A Phase 2 Study of Pevonedistat in Combination With Carboplatin and Paclitaxel in Advanced Intrahepatic Cholangiocarcinoma
Phase: PHASE2
Conditions: Metastatic Cholangiocarcinoma, Metastatic Hepatocellular Carcinoma, Stage III Hepatocellular Carcinoma AJCC v8, Stage III Intrahepatic Cholangiocarcinoma AJCC v8, Stage IIIA Hepatocellular Carcinoma AJCC v8, Stage IIIA Intrahepatic Cholangiocarcinoma AJCC v8, Stage IIIB Hepatocellular Carcinoma AJCC v8, Stage IIIB Intrahepatic Cholangiocarcinoma AJCC v8, Stage IV Hepatocellular Carcinoma AJCC v8, Stage IV Intrahepatic Cholangiocarcinoma AJCC v8, Stage IVA Hepatocellular Carcinoma AJCC v8, Stage IVB Hepatocellular Carcinoma AJCC v8, Unresectable Cholangiocarcinoma, Unresectable Hepatocellular Carcinoma, Unresectable Intrahepatic Cholangiocarcinoma
Sponsor: National Cancer Institute (NCI)

EA2187
1 
A Phase 2 Study of Pevonedistat in Combination with 
Carboplatin and Paclitaxel in Advanced Intrahepatic 
Cholangiocarcinoma
STUDY CHAIR:
STUDY STATISTICIAN:
Dustin Deming, MD
Michelle Weitz, MS
STUDY CO-CHAIR:
Anita Turk, MD
GASTROINTESTINAL COMMITTEE CHAIR:
Peter O’Dwyer, MD
Version Date:  September 1, 2021
STUDY PARTICIPANTS
ACTIVATION DATE
ALLIANCE / Alliance for Clinical Trials in 
Oncology
January 31, 2020
NRG / NRG Oncology
SWOG / SWOG
Agents
IND#
NSC#
Supply 
Pevonedistat
793435
NCI 
Carboplatin
N/A
241240
Commercial
Paclitaxel
N/A
673089
Commercial
IND Sponsor: DCTD, NCI

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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Cholangiocarcinoma Background ............................................................. 7 
1.2 
Neddylation Pathway in Cholangiocarcinoma .......................................... 7 
1.3 
Pevonedistat ............................................................................................. 8 
1.4 
Pevonedistat Single Agent Activity ........................................................... 8 
1.5 
Pevonedistat in Combination with Chemotherapy ................................... 9 
1.6 
Rationale for the Overall Study Design ................................................... 10 
2. Objectives ......................................................................................................... 11 
2.1 
Primary Endpoints ................................................................................... 11 
2.2 
Secondary Endpoints ............................................................................... 11 
2.3 
Exploratory Endpoints ............................................................................. 11 
3. Selection of Patients ......................................................................................... 12 
3.1 
Eligibility Criteria ..................................................................................... 12 
4. Registration and Randomization Procedures ................................................... 17 
4.1 
Patient Registration ................................................................................ 20 
4.2 
Additional Requirements ........................................................................ 21 
4.3 
Instructions for Patients who Do Not Start Assigned Protocol Treatment23 
5. Treatment Plan ................................................................................................. 24 
5.1 
Administration Schedule ......................................................................... 24 
5.2 
Adverse Event Reporting Requirements ................................................. 27 
5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Pevonedistat HCl (MLN4924, NSC793435) ............................................. 37 
5.4 
Dose Modifications ................................................................................. 41 
5.5 
Supportive Care ....................................................................................... 49 
5.6 
Duration of Therapy ................................................................................ 51 
5.7 
Duration of Follow-up ............................................................................. 51 
6. Measurement of Effect ..................................................................................... 52 
6.1 
Antitumor Effect – Solid Tumors ............................................................. 52 
7. Study Parameters .............................................................................................. 60 
7.1 
Therapeutic Parameters .......................................................................... 60 
7.2 
Biological Sample Submissions ............................................................... 63 
8. Drug Formulation and Procurement ................................................................. 64 
8.1 
Pevonedistat HCl (MLN4924, NSC 793435) ............................................ 65 
8.2 
Carboplatin .............................................................................................. 68 
8.3 
Paclitaxel ................................................................................................. 70 
9. Statistical Considerations .................................................................................. 73 
9.1 
Gender and Ethnicity .............................................................................. 74 
10. Specimen Submissions ...................................................................................... 75 
10.1 Collection and Submission Schedule ....................................................... 75 
10.2 Shipping Procedures ............................................................................... 75 

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10.3 Use of Specimens in Research ................................................................ 76 
10.4 ECOG-ACRIN Sample Tracking System .................................................... 76 
10.5 Sample Inventory Submission Guidelines ............................................... 77 
11. Specimen Analyses: Research Studies .............................................................. 78 
11.1 Immunohistochemistry for NEDD8, NAE1 and UBC12 ........................... 78 
11.2 Lab Data Transfer Guidelines .................................................................. 78 
12. Electronic Data Capture .................................................................................... 79 
13. Patient Consent and Peer Judgment ................................................................ 79 
14. References ........................................................................................................ 79 
Appendix I  Pathology Submission Guidelines ........................................................ 82 
Appendix II  Patient Thank You Letter ..................................................................... 86 
Appendix III  CRADA/CTA ......................................................................................... 87 
Appendix IV  ECOG Performance Status ................................................................. 89 
Appendix V  Instructions for Reporting Pregnancies on a Clinical Trial .................. 90 
Appendix VI  Patient Drug Interactions Handout and Wallet Card ......................... 93 
Appendix VII  Formula to Estimate Renal Function Using Serum Creatinine .......... 96 
 
 
 

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STUDY CHAIR 
Dustin Deming MD, 
Wisconsin Institute for Medical Research 
1111 Highland Ave, 6507 WIMR2 
Madison, WI 53705 
Phone: 608-265-1042 
Fax: 608-265-8133 
Email: ddeming@medicine.wisc.edu   
STUDY CO-CHAIR 
Anita Turk MD, 
Indiana University Simon Cancer Center 
535 Barnhill Dr, Suite 130C 
Indianapolis, IN 46202 
Phone: 317-274-0335 
Fax: 317-948-3354 
Email: aaturk@iu.edu   
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Please 
see the data submission 
section of the protocol for 
further instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 

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1. 
Introduction 
1.1 
Cholangiocarcinoma Background 
Cholangiocarcinoma is an uncommon malignancy that arises from the epithelial 
cells of bile ducts. Unfortunately, this disease has a very poor prognosis, with a 
five-year survival rate of 5-10%.1 Most patients present with advanced disease, 
with only 10% presenting with resectable disease. Unfortunately, recurrence after 
resection remains high, with rates reported between 44% and 70% at 5 years.2-4 
The ABC-02 trial demonstrated the benefit of gemcitabine and cisplatin, which is 
now considered standard of care for first-line chemotherapy in fit patients.5 
Unfortunately, resistance to therapy ultimately develops. Outcomes are quite 
poor in the second-line setting with minimal anti-tumor activity seen with second 
line chemotherapy and no clear standard of care in this setting.6 Recently, the 
ABC-06 trial demonstrated an overall survival benefit of FOLFOX (5-flurouracil, 
leucovorin, oxaliplatin) over best supportive care in the second line setting (HR 
0.69; 95% CI 0.50-0.97; p=0.031).7 The benefit seen in this trial was marginal, 
thus there is still a clear need to develop novel therapeutic strategies, enhancing 
the efficacy of cytotoxic chemotherapy regimens, and to investigate predictive 
biomarkers in cholangiocarcinoma. 
1.2 
Neddylation Pathway in Cholangiocarcinoma 
The ubiquitin proteasome system (UPS) controls a broad array of cellular 
functions via protein degradation that mediate cell growth and survival, cellular 
signaling, and transcription factor regulation.87 Ubiquitin (Ub) conjugation via 
covalent linkage to a protein tags it for degradation by a proteasome. 
Ubiquitylation 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-ligase (E3).  A subgroup of E3 ligases include Cullin 
RING ligases (CRL) which are responsible for approximately 20% of cellular 
proteins labeled for degradation.7 CRL substrates include regulators of cell cycle 
progression, apoptosis, DNA damage responses, and signaling transduction. 
This subgroup of E3 ligases are regulated via a Ub-like ligand, NEDD8 (neural 
precursor cell expressed, developmentally down-regulated 8), via covalent 
conjugation. As with Ub, neddylation to CRL occurs in three enzymatic steps that 
include NEDD8-activating enzyme (NAE), E2 conjugation (UBC12), and an E3 
ligase. Given the downstream substrates of CRLs include a number of 
oncoproteins and tumor suppressors, inhibiting neddylation is an ideal oncologic 
therapeutic target. 
Up-regulation of neddylation has been demonstrated in several malignancies 
including melanoma, NSCLC, and intrahepatic cholangiocarcinoma.10-12 Pre-
clinical work by Gao et al studied tumor samples from 322 patients with resected 
intrahepatic cholangiocarcinoma (ICC) and demonstrated that NEDD8 was 
overexpressed in malignant cells in 68.9% of cases. Notably surrounding normal 
intrahepatic bile duct cells showed weak or negative expression of NEDD8. 
Likewise, other players of neddylation including NAE1, UBA3, and UBC12 were 
also overexpressed. 
To illustrate the clinical relevance of neddylation upregulation, the authors then 
grouped patients according to high or low expression of these markers. 
Univariate analyses demonstrated that upregulation of the neddylation pathway 

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correlated with higher rate of relapsed disease after resection. Patients with low 
expression of NEDD8 had a median time to recurrence of 44.0 months compared 
to 14.0 months in patients with high expression of NEDD8. Multivariate Cox 
analysis confirmed that co-expression of NEDD8 and NAE1 is an independent 
negative prognostic factor, with double the risk of recurrent disease following 
resection compared to low expression of NEDD8 and NAE1.   
1.3 
Pevonedistat 
Pevonedistat (MLN4924) is an investigational adenosine sulfamate analogue that 
inhibits NAE by covalently forming a NEDD8 adduct. In this form, NAE is unable 
to process NEDD8 for CRL conjugation, thus inhibiting CRL activity and leading 
to accumulation of CRL substrates. Pevonedistat’s anti-tumor activity is via 
primarily via induction of DNA damage, but also includes inducing autophagy and 
inhibition of NF-NB signaling.13-20 Pevonedistat DNA-damage activity is via 
several mechanisms. Double-strand DNA break (DSB) repair is initiated by 
binding of the Ku heterodimer.21 Neddylation is essential for the degradation of 
Ku and release of nonhomologous end-joining (NHEJ) core complex from DNA 
following repair. By serving as a barrier, persistence of this repair complex 
inhibits genome replication and promotes cell death. Additionally, inhibition of 
neddylation promotes DNA re-replication during S phase of the cell cycle due to 
stabilization of CDT1, leading to DNA damage.9 Lastly, neddylation plays a 
regulatory role in inter-strand crosslinkage (ICL) repair. Neddylation is required 
for ATR/CHK1 activation and for subsequent FANCD2 monoubiquitination in the 
Fanconi anemia pathway.16 Monoubiquinated FANCD2 is required for complete 
ICL repair including the activation of nucleotide excision repair, translesion 
synthesis, and recruitment of homologous recombination repair factors such as 
BRCA1, BRCA2, RAD51, and FAN1. 
Pre-clinical data supports pevonedistat’s activity against ICC. Gao et al 
demonstrated inhibited cell proliferation and inhibition of colony formation in a 
dose-dependent fashion in ICC cell lines, including 2 of 4 primary ICC cell lines.10 
Notably, one of the primary ICC cell lines with the lowest expression of NAE1 
was resistant to treatment. Of the ICC cell lines that responded, pevonedistat 
induced G2 cell cycle arrest followed by apoptosis or senescence. Further 
analysis of protein levels demonstrate accumulation of known CRL substrates, 
including cell cycle regulators (WEE1), INB-D (inhibitor of NF-NB), and CDT1 
(regulator of DNA replication). Pevonedistat also induced DNA-damage 
response, confirmed by the elevation of phosphorylated H2AX and CHK1. Lastly, 
pevonedistat has anti-tumor activity in xenograft models. Tumor growth was 
inhibited in pevonedistat-treated cholangiocarcinoma compared to control 
tumors. Pevonedistat-treated xenograft tumors also demonstrated accumulation 
of CRL substrates and demonstrated a marked decrease in Ki-67 compared to 
controls. 
1.4 
Pevonedistat Single Agent Activity 
The clinical development of pevonedistat started with four clinical trials with 
doses ranging from 25 to 278 mg/m2.22-25 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. Because of this, a revised risk mitigation strategy, including 
limiting the dose 100mg/m2 for single-agent administration, was implemented 

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across the pevonedistat program in October 2012.  The current understanding of 
the renal toxicity observed with pevonedistat suggests that it is not a primary 
event but is likely secondary to hemodynamic changes occurring in the setting of 
a type of acute phase response. 
Pevonedistat has shown single-agent activity in patients with advanced solid 
tumors in two phase I clinical trials, at doses ranging from 25 to 209 mg/m2.22,23 
One of the initial trials by Sarantopoulos et al studied pevonedistat monotherapy 
in patients with advanced, non-hematologic malignancies to determine the 
optimal dosing schedule.23 This study included several gastrointestinal (GI) 
malignancies including colorectal, gastric, pancreatic, and esophageal cancers (n 
= 19). Though no objective responses were noted on study, 42% (n = 8) of 
patients remained on pevonedistat for >3 cycles (21 day cycle) demonstrating 
potential clinical activity in GI malignancies. The single agent recommended 
phase II dose (RP2D) is 50 mg/m2 administered on days 1, 3, and 5 of 21-day 
cycle. Of note, pevonedistat has not been investigated as a single agent in 
subjects selected for neddylation pathway activation in their cancers or in any 
patients with cholangiocarcinoma. 
1.5 
Pevonedistat in Combination with Chemotherapy 
Carboplatin is a platinum analogue chemotherapeutic agent that has been in use 
since the 1980s. Platinums function as alkylating agents by binding to cellular 
DNA to form interstrand crosslinks (ICL). Given pevonedistat’s inhibition of ICL 
repair, there is clinical interest in combining therapy with carboplatin to enhance 
cytotoxic activity. Preclinical data has validated the chemosensitizing effect of 
pevonedistat combination with cross-linking cytotoxic agents including platinum 
chemotherapy, mitomycin C, and ionizing radiation.10,21,26 In ICC cell lines, Gao et 
al validated the additive effect of cisplatin with pevonedistat.10 
A phase Ib, multi-arm study (NCT01862328) has studied the safety of 
gemcitabine (1000 mg/m2 days 1,8,15), docetaxel (75 mg/m2 day 1), and 
carboplatin/paclitaxel (AUC 5 day 1 / 175 mg/m2 day 1) in combination with 
pevonedistat in patients with solid tumors.27 The gemcitabine plus pevonedistat 
arm was discontinued early due to toxicity (grade 3/4 febrile neutropenia (n = 2) 
and grade 3 transaminitis (n = 1)) and dose escalation was not pursued. Dose-
limiting toxicities (DLTs) in the docetaxel arm were grade 3 AST/ALT elevated (n 
= 4) requiring dose hold and dose reduction, with a maximum tolerated dose 
(MTD) of pevonedistat 25 mg/m2.  DLTs in the carboplatin/paclitaxel plus 
pevonedistat arm included grade 3 febrile neutropenia (n = 1; 15 mg/m2), grade 3 
AST/ALT elevation (n = 3; 20 mg/m2, n = 2; 25mg/m2), and grade 4 
thrombocytopenia (n = 1; 15 mg/m2). One DLT of grade 3 AST elevation 
occurred during MTD expansion requiring dose reduction. The RP2D was 
determined to be pevonedistat 20 mg/m2 on days 1, 3, and 5 in combination with 
carboplatin AUC 5 and paclitaxel 175 mg/m2 of a 21-day cycle. Preliminary data 
suggest antitumor activity in patients with heavily pre-treated solid tumors. This 
includes two patients on study with cholangiocarcinoma. One patient with 
biphasic hepatocellular and cholangiocarcinoma was treated in the 
carboplatin/paclitaxel arm with a partial response on treatment for 8 cycles. The 
second patient with cholangiocarcinoma was treated on the docetaxel arm with a 
partial response, treated for 3 cycles. Overall, the combination was well tolerated 
with manageable toxicities. Of note all patients accrued in this trial had bilirubin at 
VFUHHQLQJXSSHUOLPLWVRIQRUPDO6DIHW\RISHYRQHGLVWDWLQSDWLHQWVZLWKKHSDWLF

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impairment is currently being investigated. As of August 2019 no data is available 
on the exposure of pevonedistat in patients with hepatic impairment. Common 
adverse events of any grade include fatigue (57%), nausea (39%), anemia 
(33%), increased AST (30%), and increased ALT (27%).   
1.6 
Rationale for the Overall Study Design 
Patients with cholangiocarcinoma have a poor prognosis. There is no clear 
standard of care systemic chemotherapy regimen in the second-line setting for 
patients with advanced disease. Therefore, we propose a randomized phase 2 
study evaluating single agent pevonedistat (Arm A) and the combination of 
pevonedistat with carboplatin and paclitaxel (Arm B) for patients with 
unresectable cholangiocarcinoma in the second-line setting. Pevonedistat has 
never been studied as a single agent in cholangiocarcinoma, nor has it been 
studied in cancers over-expressing components of the neddylation pathway. In 
addition, given this safety data, preliminary activity, and rationale pevonedistat 
deserves further investigation with chemotherapy for cholangiocarcinoma. 
Carboplatin and paclitaxel was chosen as the chemotherapy regimen for this 
study as this has published safety data in combination with pevonedistat and 
there is a recommended phase 2 dose. Additionally, responses were seen with 
this combination in the phase I clinical trial, warranting further investigation.28 
 

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2. 
Objectives 
2.1 
Primary Endpoints 
2.1.1 
To determine the objective response rate of pevonedistat as a single 
agent and in combination with carboplatin and paclitaxel in patients 
with unresectable intrahepatic cholangiocarcinoma. 
2.2 
Secondary Endpoints 
2.2.1 
To evaluate the safety profile of pevonedistat alone and in 
combination with carboplatin and paclitaxel in patients with 
intrahepatic cholangiocarcinoma. 
2.2.2 
To determine the clinical benefit rate of patients with advanced ICC 
treated with pevonedistat monotherapy and in combination with 
carboplatin and paclitaxel. 
2.2.3 
To determine progression-free survival of patients treated with 
pevonedistat monotherapy and in combination with carboplatin and 
paclitaxel. 
2.2.4 
To determine overall survival of patients treated with pevonedistat 
monotherapy and in combination with carboplatin and paclitaxel. 
2.3 
Exploratory Endpoints 
2.3.1 
To determine whether overexpression of NEDD8, NAE1, and UBC12 
predict response to treatment. 
2.3.2 
To identify the mutation profile of those cholangiocarcinomas with 
overexpression of the neddylation pathway. 
2.3.3 
To bank specimens for further future investigations. 
 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria 
3.1.1 
Patient must be  18 years of age. 
3.1.2 
Patient must have an ECOG Performance Status 0-1. 
3.1.3 
Patient must have a life expectancy  12 weeks  
3.1.4 
Patient must have histologically confirmed intrahepatic 
cholangiocarcinoma or biphasic hepatocellular carcinoma and 
cholangiocarcinoma that is metastatic or unresectable and who have 
progressed on or been intolerant of one prior line of systemic 
gemcitabine containing chemotherapy regimen.  
NOTE: 
Prior immunotherapy or targeted therapies are allowed and 
will not be considered a line of therapy unless administered 
with cytotoxic chemotherapy. 
3.1.5 
Patient must have measurable disease as defined in Section 6.1.2. 
For patients who have received localized therapy (embolization, 
chemoembolization, radiofrequency ablation or radiation) are eligible if 
measurable disease is not within the treatment field or the treated 
disease has clearly progressed since last localized therapy. 

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3.1.6 
Patient must not have had major surgery within 14 days before 
randomization. Patients with surgery planned during study period are 
ineligible 
3.1.7 
Women must not be pregnant or breast-feeding due to the potential 
harm to an unborn fetus and possible risk for adverse events in 
nursing infants with the treatment regimens being used. 
All females of childbearing potential must have a blood test or urine 
study within 14 days prior to randomization to rule out pregnancy. 
A female of childbearing potential is defined as any woman, 
regardless of sexual orientation or whether they have undergone tubal 
ligation, who meets the following criteria: 1) has achieved menarche 
at some point, 2) has not undergone a hysterectomy or bilateral 
oophorectomy; or 3) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (i.e., has had menses at 
any time in the preceding 24 consecutive months). 
Female of child bearing potential? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.8 
Women of childbearing potential and sexually active males must not 
expect to conceive or father children by using accepted and effective 
method(s) of contraception or by  abstaining from sexual intercourse 
for the duration of their participation in the study and continue for at 
least 4 months after the last dose of protocol treatment. 
3.1.9 
Male patients must not donate sperm during the course of this study 
or within 4 months after receiving their last dose of protocol treatment. 
3.1.10 
Female patients must not donate eggs (ova) during the course of this 
study or within 4 months after receiving their last dose of protocol 
treatment. 
3.1.11 
Patient must have adequate organ and marrow function, as defined 
below, obtained within 14 days prior to randomization. 
Leukocytes  3,000/mcL 
Leukocytes: __________ Date of Test: __________ 
Absolute neutrophil count  1,500/mcL 
ANC: __________ Date of Test: __________ 
Platelets  100,000/mcL 
Platelet: __________ Date of Test: __________ 
Total ELOLUXELQLQVWLWXWLRQDOXSSHUOLPLWRIQRUPDO8/1H[FHSWLQ
patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome 
PD\HQUROOLIGLUHFWELOLUXELQ[8/1RIWKHGLUHFWELOLUXELQ 
Bilirubin: __________ Institutional ULN: _________ 
Date of Test: __________ 
Patient with Gilbert’s syndrome: __________ (Yes or No) 

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Hemoglobin  9g/dL 
Hgb: __________ Date of Test: __________ 
AST(SGOT)/ALT(SGPT)  2.5 × institutional ULN 
ALT: _______ Institutional ULN: _________ 
Date of Test: _______ 
AST: _______Institutional ULN: _________ 
Date of Test: _______ 
&UHDWLQLQHLQVWLWXWLRQDO8/1, OR 
Glomerular filtration rate *)5 40 mL/min/1.73 m2 
Note units and please refer to Appendix VII for the formula to estimate 
renal function using serum creatinine. 
Serum creatinine ______________Date of Test: ________ 
GFR: ________________________Date of Test: ________ 
3.1.12 
Patient must not have a prolonged rate corrected QT (QTc) interval 
480 msec calculated according to institutional guidelines. 
3.1.13 
Human immunodeficiency virus (HIV)-infected patients on effective 
anti-retroviral therapy with undetectable viral load within 6 months are 
eligible for this trial. Known HIV positive patients who meet the 
following criteria will be considered eligible: 
x 
&'FRXQWFHOOVPP3 
x 
Undetectable viral load 
x 
Maintained on modern therapeutic regimens utilizing non-CYP 
interactive agents (i.e. excluding ritonavir) 
x 
No history of AIDS-defining opportunistic infections 
3.1.14 
For patients with evidence of chronic hepatitis B virus (HBV) infection, 
the HBV viral load must be undetectable on suppressive therapy, if 
indicated. 
3.1.15 
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. 
3.1.16 
Patients who have not recovered from adverse events due to prior 
anti-cancer therapy (i.e. have residual toxicities > grade 1) are 
ineligible with the exception of alopecia. 
3.1.17 
3DWLHQWVZLWKSHUVLVWHQWJUDGHGLDUUKHDODVWLQJPRUHWKDQ
consecutive days within 14 days of randomization are ineligible. 
3.1.18 
Patients who received prior platinum or taxane chemotherapy are 
eligible. 
3.1.19 
Patients with known central nervous system (CNS) involvement are 
ineligible. 

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3.1.20 
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. 
3.1.21 
Patients with known history or current symptoms of cardiac disease, 
or history of treatment with cardiotoxic agents, should have a clinical 
risk assessment of cardiac function using the New York Heart 
Association Functional Classification. To be eligible for this trial, 
patients should be class 2B or better. In addition, patients will any of 
the known cardiopulmonary disease, defined as follows, would be 
ineligible for this trial: 
x 
Unstable angina 
x 
Congestive heart failure (New York Heart Association [NYHA] 
Class III or IV;); 
x 
Myocardial infarction within 6 months prior to randomization  
(patients who had ischemic heart disease such as acute coronary 
syndrome [ACS], myocardial infarction, and/or revascularization 
greater than 6 months before randomization and who are without 
cardiac symptoms may enroll) 
x 
Symptomatic cardiomyopathy 
x 
Clinically symptomatic pulmonary hypertension requiring 
pharmacologic therapy 
x 
Clinically significant arrhythmia, defined as: 
1. History of polymorphic ventricular fibrillation or torsade de 
pointes, 
2. Permanent atrial fibrillation, defined as continuous atrial 
ILEULOODWLRQIRU 6 months, 
3. Persistent atrial fibrillation, defined as sustained atrial 
fibrillation lasting > 7 days and/or requiring cardioversion in the 
4 weeks before randomization, 
4. Grade 3 atrial fibrillation defined as symptomatic and 
incompletely controlled medically, or controlled with device 
(e.g., pacemaker), or ablation 
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. 
3.1.22 
Patient must not be receiving any other investigational agents. 
3.1.23 
Patient must not have received chemotherapy or radiotherapy within 2 
weeks prior to randomization. Prior treatment with radiation therapy 
LQYROYLQJRIKHPDWRSRLHWLFDOO\DFWLYHERQHPDUURZZLOOEH
ineligible. 
3.1.24 
Patient must not have received immunotherapy within 8 weeks prior to 
randomization. 
3.1.25 
Patient must not have a history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to 
pevonedistat, carboplatin, or paclitaxel. 

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3.1.26 
Patient must not be receiving any treatment with clinically significant 
metabolic enzyme inducers within 14 days before the first dose of the 
study drug as below. Clinically significant metabolic enzyme inducers 
are not permitted during the study. Patients must not be receiving any 
medications or substances that are strong inducers of CYP3A4/5 (i.e. 
phenytoin, rifampin, St. Johns wort) or inhibitors of BCRP (i.e. 
cyclosporine). Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated 
medical reference. As part of enrollment/informed consent 
procedures, the patient will be counseled on the risk of interactions 
with other agents, and what to do if a new medication need to be 
prescribed or if the patient is considering a new over-the-counter 
medicine or herbal product. Inhibitors of CYP3A4/5 are allowed. 
3.1.27 
Patient must not have uncontrolled intercurrent illness. 
3.1.28 
Patient must not have uncontrolled coagulopathy or bleeding disorder. 
3.1.29 
Patient must not have active, uncontrolled infection or severe 
infectious disease such as severe pneumonia, meningitis, or 
septicemia. 
3.1.30 
Patient with known moderate chronic obstructive pulmonary disease, 
interstitial lung disease, and pulmonary fibrosis are ineligible. 
3.1.31 
Patient must not have psychiatric illness/social situations that would 
limit compliance with study requirements. 
3.1.32 
Patient must have the ability to understand and the willingness to sign 
a written informed consent document. 
3.1.33 
Patients 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. 
3.1.34 
Patient must not have had prior pevonedistat treatment. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 

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4. 
Registration and Randomization Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 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 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. 
x 
IVR — MD, DO, or international equivalent; 
x 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
x 
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,); 
x 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
x 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
D 
D 
 
 
 
Financial Disclosure Form 
D 
D 
D 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
D 
D 
D 
 
 
GCP training 
D 
D 
D 
 
 
Agent Shipment Form (if 
applicable) 
D 
 
 
 
 
CV (optional) 
D 
D 
D 
 
 
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: 
x 
Addition to a site roster; 
x 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
x 
Act as the site-protocol Principal Investigator (PI) on the IRB approval. 

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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. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations. 
Sites participating with the 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 Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
x 
Holds an Active CTEP status; 
x 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
x 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
x 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
x 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
x 
An active Federal Wide Assurance (FWA) number; 
x 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
x 
Compliance with all protocol-specific requirements (PSRs). 

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Downloading Site Registration Documents: 
Site registration forms may be downloaded from the EA2187 protocol 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 PO on the protocol. 
x 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
x 
Click on the Protocols tab in the upper left of your screen 
x 
Either enter the protocol # in the search field at the top of the protocol tree, or 
x 
Click on the By Lead Organization folder to expand 
x 
Click on the (ECOG-ACRIN) link to expand, then select trial protocol #EA2187 
x 
Click on LPO Documents, select the Site Registration documents link, 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.) 
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: 
www.ctsu.org (members’ area) Æ Regulatory Tab Æ Regulatory Submission 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
x 
Log on to the CTSU member’s website; 
x 
Click on the Regulatory tab at the top of your screen; 
x 
Click on the Site Registration; 
x 
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. 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within fourteen working days after registration. 
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. 

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Requirements for OPEN access: 
x 
A valid CTEP-IAM account; 
x 
To perform enrollments or request slot reservations: Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; and 
x 
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. 
Prior to accessing OPEN, site staff should verify the following: 
x 
All eligibility criteria have been met within the protocol stated timeframes. 
x 
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 member’ 
website. Further instructional information is provided on the OPEN tab of the CTSU 
members’ side 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. 
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. 
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.  
4.1 
Patient Registration 
The following information is to be provided at the time of registration to the trial: 

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4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
x 
Institution and affiliate name 
x 
Investigator’s name 
4.1.3 
Patient Identification  
x 
Patient’s initials (first and last) 
x 
Patient’s Hospital ID and/or Social Security number 
x 
Patient demographics 
x 
Gender 
x 
Birth date (mm/yyyy) 
x 
Race 
x 
Ethnicity 
x 
Nine-digit ZIP code 
x 
Method of payment 
x 
Country of residence 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3. 
4.2 
Additional Requirements  
4.2.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.2.2 
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. To the hold Rave CRA 
role or Rave CRA (Lab Admin) role, the user must hold a minimum of 
an AP registration type. To hold the Rave Site Investigator role, the 
individual must be registered as an NPIVR or IVR. Associates can 
hold read-only roles in Rave. 
4.2.3 
Upon initial site registration approval for the study in 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 users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 

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“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users 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. 
Users 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, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab 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. 
4.2.4 
Central monitoring 
Central Monitoring (CM) Review is required for this protocol. CM 
allows Lead Protocol Organizations (LPOs) to remotely compare data 
entered in Rave to source documentation to ensure that sites are 
adhering to the protocol and central monitoring plan as well as 
accurately transcribing data from patients’ charts (i.e., source data 
verification).  
Sites can upload source documents required for CM Review as 
documented in the central monitoring plan using the Source 
Document Portal (SDP). This application is available on the CTSU 
members’ website under Auditing & Monitoring and may also be 
accessed using a direct link within Rave on the CM Alert form. Site 
staff with the CRA or Investigator roles in Rave can view and upload 
source documents. Prior to saving source documents on the SDP, 
each site is responsible for removing or redacting any Personally 
Identifiable Information (PII) (note that functionality to do this redaction 
exists within the SDP itself). Designated LPO staff will review each 
document after it has been loaded on the SDP to ensure the 
appropriate documents have been uploaded and to ensure PII is 
redacted. 
Additional information on the SDP is available on the CTSU members’ 
website under Auditing & Monitoring > Source Document Portal in the 
Help Topics button or by contacting the CTSU Help Desk (1-888-823-
5923 or ctsucontact@westat.com). 

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4.3 
Instructions for Patients who Do Not Start Assigned Protocol Treatment 
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the EA2187 Forms Completion Guidelines. 
 

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5. 
Treatment Plan 
5.1 
Administration Schedule 
Treatment will be administered on an outpatient basis. All doses are based on 
actual body weight. Body surface area (BSA) should be recalculated if  5% 
weight change. No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the patient’s 
malignancy. 
5.1.1 
Arm A: Pevonedistat Monotherapy 
Pevonedistat: 50mg/m2 intravenously (IV) over 60 minutes (±10 
minutes) on days 1, 3, and 5 
1 cycle = 21 days. 
Repeat cycles until disease progression, unacceptable toxicity, or 
patient desire to discontinue study therapy. 
Patients must not be receiving any medications or substances that are 
strong inducers of CYP3A4/5 (i.e., phenytoin, rifampin, St. John’s 
wort) or inhibitors of BCRP (i.e., cyclosporine). Please see details in 
Appendix VI. 
5.1.1.1 
Pevonedistat Administration and Premedications 
Pevonedistat is to be administered using a 250 mL D5W 
(5% dextrose in water) IV bag through central or peripheral 
venous access. The drug should be diluted in 5% dextrose 
to a final volume of 250 mL per instructions in Section 
8.1.6. 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 
5% dextrose in water immediately after IV administration is 
complete. 
5.1.2 
Arm B: Pevonedistat in Combination with Carboplatin and Paclitaxel 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Paclitaxel 
Dexamethasone 
5-HT3 antagonist 
Diphenhydramine 
Ranitidine 
175 mg/m2 
IV infusion 
over 3 
hours 
Day 1 
21 days (3 
weeks) 
Carboplatin 
Dexamethasone 
5-HT3 antagonist 
AUC=5 
IV infusion 
over 15-60 
minutes 
Day 1 
Pevonedistat 
 
20 mg/m2 
IV infusion 
over 1 
hour 
Days  
1, 3, 5 
AUC= area under the curve 

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Pevondedistat: 20 mg/m2 IV over 60 minutes (±10 minutes) on days 
1, 3, and 5 every cycle x 4, followed by: 
Paclitaxel: 175mg/m2 IV over 3 hours (+ 20 minutes), or utilizing local 
standard procedures, on day 1 of every cycle x 4, followed by: 
Carboplatin: AUC 5 IV over 15-60 minutes on day 1 of every cycle x 
4 
1 cycle = 21 days. 
Infusion times of paclitaxel and carboplatin may be adjusted/altered to 
meet local institutional standards. 
Avoid the concomitant use of inhibitors or inducers of CYP2C8 and 
CYP3A4 during Arm B of the study as paclitaxel is metabolized by 
these enzymes. Avoid the concomitant use of nephrotoxic drugs 
during Arm B of the study as carboplatin may potentiate the renal 
effects of these drugs. 
At any time after 4 cycles of combination therapy, the treating 
physician is given discretion whether to continue with: 
Option a: 
Pevonedistat 
50 mg/m2 on days 1, 3, & 5 every cycle OR 
Option b: 
Pevonedistat 
20 mg/m2 IV on days 1, 3, & 5 every cycle, followed by: 
Paclitaxel 
175 mg/m2 on day 1 every cycle, followed by: 
Carboplatin 
AUC 5 IV on day 1 every cycle 
Both option a and b treatment will continue until disease progression, 
unacceptable toxicity, or patient desire to discontinue study therapy. If 
a patient continues with option b, subsequent change to option a at 
later time points is permissible. 
If the patient required a dose reduction attributable to pevonedistat 
then the patient should be maintained at the single agent dose of 
pevonedistat that they were already dose reduced to. 
5.1.2.1 
Pevonedistat Administration and Premedications 
Pevonedistat is to be administered using a 250 mL D5W 
(5% dextrose in water) IV bag through central or peripheral 
venous access. Pevonedistat should be administered prior 
to carboplatin and paclitaxel. The drug should be diluted in 
5% dextrose to a final volume of 250 mL per instructions in 
Section 8.1.6. 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 

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infusion must not exceed 6 hours. Infusion line can be 
flushed with 5% dextrose in water immediately after IV 
administration is complete. 
5.1.2.2 
Carboplatin Administration and Dose Calculation 
Carboplatin at the appropriate dose will be given 
intravenously as a 30- minute infusion in Dextrose 5% in 
Water or Sodium Chloride 0.9%, volume per institutional 
standard. 
Carboplatin dose will be calculated using the Calvert 
formula: 
Total Dose (mg) = target AUC (GFR+25) 
NOTE: 
Calculated total dose is in mg not mg/m2 
Substitute GFR with Creatinine Clearance (CrCl).  CrCl will 
be calculated using the Cockcroft-Gault formula: 
ܥݎܥ݈=
(140 െܽ݃݁) כ ݓ݄݁݅݃ݐ(݇݃)
72 כ ݏ݁ݎݑ݉ ܿݎ݁ܽݐ݅݊݅݊݁
כ (0.85 ݂݅ ݂݈݁݉ܽ݁) 
The minimum serum creatinine value used will be 0.7 
mg/dL, and the CrCl (or GFR) will be capped at 125 
mL/min. Questions about this calculation should be 
directed to the Study Chair (also see Appendix VII). This 
calculation does not require to normalize to 1.73m2, as is 
done for the eligibility criteria GFR. 
NOTE: 
Remember to re-calculate the dose for each 
treatment cycle. The actual body weight should 
be used for all calculations 
5.1.2.3 
Paclitaxel Administration and Premedications 
Paclitaxel should be diluted in Dextrose 5% or Sodium 
Chloride 09% per institutional standard and given by 
intravenous administration. 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 one 
hour via 0.22 micron in line filter and non-DEHP tubing. 
The calculated dose of paclitaxel should be administered 
via a free-flowing intravenous line as a 3 hour infusion. 
Solution 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. 
On day 1 of each cycle, patients will receive 
dexamethasone pre-medication per institutional standards 
for paclitaxel. 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. 

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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 
(Taxol) injection, only when in the investigator’s opinion, 
patients may have been non-adherent with oral pre-
medication. 
** 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. 
NOTE: 
Pre-medications can be adjusted/altered to meet 
local institutional standards. 
5.2 
Adverse Event Reporting Requirements 
All toxicity grades described throughout this protocol and all reportable 
adverse events on this protocol will be graded using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents.  
5.2.2 
Routine Reporting of Adverse Events (Medidata Rave) 
Adverse events are reported in a routine manner at scheduled times 
during a trial using the Medidata Rave clinical data management 
system. Please refer to Section 4 of the protocol for more information 
on how to access the Medidata Rave system and the EA2187 forms 
packet for instructions on what, where and when adverse events are 
to be reported routinely. 

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5.2.3 
Expedited reporting of Adverse Events (CTEP-AERS) 
In addition to routine reporting, certain adverse events must be 
reported in an expedited manner for timelier monitoring of patient 
safety and care. The following sections provide information and 
instructions regarding expedited adverse event reporting. 
5.2.4 
Terminology 
x 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent in humans, whether or not 
considered agent related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
x 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
x 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List): An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND. Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports. 
x 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term. 
x 
Hospitalization (or prolongation of hospitalization): For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours. 
x 
Life Threatening Adverse Event: Any AE that places the subject 
at immediate risk of death from the AE as it occurred. 
x 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes: 
x 
Death  
x 
A life-threatening adverse event  
x 
Inpatient hospitalization or prolongation of existing 
hospitalization (for  24 hours) 
x 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions 
x 
A congenital anomaly/birth defect 

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x 
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. 
x 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting): A subset of AEs within the CAEPR that contains a list 
of events that are protocol specific exceptions to expedited 
reporting. If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported expeditiously if the grade being reported exceeds the 
grade listed in the parentheses next to the event. 
5.2.5 
Expedited Adverse Event Reporting Procedure 
This protocol is a Medidata Rave-CTEP-AERS Integration study.   
The general procedures outlined below describe how to report an 
Adverse Event (AE) requiring expedited reporting on an Integration 
study. 
CTEP’s 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 
AEs that occur after baseline are reported in Medidata Rave 
according to the instructions on the EA2187 Adverse Events 
Form/Late Adverse Events Form, including those that start during the 
report period, persist from the previous report period, or increase in 
grade since baseline. AEs that occur prior to the start of treatment are 
reported on the EA2187 Baseline Adverse Events Form which is not 
be included in the Medidata Rave-CTEP-AERS Integration. 
Prior to sending AEs through the rules evaluation process to 
determine if expedited reporting is required, the site must verify the 
following on the EA2187 Adverse Events Form/Late Adverse Events 
Form in Medidata Rave: 
x 
The reporting period (course/cycle) is correct and 
x 
AEs are recorded and complete (no missing fields) and the form is 
query free 
Upon completion of AE entry in Medidata Rave, the site must then 
submit the AE for rules evaluation by completing the Expedited 
Reporting Evaluation Form. Both NCI and EA2187 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 all AEs that meet expedited reporting 
requirements. The site must then complete the expedited report by 
accessing CTEP-AERS via a direct link on the Medidata Rave 
Expedited Reporting Evaluation form. 
NOTE: 
The site must report AEs in Rave at the time the 
investigator learns of the event. 

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NOTE: 
If an AE reported on the EA2187 Adverse Events Form is 
modified, it must be re-submitted for rules evaluation. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to 
x 
the AE Team at ECOG-ACRIN (857-504-2900) 
x 
the NCI (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 direct link from Medidata Rave. 
Additional information about the Medidata Rave-CTEP-AERS 
Integration system is available on the CTSU website: 
CTEP’s guidelines for expedited AE reporting and CTEP-AERS can 
be found at http://ctep.cancer.gov. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 897-7404) in the same 
timeframe. 
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
Many factors determine the requirements for expedited reporting of 
adverse events on each individual protocol. The instructions and 
tables in the following sections have been customized for protocol 
EA2187 and outline the specific expedited adverse event reporting 
requirements for study EA2187. 
5.2.6 
Guidelines for determining if an adverse event is to be reported in an 
expedited manner – Arms A and B 
x 
Site must determine if an event meets expedited reporting 
requirements so that the AE will be entered into Medidata Rave, 
triggering a CTEP-AERS report, within the mandated timeframes 
outlined in Section 5.2.7. 
x 
Do not initiate the CTEP-AERS report via the CTEP-AERS 
website. 
x 
We encourage all sites to confirm the Rules Engine assessment 
with the charts and tables below. 
x 
Once the CTEP-AERS is completed, ECOG-ACRIN, the NCI, and 
all appropriate regulatory agencies will be notified of the event in 
an expeditious manner.

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5.2.6.1
Guidelines for reporting adverse events OCCURRING 
WHILE ON PROTOCOL TREATMENT AND WITHIN 30 
DAYS of the last administration of the investigational 
agent(s). 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the table 
below in Section 5.2.7. 
Yes
No
Identify the type and 
grade of the event using 
the CTCAE.
Determine if the patient 
was hospitalized for 
KRXUVIRUWKHHYHQW
With this information, review 
the chart in Section 5.2.7 to 
determine if event requires 
expedited reporting.
Refer to Section 5.2.8 to 
determine if the event 
meets the protocol specific 
reporting requirements for 
this study. If so, 
immediately report the 
event in Medidata Rave so 
a CTEP-AERS report will 
be initiated with a link to 
complete it.
Refer to Section 5.2.8 to determine if 
the event meets the protocol specific 
reporting requirements for this study.
If so, immediately report the event in 
Medidata Rave so a CTEP-AERS 
report will be initiated with a link to 
complete it.
Is the event 
reportable?
No
Yes
Refer to Section 5.2.8 to determine if the event meets the criteria 
as an exception to reporting on this protocol. If it does not, 
immediately report the event in Medidata Rave so a CTEP-AERS 
report will be initiated with a link to complete it.

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5.2.6.2 
Guidelines for reporting adverse events OCCURRING 
GREATER THAN 30 DAYS after the last administration of 
the investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.7 OR the 
protocol specific requirements in Section 5.2.8 AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
x 
All Grade 3, 4 and Grade 5 AEs 
NOTE: 
Any death occurring greater than 30 days 
after the last dose of investigational agent 
with an attribution of possible, probable or 
definite must be reported expeditiously 
through CTEP-AERS even if the patient is 
off study. 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
5.2.7 
Expedited Reporting Requirements for Arms A and B on protocol 
EA2187 
Investigational Agents: Pevonedistat 
Commercial Agents:  Carboplatin, Paclitaxel (Arm B only) 
When an investigational agent is used in combination with a 
commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events follow the 
guidelines for investigational agents. 

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5.2.8 
Additional instructions, requirements and exceptions for protocol 
EA2187 
Additional Instructions 
x 
For instructions on how to specifically report events that result 
in persistent or significant disability/incapacity, congenital 
anomaly, or birth defect events in CTEP-AERS accessed via 
Medidata Rave, please contact the AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497. This will need to be 
discussed on a case-by-case basis. 
x 
Reporting a death on study: A death occurring while on study 
or within 30 days of the last dose of treatment requires both 
routine and expedited reporting, regardless of causality. 
Attribution to treatment or other cause must be provided. 
NOTE: 
A death due to progressive disease should be 
reported as a Grade 5 “Disease progression” under 
the System Organ Class (SOC) “General disorder 
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. 
 
EA2187 specific expedited reporting requirements: 
x 
Infusion Reaction: Any grade 3 or greater 
hypersensitivity/infusion reaction (see Section 5.4.2.6) must be 
reported in Medidata Rave, triggering a CTEP-AERS report, 
within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour 
report. 
x 
Pregnancies: Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the female patient is on 
Pevonedistat, or within 28 days of the female patient’s last 
dose of Pevonedistat, are considered immediately reportable 
events. The pregnancy, suspected pregnancy, or positive/ 
inconclusive pregnancy test must be reported in Medidata 
Rave first, which will trigger a CTEP-AERS report, within 24 
hours of the Investigator’s knowledge.  Please refer to 
Appendix V for detailed instructions on how to report the 
occurrence of a pregnancy as well as the outcome of all 
pregnancies. 
 
EA2187 specific expedited reporting exceptions: 
For study Arms A and B, the adverse events listed below do not 
require expedited reporting: 
x 
If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported 

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expeditiously if the grade being reported exceeds the grade 
listed in the parentheses next to the event. 
5.2.9 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested MUST be submitted to BOTH the NCI and ECOG-ACRIN. 
Adverse events determined to require expedited reporting must also 
be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.10 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave. 
x 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
x 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
Report the diagnosis expeditiously by initially reporting it on 
the Adverse Event Form or Late Adverse Event Form in the 
appropriate Treatment Cycle or Post Registration folder in 
Medidata Rave. Once the secondary malignancy is entered 
into Rave, the CTEP-AERS report must then be initiated 
directly from the link generated from the Expedited Reporting 
Evaluation Form in Medidata Rave. Do not initiate the CTEP-
AERS report via the CTEP-AERS website. 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 

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If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted in CTEP-AERS or by the ECOG-ACRIN 
Second Primary Form. 

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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. 

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5.4 
Dose Modifications  
Patients must meet the following treatment parameters for each cycle: 
Parameter 
Day 1 
Days 3 and 5 
Absolute Neutrophil 
Count (ANC) 
t 1 ,000/mcL 
t 1 ,000/mcL 
Hemoglobin 
t 8.0 g/dL 
t 8.0 g/dL 
Platelet Count 
t 100,000/mcL 
t 75,000/mcL 
Total Bilirubin 
d 1.5 x ULN or baseline if >ULN 
d 1.5 x ULN or baseline if 
>ULN 
AST (SGOT)/ALT 
(SGPT)  
 3.0 x ULN; 5 x ULN in 
setting of metastatic liver 
disease 
 3.0x ULN; 5 x ULN in 
setting of metastatic liver 
disease 
Creatinine/CrCL 
d institutional ULN 
Not applicable 
Laboratory assessments must be done and results reviewed by a treating 
physician prior to each pevonedistat administration. 
All other toxicities (except alopecia, lymphopenia, hyperglycemia, 
hypoalbuminemia, fatigue, elevated serum alkaline phosphatase, neuropathy 
[see Section 5.4.2.1], and hemoglobin [see Section 5.4.1.3]) 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. 
Dose holds and modifications are 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). 
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 
Study Chair. 
Treatment with study drugs will be repeated each cycle. For therapy to resume, 
toxicity considered related to treatment with study drugs must have resolved to 
Grade 1, to the patient’s baseline values, or to a level considered acceptable by 
the investigator. If a patient fails to meet the criteria for retreatment, initiation of 
the next cycle of treatment may be delayed for up to 3 weeks. At the end of that 
time, the patient should be reevaluated to determine whether the criteria for 
retreatment have been met. A dose reduction would be triggered if treatment is 
delayed for >3 weeks because of incomplete recovery from treatment related 
toxicity. If the reduced dose is well tolerated and the toxicity leading to dose 
UHGXFWLRQZDV*UDGHKDVUHVROYHGDQGGRes not reoccur, the dose may 
resume at the original dose level in the next cycle after endorsement by the 
investigator (or designee). 
For toxicity not related to drug (eg, disease-related toxicity), although a similar 
dose reduction is permitted, in general it is discouraged. If the dose is well 
WROHUDWHGDQGWKHWR[LFLW\OHDGLQJWRGRVHUHGXFWLRQZDV*UDGHKDVUHVROYHG

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and does not reoccur, the dose may resume at the original dose level in the next 
cycle.  
Retreatment within a Cycle 
If dosing of either drug is delayed for safety reasons, retreatment may be 
resumed upon resolution of the safety condition. For pevonedistat, a minimum of 
1 full calendar day between any 2 doses should be maintained. A maximum of 3 
doses of pevonedistat should not be exceeded. 
If dosing is interrupted within a cycle because of drug-related toxicity, and if the 
investigator (or designee) agrees that it is in the patient’s interest to continue 
therapy with the study drug(s), then after recovery of the toxicity or toxicities in 
queVWLRQWR*UDGHRUWRWKHSDWLHQW¶VEDVHOLQHYDOXHVWKHGRVHRIVWXG\GUXJ
may be reduced in the next cycle. For toxicity not related to drug (eg, disease-
related toxicity), although a similar dose reduction is permitted, in general it is 
discouraged. If the reduced dose is well tolerated and the toxicity leading to dose 
UHGXFWLRQZDV*UDGHKDVUHVROYHGDQGGRHVQRWUHRFFXUWKHGRVHPD\
resume at the original dose level in the next cycle after endorsement by the 
investigator (or designee). 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 to all protocol therapy due to a toxicity at least possibly related to study 
drugs will lead to removal of the patient from the study treatment. If all treatment 
related toxicities do not recover within 3 weeks to the point where patients meet 
re-treatment criteria above, then patients should be removed from study 
treatment. 
Dose reductions are permitted until pevonedistat dose is 10mg/m2 for the 
combination therapy and 25mg/m2 for the monotherapy. If untoward toxicity 
persists despite dose adjustments or if more than 2 dose reductions for the 
combination therapy or 3 dose reductions for the monotherapy 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. 
Dose Modification Levels 
Arm A: 
Dose Level 
Pevonedistat (monotherapy therapy) 
0 
50 mg/m2 
-1 
44 mg/m2 
-2 
33 mg/m2 
-3 
25 mg/m2 
Arm B: 
Dose Level 
Carboplatin 
Paclitaxel 
Pevonedistat 
(combination 
therapy) 
0 
AUC 5 
175 mg/m2 
20 mg/m2 
-1 
AUC 4 
125 mg/m2 
15 mg/m2 

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Dose Level 
Carboplatin 
Paclitaxel 
Pevonedistat 
(combination 
therapy) 
-2 
AUC 3 
100 mg/m2 
10 mg/m2 
-3 
N/A 
N/A 
N/A 
5.4.1 
Hematologic Toxicity 
5.4.1.1 
Neutrophils 
The following dose adjustments are based on the lowest 
neutrophil count of the preceding treatment course. 
Neutropenia 
Management/Next 
Dose for Pevonedistat 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for Carboplatin 
d Grade 1/2 
No change in dose 
No change in dose 
No change in dose 
Grade 3/4 (d 7 days 
and without fever) 
Hold* until d Grade 2. 
Resume at same dose 
level. 
Hold* until d Grade 2. 
Resume at same dose 
level. 
Hold* until d Grade 2. 
Resume at same dose 
level. 
Grade 3/4 (>7 days or 
any duration with 
fever 
1st episode 
Hold* until d Grade 2. 
Resume at same dose 
level. 
Hold* until d Grade 2. 
Resume at same dose 
level. 
Hold* until d Grade 2. 
Resume at same dose 
level. 
Grade 3/4 (>7 days or 
any duration with 
fever 
2nd episode 
Hold* until d Grade 2.  
Reduce by 1 dose 
level.**  
Hold* until d Grade 2. 
Reduce by 1 dose 
level.** 
Hold* until d 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. 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 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.  
 

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5.4.1.2 
Platelets 
Thrombocytopenia 
Management/Next 
Dose for Pevonedistat 
Management/Next 
Dose for Paclitaxel 
Management/Next Dose 
for Carboplatin 
d Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
For Day 1 of any cycle, 
hold* until t 100,000. 
Resume at same dose 
level. 
For Day 1 of any cycle, 
hold* until t 100,000. 
Resume at same dose 
level. 
For Day 1 of any cycle, 
hold* until t 100,000. 
Resume at same dose 
level. 
Grade 3/4 d 7 days 
and no clinically 
significant bleeding 
and > 10,000 mcL 
For Day 1 of any cycle, 
hROGXQWLO
Resume at same dose 
level. 
For Day 1 of any cycle, 
hROGXQWLO
Resume at same dose 
level.  
For Day 1 of any cycle, 
hROGXQWLO 
Resume at same dose 
level.  
Grade 3/4 lasting > 
7 days or requiring 
prophylactic 
platelet transfusion 
(d 10,000 mcL) 
1st episode 
For Day 1 of any cycle, 
hROGXQWLO
Reduce by 1 dose 
level.  
For Day 1 of any cycle, 
hROGXQWLO
Resume at same dose 
level. 
For Day 1 of any cycle, 
hROGXQWLO
Reduce by 1 dose level. 
Grade 3/4 lasting > 
7 days or requiring 
prophylactic 
platelet transfusion 
(d 10,000 mcL) 
2nd episode 
For Day 1 of any cycle, 
hROGXQWLO
Reduce by 1 dose 
level.**  
For Day 1 of any cycle, 
KROGXQWLO0,000. 
Reduce by 1 dose 
level.** 
For Day 1 of any cycle, 
hROGXQWLO
Reduce by 1 dose level. ** 
Grade 3/4 of any 
duration with 
clinically significant 
bleeding *** 
Off study treatment 
Off study treatment 
Off study treatment 
*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 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 
treatment. 
5.4.1.3 
Hemoglobin 
The hemoglobin parameters must meet the criteria 
specified in the table at the beginning of Section 5.4 on 
day 1 of each treatment cycle. Treatment should be 
delayed until recovery of the counts to the specified levels. 
Supportive transfusion is permitted after cycle 1, day 1 and 
future cycles for subjects who do not meet hemoglobin 
parameters for retreatment. 

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5.4.2 
Non-Hematologic Toxicity 
5.4.2.1 
Peripheral Sensory Neuropathy 
The following dose adjustments are based on the worst 
grade experience of sensory neuropathy of any preceding 
treatment course. 
Sensory Neuropathy 
Management/Next 
Dose for Pevonedistat 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for Carboplatin 
d 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.  
Reduce 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. If a toxicity leads to a hold of 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. 
# After 4 cycles, paclitaxel may be discontinued for neuropathy and patient may continue with other 
study agents. 
5.4.2.2 
Arthralgia/Myalgia 
Arthralgia/Myalgia 
Management/Next 
Dose for Pevonedistat 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for Carboplatin 
d 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 
Hold* until < Grade 2.  
Reduce by 1 dose 
level.** 
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 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. 
#For the first occurrence of grade 2 myalgia/arthralgia, dexamethasone can be administered for 3-4 
days (approximately 4mg BID) after chemotherapy.  If symptoms recur despite this, the next dose of 
paclitaxel will be reduced by 1 dose level. 

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5.4.2.3 
Hepatic Toxicity 
There are no dose adjustments for carboplatin based on 
hepatic toxicity. Dose adjustments are for hepatoxicity at 
least possibly related to pevonedistat or paclitaxel. 
AST and/or ALT** 
Use ULN  
Management/Next Dose 
for Pevonedistat 
Management/Next Dose 
for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
Grade 1: >1-3 x ULN 
No change in dose 
No change in dose 
No change in dose 
Grade 2: >3-5 x ULN 
Hold* until meets 
treatment parameter, no 
change in dose level 
Hold* until meets 
treatment parameter, no 
change in dose level 
Hold until meets 
treatment 
parameter, no 
change in dose 
level 
Grade 3: >5-20 x 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. 
Hold until meets 
treatment 
parameter, no 
change in dose 
level 
Grade 4:>20 x ULN 
Off study treatment 
Off study treatment 
Off study treatment 
 
Bilirubin** 
Use ULN  
Management/Next Dose 
for Pevonedistat 
Management/Next Dose 
for Paclitaxel 
Management/Next 
Dose for 
Carboplatin 
Grade 1: >1-1.5 x 
ULN 
No change in dose 
No change in dose 
No change in dose 
Grade 2: >1.5-3 x 
ULN 
Hold until meets treatment 
parameter, no change in 
dose level 
Hold until meets treatment 
parameter, no change in 
dose level 
Hold until meets 
treatment 
parameter, no 
change in dose 
level 
Grade 3: >3-10 x 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. 
Hold until meets 
treatment 
parameter, no 
change in dose 
level 
Grade 4: >10 x ULN 
Off study treatment 
Off study treatment 
Off study treatment 
* 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 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. 

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5.4.2.4 
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 Pevonedistat 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for Carboplatin 
d Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold* until d Grade 1. 
Resume at same dose 
level. 
Hold* until d Grade 1. 
Resume at same dose 
level. 
Hold* until d Grade 1. 
Resume at same dose 
level. 
Grade 3 
Hold* until d Grade 1. 
Resume at same dose 
level. 
Hold* until d Grade 1. 
Reduce by 1 dose 
level. 
Hold* until d 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. If a toxicity leads to a hold of 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. 
 
Vomiting** 
Management/Next 
Dose for Pevonedistat 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for Carboplatin 
d Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold* until d Grade 1. 
Resume at same dose 
level. 
Hold* until d Grade 1. 
Resume at same dose 
level. 
Hold* until d Grade 1. 
Resume at same dose 
level. 
Grade 3 
Hold* until d Grade 1. 
Resume at same dose 
level. 
Hold* until d Grade 1.  
Reduce by 1 dose 
level. 
Hold* until d Grade 1. 
Reduce by 1 dose 
level. 
Grade 4 
Hold* until d Grade 1. 
Reduce by 1 dose level. 
Hold* until d Grade 1.  
Reduce by 1 dose 
level. 
Hold* until d 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. If a toxicity leads to a hold of 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. 

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Diarrhea** 
Management/Next 
Dose for Pevonedistat 
Management/Next 
Dose for Paclitaxel 
Management/Next 
Dose for Carboplatin 
d Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold* until d Grade 1.  
Resume at same dose 
level. 
Hold* until d Grade 1.  
Resume at same dose 
level. 
Hold* until d Grade 1.  
Resume at same dose 
level. 
Grade 3 
Hold* until d Grade 1.  
Resume at same dose 
level. 
Hold* until d Grade 1.  
Reduce by 1 dose 
level. 
Hold* until d Grade 1.  
Reduce by 1 dose 
level. 
Grade 4 
Off study treatment 
Off study treatment  
Off study treatment 
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. If a toxicity leads to a hold of 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. 
5.4.2.5 
Hypersensitivity Reaction 
Caution: Patients who have a mild to moderate 
hypersensitivity reaction to paclitaxel and carboplatin may 
be re-challenged, but careful attention to prophylaxis and 
bedside monitoring of vital signs is recommended. 
Hypersensitivity reactions to paclitaxel and/or carboplatin 
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 

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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 serious adverse event (see 
Section 5.2). 
5.4.2.6 
Other toxicities 
Fatigue: 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 pevonedistat and/or paclitaxel and carboplatin. 
If attribution for fatigue is at least possibly related to 
pevonedistat, this agent alone should be reduced by one 
dose level. If attribution for fatigue is unlikely or unrelated 
to pevonedistat, then the chemotherapy agent(s) with 
attribution of at least possible related should be reduced by 
one dose level. 
Electrolytes: 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 pevonedistat, paclitaxel and/or 
carboplatin, if attribution at least possibly related to drug. 
Other Adverse Events: 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. 
5.5 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
5.5.1 
Growth Factor & Transfusions 
The use of prophylactic growth factors should follow the American 
Society of Clinical Oncology (ASCO) guidelines and is not allowed for 
cycle 1; and could be administered per ASCO guidelines starting with 
cycle 2. Patients may receive red blood cell and platelet transfusions 
as clinically indicated by the treating physician. Empiric platelet 
WUDQVIXVLRQVDUHUHFRPPHQGHGIRUSODWHOHWFRXQWPF/ 

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5.5.2 
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. 
5.5.3 
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. 
5.5.4 
Venous Thromboembolism 
For patient who develop an indication to start anticoagulation during 
study therapy (i.e. a DVT or 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. 
5.5.5 
Other 
Because there is a potential for interaction of pevonedistat 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. Clinically significant metabolic enzyme inducers 
are prohibited/excluded during the study. The Study Chair should be 
alerted if the patient is taking any agent known to affect or with the 
potential for drug interactions. The study team should check a 
frequently-updated medical reference for a complete list of drugs to 
avoid or minimize use of. Appendix VI (Patient Drug Information 
Handout and Wallet Card) should be provided to patients if available. 
Table 
Concomitant Medications Excluded During the Study 
Therapy 
Comment/Exceptions 
Acetaminophen and acetaminophen-
containing products 
Agents such as acetaminophen and 
acetaminophen-containing compounds 
may be used judiciously and should not 
exceed a dose of 2 g of acetaminophen in 
a 24 hour period. 
Systemic antineoplastic therapy, except for 
hydroxyurea 
 
Clinically significant metabolic enzyme 
inducers 
Excluded IN THE STUDY 
In Arm B ONLY: Avoid the concomitant 
use of inhibitors or inducers of CYP2C8 
and CYP3A4  

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Table 
Concomitant Medications Excluded During the Study 
Therapy 
Comment/Exceptions 
Known BCRP inhibitors (ie, cyclosporine) 
Excluded but limited use is permitted 
only if clinically necessary and no 
suitable alternative exists. The patient 
may receive the BCRP inhibitor from 24 
hours after the last pevonedistat dose until 
72 hours before the next pevonedistat 
dose. For example, if a patient receives 
pevonedistat on a Monday (Day 1), 
Wednesday (Day 3), Friday (Day 5) 
schedule, then the BCRP inhibitor may be 
administered from the Saturday after the 
Day 5 dose (Day 6) up to the Friday 
(Day 26) before the Monday dose of the 
next cycle. 
Avoid the concomitant use of nephrotoxic 
drugs IN Arm B of the study 
Any investigational agent other than 
pevonedistat 
For example androgens, supraphysiologic 
doses of corticosteroids, erythropoietin, 
eltrombopag [Promacta], or romiplostim 
[Nplate] are excluded. 
BCRP=breast cancer resistance protein, CYP=cytochrome P450,  
5.6 
Duration of Therapy  
Patients will receive protocol therapy unless: 
x 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
EA2187 Forms Packet. 
x 
Patient withdraws consent. 
x 
Patient experiences unacceptable toxicity. 
x 
Patient experiences disease progression. 
x 
Non-protocol therapies are administered. 
5.7 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 3 years from the date of randomization. Patients 
will undergo follow-up visits every 3 months for the first year, and every 6 months 
for years 2-3. All patients must also be followed through completion of all protocol 
therapy. 

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6. 
Measurement of Effect 
6.1 
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 international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. 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 RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before 
randomization. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers. 
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Primary Evaluation of Response Rate 
All patients who initiate study therapy will be used in the primary 
evaluation of the response rate. 
6.1.2 
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 by chest x-ray, as  10 mm with CT scan, or  10 mm 
with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area might or might not be considered measurable. If the 
investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered 
must be defined in the protocol. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be  15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At 

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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 or pathological lymph nodes with  10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
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 
of the 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 or absence of 
unequivocal progression of each should be noted throughout follow-
up.  

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6.1.3 
Methods for Evaluation of 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 randomization. 
The same method of assessment and the same technique must 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 in 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.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, 
CT is preferable.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans).  
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 must 
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. 
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 

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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 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 complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
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 
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FDG-PET 
While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning 
to complement CT scanning in assessment of progression 
(particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following 
algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD. If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be 
the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
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. 
6.1.4 
Response Criteria 
6.1.4.1 
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. 
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 

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sum must also demonstrate an absolute increase of at 
least 5 mm. 
NOTE: 
The appearance of one or more new lesions is 
also considered progression, See Section 
6.1.4.2. 
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. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 4 weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesions. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
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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 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) LQFUHDVHVLQVL]HWRPPLQWKHVKRUWD[LVRU 
b) there is new pathological confirmation that it is disease 
(regardless of size). 
new effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (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-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once  4 wks. 
from study entry 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
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. 
6.1.4.5 
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). 
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.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 4 weeks. 
 

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7. 
Study Parameters 
7.1 
Therapeutic Parameters 
Advanced Disease Protocols 
1. Prestudy scans, ECG, and x-rays used to assess all measurable or non-measurable sites of disease must be done 
within 4 weeks prior to randomization. 
2. Prestudy medical history, physical examination, vitals, performance status and CBC (with differential and platelet 
count) should be done  weeks before randomization. 
3. All required prestudy chemistries, as outlined in Section 3, should be done  weeks before randomization – unless 
specifically required on Day 1 as per protocol. 
4. The standard of care molecular testing submission and tissue submission should be completed within 4 weeks of 
randomization. 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
 
 
 
 
Prior to 
Rando-
mization 
Day 
1 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
5 
Day 
1 
Day 
3 
Day 
5 
At disease 
progression 
4 weeks 
after last 
dose of 
study drugA 
Long term 
follow-up 
off study 
treatment 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interval historyC 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Concurrent meds 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Physical examC 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital signsC 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WeightC 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Performance 
statusC 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
 
 
 
 
Prior to 
Rando-
mization 
Day 
1 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
5 
Day 
1 
Day 
3 
Day 
5 
At disease 
progression 
4 weeks 
after last 
dose of 
study drugA 
Long term 
follow-up 
off study 
treatment 
Chemistry panelD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X 
 
Tumor 
measurements 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
CT or MRI Chest 
and AbdomenF 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
CT or MRI PelvisG 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
SOC Molecular 
Testing 
SubmissionH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue 
SubmissionH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
A: A safety follow-up visit will occur 30 days (±7 days) after the last dose of treatment. 
B 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. 
C: At subsequent visits, symptom-directed history and physical examinations including vital signs, weight and performance status should be 
performed. Vital sign measurements will be taken with the patient in the supine or sitting position. 
D: To include albumin, alkaline phosphatase, ALT, AST, bicarbonate, BUN, calcium, chloride, creatinine, GGT, glucose, lactate dehydrogenase, 
phosphorus, potassium, sodium, total bilirubin, and total protein. Before each dose of pevonedistat infusion laboratory must be done and results 
reviewed by a treating physician. 
E: All females of childbearing potential must have a negative [blood test or urine test] within 14 days prior to randomization to rule out pregnancy. 
F: CT or MRI scans of chest and abdomen will be done at baseline to assess the response per RECIST v1.1 criteria.  CTs or MRIs with IV contrast 

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Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
 
 
 
 
Prior to 
Rando-
mization 
Day 
1 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
5 
Day 
1 
Day 
3 
Day 
5 
At disease 
progression 
4 weeks 
after last 
dose of 
study drugA 
Long term 
follow-up 
off study 
treatment 
are encouraged but will be done at the investigator’s discretion.  CT imaging of chest and abdomen should occur after every 6 weeks (±7 days). 
G CT or MRI scans of 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 pelvis should occur after every 6 weeks (±7 days), unless CT scans are negative at 
baseline, then they should be repeated as clinically indicated. 
H SOC molecular testing and tissue submission should be completed within 4 weeks of randomization. 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CBC=complete blood count, CT=computed 
WRPRJUDSK\&7& FLUFXODWLQJWXPRUFHOOV(.* HOHFWURFDUGLRJUDP**7 Ȗ-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, TSH=thyroid stimulating hormone. 
Scheduled assessments every week are allowed a window of ± [3] days for day 1, 8 and 15 and +[1] day for days 3 and 
5. Days 3 and 5 should not be done early. 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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7.2 
Biological Sample Submissions 
Samples are to be submitted as outlined in Section 10. Biological materials will 
be used in the correlative study described in Section 11. 
All samples must be logged and tracked in the ECOG-ACRIN Sample Tracking 
System (STS). 
Material 
Prior to Start of Treatment 
Ship To: 
MANDATORY for Defined Laboratory Research Study 
Pre-Trial Diagnostic FFPE 
tumor tissue1,2 
X 
E-A CBPF 
1. Submit within 4 weeks of registration to trial. 
2. Submission is required, if specimen is available. New biopsy is not required. 
 

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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
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. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  Refer to the 
PMB’s website for specific policies and guidelines related to agent management.   
Agent Inventory Records: 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
Investigator Brochure Availability: 
The current 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. 
NCI Supplied Agent(s) – General Information 
NOTE: 
Under no circumstances can commercially supplied pevonedistat be used or 
substituted for the NCI-supplied pevonedistat. 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must 
return the study drug to the PMB using the NCI Return Agent Form available on the NCI 
home page (http://ctep.cancer.gov) or by calling the PMB at 240-276-6575.  

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Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all 
drugs received from the PMB using the NCI Investigational Agent Accountability Record 
available on the NCI home page (http://ctep.cancer.gov) or by calling the PMB at 240-
276-6575. A separate NCI Investigational Agent Accountability Record must be 
maintained for each patient sequence number and for each agent on this protocol. 
Useful Links and Contacts: 
x 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
x 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm 
x 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
x 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
x 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov 
x 
IB Coordinator:  IBCoordinator@mail.nih.gov 
x 
PMB email:  PMBAfterHours@mail.nih.gov 
x 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
8.1 
Pevonedistat HCl (MLN4924, NSC 793435) 
8.1.1 
Other Names  
Pevonedistat, TAK924/MLN4924; MLN4924-003 (hydrochloride salt); 
MLN4924-001 (free base); ML00644807; ML644507 
8.1.2 
Classification  
NEDD8-activating enzyme (NAE) inhibitor 
8.1.3 
Mode of Action  
MLN4924 is an inhibitor of neural precursor cell expressed 
development down-regulated 8 (NEDD8)-activating enzyme or NAE.  
NAE is essential in the NEDD8-conjugation pathway to control the 
activity of a subset of multiprotein complexes that transfer NEDD8 
molecules to protein substrates by E3 ligases.  NAE inhibitors stop the 
degradations of a subset of proteins that regulated by the 
proteasomes. 
8.1.4 
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. 
8.1.5 
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 containing the following excipients: 
 

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x 
The prepared IV solution is stable when stored at ambient room 
temperature up to 6 hours and must be administered within that 
time frame. Discard the IV bag if > 6 hours from the time of 
preparation. 
x 
The prepared IV solution is stable when stored at 2 -- 8 C (36 – 46 
F) up to 18 hours. The IV solution can be brought to ambient room 
temperature before administering to patient but must be used 
within 3 hours from the time it is removed from the refrigerator to 
completion of the IV infusion. Discard the IV bag if > 3 hours. 
8.1.9 
Dose Specifics 
x 
Arm A, B: 50 mg/m2 IV on days 1, 3, and 5 every cycle 
x 
Arm B: 20 mg/m2 IV on days 1, 3, and 5 every cycle 
8.1.10 
Route of Administration  
Intravenous 
8.1.11 
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 5% Dextrose in Water immediately 
after IV administration is complete. Protecting IV bag from light during 
IV infusion is not required. 
8.1.12 
Potential Drug Interactions 
In vitro, MLN4924 is metabolized mainly by hepatic CYP3A4/5 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.  Therefore, drugs that are CYP3A/P-gp inhibitors can be 
used in patients receiving pevonedistat. Use of strong CYP3A 
inducers (e.g., rifampin, phenytoin, St. John’s wort) with MLN4924 
is prohibited. 
In vitro, MLN4924 is not an inhibitor of CYP1A2, 2C9, 2C19, 2D6, or 
3A4/5 (IC50 > 100 μM and Ki >50 ȝ0) but is a weak inhibitor of 
&<3%DQG&,& DQGȝ0UHVSHFWLYHO\ MLN4924 
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. 
MLN4924 is a substrate of P-gp and BCRP, and a weak inhibitor of P-
gp, OATP and BCRP-mediated transport. MLN4924 is unlikely to affect 
the PK of known P-gp, BCRP or OATP substrates. Co- administration 
of BCRP inhibitors (e.g., cyclosporine) is not allowed; consult the 
protocol document if no suitable alternative exists for the patient. 

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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. 
8.1.13 
Availability 
Pevonedistat will be supplied by Takeda and distributed by 
Pharmaceutical Management Branch (PMB). 
8.1.14 
Side Effects 
See Section 5.3 for the Comprehensive Adverse Events and Potential 
Risks list (CAEPR) for Pevonedistat HCl (MLN4924, NSC793435). 
8.2 
Carboplatin 
8.2.1 
Other Names 
Paraplatin® 
8.2.2 
Classification 
Carboplatin (carboplatin injection) (platinum, diammine[1,1-
cyclobutanedicarboxylato(2-)-O,O’]-, (SP-4-2)) is a platinum 
coordination compound, used as an anti-neoplastic agent. It is a 
second-generation tetravalent organic platinum compound. It is a 
crystalline powder with the molecular formula of C6H12N2O4Pt and a 
molecular weight of 371.25. It is soluble in water at a rate of 
approximately 14 mg/mL, and the pH of a 1% solution is 5 to 7. It is 
virtually insoluble in ethanol, acetone, and dimethylacetamide. 
8.2.3 
Mode of Action 
Like cisplatin, carboplatin binds to DNA, thereby inhibiting DNA 
synthesis, in a cell cycle nonspecific manner. Carboplatin must first 
undergo activation to produce antineoplastic activity. Bidentate 
carboxylate ligands of carboplatin are displaced by water forming 
(aquation) positively charged platinum complexes, which bind to 
nucleophilic sites in DNA, such as the O-6 position on guanine. 
Carboplatin produces predominantly interstrand DNA crosslinks rather 
than DNA-protein crosslinks. Intrastrand crosslinks result from the 
formation of adducts between the activated platinum complexes of the 
drug and the N-7 atom (not exclusively) atom on guanine to produce 
1,2 intrastrand links between adjacent guanine molecules, between 
neighboring guanine and adenosine molecules, or between 
neighboring guanine molecules. Interstrand cross-linking within the 
DNA helix also occurs. Platinum adducts may inhibit DNA replication, 
transcription and ultimately cell division. 
8.2.4 
Storage and Stability 
Store intact vials at room temperature at 25°C (77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Further 
dilution to a concentration as low as 0.5 mg/mL is stable at room 

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temperature (25°C) for 8 hours in NS or D5W. Stability has also been 
demonstrated for dilutions in D5W in PVC bags at room temperature 
for 9 days; however, the manufacturer recommends use within 8 
hours due to lack of preservative. Multidose vials are stable for up to 
14 days after opening when stored at 25°C (77°F) following multiple 
needle entries. 
8.2.5 
Dose Specifics 
x 
Arm B: Carboplatin at AUC 5 IV on day 1 of every 21 day cycle 
Calvert Formula for Carboplatin (AUC) Dosing 
Total dose (mg) = target AUC (in mg/mL/minute) * [GFR (in L/minute) 
+ 25] 
For the purposes of this protocol, the GFR is considered to be 
equivalent to the creatinine clearance. 
Glomerular Filtration Rate (GFR) Estimation: Calculated creatinine 
clearance of  50 cc/min using the Cockcroft-Gault formula: 
Males: 
(140 – Age in years) x Actual Body Weight in kg 
72 x Serum Creatinine (mg/dL) 
Females: Estimated creatinine clearance for males x 0.85 
Round up any creatinine  0.7 mg/dL, to 0.7 mg/dL 
With the Calvert formula, the total (final) dose of carboplatin is 
calculated in mg, not mg/m2. 
8.2.6 
Preparation 
Manufacturer’s labeling states solution can be further diluted to 
concentrations as low as 0.5 mg/mL in NS or D5W; however, most 
clinicians generally dilute dose in either 100 mL or 250 mL of NS or 
D5W. Concentrations used for desensitization vary based on protocol. 
Hazardous agent; use appropriate precautions for handling and 
disposal. Needles or IV administration sets that contain aluminum 
should not be used in the preparation or administration of carboplatin; 
aluminum can react with carboplatin resulting in precipitate formation 
and loss of potency. 
8.2.7 
Route of Administration 
Intravenous 
8.2.8 
Incompatibilities 
Amphoterecin B chloesteryl sulfate complex. Aluminum reacts with 
carboplatin causing precipitate formation and loss of potency; 
therefore, needles or intravenous sets containing aluminum parts that 
may come in contact with the drug must NOT be used for the 
preparation or administration of carboplatin. 
8.2.9 
Availability 
Carboplatin (Bristol-Myers Oncology Division) is commercially 
available in 50, 150, and 450 mg vials. 

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8.2.10 
Side Effects 
Please refer to the commercial package insert. 
8.2.11 
Nursing/Patient Implications 
x 
Monitor CBC and platelet count; nadir occurs at approximately day 
21 with recovery by day 28-30. 
x 
Premedicate with antiemetics—evaluate effectiveness. 
Ondansetron (or other 5HT3 antagonist) and dexamethasone are 
required. 
x 
Monitor fluid status—maintain adequate hydration. Pre- and post-
treatment hydration may be administered per institutional 
standards. 
x 
Assess skin/mucous membranes. 
x 
Assess for signs of peripheral neuropathy—coordination, sensory 
loss. 
8.2.12 
References 
1. Calvert AH, et al. Carboplatin dosage: Prospective evaluation of a 
simple formula based on renal function. J Clin Oncol 1989; 
7:1748-1756. 
2. Woloschuk DMM, Pruemer JM, Cluxton RJ. Carboplatin: A new 
cisplatin analog. Drug Intell Clin Pharm 1988; 22:843-849. 
3. Christian MC. Carboplatin. In: Principles and Practice of 
Oncology, PPO Updates 1989; 3(11):1-16. 
8.3 
Paclitaxel 
8.3.1 
Other Names 
Taxol, NSC 673089. 
8.3.2 
Classification 
Antimicrotubule agent. 
8.3.3 
Mode of Action 
Promotes microtubule assembly and stabilizes tubulin polymers by 
preventing their depolarization, resulting in the formation of extremely 
stable and nonfunctional microtubules, and consequently inhibition of 
many cell functions. 
8.3.4 
Storage and Stability 
The intact vials are stored under refrigeration. Freezing does not 
adversely affect the product. Solutions diluted to a concentration of 
0.3 to 1.2 mg/mL in normal saline, 5% dextrose, 5% dextrose and 
normal saline, or 5% dextrose in Ringer’s solution are stable for up to 
27 hours when stored at room temperature and normal room light. 
8.3.5 
Dose Specifics 
x 
Arm B: Paclitaxel 175mg/m2 IV on day 1 of each 21 day cycle. 
8.3.6 
Preparation 

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The concentrated solution must be diluted prior to use in normal 
saline, 5% dextrose, 5% dextrose and normal saline, or 5% dextrose 
in Ringer's solution to a concentration of 0.3 -1.2 mg/mL. Solutions 
exhibit a slight haze, common to all products containing non-ionic 
surfactants. Glass, polypropylene, or polyolefin containers and non-
PVC-containing (nitroglycerin) infusion sets should be used.  A small 
number of fibers (within acceptable limits established by the USP) 
have been observed after dilution. Therefore, a hydrophilic 0.22 
micron in-line filter should be used. Analyses of solutions filtered 
through IVEX-2 and IVEX-HP (Abbott) 0.2 micron filters showed no 
appreciable loss of potency. 
Solutions exhibiting excessive particulate formation should not be 
used. 
8.3.7 
Route of Administration 
Intravenous. 
8.3.8 
Incompatibilities 
Avoid the use of PVC bags and infusion sets due to leaching of DEHP 
(plasticizer). Ketoconazole may inhibit paclitaxel metabolism, based 
on in vitro data. 
8.3.9 
Availability 
A concentrated solution of 6 mg/mL in polyoxyethylated castor oil 
(Cremophor EL) 50% and dehydrated alcohol 50% is commercially 
available in 5 mL vials. 
8.3.10 
Side Effects 
Please refer to the commercial package insert 
8.3.11 
Nursing/Patient Implications 
x 
Monitor CBC and platelet count prior to drug administration. 
x 
Symptom management of expected nausea, vomiting, and 
stomatitis. 
x 
Monitor for and evaluate abdominal pain occurring after paclitaxel 
administration (especially in severely neutropenic patients and in 
those receiving G-CSF) due to the risk of ischemic and 
neutropenic enterocolitis. 
x 
Advise patients of possible hair loss. 
x 
Cardiac monitoring for assessment of arrhythmias in patients with 
serious conduction abnormalities. 
x 
Monitor liver function tests. 
x 
Advise patient of possible arthralgias and myalgias which may 
occur several days after treatment. Monitor for symptoms of 
peripheral neuropathy. 
x 
Monitor for signs and symptoms of hypersensitivity reactions. 
Insure that the recommended premedications have been given. 
Premedications (diphenhydramine, steroids, and H2 blocker) 
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reactions but do not provide complete protection. Emergency 
agents (diphenhydramine and epinephrine) should be available. 
x 
Evaluate IV site regularly for signs of infiltration.  It is not known if 
paclitaxel is a vesicant; however, the CremophorEL vehicle for this 
drug can cause tissue damage. 
x 
In-line filtration with a 0.22 micron filter should be used. 
8.3.12 
References 
Rowinsky EK, Casenave LA, Donehower RC.  Taxol:  A novel 
investigational microtubule agent.  J Natl Cancer Inst 1990; 82:1247-
1259. 
Gregory RE, DeLisa AF.  Paclitaxel:  A new antineoplastic agent for 
refractory ovarian cancer.  Clin Pharm 1993; 12: 401-415. 
Rowinsky EK, Eisenhauer EA, Chaudry V, et al.  Clinical toxicities 
encountered with paclitaxel.  Semin Oncology 1993; 20:1-15. 
Walker FE.  Paclitaxel:  Side effects and patient education issues.  
Semin Oncology Nurs 1993; 9(suppl 2):6-10. 
 

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9. 
Statistical Considerations 
This trial is a randomized phase II study evaluating each arm separately for an efficacy 
signal. The primary endpoint is objective response (complete or partial response by 
RECIST v1.1). Secondary endpoints are to report on PFS, toxicity, disease control rate 
and overall survival. For the primary ORR endpoint, the null (uninteresting) proportion is 
10% and the target proportion that would lead to further study is 30% (alternative). 
Within each arm there will be a two-stage minimax design such that 16 eligible and 
treated patients will be evaluated at the first stage in each arm (33 across the two arms 
to allow for ineligibility). Accrual will pause while awaiting the results of the first stage 
analysis as the accrual rate is expected to be on the order of 5 patients per month. If at 
least 2 patients in an arm achieve response, the arm will move to the second stage and 
recruit 9 additional eligible and treated patients. Success of an arm will be achieved 
(reject the null hypothesis) if 5 or more patients have a response. Within each arm there 
is a 51.5% chance of stopping at the first stage under the null hypothesis and each arm 
has type I error of no more than 10% and 90% power. If both arms move to their 
respective second stages, the recommended arm for further testing will be decided 
based on the overall profile of efficacy and safety. 
A total of up to 52 patients will be enrolled if the study moves to the second stage in both 
arms (33 at the first stage and 19 at the second stage). Accrual has been increased by 2 
patients to allow for ineligibility. 
With 25 eligible and treated patients in an arm, there is at least 80% probability of 
observing a rare adverse event with true probability of 0.065 or higher and a 90% 
confidence interval for any binomial parameter will be no wider than 36%. 
Correlative Endpoints 
Immunohistochemistry for NEDD8, NAE1 and UBC12 will be performed on FFPE pre-
trial diagnostic tissue. Biomarker quantification will be calculated as a continuous 
variable (mean optical density) and also as ordered categories (ex. 0, 1+, 2+, or 3+). 
Biomarker quantification will then be correlated with treatment response. All correlative 
studies are considered exploratory as power will be limited with 25 patients per arm. For 
example, in order to have 80% power to detect a difference in objective response 
between two groups equally split via a correlative biomarker, the true difference in 
response between the group would need to be on the order of 50%. Hence the study is 
not expected provide any definitive evidence, rather they will be hypothesis generating. 
Descriptive statistics will primarily be generated to summarize the correlative data. For 
continuous variables, descriptive statistics may include the number of subjects (n), 
mean, standard deviation, median, minimum, and maximum; frequencies and 
percentages may be displayed for categorical data. Data summaries will be presented 
by arm. Statistical significance will be determined by students’ t-test for normally 
distributed data. If data distributions are not normal, non-parametric methods will be 
used (Wilcoxon rank sum test). 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN studies. 
Reports of these analyses are sent to the ECOG-ACRIN Principal Investigator or Senior 
Investigator at the participating institutions. Expedited reporting of certain adverse 
events is required, as described in Section 5.2. 

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9.1 
Gender and Ethnicity  
Based on previous data from PrECOG study 0204 (74 patients) the anticipated 
accrual in subgroups defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
2 
4 
Not Hispanic or Latino 
29 
19 
48 
Ethnic Category: Total of all subjects 
31 
21 
52 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
0 
1 
Black or African American 
2 
2 
4 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
28 
19 
47 
Racial Category: Total of all subjects 
31 
21 
52 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses.  Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
 

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10. 
Specimen Submissions 
Tumor tissue specimens should be submitted for use in the laboratory correlative study 
described in Section 11. Residuals from the analysis will be retained for unknown future 
research for patients that answer “Yes” to “I agree that my samples and related health 
information may be kept in a biobank for use in future health research” 
All specimens must be labeled with the ECOG-ACRIN protocol number, the patient’s 
initials and ECOG-ACRIN sequence number, the collection date, and the type of sample. 
For pathology materials, it is strongly recommended that full patient names be provided. 
All specimens must be logged and tracked via the ECOG-ACRIN Sample Tracking 
System (STS) Web Application (Section 10.4) and submitted with an STS generated 
shipping manifest. 
10.1 
Collection and Submission Schedule 
See Section 7.2 for a table summarizing the submission requirements. 
10.1.1 
Tissue Submissions 
Specimens are to be submitted within 4 weeks following registration to 
the trial. 
Guidelines for pathologists are provided in Appendix I. 
10.1.1.1 
Pre-Trial Diagnostic Tissue (Mandatory if available): 
Please submit fixed, paraffin-embedded tumor tissue 
blocks. 
NOTE: 
If blocks are not available for submission, the 
following alternative is to be submitted: 1 H&E 
(from the source block), 1-2 core punches (4 
mm minimum) and 20 unstained slides (5 
microns thick). Slides, including the H&E, are to 
be numbered consecutively in the order cut. 
10.1.1.2 
Forms 
The relevant pathology and surgical reports must 
accompany all tissue submissions: 
x 
Copy of the diagnostic or surgical Pathology Report 
x 
Other Immunologic and cytologic reports 
x 
STS generated shipping manifest for all submitted 
tissue 
10.2 
Shipping Procedures  
Submissions to ECOG-ACRIN Central Biorepository and Pathology Facility 
The pathology materials are to be submitted within 4 weeks following registration 
to the trial. Tissue samples are to be shipped at ambient (use a cool pack in 
warm weather). 
Shipping manifest generated from the ECOG-ACRIN STS system must 
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Access to the shipping account for specimen shipments to the ECOG-ACRIN 
CBPF at MD Anderson can now only be obtained by logging into fedex.com with 
an account issued by the ECOG-ACRIN CBPF. For security reasons, the 
account number will no longer be given out in protocols, over the phone, or via 
email. If your site needs to have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
10.3 
Use of Specimens in Research 
Specimens submitted will be processed to maximize their utility for current and 
future research projects and may include, but not limited to, extraction of plasma, 
serum, DNA and RNA. 
The appropriate materials will be distributed to investigators for research studies. 
Specimens from patients who consented to allow their specimens to be used for 
future approved research studies, including residuals from the currently defined 
reviews and research studies, will be retained in an ECOG-ACRIN-designated 
central repository. For this trial, specimens will be retained at the ECOG-ACRIN 
Central Biorepository and Pathology Facility. Specimens will be de – identified 
prior to distribution for any approved research products. 
If future use is denied or withdrawn by the patient, the samples will be removed 
from consideration for use in any future study. Pathology materials may be 
retained for documentation purposes or returned to the site. All other specimens 
will be destroyed per guidelines of the respective repository. 
10.4 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all samples submitted to the E-
A CBPF on this trial be entered and tracked using the ECOG-ACRIN Sample 
Tracking System (STS). As of June 2007, the software will allow the use of either 
1) an ECOG-ACRIN user-name and password previously assigned (for those 
already using STS), or 2) a CTSU username and password. 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software.  A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 

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An STS generated shipping manifest must be generated and shipped with all 
sample submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu . 
Study Specific Notes: 
If the STS is unavailable, the Generic Specimen Submission Form (#2981) is to 
be used as a substitute for the STS shipping manifest. The completed form is to 
be faxed to the receiving laboratory the day the samples are shipped. Indicate 
the appropriate Lab on the submission form: 
x 
ECOG-ACRIN CBPF 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.5 
Sample Inventory Submission Guidelines  
Inventories of all samples submitted will be tracked via the ECOG-ACRIN STS 
and receipt and usability verified by the receiving laboratory. Inventories of 
specimens forwarded and utilized for the will be submitted by the laboratory to 
the ECOG-ACRIN Operations Office - Boston on a monthly basis in an electronic 
format defined by the ECOG-ACRIN Operations Office - Boston. 
 

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11. 
Specimen Analyses: Research Studies 
Pre-trial diagnostic tissue is required to be submitted for the following research study. 
This study will be performed at the University of Wisconsin, under the direction of Dustin 
Deming, MD. 
11.1 
Immunohistochemistry for NEDD8, NAE1 and UBC12 
Historic histological slides will be used to compare the efficacy of pevonedistat 
with the presence of overexpression of the neddylation pathway. The Deming 
laboratory has significant experience with immunohistochemistry (IHC) 
techniques. Immunohistochemical studies will be performed on formalin-
fixed/paraffin-embedded archival tumor tissue examining levels of NEDD8, NAE1 
and UBC12. Biomarker quantification will be calculated as a continuous variable 
(mean optical density) and also as quartiles (ex. 0, 1+, 2+, or 3+). Biomarker 
quantification will then be correlated with treatment response. Additionally, the 
molecular profile obtained as part of standard of care will be compared to the 
expression of these markers using a regression analysis. 10 slides will be 
provided by the biobank to the investigating laboratory for these analyses. 
11.2 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data is 
due at the ECOG-ACRIN Operations Office - Boston 1 week after these cut-off 
dates 
 

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12. 
Electronic Data Capture 
Please refer to the EA2187 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
Data for this study will be submitted via the Data Mapping Utility (DMU). Cumulative 
protocol- and patient-specific data will be submitted weekly to CTEP electronically via 
the DMU.  DMU Complete reporting consists of Patient Demographics, Baseline 
Abnormalities, On/Off Treatment/Study Status, Treatment/Course/Dosing information, 
Adverse Events, Late Adverse Events, and Response data as applicable. Instructions for 
setting up and submitting data via DMU are available on the CTEP Website:  
(https://ctep.cancer.gov/protocolDevelopment/dmu.html). 
NOTE: 
All adverse events (both routine and serious) that meet the protocol 
mandatory reporting requirements must be reported via DMU in addition to 
expedited reporting of serious adverse events via CTEP-AERS. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. 
Ramirez-Merino N, Aix SP, Cortes-Funes H. Chemotherapy for 
cholangiocarcinoma: An update. World J Gastrointest Oncol 2013;5:171-6. 
2. 
Ercolani G, Vetrone G, Grazi GL, et al. Intrahepatic cholangiocarcinoma: primary 
liver resection and aggressive multimodal treatment of recurrence significantly 
prolong survival. Ann Surg 2010;252:107-14. 
3. 
Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 
225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507-17; discussion 
17-9. 
4. 
Nagorney DM, Donohue JH, Farnell MB, Schleck CD, Ilstrup DM. Outcomes after 
curative resections of cholangiocarcinoma. Arch Surg 1993;128:871-7; discussion 
7-9. 
5. 
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine 
for biliary tract cancer. N Engl J Med 2010;362:1273-81. 
6. 
Fornaro L, Vivaldi C, Cereda S, et al. Second-line chemotherapy in advanced 
biliary cancer progressed to first-line platinum-gemcitabine combination: a 
multicenter survey and pooled analysis with published data. J Exp Clin Cancer Res 
2015;34:156. 
7. 
Lamarca A, Palmer DH, Wasan HS, et al. ABC-06 | A randomised phase III, multi-
centre, open-label study of active symptom control (ASC) alone or ASC with 
oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally 
advanced / metastatic biliary tract cancers (ABC) previously-treated with 
cisplatin/gemcitabine (CisGem) chemotherapy. Journal of Clinical Oncology 
2019;37:4003-. 
8. 
Wu S, Yu L. Targeting cullin-RING ligases for cancer treatment: rationales, 
advances and therapeutic implications. Cytotechnology 2016;68:1-8. 
9. 
Soucy TA, Smith PG, Milhollen MA, et al. An inhibitor of NEDD8-activating enzyme 
as a new approach to treat cancer. Nature 2009;458:732-6. 

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10. 
Gao Q, Yu GY, Shi JY, et al. Neddylation pathway is up-regulated in human 
intrahepatic cholangiocarcinoma and serves as a potential therapeutic target. 
Oncotarget 2014;5:7820-32. 
11. 
Cheng F, He R, Zhang L, et al. Expression of neddylation-related proteins in 
melanoma cell lines and the effect of neddylation on melanoma proliferation. Oncol 
Lett 2014;7:1645-50. 
12. 
Li L, Wang M, Yu G, et al. Overactivated neddylation pathway as a therapeutic 
target in lung cancer. J Natl Cancer Inst 2014;106. 
13. 
Lin JJ, Milhollen MA, Smith PG, Narayanan U, Dutta A. NEDD8-targeting drug 
MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering 
checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res 
2010;70(24):10310-20. 
14. 
Jia L, Li H, Sun Y. Induction of p21-dependent senescence by an NAE inhibitor, 
MLN4924, as a mechanism of growth suppression. Neoplasia 2011;13(6):561-9. 
15. 
Milhollen MA, Narayanan U, Soucy TA, Veiby PO, Smith PG, Amidon B. Inhibition 
of NEDD8-activating enzyme induces rereplication and apoptosis in human tumor 
cells consistent with deregulating CDT1 turnover. Cancer Res 2011;71(8):3042-51. 
16. 
Kee Y, Huang M, Chang S, et al. Inhibition of the Nedd8 system sensitizes cells to 
DNA interstrand cross-linking agents. Mol Cancer Res 2012;10:369-77. 
17. 
Bouck DC, Garcia K, Blank JL, et al. 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 2015;14(12 Suppl 2):Abstract nr C55. 
18. 
Luo Z, Yu G, Lee HW, et al. The Nedd8-activating enzyme inhibitor MLN4924 
induces autophagy and apoptosis to suppress liver cancer cell growth. Cancer Res 
2012;72(13):3360-71. 
19. 
Luo Z, Pan Y, Jeong LS, Liu J, Jia L. Inactivation of the Cullin (CUL)-RING E3 
ligase by the NEDD8-activating enzyme inhibitor MLN4924 triggers protective 
autophagy in cancer cells. Autophagy 2012;8(11):1677-9. 
20. 
Beinke S, Ley SC. Functions of NF-kappaB1 and NF-kappaB2 in immune cell 
biology. Biochem J 2004;382:393-409. 
21. 
Brown JS, Lukashchuk N, Sczaniecka-Clift M, et al. Neddylation promotes 
ubiquitylation and release of Ku from DNA-damage sites. Cell Rep 2015;11:704-
14. 
22. 
Bhatia S, Pavlick AC, Boasberg P, et al. A phase I study of the investigational 
NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients 
with metastatic melanoma. Invest New Drugs 2016;34:439-49. 
23. 
Sarantopoulos J, Shapiro GI, Cohen RB, et al. Phase I Study of the Investigational 
NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients 
with Advanced Solid Tumors. Clin Cancer Res 2016;22:847-57. 
24. 
Shah JJ, Jakubowiak AJ, O'Connor OA, et al. Phase I Study of the Novel 
Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in 
Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma. Clin Cancer 
Res 2016;22:34-43. 
25. 
Swords RT, Kelly KR, Smith PG, et al. Inhibition of NEDD8-activating enzyme: a 
novel approach for the treatment of acute myeloid leukemia. Blood 2010;115:3796-
800. 

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26. 
Garcia K, Blank JL, Bouck DC, et al. Nedd8-activating enzyme inhibitor MLN4924 
provides synergy with mitomycin C through interactions with ATR, BRCA1/BRCA2, 
and chromatin dynamics pathways. Mol Cancer Ther 2014;13:1625-35. 
27. 
Lockhart AC, Bauer TM, Aggarwal C, et al. Phase Ib study of pevonedistat, a 
NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and 
paclitaxel, or gemcitabine, in patients with advanced solid tumors. Invest New 
Drugs 2018. 
28. 
Lockhart A, Bauer, Harvey R. Phase 1b trial of investigationa NEDD8-activating 
enzyme inhibitor pevonedistat (TAK924/MLN4924) in combination with docetaxel, 
paclitaxel/carboplatin, or gemcitabine in patients with solid tumors. Mol Cancer Res 
2015;14:Abstract B26. 
29. 
Lip GY, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. 
European heart journal 2014;35:1844-55. 
 

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Advanced Intrahepatic Cholangiocarcinoma 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981) 

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Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility (CBPF): 
x 
Institutional Surgical Pathology Report 
x 
Pathology materials 
x 
ECOG-ACRIN Sample Tracking System (STS)-Generated Shipping Manifest 
Instructions: 
1. Adequate patient identifying information must be included with every submission. It is 
strongly recommended that full patient names be provided. The information will be 
used only to identify patient materials, will expedite any required communications 
with the institution (including site pathologists). 
2. Pathology materials required for research: 
x 
FFPE Pre-Trial Diagnostic, Mandatory (if available, no new biopsy required) 
Pre-trial diagnostic specimens are to be submitted within 4 weeks following 
registration to the trial. 
NOTE: 
If blocks are not available for submission, the following alternative is to be 
submitted: 1 H&E (from the source block), 20 unstained slides (5 microns 
thick) and 1-2 core punches (4 mm minimum). Slides, including the H&E, are 
to be numbered consecutively in the order cut. 
NOTE: 
Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
3. A copy of the ECOG-ACRIN STS Sample Tracking System manifest or relevant 
sample submission documents should be kept for your records. 
4. Copies of the pathology, cytology and procedure reports associated with the 
submitted tissue must be submitted. Double-check that ALL required forms, reports 
and pathology samples are included in the package. 
5. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center  
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology 
Facility. 
 

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MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA2187: A Phase 2 Study of 
Pevonedistat in Combination with Carboplatin and Paclitaxel in 
Advanced Intrahepatic Cholangiocarcinoma 
 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for laboratory studies. 
Keep a copy of the submission for your records and return any relevant completed 
forms, the surgical pathology report(s), the slides and/or blocks and any other required 
material to the Clinical Research Associate (CRA). The CRA will forward all required 
pathology material to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF). 
Pathology materials submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies per patient consent.  Paraffin blocks will be returned upon 
request for purposes of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
This review will be retrospective and will not impact patient participation in EA2187. 
If you have any questions regarding this request, please contact the Central 
Biorepository and Pathology Facility at (1-844-744-2420 (713-745-4440 Local or 
International Sites) or email: eacbpf@mdanderson.org 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
Thank you. 
 

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Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

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

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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: 
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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A Phase 2 Study of Pevonedistat in Combination with Carboplatin and Paclitaxel in 
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Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 

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A Phase 2 Study of Pevonedistat in Combination with Carboplatin and Paclitaxel in 
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Appendix V 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy 
test regardless of age or disease state) of a female patient while she is on pevonedistat, or 
within 28 days of the female patient’s last dose of pevonedistat must be reported in an 
expeditious manner. The outcome of the pregnancy and neonatal status must also be 
reported. 
How should the pregnancy be reported? 
For this study, a pregnancy, suspected pregnancy (including a positive or inconclusive 
pregnancy test) must be initially reported on the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle or Post Registration folder in Medidata Rave. Once 
the adverse event is entered into Rave, the Rules Engine on the Expedited Reporting 
Evaluation Form will confirm the pregnancy requires expedited reporting. The CTEP-AERS 
report must then be initiated directly from the Expedited Reporting Evaluation Form in 
Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-AERS website. 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy 
test need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, 
followed by a complete expedited CTEP-AERs report within 5 calendar days of the initial 24-
hour report. 
What other information do I need in order to complete the CTEP-AERs report for a 
pregnancy? 
x 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium 
and perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) 
“Pregnancy, puerperium and perinatal conditions” 
x 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
x 
The start date of the pregnancy should be reported as the calculated date of conception.   
x 
The potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” section of 
the CTEP-AERs report.  
What else do I need to know when a pregnancy occurs to a patient? 
x 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status in CTEP-AERS accessed 
via Medidata Rave 
x 
The decision on whether an individual female patient can continue protocol treatment will 
be made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office – Boston. Please contact the ECOG-ACRIN Operations Office – 
Boston to ask for a conference call to be set up with the appropriate individuals.  

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x 
It is recommended the female subject be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling.  
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERs 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself. 
However, if the outcome of the pregnancy occurred on a subsequent cycle, a new and 
separate CTEP-AERs report should be initiated (via Medidata Rave) reporting the outcome 
of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects. For 
assistance in recording the grade or category of these events, please contact the CTEP 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed 
on a case by case basis. 
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
For this study, it must initially be reported on the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle or Post Registration folder in Medidata Rave. Once 
the adverse event is entered into Rave, the Rules Engine on the Expedited Reporting 
Evaluation Form will confirm the pregnancy loss requires expedited reporting. The CTEP-
AERS report must then be initiated directly from the Expedited Reporting Evaluation Form in 
Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-AERS website. The 
pregnancy loss must be reported as a Grade 4 “Pregnancy Loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A pregnancy loss should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A death occurring during the first 28 days after 
birth” that is felt by the investigator to be at least possibly due to the investigational 
agent/intervention.  However, for this protocol, any neonatal death that occurs within 28 
days of birth, without regard to causality, AND any infant death after 28 days that is 
suspected of being related to the in utero exposure to Pevonedistat must be initially reported 
on the Adverse Event Form or Late Adverse Event Form in the appropriate Treatment Cycle 
or Post Registration folder in Medidata Rave.  Once the event is entered into Rave, the 
Rules engine on the Expedited Reporting Evaluation Form will confirm the neonatal death 
requires expedited reporting. The CTEP-AERS report must then be initiated directly from the 
Expedited Reporting Evaluation Form in Medidata Rave.  Do not initiate the CTEP-AERS 
report via the CTEP-AERS website.  The neonatal death must be reported as a Grade 4 
“Death neonatal” under the System Organ Class (SOC) “General disorder and 
administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 

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Additional Required Forms: 
When submitting CTEP-AERs reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any 
additional medical information to CTEP (301-897-7404). This form is available on CTEP's 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/PregnancyReport
Form.pdf). 

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A Phase 2 Study of Pevonedistat in Combination with Carboplatin and Paclitaxel in 
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Appendix VI 
 
Patient Drug Interactions Handout and Wallet Card 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
      
Study 
Doctor: 
      
Study Doctor 
Phone #:  
      
Study 
Drug(s): 
MLN4924 
(Pevonedistat) 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute. 
These are the things that your healthcare providers need to know: 
MLN4924 (pevonedistat) interacts with certain specific enzyme in your liver or other tissue like 
the gut and certain transport proteins that help move drugs in and out of cell. 
 
Explanation 
CYP 
isoenzymes 
The enzymes in question are CYP3A4/5.  MLN4924 (pevonedistat) is broken down 
by CYP3A4/5 and may be affected by drugs that are moderate or strong inducers of 
CYP3A4/5.  Use of CYP3A4 inducers (e.g., St. Jon’s Wort, rifampin, phenytoin) is 
not allowed while taking MLN4924. 
Transport 
proteins 
The transporter enzymes and proteins in question are P-glycoprotein (P-gp), OATP 
and BCRP.  MLN4924 is moved in and out of cells/organs by P-gp and BCRP.  Use 
caution with concomitant drugs that are inhibitors of P-gp.  Concurrent use of drugs 
that are BCRP inhibitors (e.g., cyclosporine) is not allowed.   MLN4924 may affect 
the ability of other drugs to be moved in and out of cells by inhibiting P-gp, OATP 
and BCRP.  Use substrates of these transport proteins with caution. 
These are the things that you need to know: 
The study drug MLN4924 (pevonedistat), may interact with other drugs which can cause side 
effects. For this reason, it is very important to tell your doctors about all your medicines, 
including: (a) medicines you are taking before this clinical trial, (b) medicines you start or stop 
taking during this study, (c) medicines you buy without a prescription (over-the-counter remedy), 
(d) herbals or supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or 
an updated medication list with you. 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care 
providers to review any medicines and herbal supplements that are considered moderate or 
strong inhibitors or inducers of CYP3A4/5, P-gp, OATP and BCRP. 
x 
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. 
x 
Make sure your doctor knows to avoid certain prescription medications. 
x 
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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Table 
Concomitant Medications Excluded During the Study 
Therapy 
Comment/Exceptions 
Acetaminophen and acetaminophen-containing 
products 
Agents such as acetaminophen and 
acetaminophen-containing compounds may be used 
judiciously and should not exceed a dose of 2 g of 
acetaminophen in a 24 hour period. 
Systemic antineoplastic therapy, except for 
hydroxyurea 
 
Clinically significant metabolic enzyme inducers 
Excluded IN THE STUDY 
In Arm B ONLY: Avoid the concomitant use of 
inhibitors or inducers of CYP2C8 and CYP3A4 
Known BCRP inhibitors (ie, cyclosporine) 
Excluded but limited use is permitted only if 
clinically necessary and no suitable alternative 
exists. The patient may receive the BCRP inhibitor 
from 24 hours after the last pevonedistat dose until 
72 hours before the next pevonedistat dose. For 
example, if a patient receives pevonedistat on a 
Monday (Day 1), Wednesday (Day 3), Friday 
(Day 5) schedule, then the BCRP inhibitor may be 
administered from the Saturday after the Day 5 dose 
(Day 6) up to the Friday (Day 26) before the Monday 
dose of the next cycle. 
Avoid the concomitant use of nephrotoxic drugs IN 
Arm B of the study 
Any investigational agent other than pevonedistat 
For example androgens, supraphysiologic doses of 
corticosteroids, erythropoietin, eltrombopag 
[Promacta], or romiplostim [Nplate] are excluded. 
BCRP=breast cancer resistance protein, CYP=cytochrome P450,