For patients in the dose-escalation phase of a clinical 
study, agents such as acetaminophen and 
acetaminophen-containing products should not be 
administered 24 hours before, on the day of, 
and 24 hours after dosing with pevonedistat. For 
patients not in dose escalation, agents such as 
acetaminophen and acetaminophen-containing 
compounds may be used judiciously and should not 
exceed a dose of 2 g of acetaminophen in a 24  hour 
period. 
Any investigational agent other than pevonedistat 
For example androgens, supraphysiologic doses of 
corticosteroids, erythropoietin, eltrombopag 
[Promacta], or romiplostim [Nplate] are excluded. 
BCRP=breast cancer resistance protein, CYP=cytochrome P450,  
6.5   Permitted Concomitant Medications and Procedures 
Table 5.  Concomitant Medications and Procedures Permitted During the Study 
 
Therapy 
Comment 
Anti-platelet agents (eg, aspirin, 
clopidogrel) and anticoagulants 
May be used in patients who have controlled coagulopathy at baseline, as 
well as those who develop a coagulopathy on study. Note that patients with 
active uncontrolled coagulopathy are excluded from enrollment.  
Myeloid growth factors (eg, 
G-CSF, GM-CSF) 
In general, the use of myeloid growth factors is discouraged and should be 
restricted. Growth factors may be used in specific circumstances after 
discussion with the PI. Use of growth factors may also be used in patients 
with Grade 3 or Grade 4 febrile neutropenia after discussion and agreement 
with the project clinician or designee. Additionally to avoid dose delays, 
patients who experience Grade 4 neutropenia (ANC <500/μL) with or 
without fever may receive granulocyte colony-stimulating factor (G-CSF) or 
granulocyte macrophage colony-stimulating factor (GM-CSF)  
 
Platelet transfusion 
Permitted as medically necessary per institutional guidelines (eg, for 
platelets <10,000/μL in the absence of clinical bleeding); see Section 6.9 
Red blood cell transfusion 
To be considered for all patients with anemia, especially those with 
hemoglobin values ≤8 g/dL. 
G-CSF=granulocyte colony-stimulating factor, GM-CSF=granulocyte macrophage colony-stimulating factor. 
 
6.6   Precautions and Restrictions 
Pregnancy 
It is not known what effects pevonedistat has on human pregnancy or development of the 
embryo or fetus. Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner. 


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Nonsterilized female patients of reproductive age group and male patients should use highly 
effective methods of contraception (see Appendix 5) through defined periods during and 
after study treatment as specified below. 
x Female patients must meet 1 of the following: 
x Postmenopausal (See Appendix 4) for at least 1 year before the Screening visit, or 
x Surgically sterile, or 
x If they are of childbearing potential, agree to practice 1 highly effective method  and  
1 additional effective (barrier) method of contraception, at the same time, from the 
time of signing the informed consent through 4 months after the last dose of study 
drug, or 
x Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] withdrawal, spermicides only, and lactational amenorrhea 
are not acceptable methods of contraception. Female and male condoms should not 
be used together.) 
x Female patients must agree to not donate eggs (ova) during the course of this study 
or 4 months after receiving their last dose of study drug(s).  
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following: 
x Practice highly effective barrier contraception during the entire study treatment 
period and through 4 months after the last dose of study drug, or 
x Practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.) 
Male patients must agree to not donate sperm during the course of this study or 4 months 
after receiving their last dose of study drug(s). 


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6.7  Management of Clinical Events  
Hemodynamic Compromise in Patients Receiving Pevonedistat 
It is essential that the patients receiving pevonedistat are carefully evaluated at Screening 
and before each pevonedistat dose for early symptoms and signs of hemodynamic 
compromise and/or active infection. Particular attention should be paid to unexplained fever, 
tachycardia, hypotension, orthostasis, tachypnea, recent nausea and vomiting, and clinical 
evidence of dehydration. Patients who experience an untoward reaction with pevonedistat 
should be followed closely on subsequent dosing. 
For patients for whom there is a concern of dehydration, the following guidance for 
rehydration before pevonedistat dosing may be considered: 500 mL/hour of 0.5 N saline 
given over 2 to 4 hours for a total of 1 to 2 L of fluid as clinically appropriate. 
For all patients with anemia, and especially for those with hemoglobin values <8 g/dL at 
Screening or during the conduct of the study, RBC transfusions should be considered before 
pevonedistat dosing based on the risk of inadequate oxygenation, underlying 
cardiopulmonary status, clinical judgment, and/or hospital guidelines. Note: Transfusions 
should occur the day before doses given that pevonedistat is extensively distributed in 
RBCs. 
Patients who experience signs and symptoms of hemodynamic compromise after 
pevonedistat dosing (eg, tachycardia, hypotension, orthostasis, changes in mental status, 
syncope, and dizziness) should be followed closely and managed with supportive care, 
including hospitalization, as clinically indicated. 
Guidance for Management of Extravasation 
 
Based on nonclinical findings as detailed in the IB, pevonedistat is considered a nonvesicant 
drug. Although no published guidelines are available for extravasation of nonvesicants, the 
investigator is encouraged to follow institutional guidelines. Some general advice in case of 
extravasation includes immediately stopping drug infusion and elevating the affected limb to 
minimize swelling. 
6.8 Description of Investigational Agents 
6.8.1   Pevonedistat 
Section redacted 


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<Pembrolizumab  
Standard of care supply of pembrolizumab will be utilized for the study.  
6.8.2   Preparation, Reconstitution, and Dispensing 
Pevonedistat is a cytotoxic anticancer drug, and as with other potentially toxic compounds, 
caution should be exercised when handling pevonedistat. 
The specified number of Injection Drug Product vials should be removed and allowed to 
equilibrate to room temperature prior to dilution. The vials must be kept in the original 
carton while equilibrating to room temperature. The vial must not be shaken at any time 
during dose preparation.   
Using aseptic technique, the appropriate volume of drug should be withdrawn from vial(s), 
then injected into a 250-mL IV bag containing 5% dextrose or 0.9% saline solution, and then 
gently inverted repeatedly to mix. The pevonedistat prepared IV bag must be used within 6 
hours (time to the end of an injection) if stored at ambient temperature. Alternatively, the 
prepared IV bag is chemically stable and may be stored for up to 18 hours at 2qC to 8qC.  
After 18 hours of storage at 2qC to 8°C, the prepared IV bag must be used within 3 hours 
(time to the end of an injection) upon coming to ambient temperature.   
The bag, needle, and syringe must be disposed of in a proper biohazard container 
 Preparation, Reconstitution and Dispensing for pembrolizumab will be based on standard 
guidelines for the agent.  
6.8.3    
Packaging and Labeling 
Pevonedistat (TAK-924/MLN4924) will be provided in 10-mL glass vials at a concentration 
of 10 mg/mL. 
Pembrolizumab drug supply will be labeled in accordance with current regulatory 
requirements 


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6.8.4    
Storage, Handling, and Accountability 
Vials of pevonedistat (TAK-924/MLN4924) are to be stored at 2qC to 8qC. Pevonedistat 
injection is stable at ambient temperature for 6 hours before dilution. All investigational 
supplies are to be kept in a secure area with controlled access. 
Study drug will be administered only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s).  The amount of drug to be administered will be 
based on body surface area (BSA).  BSA will be calculated using a standard nomogram on 
Cycle 1, Day 1 (see Appendix 2), and at subsequent visits if the patient experiences a > 5% 
change in body weight from the weight used for the most recent BSA calculation. 
The pharmacist will maintain records of drug receipt (if applicable), drug preparation, and 
dispensing, including the applicable lot numbers, and total drug administered in milliliters 
and milligrams.   
All patients will receive pevonedistat diluted with 5% dextrose or 0.9% saline solution in a 
250-mL IV bag via IV infusion via a 60-minute IV infusion. Pevonedistat should be 
administered through central or peripheral venous access. The infusion may be slowed or 
stopped and restarted for any associated infusion-related reactions. All infusion times must 
be recorded. The total time from drug reconstitution to end of infusion must not exceed 6 
hours. Doses of pevonedistat must be separated by at least 1 full calendar day. 
Standard guidelines for storage, handling and administration of pembrolizumab will be 
applicable for this study. 
6.9      Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the  principal investigator. The appropriate study personnel will maintain records of study 
drug receipt and dispensing. When appropriate, study drug will be destroyed per institutional 
policy. 
6.10   
Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care.  The investigator also has the right to 
withdraw patients from the study for any of the following reasons: 
x Adverse event 


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x Protocol violation 
x Lost to follow-up 
x Confirmed progressive disease using iRECIST v1.1 
x Subsequent anti-cancer therapy 
x Withdrawal by subject 
x Study terminated  
x Other 
  
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. 
7.    
STATISTICAL AND QUANTITATIVE ANALYSES 
7.1.1     
Determination of Sample Size 
This clinical trial will be a single-arm, non-randomized, open-label two stage phase I/II 
study of pembrolizumab and pevonedistat in dMMR/MSI-H cancers.With a null hypothesis 
of ≤3% response rate and an alternative hypothesis response rate of 20% with we can use 
Bayesian optimal phase II (BOP2) design: 1st stage 11 pts, if 1 or more responses, add 11 
more. Among 22 patients, 34 or more responses are regarding promising. This controls type 
I error 5%, power 81%.  
7.1.2    
Safety Analysis 
Descriptive analysis of toxicity will occur.  Continuous monitoring will occur as listed 
below in toxicity monitoring.  
 
7.1.2.1.  
Toxicity Monitoring 
Phase I - Escalation Portion: 
In order to provide RP2D, we plan to enroll on a 3+3 design with approximately 3-6 
patients per cohort followed by a phase II two stage design in which 11 to 21 patients 
will be enrolled. Approximately 14-39 patients will be enrolled overall in  the study to 
evaluate initial efficacy estimate of the proposed drug combination. 


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Phase II – Two Stage Portion: 
Based on prior studies [29, 30], total treatment-related grade 3/4 toxicity rate of 15% and 
17% may be assumed for  pevonedistat and pembrolizumab, respectively. Based on these 
prior published data if toxicities are additive then a grade 3/4 rate for these two agents would 
be approximately 32%.  
Toxicity monitoring will be implemented using the BOP2 design for possible/probable/ 
definitive treatement-related grade  >= 3 AE.   We will apply the toxicity monitoring rule in 
cohort sizes of 6, starting from the 6th patient, as indicated in Table 6 over the first 42 days 
of treatment (two cycles). AEs unrelated to the study treatments will not be included in the 
safety decision making.  Study monitoring will be done in DMI database at MD Anderson. 
The stopping rule in Table 6 is obtained by maximizing Pr(claim that the treatment is safe | 
݌௧௢௫ൌͲǤʹ), while controlling Pr(claim that the treatment is safe | ݌௧௢௫ൌͲǤͷ) = 0.197, (i.e., 
the null toxicity rate of 0.5 and the alternative toxicity rate of 0.2) based on the following 
Bayesian stopping rule: the treatment is deemed unacceptably toxic if 
ܲݎሺ݌௧௢௫൑ͲǤͷȁ݀ܽݐܽሻ൏ߣቀ݊
ܰቁ
ఈȀଷ
ǡ 
where, ݊ is the interim sample size, ܰ is the maximum sample size, and ߣ=0.68 and ߙ=0.74 
are design parameters optimized, assuming a vague prior Beta(0.5,0.5) for ݌௧௢௫ to make 
“go/no-go” decision. 
Given this is a novel combination the study will also monitor for signs of severe toxicity in 
the first three patients. If two related grade 4 events or a related grade 5 event occurs in these 
first 3 patients than the study will be stopped and discussions between Takeda and MD 
3 patients 
started at 
Pevonedistat 
20 mg/m2 
0/3 DLT 
1/3 DLT 
≥ 2/3 
DLT 
Escalate 
Dose 
Add 3 
patients 
on dose 
level 
1/6 DLT 
≥ 2/3 or  
≥2/6 DLT 
Accrue 3 or 6 
pts at lower 
dose 
≤ 1/6 
DLT 
RP2D 
≥ 2/6 
DLT 
Lower 
Dose 
Level - 
RP2D 
 
RP2D 


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Anderson will occur regarding continuation of clinical trial enrollment with an amendment 
required for further enrollment. 
Table 6.  Optimized Stopping Boundaries 
 
# patients 
treated 
Stop if # toxicity 
>= 
6 
4 
12 
6 
18 
9 
22 
10 
The operating characteristics for patient toxicity monitoring is illustrated in Table 6.  
Table 7.  Operating Characteristics for Toxicity Monitoring  
 
Toxicity 
rate 
Early stopping 
(%) 
Claim acceptable 
(%) 
Sample 
size 
0.5 
71.20 
19.67 
13.3 
0.4 
41.35 
51.05 
17.1 
0.3 
15.65 
81.90 
20.1 
0.2 
3.09 
96.72 
21.6 
 
7.1.2.2 Efficacy and Safety Monitoring: 
 
The Investigator is responsible for completing efficacy/toxicity summary reports and 
submitting them to the IND office Medical Affairs and Safety Group, for review and 
approval.  These should be submitted as follows:  
  
Phase I –Escalation: 
 
Toxicity summary report: After the first 3 evaluable patients, complete cycle 1 (first 21 
days) of study treatment, and every 3 evaluable patients thereafter, prior to changing dose 
levels or expanding to phase II. 
 
Phase II - Expansion: 
 
Efficacy/Toxicity summary report: After the first 6 evaluable patients, complete cycle 2 of 
study treatment, and every 6 patients thereafter, until enrollment is complete. 
 


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A copy of the summary report should be placed in the Investigator’s Regulatory Binder 
under “sponsor correspondence”. 
 
 
7.1.3    
Pharmacokinetics 
Blood samples will be collected for PK studies at time points indicated in the study Schedule 
of Events (Appendix 6). Specific instructions for collections will be detailed in the Research 
Blood and Tissue Collection Manual.  
Pharmacokinetic Measurements 
Serial blood samples will be collected from each patient for the determination of 
pevonedistat plasma concentrations at the time points indicated below. The timing, but not 
the number, of PK blood samples may be changed if emerging data indicate that an 
alteration in the sampling scheme is needed to better characterize the PK of pevonedistat. 
 
To ensure that the measurements are representative of plasma exposure, blood draws will be 
conducted in the arm opposite to a patient’s IV infusion. If only a single arm is available, 
blood should be drawn as distal to the site of the IV infusion as feasible, and the site of the 
blood draw should be documented.  
 
The exact date and time of each sample collection and the actual start and stop times of the 
infusion should be recorded accurately, and particular care should be given to recording 
blood sampling times that occur close to the infusion. 
 
Pharmacokinetic Assay Method 
Plasma samples will be analyzed for pevonedistat concentrations using a GLP-validated 
liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay.  
 
Pharmacokinetic Analysis 
Individual pevonedistat plasma concentration-time data will be analyzed using standard 
noncompartmental methods using WinNonlin software (Pharsight, CA). The following PK 
parameters of pevonedistat will be estimated Cmax, Tmax, AUC24, Vss and CL, and t1/2 
and AUC∞ (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.   As data permit, exploratory PK-PD relationships (e.g. 
Cmax or AUC vs response) will be examined using a direct PD model such as the Emax or 
Sigmoid Emax model. 
 
7.1.4 Translational Studies 
Paired biopsies: Biopsies aid the effort to further the study’s exploratory objectives. 


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Evaluation of patient tumors prior to and on treatment will elucidate the impact of study 
therapy on immune activity and the tumor microenvironment.  
To analyze potential mechanisms of anti-PD1/pevonedistat combination therapy 
resistance/sensitivity, we will first test if baseline factors such as neoantigen burden, 
destabilizing mutation burden, immune microenvironment characteristics, or combination 
thereof are indicative of response. Next, we will also evaluate these same type of 
parameters, but instead comparing their relative changes between pre- and post- treatment 
biopsies. 
Given the expected phase 2 sample size of approximately 22 patients and assuming 50% 
responders (defined as having a clinical benefit rate (PR + CR + SD)) and accounting for 
approximately 10% inevaluable samples (i.e., biopsy specimen with inadequate or 
insufficient tumor), a total of 20 assessable paired biopsies we will have 80% power to 
detect an effect size of 1.32 between responders and non-responders in the molecular 
changes, at the significance level of 0.05. For responders (or non-responders), we will 80% 
power to detect an effect size of 0.996 for pre-post molecular changes.  
To identify genes and pathways differentially expressed between responders and non-
responders, we will apply linear methods such as the Limma provided in R-package.  The 
associated p-values will be corrected for multiple testing using the Benjamini Hochberg 
adjustment method, resulting in highly reliable identification of differentially expressed 
genes, even when sample size is small. Logistic regression will be used to assess if baseline, 
as well as pre-post change, of neoantigen burden, destabilizing mutation burden, immune 
microenvironment characteristics, or combination thereof are indicative of response. Given 
the small sample size, the regression analysis will largely univariate with the possibility of 
multivariate with 2 or 3 predictors, when data allow 
Optimally we plan to obtain at least 5 tissue cores from the core needled biopsies but the 
number of cores obtained will be affected by the patient clinical condition at the time of 
biopsy and determined by the radiologist who is performing the procedure. Core biopsy is 
typically performed using 21-18 gauge needle and with condition permitting, up to 5 cores 
should be collected. For full processing of biopsies please see laboratory manual 
 
Blood and microbiome: Blood and stool samples will be obtained to evaluate stool 
microbiome change over time and blood will evaluate potential changes in ctDNA and 
immunological parameters over time.  Blood analysis may include plasma analysis for 
markers including, but not limited to, interleukin (IL)-1D, IL-1β, IL-2, IL-5, IL-6, IL-8, IL-
13, TNF-D, MCP, MIP-1β, G-CSF, GM-CSF, interferon-J via a cytokine assay (for example 
Meso Scale Discovery, 40 Plex). Leukocyte subpopulations and immune activation status 
will be assessed on peripheral blood mononuclear cells. 
For each subject, objective response will be determined per iRECIST v1.1, progression-free 
survival, duration of response, and overall survival will be calculated. Progression-free 
survival (PFS) is defined as the number of days from treatment start to the date of 
documented progression of disease/death and will be calculated for all patients. The overall 


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survival (OS) is defined as the time from treatment start until death or last follow-up.  The 
duration of response is defined as the time from response until progression or last follow-up. 
The distribution of time-to-event endpoints including OS and PFS will be estimated using 
the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important 
subgroups will be made using the log-rank tests. The association between response and 
patient’s clinical characteristics will be examined by Wilcoxon’s rank sum test or Fisher’s 
exact test, as appropriate. The pre- and on treatment difference regarding microbiome and 
tumor biopsy will be compared using Wilcoxon signed-rank test. 
 
8.    
ADVERSE EVENTS   
8.1    Definitions 
 
8.1.1    
Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a medicinal product; the untoward medical occurrence does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product whether or not it is related to 
the medicinal product.  This includes any newly occurring event, or a previous condition 
that has increased in severity or frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.   
8.1.1.1 Adverse Event Attribution 
Attribution is the determination of whether an adverse event is related to a medical treatment 
or procedure.  
Definite - the adverse event is clearly related to the investigational agent(s). 
Probable - the adverse event is likely related to the investigational agent(s). 
Possible - the adverse event may be related to the investigational agent(s). 


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Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational agent(s). 
8.1.1.2 Adverse Event SeverityThe severity of the adverse events (AEs) will be graded 
according to the U.S. Department of Health and Human Services, National Institutes of 
Health, National Cancer Institute, Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.0.  
Events not included in the NCI CTCAE will be scored as follows: 
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment required 
beyond prophylaxis. 
Grade 2: Moderate: discomfort present with some disruption of daily activity, require 
treatment. 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line 
treatment.  
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
  
The investigator (or physician designee) isresponsible for verifying and providing source 
documentation for all adverse events, assigning the attribution and assessing the severity of 
the AE, the causal relationship between any events and the clinical study procedure, 
activities or device.  Additionally, the Investigator is responsible for providing appropriate 
treatment for the event and for adequately following the event until resolution for all adverse 
events for subjects enrolled. 
All participants will be registered in the Clinical Oncology Research System (CORe) 
 
8.1.1.3 Adverse Event Recording 
Adverse Events will be recorded in the electronic database [______] following the NCI 
recommended Adverse Event Recording Guidelines table below. The phase I guidelines will 


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be followed during the Phase I portion of the trial, and the guidelines for phase II studies, for 
the Phase II portion. 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
  
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
8.1.2    
Serious Adverse Events 
8.1.2.1 Serious Adverse Event (SAE) Reporting Requirements for M D Anderson 
Sponsor Single Site IND Protocols 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the followingoutcomes:Death 
A life-threatening adverse event 
Inpatient hospitalization or prolongation of existing hospitalization 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
A congenital anomaly/birth defect. 
 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate 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. 


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Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 
CFR 312.32). 
 
Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator or the IND Sponsor, IND Office. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
on Reporting Adverse Events for Drugs and Devices”. 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent.  
Serious adverse events must be followed until clinical recovery is complete and laboratory 
tests have returned to baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND Office 
within 5 working days of knowledge of the event regardless of the attribution. 
Death or life-threatening events that are unexpected, possibly, probably or definitely related 
to drug must be reported (initial or follow up) to the IND Office within 24 hours of 
knowledge of the event  
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
The electronic SAE application (eSAE) will be utilized for safety reporting to the IND 
Office and MD Anderson IRB.  
All events reported to the supporting company must also be reported to the IND Office 


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Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor according to 21 CFR 
312.32. 
 
 It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
8.1.2.2 Serious Adverse Events Reporting to the Supporting Company 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
x Results in death. 
x Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
x Requires inpatient hospitalization or prolongation of an existing hospitalization 
(see clarification in the paragraph below on planned hospitalizations). 
x Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions). 
x Is a congenital anomaly/birth defect. 
x Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.   
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse; any organism, virus, or infectious particle (e.g., prion protein 
transmitting Transmissible Spongiform Encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.   


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Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) of a 
specific event; the event itself, however, may be of relatively minor medical significance 
(such as a Grade 3 headache).  This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function.  A severe AE (Grade 3 or 4) 
does not necessarily need to be considered serious.  For example, a white blood cell count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious.  Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
8.1.2.3    Procedures for Reporting Serious Adverse Events 
Adverse Events may be spontaneously identified by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or 
other diagnostic procedures.  Any clinically relevant deterioration in laboratory assessments 
or other clinical finding is considered an AE.  When possible, signs and symptoms 
indicating a common underlying pathology should be noted as one comprehensive event.   
Adverse Events which are serious must be reported to Millennium Pharmacovigilance (or 
designee) from the first dose of Pevonedistat up to and including 30 days after 
administration of the last dose of Pevonedistat Any SAE that occurs at any time after 
completion of Pevonedistat treatment or after the designated follow-up period that the  
Principal-investigator and/or sub-investigator considers to be related to any study drug must 
be reported to Millennium Pharmacovigilance (or designee).  Planned hospital admissions or 
surgical procedures for an illness or disease that existed before the patient was enrolled in 
the trial are not to be considered AEs unless the condition deteriorated in an unexpected 
manner during the trial (e.g., surgery was performed earlier or later than planned).  All SAEs 
should be monitored until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness (es). 
Since this is an investigator-initiated study, the principal investigator Michael Overman, 
MD, also referred to as the Principal-investigator, is responsible for reporting serious 
adverse events (SAEs) to any regulatory agency and to the sponsor- investigator’s EC or 
IRB.    
Regardless of expectedness or causality, all SAEs must also be reported in English to 
Millennium Pharmacovigilance or designee: 


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Fatal and Life Threatening SAEs within 24 hours of the Principal-investigator’s 
observation or awareness of the event 
 
All other serious (non-fatal/non life threatening) events within 4 calendar days of 
the Principal-investigator’s observation or awareness of the event 
 
The SAE report must include at minimum: 
x Event term(s) 
x Serious criteria 
x Intensity of the event(s): Principal-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE version specified in the protocol, as a 
guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
x Causality of the event(s): Principal-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Millennium Pharmacovigilance (or 
designee).   
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
 
 
 
 
 
 
 
 
 
 
 
Suggested Reporting Form:   
• 
SAE Report Form (a sample will be provided) 
US and Canada 
Toll-Free Fax #: 1-800-963-6290  
E-mail: TakedaOncoCases@cognizant.com  
 
All other countries (Rest of World) 
Fax #: 1-202-315-3560 
E-mail: TakedaOncoCases@cognizant.com 
 


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• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
• 
Any other form deemed appropriate by the Principal-investigator, including the    
MDACC SAE reporting form. 
8.2    Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug.  The Principal-investigator must fax a completed Pregnancy Form to the Millennium  
Pharmacovigilance or designee immediately (see Section 8.2).  The pregnancy must be 
followed for the final pregnancy outcome (i.e., delivery, still birth, miscarriage) and 
Millennium Pharmacovigilance or designee will request this information from the Principal-
investigator. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the Princiapal-investigator must also immediately fax a 
completed Pregnancy Form to the Millennium Pharmacovigilance or designee (see Section 
8.2).  Every effort should be made to follow the pregnancy for the final pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
Pregnancy Report Form (a sample will be provided)   
9.    
ADMINISTRATIVE REQUIREMENTS 
9.1       
Product Complaints   
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals 
who identify a potential product complaint situation should immediately contact Millennium 
(see below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a 
Millennium Quality representative. 
For Product Complaints, call 
Phone 1-844-ONC-TKDA (1-844-662-8532) 
Email: GlobalOncologyMedinfo@takeda.com 
Fax: 1-800-881-6092, Hours Mon-Fri, 9 a.m.- 7 p.m. ET 
 
 


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Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, anthe MDACC SAE form should be completed and sent to Millennium 
Pharmacovigilance (refer to Section 8.2). 


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The list of references will be molecule specific for each template and should be generated 
using EndNote.  See a member of the Medical Writing department for assistance with this. 
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Ades, L., et al., Phase II study of pevonedistat (P) + azacitidine (A) versus A in 
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7506. 
27. 
Swords, R.T., et al., Pevonedistat (MLN4924), a First-in-Class NEDD8-activating 
enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic 
syndromes: a phase 1 study. Br J Haematol, 2015. 169(4): p. 534-43. 
28. 
Lockhart, A.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, 2019. 37(1): p. 
87-97. 
29. 
Faessel, H.M., et al., Population pharmacokinetics of pevonedistat alone or in 
combination with standard of care in patients with solid tumours or haematological 
malignancies. British journal of clinical pharmacology, 2019. 85(11): p. 2568-2579. 
30. 
Muro, K., et al., Pembrolizumab for patients with PD-L1-positive advanced gastric 
cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol, 


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2016. 17(6): p. 717-726. 
31. 
Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. American Journal of Clinical Oncology, 1982. 5(6): p. 649-55. 
32. 
The Criteria Committee of New York Heart Association, Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. 1994, Boston, MA: 
Little, Brown & Co. 
11. 
Contact Medical Writing for standard/typical appendices (e.g., response criteria, example 
formula for calculation of body surface area).  Teams should verify that the appendix items 
are current (source information should be included).  
Appendix 1:    
Eastern Cooperative Oncology Group (ECOG) Scale for 
Performance Status 
Table 8. ECOG Scale for Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance without restriction 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work) 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.[31] 
 
 
 
 
 


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Appendix 2:    
Body Surface Area 
Body surface area (BSA) will be calculated using the standard formula that is used for all 
patients within the MD Anderson Electronic healthcare record, EPIC. 
 


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Appendix 3:    
New York Heart Association Classification of Cardiac Disease  
The following table presents the New York Heart Association (NYHA) classification of 
cardiac disease [32]. 
Table 9. NYHA Classification of Cardiac Disease 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease 


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Appendix 4:    
Definition of Postmenopausal 
 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. Please refer to the following source for additional information: European Heads 
of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_ CTFG_Contraception.pdf 
 
 


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Appendix 5:    
Methods of Contraception Considered Effective 
Acceptable Methods Considered to Highly Effective 
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective. Such methods include: 
x Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
x Oral  
x Intravaginal 
x Transdermal 
x Progestogen-only hormonal contraception associated with inhibitor of ovulation1: 
x Oral 
x Injectable 
x Implantable2 
x Intrauterine device (IUD)2 
x Bilateral tubal occlusion2 
x Vasectomized partner2,3 
x Sexual Abstinence4 
Methods that are Considered Less Highly Effective 
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include: 
x Progestogen-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action 
x
Male or female condom with or without spermicide5


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x Cap, diaphragm or sponge with spermicide5 
_________________________________________________________________________________________ 
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_ 
CTFG_Contraception.pdf 
1) Hormonal contraception may be susceptible to interaction with the investigational medicinal product, 
which may reduce the efficacy of the contraception method. 
2) Contraception methods that in the context of this guidance are considered to have low user 
dependency. 
3) Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the woman of childbearing potential participant of the study and that the vasectomised 
partner has received medical assessment of the surgical success. 
4) In the context of this guidance sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk associated with the 
study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the subject. 
5) A combination of male condom with either cap, diaphragm or sponge with spermicide (double-barrier 
methods) are also considered acceptable, but not highly effective, birth control methods. 


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Appendix 6:    
Schedule of Events 
Table 10. Schedule of Events 
 
  
Screening   
(-28 Days 
to D1) 
Treatment Cycle (21 Days)(c) 
End of 
Treatment 
(EOT) (d) 
 Long-term 
OS follow-
up (every 3-
6 months 
after EOT) 
by phone  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
(Restaging)  
Repeat steps from cycles 2-4 for subsequent cycles until PD 
Days  
1 
3 
5 
8 
15 
1 
3 
5 
1 
3 
5 
1 
3 
5 
Study 
Procedures 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/ 
Exclusion 
Criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demo-graphics 
and Medical 
History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior and 
Concomitant 
Medication 
Review (to be 
captured in 
medical 
record) 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
  
Written 
Informed 
Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pevonedistat(a)  
  
X 
X 
X 
  
  
rs 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Pembrolizuma
b(a) 
  
X 
  
  
  
  
X 
  
  
X 
  
  
X 
  
  
  
  


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HIV, HBV, HCV 
antibody 
testing 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum or urine 
pregnancy 
test(e  ) 
X 
X
  
  
  
  
  
 
  
  
 
  
  
 
  
  
  
  
Physical 
examination(a)  
X 
X 
  
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Vital signs(a,f) 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
ECOG PS(a) 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Toxicity 
Assessment(a)  
X 
X 
  
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
12-lead ECG 
and ECHO or 
MUGA (g) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Coagulation(b) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Free T4, TSH(a) 
X 
  
  
  
  
  
X 
(only 
Cycle
2) 
  
  
  
  
  
X 
  
  
X 
  
Complete 
chemistry 
panel(a, h ) 
X 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Complete 
blood count/ 
Hematology(a, i ) 
X 
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
Select 
chemistry 
panel(a, j ) 
  
  
X 
X 
X 
X 
  
X 
X 
  
X 
X 
  
X 
X 
  
  


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Urinalysis (a) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Correlative 
blood 
collection(a) 
 
X 
  
  
  
  
X 
(only 
Cycle
2) 
  
  
  
  
  
X 
(onl
y 
cycl
e 4 
+ 7) 
  
  
X  (preferr
ably may 
be done 
at time of 
progressio
n) 
  
PK blood 
collection (only 
cycles 1-3)k 
  
 
  
 
  
  
 
  
  
 
  
  
  
  
  
  
  
Microbiome 
collection(a) (only 
screening and cycle 4) 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
Tumor Imaging 
Evaluation (+/- 
10 day 
window) 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
Biopsy (+/-7 
days for on-tx 
biopsy) 
X 
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
  
  
a: +/-4 day window period  is permitted from D1 of each cycle for study drug administration and protocol related procedures (other than imaging + biopsy).  +/-1 day for day 3 
and 5 though strong preference to keep on scheduled days. +/-2days for day 8 and 15.  Also days 8 and 15 of cycle 1 labs can be done locally 
b: Coagulation panel includes PT and aPTT 
c: On dosing days, all procedures are to be performed prior to administration of study drug(s), unless otherwise specified.  
d: End of treatment visit will occur 30 days (+10 days) after last dose of study drug(s) or prior to start of subsequent antineoplastic therapy, if that occurs sooner. Can be done 
virtually, though in person preferred. 
e: only mandatory for women of child bearing potential 
f: patient vitals are to be obtained at screening, on listed days of each cycle, at end of treatment visit and as clinically indicated. Height at screening only, weight on day 1 of each 
cycle 
g:ECG to be performed as clinically indicated during treatment 


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h:includes albumin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, potassium, phosphorus, sodium, urate, direct bilirubin, total bilirubin and protein, 
and liver enzymes (ALP, AST, ALT, LDH)  . Before each dose of pevonedistat infusion ALP, ALT, AST and total bilirubin assessments must be done and results reviewed by a 
treating physician.   
i:add white blood count differential along with other standard components 
j:The select chemistry panel will include the following: BUN, creatinine, phosphate, total bilirubin, albumin, ALP, AST, and ALT. Before each dose of pevonedistat infusion ALP, 
ALT, AST and total bilirubin assessments must be done and if abnormal results reviewed by a treating physician or advanced practice provider. Treatment parameters will be 
present on treatment orders to ensure notification on abnormal values occurs.   
k:PK sampling time points are specified in Table 11 
lImaging should be standard of care imaging for that tumor type. In general this should be CT scans or MRI scans. 
Table 11. PK sampling timepoints 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
 
Day 1 
Day 2 
Day 3 
Day 5 
Day 6 
Day 7 
Day 1 
Day 1 
Phase 1 
X 
X 
X 
X 
X 
X 
X 
X 
Sampling 
Timepointsa 
Pre-doseb, 
EOI, 0.5, 1, 
2, 3,4, 8 
hours post 
dose 
24 hours 
post dose 
48 hours 
post dose 
Pre-doseb, 
EOI, 0.5, 1, 
2, 3,4, 8 
hours post 
dose 
24 hours 
post dose 
48 hours 
post dose 
EOI, 
1 hour post 
dose 
EOI, 
1 hour post 
dose 
 
Pase II 
X 
 
 
X 
 
 
X 
X 
Sampling 
Timepointsa 
Pre-doseb, 
EOI, 1, 3 
hours post 
dose 
 
 
Pre-doseb, 
EOI, 1, 3 
hours post 
dose 
 
 
EOI, 
1 hour post 
dose 
EOI, 
1 hour post 
dose 
 a Unless specified, all time points refer to end pevonedistat infusion;  b Within one hour prior to study drug administration.  
EOI: End of infusion. Times are approximate, though goal should be to obtain sample within +/-10min for each post-dose timepoint.   
 


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Appendix 7:    
Laboratory Manual 
Please refer to the related Research Blood and Tissue Collection Manual for details on various biospecimen collection processes for 
this protocol.