A Phase 2 Study of MLN4924 (Pevonedistat) in Combination With Carboplatin and Paclitaxel in Advanced NSCLC Previously Treated With Immunotherapy
Phase: PHASE2
Conditions: Metastatic Lung Non-Small Cell Squamous Carcinoma, Metastatic Lung Non-Squamous Non-Small Cell Carcinoma, Stage IIIB Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8, Unresectable Lung Non-Small Cell Carcinoma, Unresectable Lung Non-Squamous Non-Small Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #:10266 
Version Date:  December 20, 2021 
 
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DATE: 
December 20, 2021 
 
TO:  
CTEP Protocol and Information Office 
 
 
FROM:  
Ticiana Leal, MD 
 
SUBJECT: 
Amendment 10 to update the PI’s contact information. 
 
 
SUMMARY OF CHANGES – Protocol 
 
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Response to Dr. Kem’s Notice to Principal Investigators dated 8/12/21: 
 
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Header 
Updated version date. 
2. 
Title Page 
Updated Dr. Leal’s contact information at Emory University.  
 
Removed Kasey and Claire as study contacts. 
 
Added amendment version and date. 
 
 
SUMMARY OF CHANGES – Consent Form 
 
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Updated version date. 

NCI Protocol #:10266 
Version Date:  December 20, 2021 
 
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NCI Protocol #: 
10266 
 
Local Protocol #: 
NCI10266 
 
ClinicalTrials.gov Identifier: NCT03965689 
 
TITLE:  A Phase 2 Study of MLN4924 (pevonedistat) in Combination with Carboplatin and 
Paclitaxel in Advanced NSCLC Previously Treated with Immunotherapy 
 
Corresponding Organization: LAO MD017 / Johns Hopkins University SKCCC LAO 
 
Principal Investigator: 
Ticiana A. Leal, MD 
 
1365C Clifton Road, NE 
4th Floor, Room C4004 
Atlanta, GA 30322 
Tel: 404-251-5544 
ticiana.a.leal@emory.edu 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
 
 

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Protocol Contact: 
Judy Murray, CCRC 
Johns Hopkins University SKCCC 
201 N. Broadway Street, Suite 9130 
Baltimore, MD 21287 
410-955-4044 
Jmurra33@jhmi.edu (preferred) 
 
Co-Principal Investigators:  
Jyoti Malhotra, MD 
Rutgers Cancer Institute of New Jersey 
195 Little Albany St. 
New Brunswick, NJ 08901 
Tel: (732) 235-7521 
Fax: (732) 235-8808 
 
Erin M. Bertino, MD 
The Ohio State University 
300 West 10th Ave 
Columbus, OH 43210 
Tel: (614) 366-0652 
Fax: (614) 293-7529  
Erin.Bertino@osumc.edu  
 
Pharmacologist: 
Ronald Burnette, PhD, PharmD 
Professor and Chair of Pharmaceutical Sciences 
Associate Dean for Faculty Affairs 
School of Pharmacy 
University of Wisconsin – Madison  
4113 Rennebohm Hall 
777 Highland Avenue 
Madison, WI 53705 
Email: Ronald.burnette@wisc.edu  
Phone: (608) 262-3814 
Fax: (608) 262-5345 
 
Statistician: 
Jens C. Eickhoff, PhD 
600 Highland Ave, CSC K6/434 
Madison, WI 53792 
Tel:  (608) 265-5376 
Fax:  (608) 265-5579 
eickhoff@biostat.wisc.edu  
 
 

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NCI-Supplied Agent: 
MLN4924 (pevonedistat) HCL (NSC 793435) 
 
Other Agent(s): 
Carboplatin (NSC 241240), Commercial 
 
Paclitaxel (NSC 673089), Commercial  
 
IND #: 144380 
IND Sponsor: DCTD, NCI  
 
 
Protocol Type / Version # / Version Date:   
Original / December 28, 2018 
 
 
 
 
Revision 1 / March 7, 2019 
 
 
 
 
Revision 2 / April 4, 2019 
 
 
 
 
Revision 3 / May 1, 2019 
 
 
 
 
Revision 4b / June 17, 2019 
 
 
 
 
Revision 4a / June 21, 2019 
 
 
 
 
Revision 5 / August 7, 2019 
 
 
 
 
Revision 6 / September 16, 2019 
 
 
 
 
Revision 7 / November 19, 2019 
 
Revision 8 / May 14, 2020 
 
Amendment 4 / July 13, 2020 
 
Amendment 5 / September 5, 2020 
 
Amendment 6 / October 5, 2020 
 
Amendment 7 / March 3, 2021 
 
Amendment 8 / June 24, 2021 
 
Amendment 9 / August 23, 2021 
 
Amendment 10 / December 20, 2021 
 
 
SCHEMA 
 
Phase 2 single-arm study 
 
 
 
 
 
 
Accrual = 25 patients 
 
Treatment Plan: 
 
Patients will receive at least 4 cycles of therapy.  Treatment will be continued until progressive 
disease, unacceptable toxicity or patient desire to discontinue study therapy.  At any time after 4 
cycles of combination therapy, the treating physician is given discretion whether to continue with 
Carboplatin/Paclitaxel + 
MLN4924 (pevonedistat) 
Patients will continue 
study therapy until 
progression based on 
clinical benefit and /or 
tolerability 

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a) carboplatin, paclitaxel, and MLN4924 (pevonedistat), or b) continue carboplatin and 
MLN4924 (pevonedistat) without paclitaxel, or c) observe the patient on study.  All patients will 
be followed for the duration of study and until resolution or stabilization of any adverse effects 
related to study therapy.  If the patient is continued on a) or b), subsequent change to c) at later 
timepoints is also allowed. 
 
• MLN4924 (pevonedistat):  20 mg/m2 intravenous (IV), Days 1, 3, 5 
• Carboplatin:  Area under the curve (AUC) = 5 IV, Day 1 
• Paclitaxel:  175 mg/m2 IV, Day 1 
 
Cycle = 3 weeks (21 days) 
 

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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objective ....................................................................................................7 
1.2 
Secondary Objectives ...............................................................................................7 
1.3 
Correlative Objectives .............................................................................................7 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Study Diseases .........................................................................................................8 
2.2 
CTEP IND Agent ...................................................................................................10 
2.3 
Other Agents ..........................................................................................................14 
2.4 
Rationale ................................................................................................................15 
2.5 
Correlative Studies Background ............................................................................16 
3. 
PATIENT SELECTION ....................................................................................................18 
3.1 
Eligibility Criteria ..................................................................................................18 
3.2 
Exclusion Criteria ..................................................................................................20 
3.3 
Inclusion of Women and Minorities ......................................................................22 
4. 
REGISTRATION PROCEDURES ...................................................................................23 
4.1 
Investigator and Research Associate Registration with CTEP ..............................23 
4.2 
Site Registration .....................................................................................................24 
4.3 
Patient Registration ................................................................................................26 
4.4 
General Guidelines .................................................................................................27 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................28 
5.1 
Summary Table for Specimen Collection ..............................................................28 
5.2 
Specimen Procurement Kits and Scheduling .........................................................28 
5.3 
Specimen Tracking System Instructions ................................................................29 
5.4 
Specimen Collection ..............................................................................................33 
5.5 
Shipping Specimens from Clinical Site to Analysis Laboratories .........................34 
5.6 
Biomarker Plan ......................................................................................................37 
5.7 
Integrated Studies...................................................................................................39 
5.8 
Exploratory/Ancillary Studies ...............................................................................40 
6. 
TREATMENT PLAN ........................................................................................................42 
6.1 
Agent Administration .............................................................................................42 
6.2 
General Concomitant Medication and Supportive Care Guidelines ......................44 
6.3 
Duration of Therapy ...............................................................................................46 
6.4 
Duration of Follow-Up ..........................................................................................46 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................47 
7.1 
Dose Modifications for Toxicity ............................................................................47 
7.2 
Dose Modifications for Non-Hematologic Toxicity ..............................................50 

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8. 
PHARMACEUTICAL INFORMATION ..........................................................................56 
8.1 
CTEP IND Agent ...................................................................................................56 
8.2 
Commercial Agents ...............................................................................................59 
9. 
STATISTICAL CONSIDERATIONS...............................................................................61 
9.1 
Study Design/Endpoints.........................................................................................61 
9.2 
Sample Size/Accrual Rate ......................................................................................61 
9.3 
Stratification Factors ..............................................................................................62 
9.4 
Analysis of Secondary and Exploratory Endpoints ...............................................62 
9.5 
Reporting and Exclusions ......................................................................................63 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................64 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................64 
10.2 
Adverse Event Characteristics ...............................................................................68 
10.3 
Expedited Adverse Event Reporting ......................................................................68 
10.4 
Routine Adverse Event Reporting .........................................................................71 
10.5 
Pregnancy ...............................................................................................................71 
10.6 
Secondary Malignancy ...........................................................................................71 
10.7 
Second Malignancy ................................................................................................72 
11. 
STUDY CALENDAR .......................................................................................................73 
12. 
MEASUREMENT OF EFFECT........................................................................................76 
12.1 Antitumor Effect – Solid Tumors ..............................................................................76 
12.2 
Other Response Parameters ...................................................................................82 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................83 
13.1 
Study Oversight .....................................................................................................83 
13.2 
Data Reporting .......................................................................................................83 
13.3 
Data Quality Portal ................................................................................................85 
13.4 
Collaborative Agreements Language .....................................................................86 
14. 
REFERENCES ..................................................................................................................88 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................92 
APPENDIX B 
PATIENT DRUG INTERACTIONS HANDOUT AND 
WALLET CARD ...............................................................................................................93 
APPENDIX C 
ACCEPTABLE BIRTH CONTROL METHODS.....................................95 
 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objective 
 
1.1.1 To determine the overall response rate (ORR) of patients with advanced non-small cell 
lung cancer (NSCLC) treated with MLN4924 (pevonedistat) in combination with 
carboplatin and paclitaxel. 
 
1.2 
Secondary Objectives 
 
1.2.1 To estimate the progression-free survival (PFS) of patients with advanced NSCLC treated 
with MLN4924 (pevonedistat) in combination with carboplatin and paclitaxel. 
 
1.2.2 To estimate the overall survival (OS) of patients with advanced NSCLC treated with 
MLN4924 (pevonedistat) in combination with carboplatin and paclitaxel. 
 
1.2.3 To evaluate the safety profile of MLN4924 (pevonedistat) in combination with 
carboplatin and paclitaxel. 
 
1.3 
Correlative Objectives 
 
1.3.1 To evaluate expression of nuclear factor-erythroid 2 p45-related factor 2 (NRF2) target 
genes NAD(P)H: quinone oxidoreductase1 (NQO1) and the cysteine/glutamate antiporter 
solute carrier family 7 member 11 (SCL7A11). 
 
1.3.2 To determine expression of pharmacodynamic markers induced by neural precursor cell 
expressed developmentally downregulated protein 8 (NEDD-8) activating enzyme (NAE) 
inhibition: cyclic AMP-dependent transcription factor (ATF3), β2 microglobulin (B2M), 
glutamate-cysteine ligase regulatory subunit (GCLM), glutathione-disulfide reductase 
(GSR), DNA-3-methyladenine (MAG1), ribosomal protein lateral stalk subunit P0 
(RPLPO), sulfiredoxin-1 (SRXN1), thioredoxin reductase 1 (TXNRD1), and ubiquitin-
conjugating enzyme (UBC). 
 
1.3.3 To perform qualitative assessment of tumor NAE1 and ubiquitin-conjugating enzyme E2 
M (UBC12) protein expression at baseline. 
 
1.3.4 To assess circulating tumor cells (CTCs) for DNA damage repair pathway alterations 
(i.e., γH2AX induction, RAD51). 
 
1.3.5 To evaluate pharmacokinetic (PK) parameters of MLN4924 (pevonedistat) when given in 
combination with paclitaxel and carboplatin. 
 
 
 

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2. 
BACKGROUND 
 
2.1 
Study Diseases 
 
Lung cancer, one of the leading causes of all-cancer mortality, can be divided into two 
subcategories based on histological classification – NSCLC and small-cell lung cancer.  NSCLC 
accounts for nearly 85% of all lung cancers and is the leading cause of cancer-related mortality 
in the United States with an estimated 155,870 deaths from lung cancer in 2017 (American 
Cancer Society, 2017). 
The current standard of care for non-squamous NSCLC depends in large part on whether 
actionable mutations can be identified and lead to an opportunity for an effective targeted 
treatment option. Initial biopsy specimens or plasma are sent for genomic analysis to identify 
activating epidermal growth factor receptor (EGFR) mutations in exon 19 and 21 or gene 
rearrangements in anaplastic lymphoma kinase (ALK) or ROS1 and BRAF (B-Raf proto-
oncogene).  Tumors which harbor sensitizing EGFR mutations are responsive to a number of 
EGFR tyrosine kinase inhibitors (TKI) including osimertinib, erlotinib, gefitinib, and afatinib, 
and use of an EGFR TKI is recommended in the first line setting. ALK translocations should be 
treated with an ALK TKI in the first line setting such as alectinib, ceritinib or crizotinib. ROS1 
rearrangements can be treated with crizotinib in the first line setting, and BRAF mutations can be 
effectively treated with combination of trametinib and dabrafenib (Ettinger et al., 2018). 
However, the same progress has not been achieved in treating patients with advanced squamous 
cell lung cancer where there are no approved targeted therapy options.  
The majority of patients with advanced NSCLC do not have a driver mutation. For these patients 
with advanced NSCLC, the standard of care treatment options in the front-line setting include 
immunotherapy with pembrolizumab for patients whose tumor express PD-L1 ≥ 50% (Reck et 
al., 2016).  The combination of immunotherapy with chemotherapy has also led to improved 
outcomes compared to platinum-based chemotherapy and led to recent approvals for patients, 
independent of PD-L1 expression: platinum/pemetrexed/pembrolizumab in the non-squamous 
population (Gandhi et al., 2018) and platinum/taxane/pembrolizumab in the squamous 
population (Paz-Ares et al., 2018).  
 
For a disease that had a five-year survival rate of only 5% for advanced stages, the addition of 
immunotherapy has improved that rate to 16 percent (Gettinger et al., 2018).  While there have 
been significant improvements in patient outcomes and survival with the introduction of 
immunotherapy and molecularly targeted agents for patients with NSCLC, only a subset of 
patients respond and have prolonged survival (Temel et al., 2018). 
 
In the second-line setting, the mainstay of therapy has previously been single-agent 
immunotherapy with PD-1/PD-L1 inhibitors following progression on platinum-based doublet 
chemotherapy.  However, with the increasing use of immunotherapy in combination with 
platinum chemotherapy in the front-line, this is no longer an effective or recommended 
approach.  The second-line treatment option will once again include docetaxel +/- ramucirumab, 
a monoclonal antibody against the vascular endothelial growth factor receptor 2 (VEGFR2).  The 
latter treatment is associated with modest benefit in OS and potential significant toxicity (Garon 

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et al., 2014).  Other regimens in this setting include gemcitabine, or pemetrexed in patients with 
non-squamous histology who have not received it previously. 
 
Therefore, even in this era of immunotherapy and precision medicine, cytotoxic chemotherapies 
remain an essential therapeutic option for patients with advanced NSCLC in the course of their 
disease trajectory (Hellmann et al., 2016).  Development of combination strategies after 
development of resistance to front-line immunotherapy is an area of unmet need. There is a 
continued clear need to develop novel therapeutic strategies, enhancing the efficacy of cytotoxic 
chemotherapy regimens and to investigate predictive biomarkers in NSCLC. 
 
One developing novel therapeutic strategy in lung cancer considers the molecular pathway of the 
ubiquitin (Ub)/proteasome system (UPS), which is responsible for a variety of cellular functions 
via protein degradation and a potential promising oncological target (Ji et al., 2017; Zhou et al., 
2017).  
 
2.1.2.  Neddylation pathway  
 
The UPS controls a broad array of cellular functions via protein degradation that mediate cell 
growth and survival, cellular signaling, and transcription factor regulation (Wu and Yu, 2016).  
The efficacy of proteasome inhibitors such as bortezomib and carfilzomib in multiple myeloma, 
for example, has validated the UPS as a rational target for cancer therapy (Esseltine and 
Mulligan, 2012).  The therapeutic index of proteasome inhibitors may be improved through 
selective inhibition of a sub-component of the UPS, such as the neddylation pathway, which is 
responsible for about 20% of protein degradation (Soucy et al., 2009).  
 
Ub conjugation via covalent linkage to a protein tags it for degradation by a proteasome.  
Ubiquitination is a multi-step process that transfers Ub to target substrates through an enzymatic 
cascade that involves three enzymes: Ub-activation (E1), Ub-conjugating (E2), and Ub-ligasing 
(E3).  A subgroup of E3 ligases, which include Cullin RING ligases (CRL), are responsible for 
approximately 20% of cellular proteins labeled for degradation (Soucy et al., 2009). CRL 
substrates include regulators of cell cycle progression, apoptosis, DNA damage response, and 
signaling transduction.  This subgroup of E3 ligases are regulated via a Ub-like ligand, NEDD8, 
via covalent conjugation.  As with Ub, neddylation to CRL occurs in three enzymatic steps that 
include NEDD8-activating enzyme (NAE1), E2 conjugation (UBC12), and an E3 ligase.  Given 
the downstream substrates of CRLs include a number of oncoproteins and tumor suppressors, 
inhibiting neddylation is a promising oncologic therapeutic target. 
 
Up-regulation of the neddylation pathway has been shown in several malignancies including 
melanoma, intrahepatic cholangiocarcinoma, and NSCLC (Gao et al., 2014; Cheng et al., 2104; 
Li et al., 2014).  In a study evaluating expression of NEDD8-activating enzyme (NAE) (E1) and 
NEDD8-conjugating enzyme (E2) expression and global-protein neddylation, both squamous 
cell and adenocarcinoma NSCLC tumors consistently demonstrated overactivation of the entire 
neddylation pathway.  Moreover, higher expression of neddylation pathway was associated with 

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poor overall survival.  To validate the hypothesis that overactivation of the neddylation pathway 
may serve as a therapeutic target, Li et al. evaluated the efficacy of neddylation inhibition by 
adding MLN4924 (pevonedistat) in human and murine lung cancer cells and demonstrated 
statistically significantly suppressed proliferation, survival, migration, and motility of lung 
cancer cells in vitro and tumor formation and metastasis in vivo (Li et al., 2014) 
 
2.2 
CTEP IND Agent 
 
2.2.1 MLN4954 (pevonedistat)  
 
MLN4924 (pevonedistat) (also known as TAK-924 and MLN4924) 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 
(Investigator’s Brochure, 2018).  The NEDD8 conjugation (neddylation) pathway is responsible 
for much of the regulated protein turnover in the cell (Podust et al., 2000; Read et al., 2000), 
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.  For example, 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 (Velcade Package Insert, 2014).  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, an E1 ligase, is an essential component of the NEDD8 conjugation pathway, which 
initiates the neddylation of protein substrates (Investigator’s Brochure, 2018; Podust et al., 2000; 
Read et al., 2000).  Specifically, NEDD8 conjugation to Cullin-RING ubiquitin E3 ligases 
(CRLs) 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 MLN4924 (pevonedistat) results in 
the accumulation of CRL substrates, followed by a DNA damage response and cell death. 
 
2.2.1.1 
Preclinical Experience with MLN4924 (pevonedistat) 
 
MLN4924 (pevonedistat) is a potent and selective inhibitor of NAE activity (Investigator’s 
Brochure, 2018).  MLN4924 (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.  MLN4924 (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 MLN4924 (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 CRL 
substrates, including Nrf-2, and chromatin-licensing and DNA-replication factor-1 (Cdt-1).  In 

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most cell lines evaluated, NAE inhibition by MLN4924 (pevonedistat) led to DNA re-replication 
and accumulation of cells in the S phase of the cell cycle, resulting in DNA damage and 
subsequent cell death through apoptosis (Soucy et al., 2009; Lin et al., 2010; Milhollen et al., 
2011).  When administered in combination with the hypomethylating agents, azacitidine and 
decitabine, MLN4924 (pevonedistat) demonstrated synergistic activity in acute myeloid 
leukemia (AML) cell lines.  MLN4924 (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 subcutaneously (SC) 
administered to immunocompromised mice (Investigator’s Brochure, 2018).  Antitumor activity 
of MLN4924 (pevonedistat) in mice bearing HL-60 and THP-1 tumor xenografts was enhanced 
by combination treatment with azacitidine. 
 
In in vivo safety studies in rats and dogs, gastrointestinal toxicity was most common 
(Investigator’s Brochure, 2018).  Most adverse events (AEs) resolved or reversed after a 2-week 
recovery period.  Microscopic changes were observed in male and female reproductive organs in 
repeat-dose toxicology studies in both dogs and rats, therefore MLN4924 (pevonedistat) likely 
represents a substantial reproductive and developmental hazard.  MLN4924 (pevonedistat) is 
primarily eliminated hepatically, and in vitro, MLN4924 (pevonedistat) is predominantly 
metabolized by the cytochrome P450 (CYP) isozyme 3A4.  Thus, there is potential for drug-drug 
interactions if MLN4924 (pevonedistat) is co-administered with drugs that are CYP3A inhibitors 
or inducers.  MLN4924 (pevonedistat) does not markedly inhibit or induce other CYP isozymes. 
 
Detailed information regarding the nonclinical pharmacology and toxicology of MLN4924 
(pevonedistat) is provided in the MLN4924 (pevonedistat) Investigator’s Brochure (2018). 
 
2.2.1.2 
Clinical Experience with MLN4924 (pevonedistat) 
 
The clinical development of MLN4924 (pevonedistat) started with four clinical trials with doses 
ranging from 25 to 278 mg/m2 (Investigator’s Brochure, 2018; Bhatia et al., 2016; Sarantopoulos 
et al., 2016; Shah et al., 2016; Swords et al., 2010).  In these studies, toxicity involving 
multiorgan 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 ≥110mg/m2.  The current 
understanding of the renal toxicity observed with MLN4924 (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.  
 
Because of this, a revised risk mitigation strategy, including limiting the dose ≤100mg/m2 for 
single-agent administration, was implemented across the MLN4924 (pevonedistat) program in 
October 2012.  The revised risk mitigation strategy limited 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 with pevonedistat in single-agent and combination studies, and no Cycle 1 Day 1 SAEs as 
described above have been observed. These patients received pevonedistat at a dose of 50 to 

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100 mg/m2 as a single agent, a dose of 15 to 30 mg/m2 in combination with different standard of 
care (SOC) therapies, or a dose of 8 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. 
 
Accordingly, prophylactic use of dexamethasone was no longer used in all subsequent studies 
and no acute phase reactions have been observed in subsequent phase 1, phase 2 or phase 3 
clinical trials. A phase 1 open label dose-escalation study including 53 patients with treatment-
naïve AML assessed the MTD of MLN4924 (pevonedistat) on Days 1, 3, and 5 in combination 
with 75 mg/m2 azacitidine (administered on a 5-on/2-off [weekend]/2-on schedule) in a 28-day 
treatment cycle in elderly patients with AML (Swords et al., 2015).  The maximum tolerated 
dose (MTD) was determined to be 59 to 83 mg/m2. For patients with advanced solid tumors, a 
phase 1 open label, dose-escalation study was designed.  A schedule of infusion on days 1-5 for 
MLN4924 (pevonedistat) was selected.  The MTD for that schedule for patients with advanced 
solid tumors was determined to be 50 to 67 mg/m2 (Sarantopoulos et al., 2016). 
 
In a phase 1b study (C15009), MLN4924 (pevonedistat) plus docetaxel, gemcitabine, or the 
combination of carboplatin and paclitaxel was evaluated in three separate cohorts in solid tumors 
to determine the MTD and assess the safety, tolerability, and pharmacokinetics of MLN4924 
(pevonedistat).  Patients received MLN4924 (pevonedistat) with docetaxel (arm 1, n = 22), 
carboplatin plus paclitaxel (arm 2, n = 26), or gemcitabine (arm 3, n = 10) in 21-days (arms 1 
and 2) or 28-days (arm 3) cycles.  MLN4924 (pevonedistat) dose escalation was performed using 
an adaptive Bayesian continual reassessment method (CRM) on cycle 1 DLTs.  The MTD for 
MLN4924 (pevonedistat) was determined to be 25 mg/m2 with docetaxel and 20 mg/m2 with 
carboplatin plus paclitaxel.  The combination of MLN4924 (pevonedistat) plus gemcitabine was 
deemed intolerable due to myelosuppression and toxicity leading to delays and this cohort was 
closed to enrollment.  The most frequently reported DLTs across all arms included grade 3 
febrile neutropenia and increased ALT/AST; AST/ALT elevations were reversible with dose 
modifications.  In general, the adverse events (AEs) of MLN4924 (pevonedistat) plus docetaxel 
or carboplatin plus paclitaxel were manageable.  The most common AEs included fatigue, 
nausea, anemia, constipation, and diarrhea.  
 
The combination of MLN4924 (pevonedistat)with carboplatin plus paclitaxel showed the most 
promising antitumor activity in pretreated patients (≥1 prior therapies).  Notably, all but one of 
the eight responders in arm 2 and one responder in arm 2a had previously received platinum, 
taxanes, or both.  The ORR in arm 2 was 35%, including two patients with CR (bladder cancer 
and endometrial carcinoma) (Lockhart et al., 2018) 
 
These clinical studies overall demonstrated that MLN4924 (pevonedistat) was well-tolerated and 
the observed clinical benefit to patients treated with MLN4924 (pevonedistat) in combination 
with platinum-based chemotherapeutics supported further investigation with phase 2 trials.  As 
of 22 January 2018, approximately 495 subjects (220 subjects for solid tumor indications) have 
received at least 1 dose of MLN4924 (pevonedistat) as part of MLN4924 (pevonedistat) clinical 
trials (Investigator’s Brochure, 2018). 
 
 
 

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Table 1:  Summary of ongoing or recently completed studies involving MLN4924 
(pevonedistat) treatment: 
 
NCT#/Phase 
Status 
Type of Cancer Treatment 
Assessment 
NCT02122770 / Phase 1 
Investigator’s Brochure, 
(2018) 
Completed 
Solid tumors 
MLN4924 
(pevonedistat) 
(including CYP3A 
inhibitors); MLN4924 
(pevonedistat) plus 
docetaxel or 
combination of 
carboplatin and 
paclitaxel 
DDI 
NCT02782468 / Phase 1 Active, not 
recruiting 
AML/MDS 
MLN4924 
(pevonedistat); 
MLN4924 
(pevonedistat) plus 
azacitidine 
Safety, 
tolerability 
NCT02610777 / Phase 2 Active, not 
recruiting 
HR MDS, 
CMML, or 
low-blast AML 
MLN4924 
(pevonedistat) plus 
azacitidine; 
azacitidine 
Efficacy, 
safety 
NCT03057366 / Phase 1 Completed 
Advanced solid 
tumor 
MLN4924 
(pevonedistat) 
Mass balance 
NCT03330106 / Phase 1 Recruiting 
Advanced solid 
tumor 
MLN4924 
(pevonedistat); 
MLN4924 
(pevonedistat) plus 
docetaxel or 
combination of 
carboplatin and 
paclitaxel  
Corrected QT 
interval 
NCT03459859 / Phase 1 Recruiting 
AML/MDS 
MLN4924 
(pevonedistat) plus 
cytarabine 
RPD2 
NCT03486314 / Phase 1 Recruiting 
Advanced solid 
tumors 
MLN4924 
(pevonedistat) plus 
rifampin; MLN4924 
(pevonedistat) plus 
docetaxel or 
combination of 
carboplatin and 
paclitaxel  
DDI 

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NCT03323034 / Phase 1 Recruiting 
Recurrent or 
refractory solid 
tumors or 
lymphoma 
MLN4924 
(pevonedistat) plus 
temozolomide and 
irinotecan 
MTD, RPD2, 
toxicity, and 
PK in 
pediatric 
population 
NCT03386214 / Phase 1 Recruiting 
Myelofibrosis 
MLN4924 
(pevonedistat) plus 
ruxolitinib 
Safety, 
tolerability, 
MTD, 
frequency of 
AEs 
NCT03268954 / Phase 3 Recruiting 
HR MDS, 
CMML, or 
AML 
MLN4924 
(pevonedistat) plus 
azacitidine; 
azacitidine  
EFS 
NCT03009240 / Phase 1 Recruiting 
HR AML 
MLN4924 
(pevonedistat) plus 
decitabine 
DLTs, AEs, 
MTD  
NCT03745352 / Phase 2 Planned 
(not yet 
recruiting) 
Relapsed or 
refractory 
AML 
MLN4924 
(pevonedistat) plus 
azacitidine; 
azacitidine 
OS 
AE = adverse events, AML = acute myeloid leukemia, CMML = chronic myelomonocytic 
leukemia, DDI = drug-drug interaction, DLT = dose limiting toxicity, EFS = event free survival 
HR = high risk, MDS = myelodysplastic syndrome, MTD = maximum tolerated dose, OS = overall 
survival, PK = pharmacokinetics, RPD2 = recommended phase 2 dose 
 
2.3 
Other Agents 
 
2.3.1 Carboplatin 
 
Carboplatin (NSC 241240) is one of the most widely utilized chemotherapeutic agents used in 
oncology.  Carboplatin works primarily by forming DNA crosslinks that interrupt cellular DNA 
function and subsequently induce apoptosis, but also forms DNA adducts with other cellular 
components such as proteins, lipids, RNA, and mitochondrial RNA (Reed et al., 1996; Hermann 
et al.,2013).    For more detailed information, please consult the carboplatin package insert 
(2011). 
 
2.3.2 Paclitaxel 
 
Paclitaxel (NSC 125973) is an anti-neoplastic agent that works by interfering with mitotic 
spindle function, resulting in disrupted chromosome segregation, inhibition of mitotic 
progression, prevention of cell division, and eventually cell death (Ganguly et al., 2010).  In 
hepatocytes, paclitaxel is metabolized by CYP2C8 to produce the major metabolite 6α-hydroxy-
paclitaxel and is metabolized by CYP3A4 into 3-p-hydroxy-paclitaxel (Monsarrat et al., 1998).  
For more detailed information, please consult the Taxol® package insert (2011). 
 

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2.4 
Rationale 
 
Platinum-based combination therapy is superior to best supportive care for patients with 
advanced, incurable NSCLC.  Carboplatin is a platinum analog chemotherapeutic agent that has 
been in use since the 1980s.  Platinum-based therapies function as alkylating agents by binding 
to cellular DNA to form inter-strand cross-linkages (ICLs).  The DNA repair pathways that 
resolve DNA ICLs, such as nucleotide excision repair and homologous recombination, are 
coordinated by a DNA damage response pathway termed the Fanconi anemia pathway (Kee et 
al., 2012).  The key regulatory event in the Fanconi anemia pathway is monoubiquination of 
Fanconi anemia group D2 protein (FANCD2), which is required for multiple steps during ICL 
repair, including activation of the nucleotide excision repair and translesion synthesis, and 
recruitment of homologous recombination repair factors such as breast cancer 1/2 (BRCA1/2) 
and RecA-like recombinase 51 (RAD51) (Kee and D’Andrea, 2010).  Preclinical data has 
demonstrated NEDD8 conjugation is necessary for the upstream phosphorylation of CHK1 and 
subsequent monoubiquitination of FANCD2 (Kee et al., 2012).  MLN4924 (pevonedistat) 
inhibits DNA damage-induced activation of the Fanconi anemia pathway and may sensitize 
cancer cells to DNA damaging agents such as platinum-based therapies. 
 
Preclinical models demonstrate that MLN4924 (pevonedistat) chemosensitizes NSCLC cell lines 
to platinum chemotherapy (Kee et al., 2012; Li et al., 2014; Bouck et al., 2015).  In a primary 
xenograft squamous cell lung cancer model, the combination of MLN4924 (pevonedistat) and 
carboplatin led to greater tumor suppression compared to carboplatin or MLN4924 
(pevonedistat) alone, or vehicle. 
 
A phase 1b, multi-arm study (C15010) has studied the safety of carboplatin and paclitaxel in 
combination with MLN4924 (pevonedistat) in patients with solid tumors (Lockhart et al., 2018).  
Dose-limiting toxicities (DLTs) included Grade 3(G3) febrile neutropenia (n = 1; 15 mg/m2), G3 
aspartate transaminase (AST)/alanine transaminase (ALT) elevation (n = 2; 20 mg/m2, n = 2; 25 
mg/m2).  One DLT of G3 AST elevation occurred during MTD expansion.  The recommended 
phase 2 dose (RP2D) was determined to be MLN4924 (pevonedistat) 20 mg/m2 on Days 1, 3, 
and 5 in combination with carboplatin AUC = 5 and paclitaxel 175 mg/m2 on the first day of a 
21-day cycle.  Overall, the combination was well tolerated with manageable toxicities.  Common 
AEs included fatigue (56%), nausea (48%), anemia (41%), diarrhea (34%), and transaminitis 
(19%). 
 
The combination of MLN4924 (pevonedistat) with carboplatin plus paclitaxel showed the most 
promising antitumor activity in pretreated patients (≥1 prior therapies) (Lockhart et al., 2015; 
Bauer et al., 2016; Lockhart et al., 2018). Notably, all but one of the eight responders in arm 2 
and one responder in arm 2a had previously received platinum, taxanes, or both. The ORR in 
arm 2 was 35%, including two patients with CR (bladder cancer and endometrial carcinoma).  
 
Consistent with preclinical studies reporting synergy between MLN4924 (pevonedistat) and 
platinum-chemotherapy, the objective responses in patients resistant to prior platinum/taxane 
therapy suggest the potential reversal of resistance by the addition of MLN4924 (pevonedistat).  
 
Carboplatin in combination with paclitaxel has been proven effective in NSCLC and is 

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commonly used as backbone chemotherapy regimen for patients with NSCLC (Sandler et al., 
2006).  The median PFS for this regimen is 4.5 months.  Adding MLN4924 (pevonedistat) is an 
attractive strategy to further enhance the activity of this regimen and overcome platinum 
resistance; especially in the re-treatment setting.  In addition, identifying patients who are most 
likely to benefit from this strategy will be explored by qualitative assessment of NAE1 and 
UBC12 protein expression on tumor using immunohistochemistry (IHC).  The hypothesis is that 
patients with high tumor NAE1 and UBC12 expression, which could help identify patients who 
have overexpression of the neddylation pathway, will benefit from the addition of NAE1 
inhibition with MLN4924 (pevonedistat). 
 
Given these safety data, objective responses in patients resistant to prior platinum/taxane therapy, 
and rationale, we propose a phase 2, single arm study of MLN4924 (pevonedistat) 20 mg/m2 
(Days 1, 3, 5) in combination with carboplatin AUC = 5 (Day 1) and paclitaxel 175 mg/m2 (Day 
1) in patients with advanced NSCLC previously treated with immunotherapy and platinum 
chemotherapy, including patients initially treated with front-line combination of platinum-based 
chemotherapy and immunotherapy (PD-1 inhibitor such as pembrolizumab). 
 
2.5 
Correlative Studies Background 
 
2.5.1  Integrated Studies 
 
2.5.1.1 
NQO1 and SLC7A11 Gene Expression 
 
This 12-gene assay will be used to test pharmacodynamic markers for drug response based on 
MLN4924 (pevonedistat) mechanism of action, previously characterized by Takeda.  Increased 
level of NRF2 is a biomarker of MLN4924 (pevonedistat) activity.  Samples will be obtained on 
Cycle 1 Day 1, pre-treatment and 6 hours (+/- 5 min) post-infusion on all patients enrolled in this 
study. 
 
2.5.1.2 CTCs  
 
CTCs can be found in the blood of patients with advanced NSCLC and can serve as a minimally 
invasive liquid biopsy for longitudinal evaluation of markers of treatment response and 
resistance.  CTCs are isolated and quantified using Exclusion-based Sample Processing (ESP) 
technology (Salus Discovery, Madison, WI).  We will evaluate changes in the total number of 
CTCs and the percentage of CTCs positive for γH2AX and RAD51 foci.  CTCs will be obtained 
on all patients at baseline, Cycle 3 Day 1, and upon progression with MLN4942 (pevonedistat) to 
evaluate the correlation between markers of DNA damage and response to the MLN4924 
(pevonedistat) based on imaging. 
 
2.5.1.3 
Pharmacokinetic parameters (PKs) 
 
In the phase 1b study of MLN4924 (pevonedistat) in combination with carboplatin and 
paclitaxel, there was a trend toward higher MLN4924 (pevonedistat) plasma concentrations 
when given with carboplatin plus paclitaxel, compared with a single-agent administration.  
Although some overlap exists in the metabolizing enzymes and/or transporter proteins involved 

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in the drug clearance of MLN4924 (pevonedistat) and carboplatin and paclitaxel, none are 
known inhibitors or inducers.  This warrants further investigation.  PKs will be done on Cycle 1 
Day 1. 
 
2.5.2 Exploratory Studies 
 
2.5.2.1 
NAE inhibition-responsive genes: ATF3, B2M, GCLM, GSR, MAG1, RPLPO, 
TXNRD1, and UBC Gene Expression 
 
To determine the expression of pharmacodynamic markers induced by NAE inhibition: ATF3, 
B2M, GCLM, GSR, MAG1, RPLP0, SRXN1, TXNRD1, and UBC.  This will be performed pre-
treatment and 6 hours (+/- 5 min) post-treatment on Cycle 1 Day 1. 
 
2.5.2.2 Tumor NAE1 and UBC12 Protein Expression 
 
Previous studies demonstrated that higher expression of NAE1 and UBC12 was associated with 
poor overall survival in lung cancer.  The hypothesis is that patients with higher tumor NAE1 
and UBC12 expression will benefit from NAE inhibition with MLN4924 (pevonedistat).  
Identifying patients who are most likely to benefit from this strategy will be explored by 
qualitative assessment of NAE1 and UBC12 protein expression on tumors using IHC and 
correlating this with clinical outcomes (ORR, PFS, OS).  Baseline archival tumor samples will 
be optional but encouraged from patients when tissue is available.  We anticipate obtaining at 
least 20 samples. 
 
 
 

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3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 
Patients must be ≥18 years old.  Because no dosing or AE data are currently available on 
the use of MLN4924 (pevonedistat) in combination with carboplatin and paclitaxel in 
patients <18 years of age, children are excluded from this study, but may be eligible for 
future pediatric trials. 
 
3.1.2 
Patients must have histologically confirmed stage IIIB or IV NSCLC (squamous or 
nonsquamous) that is metastatic or unresectable. 
 
3.1.3 Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1. 
 
3.1.4 Patients must have progressed on prior treatment with checkpoint inhibitor (PD-1/PD-L1 
inhibitors) either as a single-agent therapy or in combination, as below.  Patients will be 
eligible if there is a contra-indication to checkpoint inhibitor therapy. 
a. Patients who have progressed after receiving a checkpoint inhibitor in combination 
with a platinum-based doublet, as first-line treatment for NSCLC. 
b. Patients who have progressed on checkpoint inhibitor as second-line therapy, after 
receiving a platinum-based doublet as first-line therapy. 
c. Patients who have progressed on platinum-based doublet as second-line therapy, after 
receiving a checkpoint inhibitor as first-line therapy. 
 
3.1.5 Patients must have disease progression on or after platinum-based chemotherapy for 
metastatic disease or within 6 months of completion of platinum-based chemotherapy 
administration as adjuvant/neoadjuvant chemotherapy or concurrent chemoradiation.  
 
3.1.6 Patients must have adequate organ function: 
 
− 
Absolute neutrophil count 
 
≥1,500/mcL 
− 
Platelet count 
 
≥150,000/mcL 
− 
Total bilirubin 
 
≤1 x institutional upper limit of normal (ULN) 
− 
Patients with Gilbert’s syndrome may enroll if 
direct bilirubin  ≤1.5 x ULN  
− 
AST(SGOT)/ALT(SGPT) 
 
≤3.0 × institutional ULN,  
− 
Patients with metastatic liver disease may enroll if 
≤5xULN 
− 
glomerular filtration rate (GFR) >30 mL/min/1.73 m2  
 
3.1.7 Known HIV positive patients who meet the following criteria will be considered eligible: 
 
• CD4 count >350 cells/mm3 
• Undetectable viral load within the last six months 
• HIV positive patients must be stable on HAART.  Clinically significant metabolic 

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enzyme inducers are not permitted during this study(e.g., ritonavir, efavirenz, 
nevirapine). 
• No history of Acquired Immune Deficiency Syndrome (AIDS)-defining opportunistic 
infections 
 
3.1.8 Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (See Appendix A). 
 
3.1.9 Life expectancy ≥ 12 weeks. 
 
3.1.10 Patients are eligible if CNS metastases are adequately treated and neurological symptoms 
have returned to baseline or are controlled for at least 2 weeks prior to enrollment.  In 
addition, subjects must be either off corticosteroids, or on stable or decreasing dose of 
steroids. Patients with leptomeningeal disease are excluded. 
 
3.1.11 The effects of MLN4924 (pevonedistat) on the developing human fetus are unknown.  
For this reason and because agents as well as other therapeutic agents used in this trial are 
known to be teratogenic, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry and for the duration of study participation.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study 
or within 4 months of completion, she should inform her treating physician immediately.  
Men treated or enrolled on this protocol must also agree to use adequate contraception 
prior to the study, for the duration of study participation, and 4 months after completion 
of MLN4924 (pevonedistat) administration.   
 
Female patients who: 
• Are postmenopausal for at least 1 year before the screening visit, or 
• Are surgically sterile, or 
If they are of childbearing potential,  
• Agree to practice 1 highly effective method and 1 additional effective (barrier) 
method of contraception (see Appendix C), 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 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, 
sympothermal, postovulation methods] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception.)   
Male patients, even if surgically sterilized (i.e., status postvasectomy), who  
• Agree to practice effective barrier contraception during the entire study treatment 
period and through 4 months after the last dose of study drug (female and male 
condoms should not be used together), OR 
• Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, 
sympothermal, postovulation methods for the female partner] withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of 

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contraception.) 
 
3.1.12 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
3.1.13 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured.  For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.14 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. 
 
3.1.15 Left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram or 
radionuclide angiography. 
 
3.1.16 Ability to understand and the willingness to sign a written informed consent document.  
Participants with impaired decision-making capacity (IDMC) who have a legally 
authorized representative (LAR) or caregiver and/or family member available will also 
be considered eligible. 
 
3.1.17 Patients with NSCLC harboring genomic aberrations (e.g. sensitizing EGFR, ALK,  
ROS1, NTRK, BRAF V600E mutation positive) must have received prior treatment with 
FDA approved targeted therapy for patients for which FDA approved targeted therapies 
is available. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have 
residual toxicities > Grade 1) with the exception of alopecia and neuropathy. 
 
3.2.2 Patients who are receiving any other investigational agents. 
 
3.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MLN4924 (pevonedistat), carboplatin, or paclitaxel. 
 
3.2.4 Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study. 
 
3.2.5 Patients with uncontrolled intercurrent illness. 
 
3.2.6 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.7 Pregnant women are excluded from this study because MLN4924 (pevonedistat), 
carboplatin, and paclitaxel have the potential for teratogenic or abortifacient effects.  

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Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with MLN4924 (pevonedistat), breastfeeding must 
be discontinued if the mother is treated with MLN4924 (pevonedistat).  These potential 
risks may also apply to other agents used in this study. 
 
3.2.8 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). 
 
3.2.9 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). 
 
3.2.10 Known cardiopulmonary disease defined as: 
• Unstable angina  
• Congestive heart failure (New York Heart Association [NYHA] Class III or IV;); 
• Myocardial infarction within 6 months prior to first dose (patients who had 
ischemic heart disease such as acute coronary syndrome [ACS], myocardial 
infarction, and/or revascularization greater than 6 months before screening and 
who are without cardiac symptoms may enroll) 
• Symptomatic cardiomyopathy 
• Clinically significant arrhythmia: 
1. History of polymorphic ventricular fibrillation or torsade de pointes, 
2. Permanent atrial fibrillation, defined as continuous atrial fibrillation for ≥6 
months, 
3. Persistent atrial fibrillation, defined as sustained atrial fibrillation lasting 
>7 days and/or requiring cardioversion in the 4 weeks before screening, 
4. Grade 3 atrial fibrillation defined as symptomatic and incompletely 
controlled medically, or controlled with device (e.g., pacemaker), or 
ablation in the past 6 months and 
5. Patients with paroxysmal atrial fibrillation or Grade <3 atrial fibrillation 
for period of at least 6 months are permitted to enroll provided that their 
rate is controlled on a stable regimen. 
• Clinically symptomatic pulmonary hypertension requiring pharmacologic therapy 
 
3.2.11 Peripheral neuropathy that is Grade ≥3, or Grade 2 with pain on clinical examination 
during the screening period.  
 
3.2.12 Uncontrolled high blood pressure (i.e., systolic blood pressure >180 mmHg, diastolic 
blood pressure >95 mmHg). 
 
3.2.13 Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to 
institutional guidelines. 
 
3.2.14 Known moderate to severe chronic obstructive pulmonary disease, interstitial lung 
disease, and pulmonary fibrosis. 
 
3.2.15 Major surgery within 14 days before the first dose of any study drug or a scheduled 

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surgery during study period. 
 
3.2.16 Life-threatening illness unrelated to cancer. 
 
3.2.17 Patients with uncontrolled coagulopathy or bleeding disorder. 
 
3.2.18 Known hepatic cirrhosis or severe pre-existing hepatic impairment. 
 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
 

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23 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to Oncology Patient Enrollment Network (OPEN), Rave, or acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• IVR:  MD, DO, or international equivalent, 
• NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
• AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System [RUMS], OPEN, Rave,), 
• Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IV
R 
NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 

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• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance).  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 

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4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website.  Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment.  To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a Participating Organization on the protocol.  
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-MD017, 
and protocol number 10266, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided.  (Note:  For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU as described above.)  
 
4.2.2 Requirements for NCI Protocol #10266 Site Registration 
 
• Site Initiation Visit. Contact the Principal Investigator and Protocol Contact to schedule 
the SIV. Documentation of the SIV will be submitted to the CTSU by the Protocol 
Contact. 
• Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU.  However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Peter Clark and Diana Vulih are the main points of contact at Theradex for the 
training (PClark@theradex.com and DVulih@theradex.com, Theradex phone: 609-
799-7580). 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website  

NCI Protocol #:10266 
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26 
 
Regulatory  Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site’s registration status on the members’ side of the CTSU website.  
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration  
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status shown only reflects institutional compliance with site registration 
requirements as outlined above.  It does not reflect compliance with protocol requirements 
for individuals participating on the protocol or the enrolling investigator’s status with the 
NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  OPEN will populate the patient enrollment data 
in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access:   
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, 
ETCTN Corresponding roster, or Participating Organization roster with the role 
of Registrar.  Registrars must hold a minimum of an AP registration type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar 
task on the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 

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Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website.  Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
4.3.2 Special Instructions for Patient Enrollment: 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
 
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
• The system is accessed through special Rave user roles:  “CRA Specimen Tracking” for 
data entry at the treating institutions and “Biorepository” for users receiving the 
specimens for processing and storage at reference labs and the Biorepository.   
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website under the Rave/DQP tab. 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Detailed instructions can be found in Section 5.3 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 business days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  If a 
patient does not receive protocol therapy following registration, the patient’s registration on the 
study may be canceled.  The Protocol Contact should be notified of cancellations as soon as 
possible. 
 
 

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5. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Summary Table for Specimen Collection 
 
Biomarker 
Name 
Collection Time Point 
Specimen and Quantity 
Send Specimens 
to: 
Baseline 
NAE1, UBC12 
protein 
expression 
Pre-study 
• 
Formalin-Fixed Paraffin Embedded 
(FFPE) tumor tissue (archival 
tissue), 6 slides per patienta,b 
University of 
Wisconsin 
Cycle 1, Day 1 
NAE 
inhibition-
responsive 
genes, 
NQO1, 
SLC7A11 
Pre-treatment;  
6hr +/- 5 min post-
infusion  
• 
Blood (PAXgene Blood RNA tube, 
2.5mL) 
Asuragen 
PK analysis 
Pre-infusion, 
immediately post 
infusion, 
3 hours (+/- 5 min),  
12 hours (+/- 2 hours) 
(optional),  
24 hours (+/- 2 hours), 
and 48 hours (+/- 2 
hours) post-infusion 
• 
3.0mL blood in K2EDTA lavender 
top Becton-Dickinson Vacutainer 
o Submit 1 cryovial 
containing plasma for each 
time point 
o Store the 2nd cryovial 
containing plasma for each 
time point on-site at -70⁰C 
or lower as backup 
QPS 
 
CTCs 
Pre-treatment 
• 
Blood (2x EDTA tubes, 10mL and 
2x CellSave tubes, 10mL) 
University of 
Wisconsin 
Cycle 3, Day 1 
CTCs 
Pre-treatment 
• 
Blood (2x EDTA tubes, 10mL and 
2x CellSave tubes, 10mL) 
University of 
Wisconsin 
Progression  
CTCs 
 
• 
Blood (2x EDTA tubes, 10mL and 
2x CellSave tubes, 10mL) 
University of 
Wisconsin 
AT=archived tumor, PK=pharmacokinetics, CTCs=circulating tumor cells 
a:  If 6 slides are not available, 4 slides will be sufficient 
b:  Optional study 
 
5.2 
Specimen Procurement Kits and Scheduling 
 
5.2.1 Specimen Collection and Shipping Kits 
 
Institutional supplies must be used for specimen collection and processing. 
 
5.2.1.1 Scheduling of Specimen Collections 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue:  
 

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• Tumor tissue specimens collected during biopsy procedures and fixed in formalin must be 
shipped on the same day of collection.  
• Tissue can be collected Monday through Wednesday and shipped overnight for arrival on 
Tuesday through Thursday at the University of Wisconsin. 
 
Specimens submitted frozen such as frozen plasma can be collected on any day but must be 
stored frozen and shipped to QPS on Monday through Thursday.  In the event that frozen 
specimens cannot be shipped immediately, they must be maintained at -70°C or lower. 
 
Fresh blood specimens for CTC analysis may be collected and shipped Monday through 
Thursday to the UWCCC Circulating Biomarker Core.  
 
Specimens submitted frozen such as frozen blood can be collected on any day but must be stored 
frozen and shipped to Asuragen on Monday through Thursday.  In the event that frozen 
specimens cannot be shipped immediately, they must be maintained at -70°C. 
 
5.3 
Specimen Tracking System Instructions 
 
5.3.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 0. 
• Additional Requirements:  Patients must provide a signed and dated, written informed 
consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this protocol that uses the ETCTN Specimen Tracking System.  The 
UPID contains no information or link to the treatment protocol.  IWRS will maintain an 
association between the UPID for ETCTN biobanking and molecular characterization and any 
treatment protocols the patient participates in, thereby allowing analysis of the molecular 
characterization results with the clinical data. 
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave.  Important:  Remove any personally identifying 
information, including, but not limited to, the patient’s name, initials, medical record 
number, and patient contact information from the institutional pathology report prior to 

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30 
 
submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact the Theradex Help Desk 
at CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
5.3.2 Specimen Labeling 
 
5.3.2.1 
Blood Specimen Labels for CTCs 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Protocol number concatenated to the Subject Study ID 
• Universal Subject ID (UPID) 
• Rave generated specimen ID (which includes the protocol number and Universal Subject 
ID along with a sequential integer representing the order the specimen was collected 
• Protocol timepoint 
• Specimen type (e.g.,. blood, serum) 
• Collection date and time 
 
5.3.2.2 Blood Specimen Lables for PK analysis 
 
• Protocol Number 
• Subject Identification Number 
• Sample Identification Code shown below. [nominal time] may be the scheduled vist 
and/or time point.  
a) Plasma PK Pevo [nominal time] Set1 
b) Plasma PK Pevo [nominal time] Set 2 
 
5.3.2.3 
Blood Specimen Labels for NAE inhibition-responsive genes and NQO1, SLC7A11 
 
Label each specimen with the following information: 
• Protocol #:  
• Study ID #  
• Specimen type:  Pharmacodynamics 
• Specimen time point:  pre or post 
• Date/time collected 
 
5.3.2.4 
Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g., formalin jar):  

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31 
 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., FFPE Block, Formalin Fixed Tissue, Fresh Tissue in Media, 
etc.) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number  
• Block number from the corresponding pathology report (archival only) 
• Collection date (to be added by hand) 
 
5.3.2.5 
Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 
 
  
 
The QR code in the above example is for the Specimen ID shown on the second line.   
NOTE:  The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
5.3.3 Overview of Process at Treating Site 
 
5.3.3.1 
OPEN Registration 
 
All registrations will be performed using the OPEN system.  OPEN communicates automatically 
with the IWRS which handles identifier assignments, any study randomization, and any 

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prescribed slot assignments.  If specimen analysis is required to determine eligibility, the 
protocol will be setup with multi-step registration. 
 
Registration without eligibility specimen analysis 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Subject Study ID and the UPID, both of 
which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.3.3.2 Rave Specimen Tracking Process Steps 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies.  Enter the 
initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded).  CRF generates unique 
Specimen ID.  
 
Step 2:  Print labels using report in EDC and collect specimen. 
• Label specimen containers and write collection date [if the study also requires recording 
the collection time on the label, include the time] on each label. 
• After collection, store labeled specimens as described in Section 5.4.2. 
• Apply an extra specimen label to each report before scanning.  Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports and Pathology Verification form (when applicable).  
Return to Specimen Tracking Enrollment CRF to upload any molecular report (one per 
specimen) and/or specimen specific pathology or related report (one per specimen).  
Uploaded reports should have protected health information (PHI) data, like name, 
mailing address, medical record number or social security number (SSN), redacted.  Do 
not redact SPID, block number or relevant dates, and include the UPID and patient study 
ID on each document.  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of containers and ship date once for the first specimen in a shipment. 
• Copy Shipping CRF:  Select additional specimens to add to an existing shipment 
referenced by the tracking number. 
 

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Step 5:  Print shipping list report and prepare to ship.  
• Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
• Print pathology or other required reports to include in the box.  Be sure the printed copy 
includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s) 
 
 
5.4 
Specimen Collection 
 
5.4.1 Archival FFPE Tumor Specimen 
 
If previously-collected FFPE tissue will be submitted, then the following criteria must be met: 
 
• Tissue collected within 6 months prior to registration is preferred. If tissue collected 
within 6 months not available, any archival tissue specimen will be acceptable.  
  
The following samples are requested, if available: 
• FFPE block samples will be shipped to the Wheeler lab, then will be submitted to the 
Translational Research Initiatives in Pathology (TRIP) lab for sectioning. 
• Six unstained slides, 4 µm on positive charged slides for immunohistochemistry analysis.  
If 6 slides are not available, 4 unstained slides will be sufficient. 
 
5.4.2 Blood Collection  
 
5.4.2.1 
Collection of Blood in PAXgene tube 
 
1. Blood samples will be collected pre-treatment and 6 hr (+/- 5 min) post-treatment.  
Collect one 2.5 mL of blood in PAXgene tube at each time point. 
2. Ensure that the PAXgene tube is at room temperature (18°C–25°C) prior to use and 
properly labeled with patient identification.  
3. Using a blood collection set, collect blood into the PAXgene Blood RNA tube using your 
institution’s recommended standard procedure for venipuncture.  
4. Hold the PAXgene blood RNA tube vertically, below the donor’s arm during blood 
collection. 
5. Allow at least 10 seconds for a complete blood draw to take place.  Ensure that the blood 
has stopped flowing into the tube before removing the tube from the holder.  
6. Gently invert PAXgene Blood RNA Tube 8 to 10 times. 
7. “Slow-freeze” tube overnight at -20⁰C. The tube may then be shipped or transferred to a  
-70⁰C freezer for long-term storage until shipped.    
 

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5.4.2.2 Collection of Blood in EDTA and CellSave Tubes  
 
1. Label tubes according to the instructions in Section 5.3.1.1. 
2. Collect blood into 2, 10 ml EDTA tubes and gently invert tube 8 – 10 times to mix. 
3. Collect blood into 2, 10 ml Cellsave tubes and gently invert tube 8 – 10 times to mix. 
4. Ship on day of collection for next day delivery according to instructions below. 
 
5.4.2.3 
Collection of Blood in K2EDTA lavender top Beckton Dickinson Vacutainers  
 
1. Legibly write the subject’s initials and subject identification number clearly using blue or 
black pen only (no markers) on blood collection tubes.  Cryovial labels must be labeled 
according to section 5.3.2.2.  
2. Collect 3.0 mL of venous blood into a chilled K2EDTA lavender top Becton-Dickinson 
Vacutainer. 
3. Gently invert the Vacutainer 8 to 10 times to mix the additive with the collected blood 
prior to centrifugation and place immediately on ice. 
4. Centrifuge the Vacutainers for 10 minutes at approximately 1100-1300 × g (RDF) at 
approximately 4 °C in a refrigerated centrifuge.  Note: if using a collection device other 
than Becton-Dickinson, refer to manufacturer’s instruction for proper centrifugation force 
and time. 
5. Immediately following centrifugation, gently remove plasma from the packed cells and 
transfer into two appropriately labeled 2.0 mL cryogenic vials.  To ensure a more 
homogenous sample, transfer all plasma into one cryovial.  From there, split the plasma 
evenly between the 2 aliquots.  A minimum of 0.6 mL needs to be obtained for each 
aliquot. 
6. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -70 °C or lower.  If a -70 °C freezer is not available, freeze and store 
samples at-20 °C.  No more than 45 minutes will elapse between blood collection and 
freezing the plasma sample. 
7. Store samples frozen at approximately -70 °C or lower until shipment. 
 
5.5 
Shipping Specimens from Clinical Site to Analysis Laboratories 
 
5.5.1 Shipping Fresh Blood (EDTA and CellSave Tubes) 
 
1. Before packaging specimens, verify that each specimen is labeled according to Section 
5.3.1.  
2. Each shipment should include a Sample Inventory. 
3. Notify the Circulating Biomarker Core of the shipment with sample inventory copy via 
email (uwctc@medicine.wisc.edu) ahead of time, or at the latest on the day of shipment, 
please include tracking information in email. 
4. Samples will be packed in Styrofoam shipping containers containing two ambient gel 
packs surrounding blood tubes.  Samples should never be frozen. 
 
 

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5.5.1.1 
Shipping to the University of Wisconsin Carbone Cancer Center (UWCCC) 
Circulating Biomarker Core  
 
Name: Dr. Joshua Lang 
Attn: Dr. Jennifer Schehr 
University of Wisconsin Carbone Cancer Center 
Address:  
Circulating Biomarker Core 
K4/517 Clinical Science Center 
University of Wisconsin Carbone Cancer Center 
600 Highland Avenue 
Madison, WI 53792 
Lab phone: (608) 265-5349 
Office phone: (608) 262-0705 
Fax: (608) 265-0614 
Email: uwctc@medicine.wisc.edu  
 
5.5.2 Shipping of Archival tissue  
 
1. Before packing specimens, verify that each specimen is labeled according to Section 
5.3.3. 
2. Each shipment should be included with a Sample Inventory. 
3. Notify the Wheeler lab ahead of the shipment with sample copy via email (address 
below) ahead of time on the day of shipment. Shipments should be done Monday – 
Thursday only for lab to receive Tuesday – Friday. 
4. Samples will be packed in biological shipment-appropriate box. 
5. Samples should be ambient, not refrigerated. 
 
5.5.2.1 
Shipping to the Wheeler Laboratory 
 
Attn: Mari Iida 
Wisconsin Institute for Medical Research 
WIMR 3100 
Address: 1111 Highland Ave, Madison, WI 53705 
Phone: (608) 265-5446 
Email: dlwheeler@wisc.edu; Iida@humonc.wisc.edu  
 
5.5.3 
Shipping of Frozen Blood (in PAXgene tubes) 
 
1. Ship the frozen samples Monday through Thursday on the day after collection or store at 
-70°C and ship on the next available day. 
 
5.5.3.1 
Shipping to Asuragen 
 
Deepa Eveleigh, Associate Director, CLIA/Custom Dx Operations / Asuragen 
Address: 2150 Woodward Street, Suite 100, Austin, TX 78744 

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36 
 
Email:  develeigh@asuragen.com 
Job Reference Code: JB13048 
 
 
5.5.4 Shipping of Frozen Blood (in K2EDTA lavender top Beckton-Dickson Vacutainers) 
 
1. All samples should be shipped to the address below. 
2. Primary and backups of samples should not be shipped together. Ship the primary 
samples together (1 cryovial per time point) and store the backup samples (2nd 
cryovial per time point) at -70 or lower until requested. 
3. Each shipment should include a sample inventory. 
4. Please notify TBD of the shipment with the sample inventory copy via email ahead of 
time or at the last day of shipment. 
5. Samples will be packed in Styrofoam shipping containers with sufficient amount of 
dry ice to maintain frozen conditions for at least 72 hours (3 days) or up to the 
expected delivery date, whichever is longer.  
 
5.5.4.1 
Shipping to QPS 
 
Attn:  Sample Coordination Team 
QPS, LLC 
3 Innovation Way 
Suite 240 
Newark, DE, 19711 
Phone:  +1 302 369 5120 
Email:  sample@qps.com 
 
 
 

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37 
 
5.6 
Biomarker Plan 
 
List of Biomarker Assays in Order of Priority 
 
Priority 
Biomarker 
Name 
Biomarker 
Assay 
Biomarker Type and Purpose 
M/O 
Specimen(s) and 
Time Points 
Laboratory 
1 
NQO1, 
SLC7A11 
RT-PCR 
Integrated 
 
Pharmacodynamic marker 
induced by NAE inhibition 
M 
Whole blood 
 
Cycle 1: Day 1 
(pre-treatment, 6 
hours (+/- 5 min) 
post infusion) 
Asuragen;  
Deepa Eveleigh 
(develeigh@asuragen.co
m) 
2 
Total CTC 
number, 
number of 
γH2AX+ 
CTC, 
number of 
RAD51+ 
CTCs 
Versa 
Integrated 
 
Identify potential prognostic and 
predictive biomarkers of 
MLN4924 (pevonedistat).  To 
compare changes in the number 
of γH2AX and RAD51 positive 
CTCs at baseline, Cycle 3, Day 1 
and progression with MLN4924 
(pevonedistat).  
M 
Blood 
 
Cycle 1: Day 1, 
Cycle 3: Day 1 
(with disease 
evaluation 
imaging) and at 
progression 
UWCCC Circulating 
Biomarker Core; 
(uwctc@medicine.wisc.e
du) 
3 
PK analysis 
LC-
MS/MS 
Integrated 
 
Confirmatory assessment: prior 
combination trial showed 
potential interaction (increased 
MLN4924 (pevonedistat)) 
M 
Blood 
 
Cycle 1: Day 1 
(pre-infusion, 
immediately post 
infusion, and 3 
hours (+/- 5 min), 
12 hours (+/- 2 
hours) (optional), 
24 hours (+/- 2 
hours), and 48 
hours (+/- 2 hours 
post infusion) 
QPS 
 
Lily Rosa 
Lily.rosa@qps.com 

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38 
 
Priority 
Biomarker 
Name 
Biomarker 
Assay 
Biomarker Type and Purpose 
M/O 
Specimen(s) and 
Time Points 
Laboratory 
4 
NAE1, 
UBC12 
protein 
expression 
IHC  
Exploratory 
 
Identify predictive biomarker: 
high expression of NAE1 and 
UBC12 proteins will correlate 
with improved outcome 
O 
Tumor tissue 
 
Baseline 
(performed on 
archival tissue) 
University of Wisconsin; 
Deric L. Wheeler 
(dlwheeler@wisc.edu) 
5 
NAE 
inhibition-
responsive 
genes: 
(ATF3, 
B2M 
GCLM, 
GSR, 
MAG1, 
RPLPO, 
SRXN1, 
TXNRD1, 
UBC) 
RT-PCR 
Exploratory 
 
Pharmacodynamic marker 
induced by NAE inhibition 
O 
Whole blood 
 
Cycle 1: Day 1 
(pre-treatment, 6 
hours (+/- 5 min) 
post infusion) 
Asuragen;  
Deepa Eveleigh 
develeigh@asuragen.co
m 
ATF3 = cyclic AMP-dependent transcription factor 3, B2M = β2 microglobulin, CTC = circulating tumor cells, GCLM = glutamate-cysteine ligase regulatory subunit, 
GSR = glutathione-disulfide reductase, IHC = immunohistochemistry, LC-MS/MS = liquid chromatography/mass spectrometry, M = mandatory, MAG1 = DNA-3-
methyladenine, NAE1 = NEDD8-activating enzyme, NQO1 = NAD(P)H: quinone oxidoreductase1, O = optional, PK = pharmacokinetics, SLC7A11 = sodium 
independent cystine-glutamate antiporter, RPLP0 = ribosomal protein lateral stalk subunit P0, RT-PCR = reverse transcription polymerase chain reaction, SRXN1 = 
sulfiredoxin-1, TXNRD1 = thioredoxin reductase 1, UBC = ubiquitin-conjugating enzyme. 
 

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39 
 
5.7 
Integrated Studies 
 
5.7.1 NQO1 and SCL7A11 (NRF2 target genes) 
 
This 12-gene assay will be used to test pharmacodynamics markers for drug response based on 
MLN4924 (pevonedistat) mechanism of action, previously characterized by Takeda.  Increased 
level of NRF-2 is a biomarker of MLN4924 (pevonedistat) activity.  Samples will be obtained on 
Cycle 1 Day 1, pre-treatment and 6 hours (+/- 5 min) post infusion on all patients enrolled in this 
study. 
 
5.7.1.1 
Specimen Receipt and Processing 
 
1. The samples are stable for up to 3 days at room temperature, up to 5 days at 2-8 °C and 
up to 4 years at – 20 °C or -70 °C. 
2. All samples to be shipped to address listed in Section 5.5. 
 
5.7.1.2 
Site Performing Correlative Study 
 
NQO1 and SCL7A11 RT-PCR will be performed in the Asuragen Lab under the direction of 
Deepa Eveleigh. 
 
5.7.2 CTCs 
 
CTCs will be obtained pretreatment, and at disease progression for all patients.  CTCs will be 
obtained on all patients at baseline, Cycle 3 Day 1, and upon progression not evaluate for number 
of γH2AX and RAD51 CTCs. 
 
5.7.2.1 Specimen receipt and processing 
1. Ship samples on the same day of blood draw. 
2. All samples to be shipped to address listed in Section 5.5. 
 
5.7.2.2 Site Performing Correlative Study 
 
CTC ESP assay will be performed at the UWCCC Circulating Biomarker Core 
 
5.7.3 PK Analysis 
 
Confirmatory assessment: prior combination trial showed potential interactions with MLN4924 
(pevonedistat).  This will be performed on Cycle 1 Day 1 pre-infusion, immediately post-
infusion, and 3 hours ± 5 minutes, 12 hours ± 1 hour, 24 hours ± 2 hours, and 48 hours ± 2 hours 
post-infusion. 
 
5.7.3.1 Specimen receipt and processing 
 
1. Keep samples frozen at -70ºC or lower until shipment. 
2. If a -70ºC freezer is not available, samples can be stored in a -20ºC freezer for up to 30 

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days. 
3. All samples to be shipped to address listed in Section 5.5. 
 
5.7.3.2 Site Performing Correlative Study 
 
PK analysis will be performed  at QPS. 
 
5.8 
Exploratory/Ancillary Studies 
 
5.8.1 NAE inhibition-responsive genes: ATF3, B2M, GCLM, GSR, MAG1, RPLPO, SRXN1, 
TXNRD1, and UBC 
 
To determine expression of pharmacodynamic markers induced by NAE inhibition: ATF3, B2M, 
GCLM, GSR, MAG1, RPLP0, SRXN1, TXNRD1, and UBC. 
 
5.8.1.1 Specimen receipt and processing 
 
• The samples are stable for up to 3 days at room temperature, up to 5 days at 2-8ºC, and 
up to 4 years at -20ºC or -70ºC. 
• All samples to be shipped to address listed in Section 5.5. 
 
5.8.1.2 Site Performing Correlative Study 
 
ATF3, B2M, GCLM, GSR, MAG1, RPLPLO, SRXN1, TXNRD1, and UBC RT-PCR will be 
performed in the Asuragen Lab under the direction of Deepa Eveleigh. 
 
5.8.2 NAE1 and UBC12 protein expression 
 
Previous study demonstrated that higher expression of NAE1 and UBC12 was associated with 
poor overall survival in lung cancer.  The hypothesis is that patients with high tumor NAE1 and 
UBC12 expression, which is negatively prognostic, will benefit from NAE inhibition with 
MLN4924 (pevonedistat).  Identifying patients who are most likely to benefit from this strategy 
will be explored by qualitative assessment of NAE1 and UBC12 protein expression on tumor 
using IHC.  Antibodies for NAE1 and UBC12 have been established for use on human FFPE 
tissue (Li et al., 2014).  Baseline archival tumor samples will be optional and encouraged to be 
obtained from patients when tissue is available.  We anticipate obtaining at least 20 samples.  
This will be correlated with clinical outcomes (PFS, ORR, OS) 
 
5.8.2.1 Specimen receipt and processing 
 
All samples to be shipped to address listed in Section 5.5. 
 
5.8.2.2 Site Performing Correlative Study 
 
NAE1 and UBC12 IHC will be performed at the University of Wisconsin laboratory of Dr. Deric 
Wheeler.  Six 4 µm slides will be utilized for immunohistochemistry analysis in Wheeler lab (1 

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no antibody, 1 NAE antibody dilution 1, and 1 NAE antibody dilution 2 as well as no antibody, 1 
UBC antibody dilution 1, and 1 UBC antibody dilution 2).  If 6 slides are not available, 4 slides 
will be sufficient. 
 
5.8.3 Banking and Use of Specimens in Future Research 
 
Any biospecimens remaining after processing will be retained indefinitely at the University of 
Wisconsin biobank under appropriate storage conditions.  Specimen types may include: 
• Blood 
• Archival tissue 
 
Specimens from patients who consented to allow their specimens to be used for future approved 
research studies, including residuals from the currently defined research studies, will be retained 
at the University of Wisconsin biobank.  Protocol-specified studies should be clearly described 
and prioritized in the protocol, and in general, should not require additional review and approval.  
Investigators are encouraged to consult with the University of Wisconsin biobank for the 
evaluation of residual tissue specimens approaching depletion for protocol-specified studies. 
 
 
 

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6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Body surface area (BSA) should be 
recalculated if ≥5% weight change. Reported adverse events and potential risks for MLN4924 
(pevonedistat), carboplatin, and paclitaxel are described in Section 10.  Appropriate dose 
modifications are described in Section 7.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
Agent* 
Dose 
Route 
Schedule 
Cycle Length 
Paclitaxel# 
175 mg / m2 
IV infusion over 
3 hours 
Day 1 
21 days 
(3 weeks) 
Carboplatin# 
AUC = 5** 
IV infusion over 
30-60 minutes*** 
Day 1 
MLN4924 
(pevonedistat) 
20 mg/m2 
IV infusion over 
1 hour 
Days 1, 3, 5 
#Suggested premedications are provided in section 6.1.3.1. 
*Paclitaxel is administered first, followed by carboplatin, and then MLN4924 (pevonedistat). 
**Doses and volume of diluent per institutional standard. 
*** Rate of infusion may be per institutional standard.  
 
Patients will receive 4 cycles of combination therapy with carboplatin, paclitaxel and MLN4924 
(pevonedistat).  After 4 cycles of combination therapy, the treating physician is given discretion 
whether to continue with a) carboplatin, paclitaxel and MLN4924 (pevonedistat), if clinical 
benefit, until progressive disease, unacceptable toxicity or patient desire to discontinue study 
therapy; or b) continue carboplatin and MLN4924 (pevonedistat) without paclitaxel, if clinical 
benefit, until progressive disease, unacceptable toxicity or patient desire to discontinue study 
therapy; or c) observe the patient on study. All patients will be followed for the duration of study 
and until resolution or stabilization of any adverse effects related to study therapy.  If the patient 
is continued on a) or b), subsequent change to c) at later timepoints is also allowed. 
 
6.1.1 MLN4924 (pevonedistat) 
 
MLN4924 (pevonedistat) will be administered after paclitaxel and carboplatin at a dose of 
20mg/m2 on Days 1, 3 and 5. Day 1 should be administered on a Monday. For sites with the 
ability to administer Day 5 on Saturday, Day 1 may begin on Tuesday. 
 
MLN4924 (pevonedistat) is to be administered as a 60-minute (±10 minutes) IV infusion, using a 
250 mL D5W (5% dextrose in water) or normal saline (NS) IV bag through central or peripheral 
venous access.  The drug can be diluted in 5% dextrose or normal saline to a final volume of 
250mL.  Infusion-related reactions have not been reported in the Pevonedistat program. If there 
is suspicion for any associated infusion-related reactions, the IV infusion can be slowed or 
stopped and restarted for any associated infusion-related reactions.  The total time from the IV 
preparation to the end of IV infusion must not exceed 6 hours.  Infusion line can be flushed with 

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5% dextrose in water or normal saline immediately after IV administration is complete. 
 
On Day 1 of each cycle patients will receive dexamethasone pre-medication per institutional 
standards for paclitaxel. Suggested pre-medications for Paclitaxel are outlined in Section 6.1.3. 
 
Toxicity management should follow the guidelines and algorithms that are provided in Section 7. 
 
If MLN4924 (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 MLN4924 (pevonedistat) 
should not be exceeded.   
 
The amount of study drug to be administered will be based on body surface area (BSA).  BSA 
will be calculated using a standard formula per institutional standards 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. 
 
Pevonedistat may be continued as monotherapy if paclitaxel and carboplatin are discontinued. 
 
6.1.2 Carboplatin 
 
Carboplatin will be administered on Day 1 after the paclitaxel infusion is completed.  
Carboplatin at the appropriate dose will be given intravenously as a 30-60 minute infusion or per 
institutional standard in Dextrose 5% in Water or Sodium Chloride 0.9%, volume per 
institutional standard.  
 
6.1.2.1 
Carboplatin Dose Calculation and Administration  
 
Carboplatin dose will be calculated using the Calvert formula:  
Total Dose (mg) = target AUC* (GFR+25), GFR may be substituted by Creatinine Clearance 
(CrCl) calculation.  
 
Note: Calculated total dose is in mg – not mg/m2  
 
The CrCl 75 (replaces GFR in Calvert formula) will be calculated for each treatment course 
using the formula: 
 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶= (140 −𝑎𝑎𝑎𝑎𝑎𝑎) ∗𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡(𝑘𝑘𝑘𝑘)
72 ∗𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐
∗(0.85 𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓) 
 
The minimum serum creatinine value used will be 0.7 mg/dL and a CrCl cap will be 125 
mL/min. Questions about this calculation should be directed to the PI. 
 
Note: Remember to re-calculate the dose for each treatment cycle.  The actual body weight 
should be used for all calculations. 
 

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6.1.3 Paclitaxel 
 
Paclitaxel should be diluted in Dextrose 5% or Sodium Chloride 09% per institutional standard 
and given by intravenous infusion.  The concentration of the final solution should be between 0.3 
and 1.2 mg/mL.  Prepare in non-PVC infusion container and administer IV over 3 hours via 0.22 
micron in line filter and non-DEHP tubing.  Solutions exhibiting excessive particulate formation 
should be discarded. 
 
Concentrations of up to 1.2 mg/mL in 5% dextrose or normal saline solution have demonstrated 
chemical and physical stability for at least 27 hours at room temperature.  
 
Due to known allergic reactions to paclitaxel and/or of the Cremophor vehicle, the following 
precautions must be taken to minimize the chances of a hypersensitivity reaction. 
 
6.1.3.1 
Suggested pre-medications for Paclitaxel 
 
Agent 
Dose 
Route 
Duration 
Dexamethasone 
20 mg * 
PO 
12 and 6 hours prior to paclitaxel 
5-HT3 Antagonist 
** 
PO 
Per institutional guidelines, prior to infusion of 
paclitaxel 
Diphenhydramine 
50 mg 
IV 
30 minutes prior to paclitaxel 
Ranitidine 
50 mg 
IV 
30 minutes prior to paclitaxel 
* 20 mg is the dose for Cycle 1 Day 1.  Subsequently, may be decreased to 12 mg on Cycle 2 
Day 1 and to 8 mg on Cycle 3 Day 1 and all future doses of paclitaxel.  Alternatively, a single 
intravenous dose of 20 mg, 30 minutes prior to paclitaxel injection, only when patients may 
have been non-adherent with oral pre-medication, in the investigator’s opinion. 
 
** Dose to be based on 5-HT3 Antagonist used. 
 
Epinephrine and diphenhydramine for injection should be readily available during the infusion 
for emergency treatment of hypersensitivity reactions. 
 
Dexamethasone + 5-HT3 will not be repeated prior to carboplatin, unless clinically indicated. 
 
Note: Pre-medications can be adjusted/altered to meet local institutional standards. 
 
 
6.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Growth factor: the use of prophylactic growth factors should follow the American Society of 
Clinical Oncology (ASCO) guidelines and is not allowed prior to cycle 1, day 1.  Growth factor 
may be administered after cycle 1 day 1, if patient meets indication per ASCO guidelines.  
Patients may receive red blood cell and platelet transfusions as clinically indicated by the treating 
physician.  Empiric platelet transfusions are recommended for platelet count ≤10,000/mcL. 
 

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Supportive care agents for bone metastases:  Patients with known metastatic disease to the bones 
are allowed to take bisphosphonates or denosumab as directed by the treating physician. 
 
Post-treatment anti-emetic medications:  It is recommended that patients be given take home 
prescriptions for an oral 5- HT3 antagonist (i.e., ondansetron, granisetron) to take as needed for 
nausea or emesis. Aprepitant or fosaprepitant are allowed on study per institutional standards. 
 
For patient who develop an indication to start anticoagulation during study therapy (i.e., a deep 
vein thrombosis (DVT) or pulmonary embolism (PE), anticoagulants including warfarin (with 
PT/INR monitoring), low molecular weight heparin, and factor Xa inhibitors are permitted and 
the patient may stay on trial as long as they personally have not developed grade 3 or worse 
thrombocytopenia or medically significant bleeding at the current dose level that they are 
receiving on trial.  
 
Because there are potential drug-interactions with other concomitantly administered drugs, the 
case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any drug known to affect or with the potential for drug interactions. 
 
Paclitaxel is metabolized by CYP2C8 or CYP3A4.  Use caution when administering with drugs 
that have pharmacokinetic interaction potential with these CYP-enzymes.  Refer to the drug 
package insert for additional information on the potential drug-interactions. 
 
Because the metabolic and excretion pathways of pevonedistat remain to be characterized in 
humans, the risk of DDIs between pevonedistat and concomitantly administered drugs is 
currently informed by available nonclinical and clinical data.  On the basis of preliminary 
findings, administration of pevonedistat with moderate and strong CYP3A inhibitors and P-gp 
inhibitors is permitted. The effect of rifampin, a strong CYP3A inducer, on pevonedistat PK was 
evaluated in Study P1015. The result indicated that co-administration of rifampin did not result 
in clinically meaningful alteration of pevonedistat systemic exposures in the context of 28% of 
inter-individual variability in pevonedistat clearance. CYP3A inducers are no longer included in 
the list of excluded concomitant medications.  The pevonedistat physiological based PK model 
indicates that the systemic exposure of pevonedistat was not sensitive to the perturbations of 
enzyme activity when the hepatic uptake becomes the rate-determining step of its clearance. 
Therefore, BCRP inhibitors are no longer included in the list of excluded concomitant 
medications. The study team should check a frequently-updated medical reference for a complete 
list of drugs to avoid.  Patients will be provided with a Patient Drug Interactions Handout and 
Wallet Card (see Appendix B). 
 
Table 2: Concomitant Medications Excluded During the Study 
Therapy 
Comment/Exceptions 
Clinically significant metabolic enzyme 
inducers (see Appendix B) 
Excluded. 

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Therapy 
Comment/Exceptions 
Any investigational agent other than 
MLN4924 (pevonedistat) 
For example, androgens, supraphysiologic 
doses of corticosteroids, erythropoietin, 
eltrombopag [Promacta], or romiplostim 
[Nplate] are excluded. 
BCRP = breast cancer resistance protein, CYP = cytochrome C450 
 
6.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue beyond 4 
cycles if the patient is deriving clinical benefit until one of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the CRF. 
 
6.4 
Duration of Follow-Up 
 
Patients will be followed for 5 years after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
 
 

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7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 
Dose Modifications for Toxicity 
 
Patients must meet the following treatment parameters on Cycle 1 Day 1: 
 
Parameter 
Day 1 
Day 3, 5 
Absolute Neutrophil Count 
(ANC) 
≥ 1,000/mcL 
≥ 1000/mcL 
Platelet Count 
≥100,000/mcL 
≥75,000/mcL 
Total Bilirubin* 
≤1 x ULN with exception of 
≤1.5 x ULN direct bilirubin 
for patients with Gilbert’s 
syndrome 
≤1 x ULN with exception of 
≤1.5 x ULN direct bilirubin 
for patients with Gilbert’s 
syndrome 
AST (SGOT)/ALT (SGPT)*  
≤ 3.0 x ULN; ≤ 5 x ULN in 
setting of metastatic liver 
disease 
≤ 3.0 x ULN; ≤ 5 x ULN in 
setting of metastatic liver 
disease 
Creatinine 
≤1.5 mg/dL or Cockcroft-
Gault calculated clearance ≥ 
30mL/min 
N/A 
* ALT, AST and bilirubin grading will be determined by CTCAE version 5.0 in times per ULN, 
irrespective of baseline levels. 
 
All other toxicities (except alopecia, lymphopenia, hyperglycemia, hypoalbuminemia, fatigue, 
elevated serum alkaline phosphatase, neuropathy [see section 7.2.1], and hemoglobin [see 
section 7.1.3]) at least possibly related to study treatment should have resolved to grade 1 or 
lesser severity or pre-study baseline before initiation of the next cycle of therapy.  Furthermore, 
dose modifications for white blood cell (WBC) or other components of the differential (such as 
lymphocytes, monocytes) are not planned and therefore, not included in Section 7. 
 
Qualifying laboratory tests can be obtained 24-72 hours before planned initiation of therapy as 
per study calendar (Section 11).  
 
Dose holds and modifications are to made according to the organ system showing the greatest 
degree of toxicity.  Toxicity will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) (version 5.0). 
 
Tables below are general guidance for adverse events.  Treating physicians may use discretion to 
hold or reduce dose for these events with the approval of the PI.  
 
If a toxicity leads to hold on Day 1 of a cycle, the whole cycle is to be delayed until the toxicity 
meets treatment criteria.  If a toxicity leads to a hold of MLN4924 (pevonedistat) (i.e., Day 3 or 
5), the dose will be skipped and the dose modification will be with the next scheduled dose.  
 
Initiation of the next cycle of therapy may be delayed no more than 3 weeks to allow recovery 
from toxicity.  Treatment delay of >3 weeks due to a specific toxicity to all protocol therapy at 

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least possibly related to study drugs will lead to removal of the patient from the study.  If all 
treatment related toxicities do not recover within 3 weeks to the point where patients meet re-
treatment criteria in Section 7.0 above, then patients should be removed from therapy on trial.  If 
MLN4924 (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 MLN4924 (pevonedistat) 
should not be exceeded. 
 
All dose reductions are permanent.  Dose reductions are permitted until MLN4924 
(pevonedistat) dose is 10mg/m2.  If untoward toxicity persists despite dose adjustments or if 
more than 2 dose reductions are required, the patient will be removed from protocol treatment. 
 
Since fatigue is multifactorial and can be a symptom of cancer progression, dose reduction for 
fatigue will only be done if the fatigue is deemed to be drug-related in the opinion of the 
investigator. 
 
Pevonedistat may be continued as monotherapy in the event paclitaxel and carboplatin are 
discontinued. 
 
Dose Modifications for Paclitaxel 
Dose Modification Levels 
Paclitaxel Dose 
Dose level 1# 
175 mg/m2 
Dose level -1 
125 mg/m2 
Dose level -2 
100 mg/m2 
#Starting dose 
 
Dose Modifications for Carboplatin 
Dose Modification Levels 
Carboplatin Dose 
Dose level 1# 
AUC 5 
Dose level -1 
AUC 4 
Dose level -2 
AUC 3 
#Starting dose 
 
Dose modifications for MLN4924 (Pevonedistat) 
Dose Modification Levels 
MLN4924 (Pevonedistat) Dose 
Dose level 1# 
20 mg/m2 
Dose level -1 
15 mg/m2 
Dose level -2 
10 mg/m2 
#Starting dose 
 
7.1.1 Neutrophils 
 
The following dose adjustments are based on the lowest neutrophil count of the preceding 
treatment course. 
 

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Neutropenia** 
Management/Next 
Dose for MLN4924 
(pevonedistat) 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
≤ Grade 1/2 
No change in dose 
No change in dose 
No change in dose 
Grade 3/4 (≤7 days 
and without fever) 
Hold* until ≤ Grade 
2.  Resume at same 
dose level. 
Hold* until ≤ Grade 
2.  Resume at same 
dose level. 
Hold* until ≤ Grade 
2.  Resume at same 
dose level. 
Grade 3/4 (>7 days 
or any duration 
with fever 
 
1st episode Hold* until ≤ Grade 
2.  Resume at same 
dose level. 
Hold* until ≤ Grade 
2.  Resume at same 
dose level. 
Hold* until ≤ Grade 
2.  Resume at same 
dose level. 
2nd episode Hold* until ≤ Grade 
2.  Reduce by 1 dose 
level. * 
Hold* until ≤ Grade 
2.  Reduce by 1 dose 
level. * 
Hold* until ≤ Grade 
2.  Reduce by 1 dose 
level. * 
*Patients requiring a delay of all protocol therapy >3 weeks due to toxicity should go off 
protocol therapy. 
 
**Patients requiring > two dose reduction of chemotherapy should go off protocol therapy.  
Dose reductions are permitted for MLN4924 (pevonedistat) until dose is 10mg/m2.  If a 
toxicity leads to a hold on Day 1 of a cycle, the whole cycle is to be delayed until the toxicity 
meets treatment criteria.  If a toxicity leads to a hold of MLN4924 (pevonedistat) during the 
cycles (i.e., Day 3 or 5), the dose will be skipped and the dose modification will be with the 
next scheduled dose. 
 
NOTE: Use of prophylactic granulocyte colony stimulating factor is permitted per 
investigator discretion. Use of ASCO guidelines is recommended.  
 
7.1.2 Platelets 
 
Thrombocytopenia** Management/Next 
Dose for MLN4924 
(pevonedistat) 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold until ≥100,000.  
Resume at same dose 
level. 
Hold dose until ≤ 
Grade 1.  Resume at 
same dose level. 
Hold until ≥100,000.  
Resume at same dose 
level. 
Grade 3/4 ≤7 days 
and no clinically 
significant bleeding 
and > 10,000 mcL 
Hold* until 
≥100,000.  Resume 
at same dose level. 
Hold* until 
≥100,000.  Resume 
at same dose level.  
Hold* until 
≥100,000.  Resume 
at same dose level.  
Grade 4 lasting >7 
days or requiring 
prophylactic platelet 
 

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transfusion (≤10,000 
mcL) 
1st episode Hold* until 
≥100,000.  Reduce 
by 1 dose level.  
Hold* until 
≥100,000.  Resume 
at same dose level. 
Hold* until 
≥100,000.  Reduce 
by 1 dose level. 
2nd episode Hold* until 
≥100,000.  Reduce 
by 1 dose level.  
Hold* until 
≥100,000.  Reduce 
by 1 dose level. 
Hold* until 
≥100,000.  Reduce 
by 1 dose level.  
Grade 3/4 of any 
duration with 
clinically significant 
bleeding *** 
Off study 
Off study 
Off protocol 
*Patients requiring a delay of all protocol therapy >3 weeks due to toxicity should go off 
protocol therapy. 
 
**Patients requiring > two dose reduction of chemotherapy should go off protocol therapy.  
Dose reductions are permitted for MLN4924 (pevonedistat) until dose is 10mg/m2.  If a 
toxicity leads to a hold on Day 1 of a cycle, the whole cycle is to be delayed until the toxicity 
meets treatment criteria.  If a toxicity leads to a hold of MLN4924 (pevonedistat) during the 
cycles (i.e., Day 3 or 5), the dose will be skipped and the dose modification will be with the 
next scheduled dose. 
 
***Clinically significant bleeding for this protocol is defined as potentially serious or life-
threatening (i.e., GI bleed, intracranial hemorrhage).  Patients with more minor bleeding may 
be continued on study. 
 
7.1.3 Hemoglobin 
 
Patients must have stable hemoglobin for ≥ 2 weeks prior to Cycle 1 Day 1. Supportive 
transfusion is permitted after Cycle 1 Day 1 and future cycles for subjects as clinically indicated 
per treating physician. 
 
7.2 
Dose Modifications for Non-Hematologic Toxicity 
 
Patients must meet the following treatment parameters: 
 
Parameter 
Day 1 
Day 3, 5 
Creatinine 
≤1.5 mg/dL or Cockcroft-
Gault calculated clearance ≥ 
30mL/min  
N/A 
 
 
7.2.1 Peripheral Sensory Neuropathy 
 
The following dose adjustments are based on the worst grade experience of sensory neuropathy 
of any preceding treatment course. 

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Sensory 
Neuropathy** 
Management/Next 
Dose for MLN4924 
(pevonedistat) 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2, tolerable 
and <7 consecutive 
days 
No change in dose 
No change in dose 
No change in dose 
Grade 2, intolerable 
or >7 consecutive 
days 
No change in dose  
Hold* until < Grade 
2.  Resume by 1 dose 
level. 
No change in dose 
Grade 3 
No change in dose 
Discontinue 
paclitaxel# 
Hold* until < Grade 
2.  Reduce by one 
dose level.  
Grade 4 
Off study 
Off study 
Off study 
*Patients requiring a delay of all protocol therapy >3 weeks due to toxicity should go off 
protocol therapy. 
 
**Patients requiring > two dose reduction of chemotherapy should go off protocol therapy.  If 
a toxicity leads to a hold on Day 1 of a cycle, the whole cycle is to be delayed until the toxicity 
meets treatment criteria.  
 
#After 4-6 cycles, paclitaxel may be discontinued per investigator discretion (including for 
neuropathy) and patient may continue on study. 
 
7.2.2 Arthralgia/Myalgia 
 
Use CTCAE bone pain criteria for grading all arthralgias. 
 
Arthralgia/Myalgia** Management/Next 
Dose for MLN4924 
(pevonedistat) 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2# 
No change in dose 
Hold* until < Grade 
2.  Reduce by 1 dose 
level. 
No change in dose 
Grade 3 
No change in dose 
Hold* until < Grade 
2.  Reduce by 1 dose 
level. 
No change in dose 
*Patients requiring a delay of all protocol therapy >3 weeks due to toxicity should go off 
protocol therapy. 
 
**Patients requiring > two dose reduction of chemotherapy should go off protocol therapy.  If 
a toxicity leads to a hold on Day 1 of a cycle, the whole cycle is to be delayed until the toxicity 
meets treatment criteria.  If a toxicity leads to a hold of MLN4924 (pevonedistat) during the 

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cycles (i.e. Day 3 or 5), the dose will be skipped and the dose modification will be with the 
next scheduled dose. 
 
#For the first occurrence of Grade 2 myalgia/arthralgia, dexamethasone can be administered 
for 3-4 days (approximately 4 mg BID) after chemotherapy.  If symptoms recur despite this, 
the next dose of paclitaxel will be reduced by 1 dose level. 
 
7.2.3 Gastrointestinal toxicity 
 
Nausea and/or vomiting should be controlled with adequate antiemetic therapy.  Prophylactic 
anti-emetic therapy can be used at the discretion of the treating physician.  Diarrhea should be  
managed with adequate anti-diarrheal medications.  Patients are encouraged to take plenty of oral 
fluids.  Dose holds and modifications are for symptoms at least possibly related to the study 
therapy and occurring despite maximal medical management. 
 
Nausea** 
Management/Next 
Dose for MLN4924 
(pevonedistat) 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Grade 3 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Hold* until ≤ Grade 
1.  Reduce by 1 dose 
level. 
Hold* until ≤ Grade 
1.  Reduce by 1 dose 
level. 
After optimal anti-emetic therapy.  Use of prophylactic or scheduled antiemetics are 
recommended in future cycles for patients experiencing Grade 2 or higher nausea. 
 
*Patients requiring a delay of all protocol therapy >3 weeks due to toxicity should go off 
protocol therapy. 
 
**Patients requiring > two dose reduction of chemotherapy should go off protocol therapy.  If 
a toxicity leads to a hold on day 1 of a cycle, the whole cycle is to be delayed until the toxicity 
meets treatment criteria. 
 
Vomiting** 
Management/Next 
Dose for MLN4924 
(pevonedistat) 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Grade 3 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Hold* until ≤ Grade 
1.  Reduce by 1 dose 
level. 
Hold* until ≤ Grade 
1.  Reduce by 1 dose 
level. 

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53 
 
Vomiting** 
Management/Next 
Dose for MLN4924 
(pevonedistat) 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
Grade 4 
Hold* until ≤ Grade 
1.  Reduce by 1 dose 
level. 
Hold* until ≤ Grade 
1.  Reduce by 1 dose 
level. 
Hold* until ≤ Grade 
1.  Reduce by 1 dose 
level. 
After optimal anti-emetic therapy.  Use of prophylactic or scheduled antiemetics are 
recommended in future cycles for patients experiencing Grade 2 or higher nausea. 
 
*Patients requiring a delay of all protocol therapy >3 weeks due to toxicity should go off 
protocol therapy. 
 
**Patients requiring > two dose reduction of chemotherapy should go off protocol therapy.  If 
a toxicity leads to a hold on Day 1 of a cycle, the whole cycle is to be delayed until the toxicity 
meets treatment criteria. 
 
Diarrhea** 
Management/Next 
Dose for MLN4924 
(pevonedistat) 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Grade 3 
Hold* until ≤ Grade 
1.  Resume at same 
dose level. 
Hold* until ≤ Grade 
1.  Reduce by 1 dose 
level. 
Hold* until ≤ Grade 
1.  Reduce by 1 dose 
level. 
Grade 4 
Off study 
Off study 
Off study 
After optimal anti-diarrheal therapy.  
 
Recommended management: Loperamide anti-diarrheal therapy. 
Dosage Schedule: 4 mg at first onset, followed by 2 mg with each loose bowel movement until 
diarrhea-free for 12 hours (maximum dosage: 16 mg/24 hours). 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
*Patients requiring a delay of all protocol therapy >3 weeks due to toxicity should go off 
protocol therapy. 
 
**Patients requiring > two dose reduction of chemotherapy should go off protocol therapy. If a 
toxicity leads to a hold on day 1 of a cycle, the whole cycle is to be delayed until the toxicity 
meets treatment criteria. 
 
7.2.4 Hepatic toxicity 
 
There are no dose adjustments for carboplatin based on hepatic toxicity. Dose adjustments are 
for hepatoxicity at least possibly related to MLN4924 (pevonedistat) or paclitaxel. 

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54 
 
 
AST and/or ALT** 
Management/Next Dose for 
MLN4924 (pevonedistat) 
Management/Next Dose for 
Paclitaxel 
Grade 1-2 
No change in dose 
No change in dose 
Grade 3 
 
 
Baseline 2.5-5x ULN and 
result <10x ULN  
 
No change 
No change 
Baseline <2.5x ULN or result 
≥10x ULN. 
Hold* until meeting 
treatment criteria and then 
reduce by 1 dose level 
Hold* until meeting 
treatment criteria and then 
reduce by 1 dose level. 
Grade 4*** 
Off study 
Off study 
Bilirubin** 
Management/Next Dose for  
MLN4924 (pevonedistat) 
Management/Next Dose for 
Paclitaxel 
Grade 1-2 
No change in dose 
No change in dose 
Grade 3  
Hold* until meeting 
treatment criteria and then 
reduce by 1 dose level.  
Hold* until meeting 
treatment criteria and then 
reduce by 1 dose level. 
Grade 4 
Off study 
Off study 
*Patients requiring a delay of all protocol therapy >3 weeks due to toxicity should go off 
protocol therapy. 
 
**Patients requiring >2 dose reductions of chemotherapy should go off protocol therapy.  
Dose reductions are permitted for MLN4924 (pevonedistat) until dose is 10 mg/m2.  If a 
toxicity leads to a hold on Day 1 of a cycle, the whole cycle is to be delayed until the toxicity 
meets treatment criteria.  If a toxicity leads to a hold of MLN4924 (pevonedistat) during the 
cycle (i.e. Day 3 or 5), the dose will be skipped and the dose modification will be with the 
next scheduled dose. 
 
*** Transient high elevations of AST/ALT have been seen in a small percentage of patients in 
early courses of MLN4924 (pevonedistat) dosing.  This has been rapidly reversible and does 
not usually recur. If a grade 4 ALT/AST elevation reverses in 7 days or less, please contact PI 
to discuss whether it may be appropriate to continue on study, if patient is clinically 
benefitting, once treatment criteria met.  
 
7.2.5 Hypersensitivity reaction 
 
Caution:  Patients who had a mild to moderate hypersensitivity reaction to paclitaxel and 
carboplatin have been successfully re-challenged, but careful attention to prophylaxis and 
bedside monitoring of vital signs is recommended.  

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55 
 
 
Hypersensitivity reactions to paclitaxel and/or carboplatin and/or pevonedistat will be managed 
as follows:  
Mild symptoms (e.g., mild flushing, rash, pruritus) – Complete infusion.  Supervise at bedside.  
No treatment required.  
 
Moderate symptoms (e.g., moderate rash, flushing, mild dyspnea, chest discomfort) – Stop 
infusion.  Give intravenous diphenhydramine 25 mg and intravenous dexamethasone 10 mg.  
Resume infusion after recovery of symptoms at a low rate, 20 mg/hr.  For 15 minutes, then, if no 
further symptoms, at full dose rate until infusion is complete.  If symptoms recur, stop infusion.  
The patient should receive no additional paclitaxel and/or carboplatin for that cycle, but may be 
retreated after discussion with the principal investigator. 
 
Severe life-threatening symptoms (e.g., hypotension requiring pressor therapy, angioedema, 
respiratory distress requiring bronchodilation therapy, generalized urticaria) – Stop infusion. 
Give intravenous diphenhydramine and dexamethasone as above.  Add epinephrine or 
bronchodilators if indicated.  If wheezing is present, that is not responsive to bronchodilators, 
epinephrine is recommended.  Patient should be removed from further protocol therapy.  Report 
as adverse event. 
 
7.2.6 Other toxicities 
 
Grade 3 fatigue should be medically managed. If lasting more than 7 days, then all study 
treatment should be held until the fatigue recovers until Grade 1 or less.  The treatment may then 
be resumed at one dose level reduction of MLN4924 (pevonedistat) and/or paclitaxel and 
carboplatin.  If attribution for fatigue is at least possibly related to MLN4924 (pevonedistat), this 
agent alone should be reduced by one dose level.  If attribution for fatigue is unlikely or 
unrelated to MLN4924 (pevonedistat), then the chemotherapy agent(s) with attribution of at least 
possible related should be reduced by one dose level.  
 
Grade 3 or 4 depletion of electrolytes (e.g., K, Mg, Phos) should be optimally medically 
managed.  If these persist for >48 hours despite attempts at repletion, then all study treatment 
should be held until the electrolytes return to Grade 1 or less.  The treatment may then be 
resumed at one dose level reduction of MLN4924 (pevonedistat), paclitaxel and/or carboplatin, if 
attribution at least possibly related to drug.  
 
For any grade 3 or 4 toxicity, not mentioned above, the treatment with the likely inciting agent 
should be withheld until the patient recovers to Grade 1 or less toxicity.  The treatment may then 
be resumed at one dose level reduction.  For intolerable Grade 2 toxicities, withhold treatment 
until the patient recovers, then resume treatment at a one dose level reduction.  Dose reduction 
will be done for the drug that is most likely to have caused the toxicity.  For Grade 1 or tolerable 
Grade 2 toxicities or clinically insignificant laboratory changes, no dose reduction should be 
made. 
 
 

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56 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agent 
 
MLN4924 (pevonedistat) (NSC #793435) 
 
Chemical Name:  ((1S,2S,4R)-4-{(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d] 
pyrimidin-7-yl}-2-hydroxycyclopentyl) methyl sulfamate hydrochloride 
 
Classification:  NAE inhibitor 
 
Other Names:  TAK924/MLN4924; MLN4924-003 (hydrochloride salt); MLN4924-001 (free 
base); ML00644807; ML644507 
 
CAS Registry Number:  905579-51-3 (free base); 1160295-21-5 (hydrochloride salt) 
 
Molecular Formula:  C21H26CIN5O4S 
 
M.W.:  443.52 (free base); 479.98 (hydrochloride salt) 
 
Mode of Action:  MLN4924 (pevonedistat) is an inhibitor of NEDD8-activating enzyme, or 
NAE.  NAE is essential in the NEDD8-conjugation pathway to control the activity of a subset of 
multiprotein complexes that transfer NEDD8 molecules to protein substrates by E3 ligases.  
NAE inhibitors stop the degradations of a subset of proteins that regulated by the proteasomes. 
 
Description:  White to off-white solid with an assay value of 96.0% to 103.0% (w/w) on an 
anhydrous basis.  Acid dissociation constants of pKa1= 5.16 and = 8.81. 
 
How Supplied:  Takeda supplies and PMB distributes MLN4924 (Pevonedistat HCl) formulated as 
10 mg/mL Concentrate for Solution for Infusion. Each single-use vial contains either 50 mg (5 mL) 
or 44 mg (4.4 mL) free base equivalent                                                                                                              
.                                                                                                                                                   The 
sterile solution is packaged in USP Type I glass vials with rubber stoppers (latex free), aluminum 
seals with plastic caps.  
 
The current supply is 50 mg (5 mL) with 0.3 mL overfill volume. At a future date, the 44 mg (4.4 
mL) vial configuration will replace the 50 mg (5 mL) vial configuration. The 44 mg (4.4 mL) vial 
contains 0.3 mL overfill volume. 
 
Preparation: Before use, bring MLN4924 (Pevonedistat HCl) vials to ambient room 
temperature (15⁰ – 30⁰ C / 59⁰ – 86⁰ F) for 15 minutes. Do not use a water bath to warm up the 
vials. Return vials to 2⁰ – 8⁰ C (36⁰ – 46⁰ F) storage if not used within 6 hours.  
 

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57 
 
− 
Use a 250 mL prefilled 5% Dextrose (D5W) or 0.9% Normal Saline (NS) IV bag:  
o 
Remove excess volume from 250 mL D5W or NS prefilled IV bag  
o 
Add the calculated dose (mL) of pevonedistat  
o 
Final volume (250 mL) = drug + D5W or NS  
o 
Do not shake; gently mix the IV solution by inverting the IV bag several times  
o 
Inspect the IV solution to ensure it is clear and free of visible particles  
 
− 
Alternatively, a 250 mL empty IV bag can be used:  
o 
Add the required volume of D5W or NS into the empty IV bag  
o 
Add the calculated dose (mL) of pevonedistat  
o 
Final volume (250 mL) = Drug + D5W or NS  
o 
Do not shake; gently mix the IV solution by inverting the IV bag several times  
o 
Inspect the IV solution to ensure it is clear and free of visible particles  
 
Compatibility: PVC or Polyolefin bags; non-DEHP IV bag is preferred but not required; BP 
Phaseal closed system transfer device, Spiros closed system transfer device. 
 
Storage: Store MLN4924 (Pevonedistat HCl) refrigerated at 2⁰ – 8⁰ C (36⁰ – 46⁰ F) in its original 
carton to protect from light.  
 
If a storage temperature excursion is identified, promptly return MLN4924 (Pevonedistat HCl) 
to 2⁰ – 8⁰ C (36⁰ – 46⁰ F) and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:   Stability studies of the intact vials are ongoing. 
 
o Once MLN4924 (Pevonedistat) prepared IV solution is complete, the prepared IV 
solution must be used within 6 hours when stored at ambient room temperature. 
Discard the IV bag if it cannot be used within 6 hours.  
o Alternatively, the prepared IV solution is stable up to 18 hours when stored at 2⁰ - 8⁰ 
C (36⁰ – 46⁰ F), after which the IV bag can be used within 3 hours upon removal from          
2⁰ - 8⁰ C storage.  The prepared IV solution must be brought up to ambient room 
temperature before administering to patient.  If cannot used within 3 hours, the 
prepared IV solution must be discarded. 
 
Route of Administration:  Intravenous 
 
Method of Administration:  Infuse over 60 minutes (+/- 10 minutes) through central or 
peripheral venous access.  The IV infusion can be slowed or stopped and restarted for any 
associated infusion-related reactions.  The total time from the IV preparation to end of IV 
infusion must not exceed 6 hours.  Infusion line can be flushed with normal saline or 5% 
dextrose in water immediately after IV administration is complete. Protecting IV bag from light 
during IV infusion is not required. 
 
Potential Drug Interactions: In vitro, pevonedistat is metabolized mainly by hepatic CYP3A4/5 

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58 
 
and to some extent by CYP2D6 (3%). CYP1A1 and 2J2 appear to be involved in extrahepatic 
metabolism, which may explain the lack of drug-drug interaction with CY3A4/5 inhibitors.  This was 
demonstrated in an in vivo PK study where a moderate CYP3A inhibitor (e.g., fluconazole) and a 
strong CYP3A4 inhibitor (e.g., itraconazole, which is also a strong P-gp inhibitor) did not result in 
interactions when administered with pevonedistat.  
 
The geometric mean AUC from time 0 to infinity of pevonedistat in the presence of rifampin was 
79% of that in the absence of rifampin (90% CI: 69.2%, 90.2%). The result indicated that co-
administration of rifampin did not result in clinically meaningful alteration of pevonedistat 
systemic exposures in the context of 28% of inter-individual variability in pevonedistat 
clearance. Based on that, its exposure is unlikely to be affected by concomitant administration of 
CYP3A4 inducers. 
 
In vitro, pevonedistat is not an inhibitor of CYP1A2, 2C9, 2C19, 2D6, or 3A4/5 (IC50 > 100 µM and 
Ki >50 μM) but is a weak inhibitor of CYP2B6 and 2C8 (IC50 = 97.6 and 23.1 μM, respectively). 
Pevonedistat causes concentration-dependent decreases in CYP1A2, 2B6, and 3A4/5 mRNA 
expression and/or activities but is not expected to affect the PK of CYP1A2, 2B6 or 3A4/5 substrates.  
 
Pevonedistat is a substrate of P-gp and BCRP, and a weak inhibitor of P-gp, OATP and BCRP-
mediated transport. Pevonedistat is unlikely to affect the PK of known P-gp, BCRP or OATP 
substrates. The pevonedistat PBPK model indicates that the systemic exposure of pevonedistat 
was not sensitive to the perturbations of enzyme activity when the hepatic uptake becomes the 
rate-determining step of its clearance. Considering the minimum effect on P-gp inhibition and 
hepatic uptake being the rate-determining step of pevonedistat clearance, the effect of BCRP 
inhibition is not expected to be clinically meaningful. 
 
Because the metabolic and excretion pathways of pevonedistat remain to be fully characterized 
in humans, the risk of drug-drug interactions between pevonedistat and concomitantly 
administered drugs are currently informed by available nonclinical and clinical data. As a general 
precaution, patients receiving concomitant medications, particularly those with narrow 
therapeutic indices, should be carefully monitored. 
 
Availability:  MLN4924 (pevonedistat) is an investigational agent supplied to investigators by 
DCTD, NCI.  MLN4924 (pevonedistat) is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.3). 
 
8.1.1 Agent Ordering and Agent Accountability 
 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 

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59 
 
 
Confirmation of patient enrollment onto study is required for initial supply.  Submit agent 
requests through the PMB Online Agent Order Processing (OAOP) application.  Access to 
OAOP requires the establishment of a CTEP IAM account and the maintenance of an “active” 
account status, a “current” password, and active person registration status.  For questions about 
drug orders, transfers, returns, or accountability, call or email PMB any time.  Refer to the 
PMB’s website for specific policies and guidelines related to agent management. 
 
8.1.1.1 
Agent Inventory Records 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
8.1.2 Investigator Brochure Availability  
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.3 Useful links and contacts 
 
• CTEP Forms, Templates, Documents:  https://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: https://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB OAOP application:  https://ctepcore.nci.nih.gov/OAOP 
• CTEP IAM account:  https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service:  (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) 
 
8.2 
Commercial Agents 
 
8.2.1 Carboplatin 
 
Molecular Formula:  C6H12N2O4Pt 
 
M.W.:  371.25 
 
Description:  Crystalline powder 

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60 
 
 
How Supplied:  Carboplatin for injection is supplied as a sterile pyrogen-free powder in 10 
mg/mL aqueous solution in multi-dose vials.  Each vial contains 10 mg of carboplatin and water 
for injection.  Carboplatin is commercially available from commercial sources. 
 
Storage:  Store un-reconstituted vials at 20-25 °C (68-77 °F) protected from light. 
 
Preparation:  Reconstitute with sterile water.  Consult a carboplatin package insert for detailed 
formulation and storage instructions. 
 
Administration:  IV infusion over 15-60 minutes. 
 
Agent Ordering:  Carboplatin is commercially available. 
 
For more detailed information, please consult a carboplatin package insert (Carboplatin Package 
Insert, 2011). 
 
8.2.2 Paclitaxel 
 
Molecular Formula:  C47H51NO14 
 
M.W.:  853.9 
 
Description:  White to off-white crystalline powder. 
 
How Supplied:  Paclitaxel for injection is supplied as 6.0mg/mL aqueous solution in multi-dose 
vials.  Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg purified 
Cremophor® EL (polyoxyethylated castor oil), and 49.7% (v/v) dehydrated alcohol.  Paclitaxel is 
commercially available from commercial sources. 
 
Storage:  Store un-reconstituted vials at 20-25 °C (68-77 °F) protected from light. 
 
Preparation:  Consult a paclitaxel package insert for detailed formulation and storage 
instructions. 
 
Administration:  IV infusion over 3 hours.  
 
Agent Ordering:  Paclitaxel is commercially available. 
 
For more detailed information, please consult a paclitaxel package insert (Taxol Package Insert, 
2011). 
 
 
 
 

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61 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
This is a single arm, two-stage study design with one interim analysis that will be used to 
evaluate the efficacy of the proposed MLN4924 (pevonedistat) /carboplatin/paclitaxel 
combination.  The primary efficacy endpoint is the ORR.  An ORR of 10% or less will be 
considered unacceptably low for this patient population.  It is hypothesized that MLN4924 
(pevonedistat) in combination with carboplatin and paclitaxel will result in an ORR of at least 
30%.  A two-stage Minimax design will be used to evaluate the ORR.  In the first stage, 16 
evaluable patients will be enrolled.  If less than two patients have a response, then accrual will be 
terminated due to lack of efficacy.  Otherwise, an additional evaluable 9 patients will be accrued 
for a total of 25 evaluable patients.  This will test the null hypothesis that the ORR is 10% versus 
the alternative hypothesis that the rate is at least 30%.  Assuming that the number of patients 
with an overall response is binomially distributed, this two-stage design has a significance of 
10% and 90% power for detecting a response rate of 30%. 
 
9.1.1 Definition of Primary Endpoint 
 
The primary efficacy endpoint is ORR, which is defined as the proportion of evaluable subjects 
with a response.  Response will be evaluated in this study using the new international criteria 
proposed by the revised RECIST guideline (Version 1.1).  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria.  Patients will be re-evaluated for 
response every 6 weeks.  The number and frequencies of responses will be summarized in 
tabular format.  The ORR will be calculated and reported along with the corresponding 95% 
confidence interval which will be constructed using the Wilson score method.  
 
9.1.2 Definition of Secondary Endpoints 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.  If a patient does not experience a progression or death event, then PFS 
will be censored as the last available disease assessment date.  OS is defined as the duration of 
time from start of treatment to time of death.  The overall survival time of patients still alive at 
the last follow-up assessment date will be censored.  Toxicities and AEs will be evaluated by 
type and severity using the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0.  
 
9.2 
Sample Size/Accrual Rate 
 
It is anticipated that the accrual of 25 patients will be completed within 18 months. 
 

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62 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
1 
1 
0 
0 
2 
White 
11 
12 
0 
0 
23 
More Than One Race 
0 
0 
0 
0 
0 
Total 
12 
13 
0 
0 
25 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
9.3 
Stratification Factors 
 
N/A 
 
9.4 
Analysis of Secondary and Exploratory Endpoints 
 
9.4.1 Analysis of Secondary Endpoints 
 
PFS and OS will be analyzed using the Kaplan-Meier method.  Median PFS and OS will be 
calculated along with the corresponding 95% confidence interval which will be constructed using 
the non-parametric Brookmeyer-Crowley method.  All toxicities observed will be summarized in 
terms of types and severity.  Toxicities will be tabulated and summarized by organ systems.  
Incidence rates of toxicities will be analyzed descriptively. 
 
9.4.2 Analysis of Correlative Endpoints 
 
NQO1 and SCL7A11 expression levels will be summarized using standard descriptive statistics.  
Ratios of the Day 1 pre-treatment over the 6 hours post-infusion levels will be calculated and 
reported along with the corresponding 95% confidence intervals.  A one sample t-test or 
Wilcoxon Signed Rank test will be used to evaluate changes from the Day 1 pre-treatment to the 

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63 
 
6 hourspost-infusion assessment.  A two-sample t-test or nonparametric Wilcoxon Rank Sum test 
will be used to compared changes in NQO1 and SLC7A11 expression levels from Day 1 pre-
treatment to 6 hours post-infusion between responders and non-responders.  Qualitative 
assessment of tumor NAE1 and UBC12 expression will be conducted by evaluating descriptive 
summaries of NAE1 and UBC12 expression levels.  A linear mixed effects model with patient –
specific random effects will be utilized to compared changes in γH2AX and RAD51 in CTCs at 
baseline and after treatment with MLN4924 (pevonedistat).  ATF3, B2M, GCLM, GSR, MAG1, 
RPLP0, SRXN1, TXNRD1, and UBC expression levels will be summarized in terms of means, 
standard deviations, and ranges, stratified by assessment time point (pre-treatment and 6 hours 
post-infusion on Cycle 1, Day 1).  Changes from the pre-treatment to post-infusion assessment 
will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test. 
 
PK parameters will be summarized in terms of means, standard deviations, medians, and ranges, 
stratified by assessment time point.  Changes in PK parameters between assessment time points 
will be evaluated using a paired t-test. 
 
9.5 
Reporting and Exclusions 
 
9.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with MLN4924 
(pevonedistat). 
 
9.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ultimately deemed to be ineligible (identified 
after start of protocol therapy).  Each patient will be assigned one of the following categories:  1) 
complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death 
from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data).  [Note:  By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided.  

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10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
NOTE:  Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.  
 
10.1.1 CAEPR for MLN4924 (pevonedistat) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MLN4924 (Pevonedistat HCl, NSC 793435) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer to 
the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguideli
nes.pdf for further clarification. Frequency is provided based on 474 patients. 
Below is the CAEPR for MLN4924 (Pevonedistat HCl). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade 
noted in parentheses next to the AE in the SPEER. If this CAEPR is part 
of a combination protocol using multiple investigational agents and has 
an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 

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65 
 
 
 
Version 2.3, July 10, 20201 
 
 Adverse Events with Possible  
 Relationship to MLN4924 (Pevonedistat HCl) 
 (CTCAE 5.0 Term) 
[n= 474] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Sinus tachycardia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
Fever 
 
 
 Fever (Gr 2) 
 
Pain 
 
 Pain (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Lung infection 
 
 Lung infection (Gr 2) 
 
Upper respiratory infection 
 
  
 
Urinary tract infection 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
 Bruising (Gr 2) 
INVESTIGATIONS 
  
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase 
increased (Gr 2) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Creatinine increased 
 
  
 
GGT increased 
 
  
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
 
Hypercalcemia 
 
  
 
Hyperglycemia 
 
  
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
 Hypokalemia (Gr 2) 

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66 
 
 
 Adverse Events with Possible  
 Relationship to MLN4924 (Pevonedistat HCl) 
 (CTCAE 5.0 Term) 
[n= 474] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
  
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
Myalgia 
 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
Nervous system disorders - 
Other (neuropathy peripheral, 
peripheral neuropathy) 
 
  
 
Paresthesia 
 
  
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Confusion 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
  
 
Hypoxia 
 
  
 
Pleural effusion 
 
  
 
Productive cough 
 
  
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(rales) 
 
  
 
Wheezing 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
Pruritus 
 
  
 
Purpura 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
 Hypotension (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
 
 

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67 
 
 
Adverse events reported on MLN4924 (Pevonedistat HCl) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that MLN4924 
(Pevonedistat HCl) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocarditis 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Ascites; Dyspepsia; Gastrointestinal disorders - Other 
(gastrointestinal necrosis); Gastrointestinal disorders - Other (gastrointestinal hemorrhage); Ileus; Small 
intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Generalized edema; Multi-organ 
failure; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Bacteremia; Sepsis; Sinusitis; Skin infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall 
INVESTIGATIONS - Investigations - Other (brain natriuretic peptide increased); Neutrophil count 
decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hyperuricemia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Spinal cord compression 
PSYCHIATRIC DISORDERS - Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Dysuria; Renal and urinary disorders - Other (renal impairment); 
Urinary retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Nasal congestion; Oropharyngeal pain; Respiratory failure; Rhinorrhea 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Rash maculo-papular 
VASCULAR DISORDERS - Hypertension; Phlebitis; Thromboembolic event 
 
 
Note: MLN4924 (Pevonedistat HCl) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
10.1.2 Adverse Event List for Carboplatin 
 
The most common adverse reactions for carboplatin are included below.  See a carboplatin 
package insert for more information. 
 
Myelosuppression, nausea, vomiting, diarrhea, weight loss, constipation, gastrointestinal pain, 
electrolyte imbalances, hypomagnesemia, hypocalcemia, hyponatremia, hyperuremia elevated 
alkaline phosphatase, AST, and total bilirubin,  
peripheral neuropathies (mild paresthesias, clinical ototoxicity and other sensory abnormalities 
are rare),  
renal tubular damage, renal insufficiency, impotence, sterility, amenorrhea, gynecomastia 
anaphylactoid and urticarial reactions (acute), flushing, rash, pruritis and rarely hypotension or 
bronchospasm,  
alopecia, pain, asthenia and mucosal side effects, decreased serum electrolytes values (sodium, 
magnesium, calcium and potassium). 

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68 
 
 
 
 
10.1.3 Adverse Event List for Paclitaxel 
 
The most common adverse reactions for paclitaxel are included below.  See a taxol package 
insert for more information. 
 
Myelosuppression, nausea and vomiting, diarrhea, stomatitis, mucositis,  
arrhythmia, heart block, ventricular tachycardia, hypotension, myocardial infarction (MI), 
peripheral neuropathy, seizures, 
anaphylactoid and urticarial reactions (acute), flushing, rash, pruritus,  
alopecia, malaise, arthralgia, myalgia, elevated AST, alkaline phosphatase and bilirubin.  
Note: Cardiac toxicities are rare and continuous cardiac monitoring is not required except for 
patients with serious conduction abnormalities or other underlying, serious cardiac risk factors. 
 
10.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 RAVE-CTEP-AERS Integration 
 
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting.    
 

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69 
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to 
collect AEs that start during the period or persist from the previous reporting period.  The 
Clinical Research Associate (CRA) will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS integration.  
AEs that occur prior to enrollment must begin and end on the baseline Adverse Event 
form and should not be included on the standard Adverse Events form that is available at 
treatment unless there has been an increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free 
(fields added to the form during study build do not need to be query-free for the 
integration call with CTEP-AERS to be a success). 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the deep link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
• Study specific documents:  Protocols > Documents > Education and Promotion, 
and   
• Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU 
Operations Information > User Guides. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 

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70 
 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 

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71 
 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 

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72 
 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
MDS  
Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 

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73 
 
11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week (7 days) prior to start of protocol therapy.  Scans, x-rays, and ECHO/MUGA 
must be done <4 weeks (28 days) prior to the start of therapy. In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 72 hours prior to initiation of the next cycle of therapy. 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
 
 
 
 
Pre-study 
Day 
1 
Day 
3 
Day 
5 
Day  
8 
Day  
15 
Day 
1 
Day 
3 
Day 
5 
Day 
1 
Day 
3 
Day 
5 
Day 
1 
Day 
3 
Day 
5 
At disease 
progression 
4 weeks 
after last 
dose of 
study drugD 
Long term 
follow-up 
off study 
treatmentE 
MLN4924 
(pevonedistat)A 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
CarboplatinB 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
PaclitaxelC 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interval historyG 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Concurrent meds 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Physical examG 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital signsG 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WeightG 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Performance statusG 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
CBC w/differential and 
platelets 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Coagulation panelH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry panelI, J 
XI 
XJ 
XJ 
XJ 
XJ 
XJ 
XI 
XJ 
XJ 
XI 
XJ 
XJ 
XI 
XJ 
XJ 
XI 
 
 
Pregnancy testK 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
LVEF assessment by 
echocardiogram or 
radionuclide angiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKGQ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Adverse event evaluation 
X--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
Tumor measurements 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
ImagingL 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 

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74 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
 
 
 
 
Pre-study 
Day 
1 
Day 
3 
Day 
5 
Day  
8 
Day  
15 
Day 
1 
Day 
3 
Day 
5 
Day 
1 
Day 
3 
Day 
5 
Day 
1 
Day 
3 
Day 
5 
At disease 
progression 
4 weeks 
after last 
dose of 
study drugD 
Long term 
follow-up 
off study 
treatmentE 
Archival tissue 
collectionM 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UrinalysisN 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw - PK 
analysisP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw - CTCs 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Blood draw – NAE, 
NQO1, SCL7A11O 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
A: MLN4924 (pevonedistat):  20 mg/m2 over 60 minutes IV Days 1,3, and 5 of each cycle. Day 1 should be administered on Monday. Sites with the ability to administer Day 5 on Saturday may start Day 1 
on Tuesday. 
B: Carboplatin:  AUC 5 IV on day 1 of each cycle 
C: Paclitaxel:  175mg/m2 IV on day 1 of each cycle 
D: A safety follow-up visit will occur 30 days (±7 days) after the last dose of treatment. 
E: Subjects without documented disease progression will be followed for every 3 months for 1 year, then every 6 months until 5 years from end of treatment or until death. Once disease progression is 
documented, subjects will be followed every 3 months for 1 year, then every 6 months until 5 years from the time of documented progression or death. 
F: Medical history to include prior treatments, radiation and surgical history, and smoking history. Diagnosis and staging to include pathology report and Tumor Node Metastasis (TNM) staging 8th edition. 
G: At subsequent visits, symptom-directed history and physical examinations including vital signs, weight and performance status should be performed.  Vital signs include diastolic and systolic blood 
pressure, heart rate, and body temperature.  Vital sign measurements will be taken with the patient in the supine or sitting position. 
H: To include PT and PTT 
I: 
Complete chemistry panel will include BUN, creatinine, sodium, potassium, chloride, carbon dioxide, glucose, urate, total bilirubin, direct bilirubin, ALP, LDH, AST, ALT, albumin, magnesium, 
phosphate, and calcium.  ALP, ALT, AST, and total bilirubin assessments must be performed and reviewed by the treating physician prior to each infusion of MLN4924 (pevonedistat).   
J:    Select chemistry panel to be completed on D1, 3, 5, 8, 15, of Cycle 1 and D3+5 of Cycles 2 and beyond will include BUN, creatinine, phosphate, total bilirubin, albumin, ALP, AST, and ALT.  ALP, ALT, 
AST, and total bilirubin assessments must be performed and reviewed by the treating physician prior to each infusion of MLN4924 (pevonedistat). 
K: Serum or urine pregnancy test (women of childbearing potential only) will be performed at least seven days before beginning study therapy.  A negative serum or urine pregnancy test is also required at the 
beginning of each treatment cycle. 
L: CT or MRI scans of chest, abdomen, and pelvis will be done at baseline to assess the response per RECIST v1.1 criteria.  CTs or MRIs with IV contrast are encouraged but will be done at the 
investigator’s discretion.  CT imaging of chest, abdomen, and pelvis should occur after every 6 weeks (±7 days).  If the pelvis CT scans are negative at baseline, they should be repeated as clinically 
indicated, however CT imaging of the chest and abdomen should occur every 6 weeks (±7 days). 
M:  Archival tissue collection is optional.  
N:  Urinalysis will be required at pre-study evaluation for all patients and then as clinically indicated.   Urinalysis with microscopic analysis must be performed at screening.  Urinalysis will include 
assessments of turbidity and color, pH, specific gravity, protein, ketones, bilirubin, occult blood, nitrite, glucose, and leukocyte esterase.  Urine microscopic analysis will include erythrocytes, leukocytes, 
bacteria casts, and crystals. 
O:  To be done on Cycle 1 Day 1 pre-treatment and 6h post-treatment with MLN4924 (pevonedistat). 
P:  To be collected on Cycle 1 Day 1 pre-infusion, immediately post infusion, and 3 hours ±5 minutes, 12 hours ±2 hours (optional), 24 hours ±2 hours, and 48 hours ±2 hours post-infusion 
Q: To be performed pre-study, disease progression, end of treatment, and whenever medically necessary. 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CBC=complete blood count, CT=computed tomography, CTC = circulating tumor cells, EKG=electrocardiogram, 
GGT=γ-glutamyl transferase, IV=intravenous, MRI=magnetic resonance imaging, NAE1 = neural precursor cell expressed developmentally downregulated protein 8 (NEDD-8) activating enzyme, 
PBMC=peripheral blood mononuclear cell, PK = pharmacokinetics,  PO=orally, PT= prothrombin time, PTT=partial thromboplastin time, TSH=thyroid stimulating hormone. 
 
Scheduled assessments every week are allowed a window of ±[3] days for Day 1 and ±[1] day for Days 3 and 5. A minimum of 1 full 

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calendar day between any 2 doses should be maintained   This window should be calculated from the scheduled date of the 
procedure/assessment. If scheduled dosing and study assessments are precluded because of a holiday, weekend, or other event, then 
dosing may be postponed to the soonest following date, with subsequent dosing continuing on a 21-day schedule. 

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12. MEASUREMENT OF EFFECT 
 
12.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised RECIST guideline (Version 1.1).  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with MLN4924 (pevonedistat). 
 
Evaluable for objective response.  All patients who start the study treatment will be used in the 
primary calculation of the response rate. These patients will have their response classified 
according to the definitions stated below. 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
12.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 

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short axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 

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Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, Computerized Tomography (CT) is 
preferable.  
 
Conventional CT and Magnetic Resonance Imaging (MRI)  This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
(0.5 cm) or less.  If CT scans have slice thickness greater than 5 mm (0.5 cm), the minimum size 
for a measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
Positron Emission Tomography (PET)-CT  At present, the low dose or attenuation correction CT 
portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the 
CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  Note, 
however, that the PET portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 

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clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial responses 
(PR) and CR in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
Fluorodeoxyglucose (FDG)-PET  While FDG-PET response assessments need additional study, 
it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible 'new' disease).  New lesions on the 
basis of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
progressive disease (PD) based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 

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Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or PI). 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
 
 

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For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 

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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
12.2 
Other Response Parameters 
 
Overall survival (OS) will be defined as time from study therapy initiation to death.  Subjects 
who are still alive will be censored at the last follow-up. 
 
 
 
 

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13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s). At a minimum, a monthly conference 
call with participating sites will be conducted. 
 
During the Phase 2 portion of this study, the Protocol Principal Investigator and statistician have 
access to the data at all times through the CTMS web-based reporting portal.   
 
The Protocol PI will have, at a minimum, quarterly conference calls with the Study Investigators 
and the CTEP Medical Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions 
to proceed to the second stage of a Phase 2 trial will require sign-off by the Protocol Principal 
Investigator and the Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  To access Rave via iMedidata: 
 
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site:  Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 

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o To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.  
 
13.2.1 Method 
 
For studies assigned for CTMS Routine Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 619-7862 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 

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that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D) and a description of any DLTs.  CTMS will utilize a core set of eCRFs that 
are Cancer Data Standards Registry and Repository (caDSR) compliant 
(http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 
unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
13.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 

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The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports.  Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note:  Some Rave protocols may not have delinquent form details or reports specified on 
the DQP.  A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP.  Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.  
 
13.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 

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proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
Email :  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 

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14. REFERENCES 
 
American Cancer Society.  (2017).  Cancer Facts & Figures 2017.  Atlanta: American Cancer 
Society. 
 
 
Bauer, T.M., D.R. Harvey, C.B. Lee, et al.  (2016).  Investigational NEDD8-activating enzyme 
inhibitor pevonedistat plus chemotherapy in patients with solid tumors (phase 1b study):  
Activity of pevonedistat plus carboplatin/paclitaxel.  J Clin Oncol.  34:2580. 
 
Bhatia, S., A.C. Pavlick, P. Boasberg, et al.  (2016).  A phase I study of the investigational 
NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with 
metastatic melanoma.  Invest New Drugs.  34:439-449. 
 
Bouck, D.C., K. Garcia, J.L. Blank, et al.  (2015).  Nedd8-activating enzyme inhibitor 
pevonedistat synergizes with cisplatin and carboplatin through interference with nucleotide 
excision repair and interstrand cross-link repair mechanisms in non-small cell lung cancer.  Mol 
Cancer Ther.  14:C55. 
 
Carboplatin Package Insert.  (2011).  Carboplatin Injection.  Teva Pharmaceutical Industries, 
Petah Tikva, Israel. 
 
Cheng, F., R. He, L. Zhang, et al.  (2014).  Expression of neddylation-related proteins in 
melanoma cell lines and the effect of neddylation on melanoma proliferation.  Oncol Lett.  
7:1645-1650. 
 
Esseltine, D.L. and G. Mulligan.  (2012).  An historic perspective of proteasome inhibition. 
Semin Hematol.  49:196-206. 
 
Ettinger, D.S., D. L. Aisner, D.E. Wood, et al.  (2018).  NCCN Guidelines Insights: Non-Small 
Cell Lung Cancer, Version 5.2018.  J Natl Compr Canc Netw.  16:807-821. 
 
Gandhi, L., D. Rodríguez-Abreu, S. Gadgeel, et al.  (2018).  Pembrolizumab plus Chemotherapy 
in Metastatic Non-Small-Cell Lung Cancer.  N Engl J Med.  378:2078-2092. 
 
Ganguly, A., H. Yang, and F. Cabral.  (2010).  Paclitaxel-dependent cell lines reveal a novel 
drug activity.  Mol Cancer Ther.  9:2914-2923. 
 
Gao, Q, G.Y. Yu, J.Y. Shi, et al.  (2014).  Neddylation pathway is up-regulated in human 
intrahepatic cholangiocarcinoma and serves as a potential therapeutic target.  Oncotarget.  
5:7820-7832.  
 
Garon, E.B., T.E. Ciuleanu, O. Arrieta, et al.  (2014).  Ramucirumab plus docetaxel versus 
placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after 
disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, 
randomised phase 3 trial.  Lancet.  384:665-673. 

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Gettinger, S., L. Horn, D. Jackman, et al.  (2018).  Five-Year Follow-Up of Nivolumab in 
Previously Treated Advanced Non-Small-Cell Lung Cancer: Results From the CA209-003 
Study.  J Clin Oncol.  36:1675-1684. 
 
 
Harvey, R.D., W.S. Rubinstein, G. Ison  (2019).  Impact of broadening clinical trial eligibility 
criteria for advanced non-small cell lung cancer patients: Real-world analysis.  J Clin Oncol.  
37:suppl; abstr LBA108. 
 
Hellmann, M.D., B.T. Li, J.E. Chaft, et al.  (2016).  Chemotherapy remains an essential element 
of personalized care for persons with lung cancer.  Ann Oncol.  27:1829-1835. 
 
Hermann, G., P. Heffeter, T. Falta, et al.  (2013).  In vitro studies focusing on kinetic aspects of 
intracellular chemistry by LC-ICP-MS.  Metallomics.  5:636-647. 
 
Investigator’s Brochure, Pevonedistat (TAK-924/MLN4924).  (2018).  Edition 10.  Millennium 
Pharmaceuticals, Inc., Cambridge, MA. 
 
Ji, C.H. and Y.T. Kwon.  (2017).  Crosstalk and interplay between the ubiquitin-proteasome 
system and autophagy.  Mol Cells.  40:441-449. 
 
Kee, Y., M. Huang, S. Chang, et al.  (2012).  Inhibition of the NEdd8 system sensitizes cells to 
DNA interstrand cross-linking agents.  Mol Cancer Res.  10:369-377. 
 
Kee, Y. and A.D. D’Andrea.  (2010).  Expanded roles of the Fanconi anemia pathway in 
preserving genomic stability.  Genes Dev.  24:1680-1694 
 
Li, L., M. Wang, G. Yu, et al.  (2014).  Overactivated neddylation pathway as a therapeutic 
target in lung cancer.  J Natl Cancer Inst.  106:dju083. 
 
Lin, J.J., M.A. Milhollen, P.G. Smith, et al.  (2010).  NEDD8-targeting drug MLN4942 elicits 
DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, 
and senescence in cancer cells.  Cancer Res.  70:10310-10320. 
 
Lockhart, C.A., T.M. Bauer, D. Harvey, et al.  (2015).  Phase 1b trial of investigational NEDD8-
activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in combination with 
docetaxel, paclitaxel/carboplatin, or gemcitabine in patients with solid tumors.  Mol Cancer 
Ther.  14:B26. 
 
Lockhart, C.A., T.M. Bauer, C. Aggarwal, et al.  (2018).  Phase 1b study of pevonedistat, a 
NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, 
or gemcitabine, in patients with solid tumors.  Invest New Drugs.  21: [epub ahead of print].  
 
Milhollen, M.A., U. Narayanan, T.A. Soucy, et al.  (2011).  Inhibition of NEDD8-activating 
enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating 

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CDT1 turnover.  Cancer Res.  71:3042-3051. 
 
Monsarrat, B., E. Chatelut, I. Royer, et al.  (1998).  Modification of paclitaxel metabolism in a 
cancer patient by induction of cytochrome P450.  Drug Metab Dispos.  26:229-233. 
 
Paz-Ares, L., A. Luft, D. Vincente, et al.  (2018).  Pembrolizumab plus Chemotherapy for 
Squamous Non-Small-Cell Lung Cancer.  N Engl J Med.  379:2040-2051. 
 
Podust, V.N., J.E. Brownell, T.B. Gladysheva, et al.  (2000).  A Nedd8 conjugation pathway is 
essential for proteolytic targeting of p27(Kip1) by ubiquitination.  Proc Natl Acad Sci U.S.A.  
97:4579-4584. 
 
Read, M.A., J.E. Brownell, T.B. Gladysheva, et al.  (2000).  Nedd8 modification of cul-1 
activates SCF(beta(TrCP))-dependent ubiquitination of IκBα.  Mol Cell Biol.  20:2326-2333. 
 
Reck, M., D. Rodríguez-Abreu, A.G. Robinson, et al.  (2016).  Pembrolizumab versus 
Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.  N Engl J Med.  375:1823-
1833. 
 
Reed, E., M. Dabholkar, B. Chabner, et al.  (1996).  Platinum analogues cancer chemotherapy. 
Lippincott-Raven Publishers, Philadelphia: 357. 
 
Sandler, A., R. Gray, M.C. Perry, et al.  (2006).  Paclitaxel-carboplatin alone or with 
bevacizumab for non-small-cell lung cancer.  N Engl J Med.  355:2542-2550. 
 
Sarantopoulos, J., G.I. Shapiro, R.B. Cohen, et al.  (2016).  Phase I study of the investigational 
NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with 
advanced solid tumors.  Clin Cancer Res.  22:847-857. 
 
Shah, J.J., A.J. Jakubowiak, O.A. O'Connor, et al.  (2016).  Phase I study of the novel 
investigational NEDD8-activating enzyme inhibitor pevonedistat (MLN4924) in patients with 
relapsed/refractory multiple myeloma or lymphoma.  Clin Cancer Res.  22:34-43. 
 
Soucy, T.A., P.G. Smith, M.A. Millhollen, et al. (2009).  An inhibitor of NEDD8-activating 
enzyme as a new approach to treat cancer.  Nature.  458:732-736.  
 
Swords, R.T., K.R. Kelly, P.G. Smith, et al. (2010).  Inhibition of NEDD8-activating enzyme: a 
novel approach for the treatment of acute myeloid leukemia.  Blood.  115:3796-3800. 
 
Swords, R.T., H.P. Erba, D.J. DeAngelo, et al.  (2015).  Pevonedistat (MLN4924), a first-in-
class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and 
myelodysplastic syndromes: a phase 1 study.  Br J Haematol.  169:534-543. 
 
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NJ. 
 

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Temel, J.S., J.F. Gainor, J.R. Sullivan, et al.  (2018).  Keeping expectations in check with 
immune checkpoint inhibitors.  J Clin Oncol.  36:1654-1657. 
 
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Pharmaceuticals, Cambridge, MA. 
 
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advances and therapeutic implications.   Cytotechnology.  68:1-8. 
 
Zhou, W., J. Xu, H. Li, et al.  (2017).  Neddylation E2 UBE2F promotes the survival of lung 
cancer cells by activating CRL5 to degrade NOXA via the K11 linkage.  Clin Cancer Res.  
23:1104-1116.  
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX B 
PATIENT DRUG INTERACTIONS HANDOUT AND WALLET 
CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
      
Study 
Doctor: 
      
Study Doctor 
Phone #:  
      
Study 
Drug(s): 
MLN4924 
(Pevonedistat) 
 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute.  
 
 
These are the things that you need to know: 
The study drug MLN4924 (pevonedistat), may interact with other drugs which can cause side 
effects. For this reason, it is very important to tell your doctors about all your medicines, 
including: (a) medicines you are taking before this clinical trial, (b) medicines you start or stop 
taking during this study, (c) medicines you buy without a prescription (over-the-counter remedy), 
(d) herbals or supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or 
an updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health 
care providers to review any medicines and herbal supplements. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects. Avoid ingesting grapefruit and 
grapefruit juice. 
• 
Make sure your doctor knows to avoid certain prescription medications.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.   
 
 

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PATIENT DRUG INTERACTION WALLET CARD  
 
 
 
 
 
 
EMERGENCY INFORMATION 
 
DRUG INTERACTIONS  
Show this card to all of your 
healthcare providers. Keep it with 
you in case you go to the 
emergency room. 
Tell your doctors before you start or 
stop any medicines. 
Check with your doctor or pharmacist 
if you need to use an over-the-counter 
medicine or herbal supplement! 
Carry this card with you at all times   
MLN4924 (pevonedistat) interacts with enzymes in your liver or other tissue 
like the gut, transport proteins that help move drugs in and out of cells and 
must be used very carefully with other medicines. 
Patient Name:       
 
 
 
Diagnosis:       
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:       
Before prescribing new medicines, your health care provider should check a 
frequently-updated medical reference for a list of drugs to avoid or contact 
your study doctor. 
Study Drug(S): MLN4924 (pevonedistat) 
 
             Version SEP/2020 
 
For more information: 1-800-4-CANCER 
For more information: 1-800-4-CANCER 
For more information: 1-800-4-CANCER 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
 
 

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APPENDIX C 
ACCEPTABLE BIRTH CONTROL METHODS  
 
Highly effective methods 
Additional effective (barrier) methods 
Combined (estrogen and progestogen 
containing) hormonal contraception 
associated with inhibition of ovulation.  May 
be oral, intravaginal, or transdermal. 
Male or female condom with or without 
spermicide (female and male condoms 
should not be used together) 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation.  May 
be oral, injectable, or implantable. 
Intrauterine device (IUD) 
Cap, diaphragm, or sponge with 
spermicide 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partner 
Sexual abstinence