Conditions: Mesothelioma
Keywords: Pevonedistat Pemetrexed Cisplatin 17-361
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 9
Healthy volunteers: no

Brief summary:
The purpose of this study is to test any good and bad effects of activity pevonedistat taken alone, and also to test the safety of pevonedistat in combination with standard chemotherapy, pemetrexed/cisplatin.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: pevonedistat intervention 2: Pemetrexed and cisplatin
Intervention descriptions: intervention 1: Pevonedistat will be administered as an IV infusion at a dose of 50 mg/m2 days 1, 3, and 5 of a 21-day cycle.Treatment will be administered as an outpatient. intervention 2: Pemetrexed, 500 mg/m2 and cisplatin, 75 mg/m2, will be given at fixed doses on day 1 of each cycle.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 1 of 52 
 
 
 
 
 
 
 
Pevonedistat as a Single Agent and in Combination with Chemotherapy in Patients with 
Malignant Mesothelioma 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
Principal Investigator/Department: 
Marjorie G. Zauderer, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Andrea Cercek, MD 
Medicine 
Investigator(s)/Department: 
Charles Rudin, MD, PhD 
Mark Kris, MD 
Gregory Riely, MD, PhD 
Jamie Chaft, MD 
Alexander Drilon, MD 
Helena Yu, MD  
Stephen Veach, MD 
Matthew Hellmann, MD 
Bob Li, MD 
Piro Lito, MD 
Paul Paik, MD 
Robert Daly, MD 
Victoria Lai, MD 
Kathryn Arbour, MD 
Michael Offin, MD 
Glenn Heller, MD, PhD 
Michelle Ginsberg, MD 
Etay Ziv, MD, PhD 
Stephen Solomon, MD 
Leonard B Saltz, MD 
David H Ilson, MD, PhD 
David P Kelsen, MD 
Nancy Kemeny, MD 
Eileen O'Reilly, MBBCh BAO 
Andrew Saul Epstein, MD 
James Joseph Harding, MD 
Yelena Yuriy Janjigian, MD 
Geoffrey Yuyat Ku, MD 
Diane Lauren Reidy, MD  
Neil Howard Segal, MD, PhD 
Armin Shahrokni, MD 
Anna Mary Varghese, MD 
Rona Denit Yaeger, MD 
Kenneth Ho-Ming Yu, MD 
Ghassan Abou-Alfa, MD 
Zsofia Stadler, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Epidemiology/Biostats 
Radiology 
Radiology  
Interventional Radiology 
Medicine 
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Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Medicine 
Medicine 
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Medicine 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 2 of 52 
 
 
 
 
 
Elizabeth Won, MD 
Medicine 
Nitya Raj, MD 
Medicine 
Karuna Ganesh, MD 
Medicine 
Luis Diaz, MD 
Medicine 
Danny Khalil, MD 
Medicine 
Afsheen Iqbal, MD 
Medicine 
Juliana Eng, MD 
Medicine 
John Fiore, MD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Pamela Drullinsky,  MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Han Xiao, MD 
Medicine 
Loren Michel, MD 
Medicine 
Curtis Chong, MD 
Medicine 
Sree Chalasani, MD 
Medicine 
Avni Desai, MD 
Medicine 
Stuart Lichtman, MD 
Medicine 
Jia Li, MD 
Medicine 
Jahan Aghalar, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Parisa Momtaz, MD 
Medicine 
Colette Owens, MD 
Medicine 
Marina Shcherba, DO 
Medicine 
Isabel Preeshagul, MD 
Medicine 
Daniel Danila, MD 
Medicine 
Ping Gu, MD 
Medicine 
Anuja Kriplani, MD 
Medicine 
Louise Ligresti, MD 
Medicine 
Rui Wang, MD 
Medicine 
Leslie Tyson, NP 
Nursing 
Linda Ahn, NP 
Nursing 
Alison Massey, NP 
Nursing 
Michelle Lyn, NP 
Nursing 
Elizabeth Panora, NP 
Nursing 
Diana Velez, NP 
Nursing 
Christina Larsen, NP 
Nursing 
Leticia Smith, APN 
Nursing 
Christine Anderson, NP 
Nursing 
Karen Flynn, APN 
Nursing 
Joanne Wells, APN 
Nursing 
Janet Cogswell, RN 
Nursing 
Raylene Langish, RN 
Nursing 
Sherie Mar-Chaim, RN 
Nursing 


Page 3 of 52 
 
 
 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Gloria Wasilewski, RN 
Lisa Sarmasti,RN 
Nicole Heinz, RN 
Jessica Marchisotto, RN 
Maureen Kennedy, RN 
Irene Kelly, RN 
Geri Arnell, RN 
Megan Stasi, RN 
Ofer Maimran, RN 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Consenting 
Professional(s)/Department: 
Marjorie G. Zauderer, MD 
Andrea Cercek, MD 
Charles Rudin, MD, PhD 
Mark Kris, MD 
Gregory Riely, MD, PhD 
Jamie Chaft, MD 
Alexander Drilon, MD 
Helena Yu, MD  
Stephen Veach, MD 
Matthew Hellmann, MD 
Bob Li, MD 
Piro Lito, MD 
Paul Paik, MD 
Robert Daly, MD 
Victoria Lai, MD 
Kathryn Arbour, MD 
Michael Offin, MD 
Leonard B Saltz, MD 
David H Ilson, MD, PhD 
David P Kelsen, MD 
Nancy Kemeny, MD 
Eileen O'Reilly, MBBCh BAO 
Andrew Saul Epstein, MD 
James Joseph Harding, MD 
Yelena Yuriy Janjigian, MD 
Geoffrey Yuyat Ku, MD 
Diane Lauren Reidy, MD  
Neil Howard Segal, MD, PhD 
Armin Shahrokni, MD 
Anna Mary Varghese, MD 
Rona Denit Yaeger, MD 
Kenneth Ho-Ming Yu, MD 
Ghassan Abou-Alfa, MD 
Zsofia Stadler, MD 
Elizabeth Won, MD 
Nitya Raj, MD 
Karuna Ganesh, MD 
Luis Diaz, MD 
Danny Khalil, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Page 4 of 52 
 
 
 
 
 
Afsheen Iqbal, MD 
Medicine 
Juliana Eng, MD 
Medicine 
John Fiore, MD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Pamela Drullinsky,  MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Han Xiao, MD 
Medicine 
Loren Michel, MD 
Medicine 
Curtis Chong, MD 
Medicine 
Sree Chalasani, MD 
Medicine 
Avni Desai, MD 
Medicine 
Stuart Lichtman, MD 
Medicine 
Jia Li, MD 
Medicine 
Jahan Aghalar, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Parisa Momtaz, MD 
Medicine 
Colette Owens, MD 
Medicine 
Marina Shcherba, DO 
Medicine 
Isabel, Preeshagul, MD 
Medicine 
Daniel Danila, MD 
Medicine 
Ping Gu, MD 
Medicine 
Anuja Kriplani, MD 
Medicine 
Louise Ligresti, MD 
Medicine 
Rui Wang, MD 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK Sites 
Manhattan 
All Protocol Activities 
Basking Ridge 
All Protocol Activities 
Rockville Centre 
All Protocol Activities 
Westchester 
All Protocol Activities 
Commack 
All Protocol Activities 
Monmouth 
All Protocol Activities 
Bergen 
All Protocol Activities 
Nassau 
All Protocol Activities 


Page 5 of 52 
 
 
 
Memo 
Participating Institutions – If multicenter 
study coordinated by MSK: 
rial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
PI's Name 
Site's Role 
MD Anderson Cancer Center 
Filippo Giancotti, MD 
Specimen Analysis 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 6 of 52 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEM A ....................................................................... 8 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................. 12 
3.0 
BACKGROUND AND RATIONALE ........................................................................................... 12 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................ 20 
4.1 
Design ............................................................................................................................. 20 
4.2 
Intervention ........................................................................................................................ 21 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ..................................................................................... 21 
Packaging and Labeling ............................................................................................................... 22 
Storage, Handling, and Accountability ............................................................................................ 22 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................. 23 
6.1 
Subject Inclusion Criteria ....................................................................................................... 23 
6.2 
Subject Exclusion Criteria .................................................................................................... 24 
7.0 
RECRUITM ENT PLAN ........................................................................................................................... 26 
8.0 
PRETREATM ENT EVALUATION ............................................................................................ 26 
9.0 
TREATM ENT/INTERVENTION PLAN ................................................................................................ 27 
10.0 EVALUATION DURING TREATM ENT/INTERVENTION ....................................................... 28 
11.0 TOXICITIES/SIDE EFFECTS .................................................................................................. 30 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOM E ASSESSM ENT ..........................38 
13.0 CRITERIA FOR REM OVAL FROM STUDY .............................................................................. 40 
14.0 BIOSTATISTICS .........................................................................................................................40 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOM IZATION PROCEDURES 
42 
15.1 Research Participant Registration ....................................................................................... 42 
15.2 Randomization ................................................................................................................... 42 
16.0 DATA M ANAGEM ENT ISSUES ................................................................................................. 42 
16.1 Quality Assurance ...................................................................................................................43 
16.2 Data and Safety Monitoring ............................................................................................... 43 
16.3 Regulatory Documentation .................................................................................................. 43 
17.0 PROTECTION OF HUM AN SUBJECTS ...................................................................................... 45 
17.1 Privacy ............................................................................................................................. 47 
17.2 Serious Adverse Event (SAE) Reporting ............................................................................. 47 
17.2.1 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........ 49 
Product Complaints ......................................................................................................................... 49 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 7 of 52 
 
 
18.0 INFORMED CONSENT PROCEDURES ................................................................................... 50 
19.0 REFERENCES ........................................................................................................................... 50 
20.0 APPENDICES ................................................................................................................................... 52 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 8 of 52 
 
 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Title: Pevonedistat as a Single Agent and in Combination with Chemotherapy in Patients with 
Malignant Mesothelioma 
Study 
Design: 
This study is a single institution trial with two cohorts to test the efficacy of the NEDD8 
inhibitor, pevonedistat as a single agent in patients with NF2 mutant MM (Cohort 1), 
and also to test the safety of pevonedistat in combination with standard chemotherapy, 
pemetrexed/cisplatin (Cohort 2). 
Study 
Objectives: 
Primary Objectives 
Cohort 1: To determine the clinical benefit rate (CR + PR + SD) of single agent 
pevonedistat at 18 weeks in patients with previously treated MM that has an NF2 
mutation 
Cohort 2: To establish the safety of the combination of pevonedistat and 
pemetrexed/cisplatin in patients with previously untreated MM, and determine the 
recommended phase II dose. 
Secondary Objectives 
To determine the progression-free and overall survival in both cohorts. 
To determine the response rate of single agent pevonedistat in previously treated 
patients with MM, and the response rate of pevonedistat plus pemetrexed/cisplatin in 
previously untreated patients. 
To explore downstream mechanistic biomarkers of pevonedistat in on-treatment biopsy 
samples from patients in cohort 1. 
Patient 
Population: 
Patients with unresectable malignant pleural or peritoneal mesothelioma 
Number of 
patients: 
Cohort 1: Maximum of 18 patients 
Cohort 2: Maximum of 24 patients 
Inclusion 
Criteria: 
Both cohorts: 
o Patients must have a histologically confirmed diagnosis of epithelioid, 
sarcomatoid, or mixed-type malignant pleural or peritoneal 
mesothelioma that is not amenable to surgery. 
o Patients must have measurable disease according to the modified 
RECIST criteria for pleural mesothelioma, or standard RECIST for 
peritoneal mesothelioma. 
o Patients must have adequate tissue sample available for molecular 
profiling with MSK-IMPACT (archived tissue block or 15-20 unstained 
slides). Patients will sign a separate informed document (IRB #12-245) 
to allow this to be performed. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 9 of 52 
 
 
 
 
 
o Patients must be at least 18 years of age. 
o Karnofsky performance status > 70%. 
o Adequate renal function: serum creatinine ≤ 1.5 x ULN. 
o Clinical laboratory values within the following parameters (repeat if more 
than 7 days before the first dose): 
▪ 
Albumin > 2.7 g/dL 
o Patients must have adequate hepatic function as defined by: 
▪ 
AST and ALT ≤ 2.5 x ULN 
▪ 
Total bilirubin ≤ upper limit of normal (ULN) except in patients 
with Gilbert’s syndrome. Patients with Gilbert’s syndrome may 
enroll if direct bilirubin ≤ 1.5 x ULN of the direct bilirubin. 
o Patients must have adequate bone marrow function as defined by: 
▪ 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
▪ 
Platelets ≥ 100 x 109/L 
▪ 
Hemoglobin ≥ 9 g/dL. 
o Female patients who 
▪ 
Are postmenopausal (see Appendix for definition) for at least 1 
year before the screening visit, OR 
▪ 
Are surgically sterile, OR 
▪ 
If they are of childbearing potential: 
• 
Agree to practice 1 highly effective method and 1 
additional effective (barrier) method of contraception (see 
Appendix), at the same time, from the time of signing the 
informed consent through 4 months after the last dose of 
study drug (female and male condoms should not be 
used together), or 
• 
Agree to practice true abstinence, when this is in line with 
the preferred and usual lifestyle of the subject. (Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of 
contraception.) 
o Male patients, even if surgically sterilized (i.e., status post vasectomy), 
who: 
▪ 
Agree to practice effective barrier contraception during the entire 
study treatment  period and through 4 months after the last dose 
of study drug (female and male condoms should not be used 
together), or 
▪ 
Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
[e.g., calendar, ovulation, symptothermal, postovulation methods 
for the female partner] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of 
contraception.) 
o Signed informed consent 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 10 of 52 
 
 
 
 
 
Cohort 1: 
o Patients must have received at least one and no more than four prior 
systemic therapy regimens. At least one of the regimens must have 
included pemetrexed and a platinum. 
o Patients must have MM that harbors an NF2 mutation as determined by 
any CLIA lab certified NGS platform. 
Cohort 2: 
o Patients must not have previously received treatment with chemotherapy 
for MM. 
o Patients must not have ≥ grade 2 peripheral neuropathy. 
o Patients must not have hearing deficits requiring the use of a hearing 
aid. 
Exclusion 
Crite ria: 
o Patients currently receiving anticancer therapies or who have received 
anticancer therapies within 3 weeks of the start of study drug including 
chemotherapy, biologics, targeted therapies, or immunologics. 
o Treatment with any investigational products within 4 weeks before the 
first dose of any study drug. 
o Any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of study procedures. 
o Patients currently receiving radiation therapy, or who have received 
radiation within 2 weeks from the start of therapy. 
o Patients who have had a major surgery or significant traumatic injury 
within 4 weeks of start of study drug, patients who have not recovered 
from the side effects of any major surgery (defined as requiring general 
anesthesia) or patients that may require major surgery during the course 
of the study. 
o Diagnosed or treated for another malignancy within 2 years before 
randomization or previously diagnosed with another malignancy and 
have any evidence of residual disease. Patients with nonmelanoma skin 
cancer or carcinoma in situ of any type are not excluded if they have 
undergone resection. 
o Life-threatening illness unrelated to cancer. 
o Patients with uncontrolled coagulopathy or bleeding disorder. 
o Patients who have any severe and/or uncontrolled medical conditions or 
other conditions that could affect their participation in the study such as: 
▪ 
Known cardiopulmonary disease defined as: 
• 
Unstable angina 
• 
Congestive heart failure (New York heart Association 
Class III or IV) 
• 
Myocardial infarction (MI) within 6 months prior to first 
dose (patients who had ischemic heart disease such as 
ACS, MI and/or revascularization greater than 6 months 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 11 of 52 
 
 
 
 
 
before screening and who are without cardiac symptoms 
may enroll). 
• 
Cardiomyopathy 
• 
Clinical significant arrhythmia 
o Polymorphic ventricular fibrillation or torsade de 
pointes. 
o Permanent atrial fibrillation [a fib], defined as 
continuous a fib ≥ 6 months. 
o Persistent a fib, defined as sustained a fib lasting > 
7  days  and/or  requiring cardioversion in  the  4 
weeks before screening 
o Grade 3 a fib defined as symptomatic and 
incompletely controlled medically, or controlledwith 
device (e.g. pacemaker), or ablation 
o Patients with paroxysmal a fib or < Gr 3 a fib for 
period of at least 6 months are permitted to enroll 
provided that their rate is controlled on a stable 
regimen. 
o Implantable cardioverter defibrillator 
o Moderate to severe aortic and/or mitral stenosis or 
other valvulopathy (ongoing) 
o Symptomatic pulmonary hypertension 
▪ 
Active infection requiring IV antibiotic, antiviral, or anti-fungal 
medications within 2 weeks of starting study drug. 
▪ 
Known history of HIV seropositivity 
o Known hepatitis B surface antigen seropositive or known or suspected 
active hepatitis C infection 
Note: Patients who have isolated positive hepatitis B core 
antibody (i.e., in the setting of negative hepatitis B surface antigen 
and negative hepatitis B surface antibody) must have an 
undetectable hepatitis B viral load. Patients who have positive 
hepatitis C antibody may be included if they have an undetectable 
hepatitis C viral load. 
o Known hepatic cirrhosis or severe pre-existing hepatic impairment 
o Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm 
Hg, diastolic blood pressure > 95 mm Hg). 
o Prolonged rate corrected QT (QTc) interval ≥500 msec, calculated 
according to institutional guidelines. 
o Left ventricular ejection fraction (LVEF) < 50% as assessed by 
echocardiogram or radionuclide angiography. 
o Known central nervous system (CNS) involvement. 
o Female patients who are both lactating and breast feeding or have a 
positive serum pregnancy test during the screening period or a positive 
urine pregnancy test on Day 1 before first dose of study drug. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 12 of 52 
 
 
 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objectives 
 
 
Cohort 1: To determine the clinical benefit rate (CR + PR + SD) of single agent pevonedistat 
at 18 weeks in patients with previously treated MM that has an NF2 mutation. 
 
Cohort 2: To establish the safety of the combination of pevonedistat 
and 
pemetrexed/cisplatin in patients with previously untreated MM, and determine the 
recommended phase II dose. 
 
Secondary Objectives 
 
To determine the progression-free and overall survival in both cohorts. 
 
To determine the response rate of single agent pevonedistat in previously treated patients 
with MM, and the response rate of pevonedistat plus pemetrexed/cisplatin in previously 
untreated patients. 
To determine the PK for pevonedistat in combination with chemotherapy. 
 
To explore downstream mechanistic biomarkers of pevonedistat activity in on treatment 
biopsy samples from patients in cohort 1. NEDD8-Cullin4 adduct, phosphorylated YAP and 
TAZ in on-treatment biopsy samples using western blot and qPCR. 
 
 
 
 
 
3.1 
BACKGROUND AND RATIONALE 
 
Malignant Mesothelioma (MM) 
 
MM is an uncommon tumor afflicting up to 3,000 patients annually in the United States. 
While MM primarily spreads locally within the pleura, the majority of patients present with 
disease invading the chest wall or mediastinum and therefore not amenable to surgery. For 
those patients, palliative chemotherapy is the only treatment option. The standard first-line 
chemotherapy regimen for both pleural and peritoneal disease, pemetrexed/cisplatin, has 
o Female patients who intend to donate eggs (ova) during the course of this 
study or 4 months after receiving their last dose of study drug(s). 
o Male patients who intend to donate sperm during the course of this study 
or 4 months after receiving their last dose of study drug(s). 
o Patients with a currently active second malignancy requiring treatment. 
o Treatment with clinically significant metabolic enzyme inducers within 14 
days before the first dose of the study drug. Clinically significant 
metabolic enzyme inducers are not permitted during this study. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 13 of 52 
 
 
 
 
 
limited benefit. In a phase III  trial, treatment with pemetrexed/cisplatin improved survival 
compared to cisplatin alone from 9 to 12 months.1 Second-line chemotherapy has no proven 
benefit.2 In order to develop the targeted therapies necessary to radically alter the clinical 
course of MM, it is important to identify the oncogenic mutations and signaling pathways 
that drive its development and sustain its maintenance.3 
NF 2 mutations 
 
About 75% of MMs carry inactivating mutations in the tumor suppressor gene NF2. 
Mutations at the BAP1 locus are also frequent in MM but appear to be mutually exclusive 
with NF2 mutations.4 From our MSK-IMPACT data, we are identifying NF2 alterations in 
about 40% of patients. NF2 was first identified in 1993 as the gene responsible for Type II 
familial Neurofibromatosis, a rare, autosomally dominant inherited disease that causes 
central nervous system tumors such as Schwannomas, meningiomas, and ependymomas. 
Since that time, NF2 mutations or loss of function have been identified in several other 
malignancies including mesothelioma and a small percentage of renal cell, cervical and 
bladder cancers. Althoughwe have known about NF2 for 20 years, the mechanismby which 
it suppresses tumor formation until recently has remained unclear.5 
NF2 encodes for the FERMdomain protein Merlin, which is homologous to the ERM proteins 
Ezrin, Radixin, and Moesin. The function of canonical ERM proteins is to mediate 
association of various membrane receptors with the actin cytoskeleton. Merlin has 
homology with other ERM proteins with the presence of a FERM domain, an α-helical 
domain, and a C-terminal domain. However, canonical ERM proteins have an actin-binding 
motif in their C-terminal domain, which is not present in Merlin, whereas Merlin has a unique 
N-Terminal extension. ERM proteins are maintained in a dormant state by association of 
the FERM domain with the C-terminal domain resulting in a “closed” conformation. With 
activation of Rho, its target Rho-kinase phosphorylates the actin binding motif, disrupting its 
association with the FERM domain. The newly generated “open” conformer associates 
through its FERM domain with the cytoplasmic segment of cell adhesion molecules, 
whereas the C-terminal actin binding motif interacts with actin filaments, regulating the 
organization of the cytoskeleton. In contrast, Merlin’s C-terminal domain is phosphorylated 
by PAK at Ser 518, resulting in inactivation of the growth suppressor activity of the protein.5 
Cell-to-cell contact, mediated by cadherins, or loss of matrix adhesion, mediated by 
integrins, inactivates PAK, leading to the accumulation of the de-phosphorylated, growth 
inhibitory form of Merlin.6 We have recently discovered that the de-phosphorylated, active 
conformer of Merlin translocates into the nucleus, where it binds to the pro-oncogenic E3 
ubiquitin ligase CRL4DCAF1, inhibiting its ability to ubiquitylate target proteins.7 Notably, 
Merlin inhibits CRL4DCAF1, which in turn promotes a broad oncogenic gene expression 
program, which includes targets of the oncogenic transcriptional co-activator YAP. Genetic 
epistasis experiments and an analysis of several Merlin missense mutations from NF2 
patients have demonstrated  that the de-phosphorylated form of Merlin suppresses 
tumorigenesis by inhibiting CRL4DCAF1.7 
Cullin-RING finger ligases (CRLs) 
 
CRLs make  up the largest family of ubiquitin ligases in  eukaryotic cells. CRL4 ligase 
complexes are comprised of the Cul4 scaffold, with the N-terminal segment associating - 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 14 of 52 
 
 
 
 
 
via the adaptor DDB1 - to one of several (>50) specific substrate receptors (DCAFs), and 
the C-terminal domain interacting with Rbx1 and the E2 ubiquitin-conjugating enzyme.8,9 All 
known CRL4 ubiquitin ligases are nuclear and regulate cell proliferation, survival, and DNA 
repair by ubiquitinating transcription factors, histones, or chromatin remodeling enzymes.10 
However, no physiological target of CRL4DCAF1 has been identified until recently. In our 
Preliminary Studies, we found that de-repressed CRL4DCAF1 functions in the nucleus to 
suppress the output of Hippo signaling. Mechanistically, CRL4DCAF1 binds directly to the 
tumor suppressor kinases Lats1 and 2 and directs their conjugation to ubiquitin. Whereas 
Lats1 is poly-ubiquitylated and targeted for proteasomal-dependent degradation, Lats2 is 
oligo-ubiquitylated at multiple sites, resulting in both cases in loss of kinase activity. As a 
consequence, the transcriptional co-activators and oncogenes, YAP and TAZ, which are 
inactivated by Lats 1 and 2, become active and function redundantly to support the ability 
of NF2 mutant cells to proliferate under standard culture conditions, to form colonies in soft 
agar, and to form tumors in mice. These results indicate that de-repressed CRL4DCAF1 
promotes tumorigenesis by inhibiting the tumor suppressor Lats1 and 2, thus unleashing 
YAP/TAZ and TEAD-dependent transcription.11 These results reveal the molecular 
underpinnings of the tumor suppressor function of Merlin. Intriguingly, LATS1 and 2 are 
mutated in ~ 8% of MM cases and this subset of tumors does not include NF2 mutations.12 
Hence, the tumor suppressor pathway we have identified appears to be inactivatedin ~ 83% 
of MM cases. 
 
Strategies for inhibiting oncogenic signaling in NF2 mutant MM 
 
We have previously shown that inactivation of Merlin leads to constitutive activation of 
mTORC1 in MM cells, and these cells are particularly sensitive to rapamycin.13 This finding 
led to a phase II trial that we opened at MSK testing everolimus in patients with previously 
treated MM using NF2 as a biomarker. Unfortunately that trial closed early due to loss of 
funding from the sponsor; a SWOG trial with everolimus was completed but did not meet 
the prespecified PSF endpoint.14 Other trials with dual PI3K/mTOR inhibitors, such as 
GDC0980, have shown promising activity15, presumably because these inhibitors block 
mTOR more effectively relative to rapalogs, and at the same time prevent the negative 
feedback loops which lead to activation of PI3K in cells treated with rapalogs.16 We reason, 
however, that MM cells display activation of multiple signaling pathways as a result of 
activation of CRL4DCAF1 and YAP/TEAD-dependent gene expression. To block activation 
of all these pathways, it is necessary to target upstream oncogenic signaling via inhibition 
of CRL4DCAF1. Conjugation of the ubiquitin-like protein NEDD8 to cullin is required for the 
assembly of active CRL complexes.17 Takeda has developed a potent and selective inhibitor 
of the NEDD8-activating enzyme, pevonedistat, which exhibits antitumor activity in 
xenograft models.18 
 
 
 
 
Pevonedistat 
 
Pevonedistat (TAK-924, formerly MLN4924) is a first-in-class small molecule inhibitor of 
NAE.  Inhibition of Nedd8-activating enzyme (NAE) stabilizes a subset of the proteins that 


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are also stabilized by inhibition of the proteasome. Pevonedistat exhibits potent in vitro 
cytotoxic activity against a variety of human tumor-derived cell lines in which cell death was 
shown to correlate with NAE inhibition. In most cancer cell lines studied, including those 
derived from lung, colon, and lymphoma tissues, the mechanism of cell death appeared to 
be a consequence of uncontrolled DNA synthesis in the S phase of the cell cycle followed 
by a DNA-damage response and induction of cell death However, in the NF-B-dependent 
lymphoma line, OCI-Ly10, apoptosis was observed following a G1 arrest suggesting that 
there may be multiple consequences of NAE inhibition that lead to cell death depending on 
the genetic background of the malignant cells. Hematologic and nonhematologic xenograft 
models support that inhibition of NAE activity may target a broad range of tumors. 
 
 
Preclinical efficacy of the CRL inhibitor pevonedistat 
 
Pevonedistat is a potent and selective inhibitor of NAE activity (pevonedistat was at least 
300- and 1800- fold more selective for NAE than for the closely related ubiquitin activating 
enzyme and sumo activating enzyme, respectively). Pevonedistat treatment of cultured 
tumor cells resulted in growth inhibition of a wide variety of cell lines derived from acute 
leukemias, lymphomas, multiple myeloma, and a range of solid tumor types. Changes in 
protein levels observed in cultured cells treated with pevonedistat were consistent with the 
inhibition of NAE, in particular a decrease in NEDD8-cullin levels and a reciprocal increase 
in the levels of known CDL substrates, including NFE2-related factor 2 (Nrf2) and chromatin- 
licensing and DNA-replication factor-1 (Cdt-1). In most cell lines evaluated, NAE inhibition 
by pevonedistat led to DNA re-replication and accumulation of cells in the S phase of the 
cell cycle; this resulted in DNA damage and subsequent cell death through apoptosis. When 
administered in combination with hypomethylating agents azacitidine and decitabine 
demonstrated synergistic activity in AML cell lines. 
Pevonedistat demonstrated pharmacodynamic and antitumor activity in solid tumor, 
lymphoma, and AML xenograft models when administered to immunocompromised mice by 
the subcutaneous (SC) route. Antitumor activity of pevonedistat in mice bearing HL-60 and 
THP-1 tumor xenografts was enhanced  by combination treatment with azacitidine. 
Combination treatment with pevonedistat and docetaxel significantly inhibited tumor growth 
in the PHTX-02B primary human breast cancer model and the LU1143 primary human 
squamous non-small cell lung cancer (sqNSCLC) xenograft model. Combination treatment 
with pevonedistat and carboplatin in both NCI-H69 human small cell lung cancer (SCLC) 
xenografts and LU1143 primary sqNSCLC xenografts resulted in significant antitumor 
activity. 
In vitro assay results indicated a low risk for human ether-à-go-go related gene (hERG) 
channel inhibition by pevonedistat or its 3 major circulating metabolites. In a Good 
Laboratory Practices (GLP)-compliant cardiovascular safety pharmacology assessment in 
male beagle dogs dosed via intravenous (IV) infusion at 15, 30, or 40 mg/kg (300, 600, or 
800mg/m2, respectively), pevonedistat was not well tolerated at doses ≥30 mg/kg 
(≥600mg/m2). Mortality and/or moribundity were observed within 24 hours postdose as a 
result of gastrointestinal injury at 40 mg/kg. Increased heart rate was observed at all doses. 
In a separate GLP-compliant, 2-cycle, repeat-dose toxicology study in dogs, no test article- 
related effects were noted in the electrocardiogram (ECG) data. 


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The dose-limiting toxicities (DLTs) in the 2-cycle studies for rats and dogs were 
gastrointestinal toxicity and bone marrow and lymphoid tissue depletion. Most adverse 
effects were resolving or had resolved after a 2-week recovery period. Pevonedistat did not 
result in lethality in either of the 5-cycle studies. The primary adverse test article-related 
effects in IV-dosed dogs included an acute phase response (increased body temperature, 
decreased albumin, increased globulin, increased monocytes and neutrophils,  and 
increased fibrinogen levels); neutrophilic infiltrates in multiple tissues; and in males, 
vacuolation and degeneration of the seminiferous epithelium of the testes. Most adverse 
effects were reversing or had reversed aftera 2-week recovery period in both rats and dogs. 
Given that there were prominent effects on testes and ovaries noted at all doses tested in 
the GLP-compliant repeat-dose toxicology studies in both dogs and rats, pevonedistat likely 
represents a substantial reproductive and developmental hazard. Pevonedistat was not 
mutagenic in the bacterial reverse mutation assay (Ames assay). 
Pevonedistat was highly bound in whole blood and plasma of mice, rats, dogs, monkeys 
and humans. No metabolite unique to humans was observed in vitro. In vitro, pevonedistat 
is predominantly metabolized by the cytochrome P450 (CYP) isozyme 3A4. There is 
potential for drug drug interactions (DDIs) if pevonedistat is coadministered with drugs that 
are CYP3A inhibitors or inducers. Pevonedistat is neither an inhibitor of CYP1A2, 2C9, 
2C19, 2D6, or 3A4/5 (IC50 > 100 µM and Ki > 50 µM) nor an inducer of CYP1A2, 2B6, or 
3A4/5 (at concentrations up to 30 µM), but is a weak inhibitor of CYP2B6 and 2C8 (IC50  = 
97.6 and 23.1 µM, respectively). The major elimination pathway of pevonedistat in animals 
is through the hepatic route. Pevonedistat is a substrate of P-glycoprotein (P-gp), breast 
cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) in Caco 2 
cells. Pevonedistat is also a weak inhibitor of P-gp (IC50 = 41.2 to 56.0 µM) and BCRP (IC50 
= 6.3 µM), but not of MRP2 (IC50 > 200 µM). Additionally, pevonedistat is not a substrate for 
organic anion-transporting proteins (OATPs). 
Detailed information regarding the nonclinical pharmacology and toxicology of pevonedistat 
is provided in the Investigator’s Brochure (IB). 
 
 
Preclinical efficacy of the CRL inhibitor pevonedistat in MM 
 
To investigate the potential efficacy  of the NEDD8-Activating Enzyme inhibitor, 
pevonedistat, in NF2 mutant tumor cells, we selected the Nf2-/- FC-1801 mouse 
Schwannoma cells, which were generated by infecting primary mouse Schwann cell 
cultures from E12.5 Nf2f lox/flox embryos with adenoviral Cre 19, and a panel of NF2 mutant 
MPM cells, which we have previously characterized.20 We have previously shown that 
silencing of DCAF1 inhibits the ability of NF2 mutant MPM Meso-33 cells to grow in soft 
agar and suppresses the capacity of FC-1801 Schwannoma cells to form benign tumors 
upon subcutaneous injection in nude mice 7. We found that 0.5-1 micromolar pevonedistat 
completely suppresses conjugation of NEDD8 to total Cullin 4 in both FC-1801 and Meso- 
33 cells (IC50 ~ 0.1 micromolar). Provocatively, significantly lower concentrations of the drug 
were sufficient to  block NEDD8 conjugation to the fraction of Cullin 4 associated with 
CRL4DCAF1 in both types of cells, suggesting that CRL4DCAF1 is especially sensitive to 
pevonedistat. Furthermore, in vivo ubiquitylation assays demonstrated that 0.5 micromolar 
pevonedistat efficiently inhibits the E3 ligase activity of CRL4DCAF1. As anticipated from our 


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observation that CRL4DCAF1 inhibits Lats1 and 2, pevonedistat activated Lats1/2 and thereby 
induced accumulation of the phosphorylated and inactive form of its target oncoprotein YAP 
in Meso-33 cells. In addition, pevonedistat blocked TOR signaling in NF2 mutant cells, 
suggesting that that de-regulated CRL4DCAF1 also drives the expression of genes that 
overactivate TOR in these cells. Finally, the drug inhibited phosphorylation of Rb and 
histone H3 and induced accumulation of p27. These results indicate that pevonedistat 
blocks the oncogenic signaling pathways activated by loss of NF2, inducing cell cycle arrest. 
We next evaluated the ability of pevonedistat to inhibit the proliferation of NF2 mutant 
mesothelioma cells in vitro. Notably, MTT assay indicated that 0.5-1 micromolar 
pevonedistat completely inhibits the proliferation of four NF2 mutant mesothelioma cell lines, 
which do not harbor additional mutations at the BAP1 tumor suppressor locus [Meso-33, 
JMN, H2052, VAMT; 20,21]. In contrast, 5 micromolar pevonedistat did not exert an inhibitory 
effect on two NF2 mutant mesothelioma cell lines carrying additional mutations at the BAP1 
locus [Meso-9 and Meso-10; 20,21], suggesting that the presence of additional oncogenic 
mutations may influence the sensitivity of NF2 mutant tumor cells to pevonedistat. 
Importantly, treatment of several NF2 mutant MPM cell lines with 0.5 micromolar 
pevonedistat significantly increased their sensitivity to pemetrexed or cisplatin. Interestingly, 
xenograft studies indicated that pevonedistat at 90 mg/kg Q2Dx3/week significantly inhibits 
the ability of the NF2 mutant VAMT cells to grow as subcutaneous tumors in NOG mice, but 
did not induce tumor regression (n=6; P<0.001). 
 
To examine the in vivo efficacy of pevonedistat in combination with pemetrexed/cisplatin, 
we conducted xenograft studies. We have an MTA in place and have obtained large 
quantities of pevonedistat required for in vivo studies. In addition, we have an ongoing 
collaboration with Takeda and thus  have access  to the pharmacokinetics and 
pharmacodynamics properties as well as toxicity profiles of pevonedistat in various strains 
of mice. Based on their experience, we have selected doses and schedules of 
administration of the drug that inhibit neddylation of Cullins in vivo without causing toxicity. 
 
Clinical experience with pevonedistat 
 
The clinical development program of pevonedistat began with 4 phase 1 studies of single 
agent pevonedistat at doses ranging from 25 to 278 mg/m2: 
• 
Study C15001 in patients with solid tumors. 
• 
Study C15002 in patients with lymphoma or multiple myeloma. 
• 
Study C15003 in patients with AML, high-grade myelodysplastic syndrome (MDS), or 
acute lymphoblastic leukemia (ALL). 
• 
Study C15005 in patients with melanoma. 
 
In these studies, toxicity involving multi organ failure on C1D1, including serious adverse 
events (SAEs) of renal, hepatic, and cardiac failure, some  with a  fatal outcome, was 
identified at doses equal to or above 110 mg/m2. On the basis of a comprehensive review 
of the available phase 1 clinical safety data at the time, a revised risk mitigation strategy, 
including limiting the dose to no higher than 100 mg/m2 for single agent administration, was 
implemented across the pevonedistat program in October 2012. The current understanding 


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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. 
 
As of January 2016, approximately 180 additional patients were treated in single agent and 
combination studies, and no C1D1 SAEs of multi-organ failure as described above have 
been observed. These patients received pevonedistat at a dose of 50 to 100 mg/m2 as a 
single agent, a dose of 15 to 30 mg/m2 in combination with different standard of care 
therapies, or a dose of 8 mg/m2 to 20 mg/m2 in combination with a CYP3A inhibitor. 
 
Current development is focused on pevonedistat in combination with standard clinically 
available therapies in hematologic malignancies and solid tumors. Two phase 1b clinical 
studies are closed to enrollment but are still ongoing with active patients: 
• 
Study C15009 (phase 1b) evaluated the maximum tolerated dose (MTD) of pevonedistat 
on Days 1, 3, and 5 in combination with 75 mg/m2 azacitidine (administered on a 5-on/2- 
off [weekend]/2-on schedule) in a 28 day treatment cycle in  elderly patients with 
treatment-naïve AML [11]. 
• 
Study C15010 (phase 1b) evaluated the MTD of pevonedistat plus docetaxel, 
gemcitabine, or the combination of carboplatin and paclitaxel, in patients with solid 
tumors [12-13]. 
 
Additionally, Study C15011 (phase 1) is evaluating the effects of CYP3A mediated inhibition 
of pevonedistat in patients with solid tumors (DDI assessment; Part A). After completion of 
the DDI assessment portion of the study, patients have the opportunity to continue in the 
study by participating in Part B (pevonedistat plus docetaxel or the combination of 
carboplatin and paclitaxel). 
 
The cumulative enrollment in all clinical studies through 22 January 2016 is approximately 
390 patients (defined as having received at least 1 dose of study drug). 
 
Two studies are currently enrolling: 
• 
Study 2001: A Phase 2, randomized, controlled Open-Label Clinical study of the efficacy 
and safety of Pevonedistat plus Azacitidine versus single-agent azacitidine in patients 
with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia and low- 
blast acute myelogenous leukemia. 
• 
Study 1012: A phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as 
Single Agent and in Combination with Azacitidine in adult East Asian patients with acute 
myeloid leukemia or myelodysplastic syndromes. 
Pharmacokinetics 
 
The clinical pharmacokinetics (PK) of pevonedistat have been evaluated in 4 monotherapy 
phase 1 studies in 96 patients with solid tumors (C15001 and C15005) and 109 patients 
with hematologic malignancies (C15002 and C15003). These studies have evaluated the 


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single- and multiple-dose PK of pevonedistat administered via IV infusion across the 25 to 
278 mg/m2 dose range and at various daily or intermittent dosing schedules within 21 day 
treatment cycles. 
 
Plasma concentrations of pevonedistat declined in a bi-exponential manner at the end of IV 
infusion, with little or no drug accumulation following intermittent dosing or once-daily dosing 
for 5 consecutive days of a 21 day cycle. Mean terminal disposition t1/2z was estimated to 
be approximately 10 hours (range 7.7-15.2) across doses and schedules. Consistent with 
in vitro data, pevonedistat is extensively partitioned in human blood (mean blood-to-plasma 
concentration ratio of approximately 65) with whole blood and plasma kinetics declining in 
parallel over time. Pevonedistat generally exhibited linear PK over the dose range studied. 
Observed interindividual variability (IIV) was generally moderate with 18% to 41% coefficient 
of variation (CV) for maximum concentration (Cmax), 12% to 56% CV for area under the 
plasma concentration-time curve from time zero to 24 hours postdose (AUC24), and 15% to 
33% CV for the area under the plasma concentration-time curve from time zero to the end 
of the dosing interval when pevonedistat was administered on Days 1, 3, and 5. Body size 
influences pevonedistat systemic clearance andvolume of distribution, thus supporting body 
surface area (BSA)-normalized dosing to reduce variation in systemic exposure of 
pevonedistat in cancer patients. Pevonedistat clearance tended to gradually decrease in 
elderly patients (by approximately 25% over the 30-90 age range). There was also no 
apparent effect of renal function status (as assessed by estimated creatinine clearance > 
30 mL/min) on pevonedistat PK. 
 
Additionally, evaluation of pevonedistat PK is ongoing for 2 studies of pevonedistat in 
combination with different standard-of-care therapies, and for a DDI study evaluating the 
effects of CYP3A mediated inhibition on pevonedistat. Pevonedistat PK was not altered in 
the presence of azacitidine when compared to historical single agent data. Also, no obvious 
changes in the PK behavior of pevonedistat in the presence of docetaxel or gemcitabine 
have been observed whereas a trend towards increasing plasma concentrations of 
pevonedistat in the presence of carboplatin + paclitaxel was evident. This apparent drug 
interaction effect, which cannot be explained at this time, warrants further understanding of 
the disposition properties of pevonedistat in humans. Lastly, multiple doses of fluconazole, 
a moderate CYP3A inhibitor, had minimal effect (13% increase in mean area under the 
plasma concentration time curve from zero to infinity [AUCinf ]) on the single-dose IV PK of 
pevonedistat, while pevonedistat systemic exposure increased by 23% on average in the 
presence of the strong CYP3A inhibitor, itraconazole. 
 
Pharmacodynamics 
 
Preliminary data provide evidence of pathway inhibition downstream of NAE and biological 
activity of pevonedistat in skin and tumor tissue (solid tumor or AML bone marrow derived 
blasts) at all doses tested in pharmacodynamic assays. These doses range from 25 to 261 
mg/m2 across the various single-agent, phase 1 pevonedistat trials. 
 
Rationale for clinical trial design 


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To test the efficacy and safety of pevonedistat in patients with pleural or peritoneal MM, we 
will conduct this single institution clinical trial comprised of two cohorts: 1) a phase II trial to 
assess the clinical benefit rate of single agent pevonedistat in patients with NF2 mutant MM, 
and 2) a phase I trial to establish the safety of combining pevonedistat with 
pemetrexed/cisplatin in previously untreated patients. 
Cohort 1 will assess the clinical activity of pevonedistat as a single agent in patients selected 
for NF2 mutations. This cohort will enroll patients with pleural or peritoneal mesothelioma 
MM with progression of disease after prior treatment with one or two prior chemotherapy 
regimens. There are no approved therapies for these patients, and the response rate of 
standard chemotherapy is negligible.2 Patients will typically have MSK IMPACT performed 
for molecular phenotyping while they are receiving first-line therapy (testing takes several 
weeks), and so we will be able to select patients for this cohort whose tumors demonstrate 
NF2 mutations. Based on the preclinical data described above showing growth inhibition 
with pevonedistat as a single agent, we are interested in also including disease stabilization 
in the efficacy assessment. Thus, the primary endpoint of this cohort will be clinical benefit 
rate (CBR) as measured by complete or partial response or stable disease at 18 weeks (6 
cycles). 
 
Cohort 2 will assess the combination of pevonedistat with chemotherapy, which is of 
particular interest given the data described in the preliminary studies. Cohort 2 will enroll 
patients with previously untreated, unresectable, pleural or peritoneal MM. Because of the 
time required to obtain molecular genotyping, these patients will not be selected up-front for 
NF2 mutations, but MSK IMPACT will be performed during the courseof their therapy.Since 
there are 
no clinical 
data 
regarding the 
combination 
of 
pevonedistat with 
pemetrexed/cisplatin, the primary endpoint will be to assess safety, and establish a 
recommended phase II dose. 
 
If activity is demonstrated in the single-agent cohort, and safety demonstrated in the 
combination cohort, we would propose a subsequent multicenter, randomized phase II trial 
of pemetrexed/cisplatin +/- pevonedistat. 
 
 
 
 
 
 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This study is a single institution trial with two cohorts to test the efficacy of the NEDD8 
inhibitor, pevonedistat, as a single agent in patients with NF2 mutant MM (Cohort 1), and 
also to test the safety of pevonedistat in combination  with standard chemotherapy, 
pemetrexed/cisplatin (Cohort 2). 


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4.3 
Intervention 
 
Cohort 1: This cohort will enroll patients with advanced MM previously treated with 1-2 prior 
chemotherapy regimens. Patients in this cohort must have tumors with NF2 mutations as 
previously determined by any CLIA lab certified NGS platform. Patients will receive single 
agent pevonedistat at the recommended phase II dose of 50 mg/m2 IV days 1, 3, 5 in 21- 
day cycles. Patients will be assessed for toxicity on day 1 of each cycle. Patients will 
undergo imaging after every two cycles to assess response. The primary endpoint is the 
clinical benefit rate (CBR) defined as CR + PR + SD at 18 weeks (6 cycles). As an 
exploratory endpoint, the first 10 patients in this cohort will have on-treatment core biopsies 
performed one to two weeks after starting therapy to obtain tissue for confirmation of 
expected drug effects. 
 
Cohort 2: This cohort will enroll patients with advanced MM previously untreated with 
chemotherapy. There will be no genotyping restriction for enrollment of these patients, but 
MSK-IMPACT will be performed while they are receiving therapy. Patients will receive 
pemetrexed/cisplatin at the standard doses. Pevonedistat will be given in dose escalation 
groups using a 3+3 design. The starting dose will be 15 mg/m2 days 1, 3, 5, followed by 
escalation to 20 and 25 mg/m2 or de-escalation to 10 mg/m2. Patients will receive up to 6 
cycles of pemetrexed/cisplatin + pevonedistat, and following that will be treated with 
pevonedistat alone (maintenance therapy) until progression. Patients will be assessed for 
toxicity weekly with cycle 1, and then on day 1 of each subsequent cycles. Criteria for dose 
limiting toxicities (DLTs) are described in Section 11.0. The primary endpoint of this cohort 
is to establish the safety and the recommended phase II dose of this combination. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Pevonedistat 
 
The drug product is labeled Pevonedistat (TAK-924/MLN4924) Concentrate for Solution for 
Infusion. Pevonedistat injection drug product formulation consists of 10 mg/mL (as free 
base) of pevonedistat HCl in an aqueous solution of 7.45 mg/mL citric acid (anhydrous), 
3.29 mg/mL trisodium citrate dihydrate, and 100 mg/mL ß-Cyclodextrin sulfobutyl ether 
(Captisol®) at pH 3.3. Each USP Type I glass vial nominally contains 5 mL of compounded 
sterile solution, sealed with a Teflon®-coated butyl rubber stopper and oversealed with an 
aluminum seal and a plastic cap. 
 
Full details are available in the IB. 
Preparation, Reconstitution, and Dispensation 
Pevonedistat (TAK-924/MLN4924) is acytotoxic anticancer drug, and as with other 
potentially toxic compounds, caution should be exercised when handling pevonedistat. 
 
The specified number of pevonedistat Injection Drug Product vials should be removed and 
allowed to equilibrate to room temperature prior to dilution. The vial must not be shaken at 
any time during dose preparation. 


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Using aseptic technique, the appropriate volume of drug should be withdrawn from vial(s), 
then injected into a 250-mL IV bag containing 5% dextrose solution, and then gently inverted 
repeatedly to mix. The pevonedistat prepared IV bag must be used within 6 hours (time to 
the end of an injection) if stored at ambient temperature. Alternatively, the prepared IV bag 
is chemically stable and may be stored for up to 18 hours at 2˚C to 8˚C.  After 18 hours of 
storage at 2˚C to 8°C, the prepared IV bag must be used within 3 hours (time to the end of 
an injection) upon coming to ambient temperature. 
 
The bag, needle, and syringe must be disposed of in a proper biohazard container.  
Packaging and Labeling 
Pevonedistat (TAK-924/MLN4924) will be provided in 10-mL glass vials at a concentration 
of 10 mg/mL. 
 
Storage, Handling, and Accountability 
 
Vials of pevonedistat (TAK-924/MLN4924) are to be stored at 2C to 8C. Pevonedistat 
injection is stable at ambient temperature for 8 hours before dilution. All investigational 
supplies are to be kept in a secure area with controlled access. 
 
Study drug will be  administered only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). The amount of drug to be administered will be 
based on body surface area (BSA). BSA will be calculated using a standard nomogram on 
Cycle 1, Day 1 (see Appendix), and at subsequent visits if the patient experiences a > 5% 
change in body weight from the weight used for the most recent BSA calculation. 
The pharmacist will maintain records of drug receipt (if applicable), drug preparation, and 
dispensing, including the applicable lot numbers, and total drug administered in milliliters 
and milligrams. 
All patients will receive pevonedistat diluted with 5% dextrose in a 250-mL IV bag via IV 
infusion via a 60-minute IV infusion. Pevonedistat should be administered through central 
or peripheral venous access. The infusion may be slowed or stopped and restarted for any 
associated infusion-related reactions. All infusion times must be recorded. The total time 
from drug reconstitution to end of infusion must not exceed 6 hours. Doses of pevonedistat 
must be separated by at least 1 full calendar day. 
 
Drug accountability: All study drug supplies must be kept in a locked room with limited 
access. The study drug must not be used outside the context of this protocol. Under no 
circumstances should the investigator or other site personnel supply study drug to other 
investigators, patients, or clinic, or allow supplies to be used other than directed by this 
protocol without prior authorization from Takeda. The pharmacist will maintain a complete 
drug accountability record with lot numbers, the dates drug was dispensed, and the dose of 
pevonedistat the patient received. The prescribed dose should also be recorded in the 
patient’s medical records. At the conclusion of the study, all unused pevonedistat will be 
destroyed on-site as described in a standard operating procedure for the destruction of 
chemotherapeutic waste. 


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Pemetrexed: 
 
Pemetrexed (Alimta®, Eli Lilly) is a commercially available medication with a complete 
description of the drug, its clinical pharmacology, contraindications, warnings, precautions 
and adverse reactions available in the package insert. Pemetrexed will be administered as 
per institutional guidelines. 
 
Cisplatin: 
 
Cisplatin (Platinol®, Bristol Myers) is a commercially available medication with a complete 
description of the drug, its clinical pharmacology, contraindications, warnings, precautions 
and adverse reactions available in the package insert. Cisplatin will be administered as per 
institutional guidelines. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Patients must meet all of the following criteria for eligibility: 
 
6.2 
Subject Inclusion Criteria 
 
Both cohorts: 
 
o Patients must have a histologically confirmed diagnosis of epithelioid, sarcomatoid, 
or mixed-type malignant pleural or peritoneal mesothelioma that is not amenable to 
surgery. 
o Patients must have measurable disease according to the modified RECIST criteria 
for pleural mesothelioma, or standard RECIST for peritoneal mesothelioma. 
Patients must have adequate tissue sample available for molecular profiling with 
MSK-IMPACT (archived tissue block or 15-20 unstained slides). Patients will sign a 
separate informed document (IRB #12-245) to allow this to be performed. 
o Patients must be at least 18 years of age. 
o Karnofsky performance status > 70%. 
o Adequate renal function: serum creatinine ≤ 1.5 x ULN. 
o Clinical laboratory values within the following parameters (repeat if more than 7 
days before the first dose): 
▪ 
Albumin > 2.7 g/dL 
o Patients must have adequate hepatic function as defined by: 
▪ 
AST and ALT ≤ 2.5 x ULN 
▪ 
Total bilirubin ≤ upper limit of normal (ULN) except in patients with Gilbert's 
syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin 
≤1.5 x ULN of the direct bilirubin. 
o Patients must have adequate bone marrow function as defined by: 
▪ 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
▪ 
Platelets ≥ 100 x 109/L 
▪ 
Hemoglobin ≥ 9 g/dL. 
o Female patients who 
▪ 
Are postmenopausal (see Appendix for definition) for at least 1 year before 
the screening visit, OR 


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▪ 
Are surgically sterile, OR 
▪ 
If they are of childbearing potential: 
• 
Agree to practice 1 highly effective method and 1 additional effective 
(barrier) method of contraception (see Appendix), at the same time, 
from the time of signing the informed consent through 4 months 
after the last dose of study drug (female and male condoms should 
not be used together), or 
• 
Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
[e.g., calendar, ovulation, symptothermal, postovulation methods] 
withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception.) 
o Male patients, even if surgically sterilized (i.e., status post vasectomy), who: 
▪ 
Agree to practice effective barrier contraception during the entire study 
treatment  period and through 4 months after the last dose of study drug 
(female and male condoms should not be used together), or 
▪ 
Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, postovulation methods for the female partner] withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods 
of contraception.) 
o Signed informed consent 
Cohort 1: 
o Patients must have received at least one and no more than four prior systemic 
therapy regimens. At least one of the regimens must have included pemetrexed 
and a platinum. 
o Patients must have MM that harbors an NF2 mutation believed to cause functional 
loss of the NF2 protein as determined by any CLIA lab certified NGS platform or 
NF2 loss must be documented by CLIA certified IHC. 
 
Cohort 2: 
 
o Patients must not have previously received treatment with chemotherapy for MM. 
o Patients must not have ≥ grade 2 peripheral neuropathy. 
o Patients must not have > grade 2 hearing deficits. 
 
6.3 
Subject Exclusion Criteria 
 
o Patients currently receiving anticancer therapies or who have received anticancer 
therapies within 3 weeks of the start of study drug including chemotherapy, biologics, 
targeted therapies, or immunologics. 
o Treatment with any investigational products within 4 weeks before the first dose of 
any study drug. 
o Any serious medical or psychiatric illness that could, in the investigator's opinion, 
potentially interfere with the completion of study procedures. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 25 of 52 
 
 
 
 
 
o Patients currently receiving radiation therapy, or who have received radiation within 
2 weeks from the start of therapy. 
o Patients who have had a major surgery or significant traumatic injury within 4 weeks 
of start of study drug, patients who have not recovered from the side effects of any 
major surgery (defined as requiring general anesthesia) or patients that may require 
major surgery during the course of the study. 
o Diagnosed or treated for another malignancy within 2 years before randomization 
or previously diagnosed with another malignancy and have any evidence of 
residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of 
any type are not excluded if they have undergone resection. 
o Life-threatening illness unrelated to cancer. 
o Patients with uncontrolled coagulopathy or bleeding disorder. 
o Patients who  have any severe and/or uncontrolled medical conditions or other 
conditions that could affect their participation in the study such as: 
▪ 
Known cardiopulmonary disease defined as: 
• 
Unstable angina 
• 
Congestive heart failure (New York Hear Association [NYHA] Class 
III or IV 
• 
Myocardial infarction (MI) within 6 months prior to first dose (patients 
who had ischemic heart disease such as ACS, MI and/or 
revascularization greater than 6 months before screening and who 
are without cardiac symptoms may enroll). 
• 
Cardiomyopathy 
• 
Clinically significant arrhythmia: 
o Polymorphic ventricular fibrillation or torsade de pointes. 
o Permanent atrial fibrillation [a fib], defined as continuous a fib 
≥ 6 months. 
o Persistent a fib, defined as sustained a fib lasting > 7 days 
and/or requiring cardioversion in the 4 weeks before 
screening 
o Grade 3 a  fib defined as symptomatic and incompletely 
controlled medically, 
or 
controlled with device 
(e.g. 
pacemaker), or ablation 
o Patients with paroxysmal a fib or < Gr 3 a fib for period of at 
least 6 months are permitted to enroll provided that their rate 
is controlled on a stable regimen. 
o Implantable cardioverter defibrillator 
• 
Moderate to severe aortic and/or mitral stenosis or other valvulopathy 
(ongoing) 
• 
Symptomatic pulmonary hypertension 
▪ 
Active infection requiring IV antibiotic, antiviral, or anti-fungal medications 
within 2 weeks of starting study drug. 
▪ 
Known history of HIV seropositivity 
o Known  hepatitis B  surface antigen seropositive or  known  or  suspected active 
hepatitis C infection 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 26 of 52 
 
 
 
 
 
Note: Patients who have isolated positive hepatitis B core antibody (i.e., in 
the setting of negative hepatitis B surface antigen and negative hepatitis B 
surface antibody) must have an undetectable hepatitis B viral load. Patients 
who have positive hepatitis C antibody may be included if they have an 
undetectable hepatitis C viral load. 
o Known hepatic cirrhosis or severe pre-existing hepatic impairment 
o Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, 
diastolic blood pressure > 95 mm Hg). 
o Prolonged rate corrected QT (QTc) interval ≥500 msec, calculated according to 
institutional guidelines. 
o Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or 
radionuclide angiography. 
o Known central nervous system (CNS) involvement. 
o Female patients who are both lactating and breastfeeding or have a positive serum 
pregnancy test during the screening period or a positive urine pregnancy test on Day 
1 before first dose of study drug. 
o Female patients who intend to donate eggs (ova) during the course of this study or 
4 months after receiving their last dose of study drug(s). 
o Male patients who intend to donate spermduring the courseof this study or 4 months 
after receiving their last dose of study drug(s). 
o Patients with a currently active second malignancy requiring treatment. 
o Treatment with clinically significant metabolic enzyme inducers within 14 days 
before the first dose of the study drug. Clinically significant metabolic enzyme 
inducers are not permitted during this study. 
 
7.0 
RECRUITMENT PLAN 
 
Eligible patients with MM will be recruited from the Thoracic Oncology Service at MSKCC 
among patients that are cared for at that institution or through referrals. Every attempt will 
be made to recruit women and minorities in this study. Participation is voluntary. The 
consenting physician will inform patients of  their diagnosis, current treatment options, 
including standard treatment, and the risks, benefits and experimental nature of this 
treatment program. Patients under the age of 18 are excluded because this disease does 
not occur in patients that age, and the safety of these treatments has not been established 
for them. There are no gender or racial restrictions. 
8.1 
PRETREATMENT EVALUATION 
 
To be completed within 14 days of initiating treatment: 
 
o Updated history 
o Physical examination including vitals signs, weight, and performance status 
o Concomitant medications 
o Complete blood count (CBC) 
o Comprehensive panel 
o Pregnancy test (for women of childbearing potential) 
o ECG 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 27 of 52 
 
 
 
 
o Echocardiogram (for patients who have not had this performed within 1 year) 
o CT scan of chest and any other relevant sites of disease (within 28 days) 
o Urinalysis with microscopic analysis 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
Cohort 1: 
 
Patients in Cohort 1 will be treated with single-agent pevonedistat. Pevonedistat will be 
administered as an IV infusion at a dose of 50 mg/m2 days 1, 3, and 5 of a 21-day cycle. 
Treatment will be administered as an outpatient. Patients will be evaluated prior on day 1 of 
each cycle for toxicity assessment. CT scans will be performed to assess for response every 
6 weeks (2 cycles). 
 
 
Cohort 2: 
 
Patient in Cohort 2 will be treated with pevonedistat in combination with pemetrexed and 
cisplatin. Pemetrexed, 500 mg/m2 and cisplatin, 75 mg/m2, will be given at fixed doses on 
day 1 of each cycle. Folic acid 800 mcg will be given daily at least 5 days prior to the first 
dose of pemetrexed and continued daily until 3 weeks after the last dose of pemetrexed. 
Vitamin B12 1000 mcg will be administered as an intramuscular injection approximately 1 
week prior to the first dose of pemetrexed and repeated approximately every 9 weeks until 
3 weeks after the last dose of pemetrexed. Anti-emetics will be administered per institutional 
guidelines. Dexamethasone 12 mg will be given for days 2 and 3 after cisplatin 
administration. Patients will be instructed to drink 1-2 liters of fluid the night prior to 
chemotherapy and will be given >1000 mL D5W or normal saline over 1-2 hours before and 
after cisplatin administration. Patients will receive a bolus of mannitol 12.5 grams prior to 
cisplatin administration. Patients will receive up to 6 cycles of pemetrexed/cisplatin + 
pevonedistat, and following that will be treated with pevonedistat alone (maintenance 
therapy) until progression. CT scans will be performed to assess for response every 6 weeks 
(2 cycles). 
 
 
 
 
Pevonedistat will be given in a 3-by-3 dose escalation based on the table below: 
 
Dose level 
Dose 
-1 
10 mg/m2 days 1, 3, 5 
0 
15 mg/m2 days 1, 3, 5 
1 
20 mg/m2 days 1, 3, 5 
2 
25 mg/m2 days 1, 3, 5 
 
 
Patients in Cohort 2 will be assessed weekly in the first cycle to assess for toxicity. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 28 of 52 
 
 
 
 
 
The initial 3 patients of each cohort must complete cycle 1 prior to making a decision 
regarding dose escalation. If none of the 3 patients at dose level 0 has a dose-limited toxicity 
(DLT, as defined in Section 11.0), the dose level will be escalated. If one has a DLT that 
dose level will be expanded with 3 more patients. Dose escalation will stop if ≥2 DLTs are 
seen at a dose level. The MTD is defined as the highest dose level at which no more than 
1 of the 6 patients at that level has a DLT. If no patient in the 3-patient cohort has a DLT 
and the dose level is under final consideration for the MTD, an additional three patients will 
be treated at that level for confirmation. 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
COHORT 1* 
Baseline1 
Cycle 1 
Cycle 2 
Cycle 3 and 
beyond 
EOT 
Day 
1 
Day 
2 
Day 
3 
Day 
5 
Day 
8 & 
15 
Day 
1 
Day 
3 
Day 
5 
Day 
1 
Day 
3 
Day 
5 
Informed consent 
X 
Pathology sample for 
MSK-IMPACT (if not 
already  performed) 
X 
History, physical exam, 
performance status 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive panel2 
X 
X 
X 
X 
Select chemistry panel3 
X 
X 
X 
X 
X 
X 
X 
X 
PT and aPTT 
X 
X 
X 
X 
Serum pregnancy test 
(for women of 
childbearing potential) 
X 
Serum or urine 
pregnancy test (for 
women of childbearing 
potential) 
X 
X 
X 
ECG4 
X 
X 
X 
X 
X 
Echocardiogram5 
X 
Urinalysis with 
microscopic analysis6 
X 
CT chest and other 
relevant disease sistes7 
X 
X 
Pevonedistat 
administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor Biopsy8 
X 
(D15 
only) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 29 of 52 
 
 
 
 
 
. * All assessments (including pevonedistat administration) will be performed with a window of +/- 3 
days. 
1 Within 14 days of starting therapy, except for CT scan which can be within 28 days. 
2 Includes electrolytes, BUN/creatinine, sodium, potassium, chloride, carbon dioxide, glucose, 
urate, total bilirubin, direct bilirubin, ALP, LDH, AST, ALT, albumin, magnesium, phosphate and 
calcium. 
3 Includes BUN, creatinine, phosphate, total bilirubin, albumin, ALP, AST, and ALT 
4 ECG to be performed after infusion and subsequently as needed 
5 Patients who have not had this performed within 1 year 
6 Urinalysis will include assessments of turbidity and color, pH, specific gravity, protein, ketones, 
bilirubin, occult blood, nitrite, glucose, and leukocyte esterase. Urine microscopic analysis will 
include erythrocytes, leukocytes, bacteria, casts, and crystals. 
7CT scan will be performed at the completion of every 2 cycles (i.e. every 6 weeks). 
8First 10 patients from cohort 1. Day 15 +/-7 days. See below for description of correlative studies. 
 
 
 
COHORT 2* 
Base 
-line1 
Cycle 1 
Cycle 2 
Cycle 3 and beyond 
EOT 
Da 
y 1 
Da 
y 2 
Da 
y 3 
Da 
y 5 
Day 
8 & 
15 
Day 
1 
Day 3 
Day 5 
Day 1 
Da 
y 3 
Day 
5 
Informed consent 
X 
History, physical 
exam, performance 
status 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive panel2 
X 
X 
X 
X 
Select chemistry 
panel3 
X 
X 
X 
X 
X 
X 
X 
X 
PT and aPTT 
X 
X 
X 
X 
X 
Serum pregnancy test 
(for women of 
childbearing potential) 
X 
Serum or urine 
pregnancy test (for 
women of childbearing 
potential) 
X 
X 
X 
ECG4 
X 
X 
X 
X 
X 
Echocardiogram5 
X 
Urinalysis with 
microscopic analysis6 
X 
CT chest and other 
relevant disease sites7 
X 
X6 
Pevonedistat 
administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pemetrexed/ cisplatin 
administration8 
X 
X 
X 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 30 of 52 
 
 
 
 
 
PK assessment9 
X 
X 
X 
 
* All assessments (including pevonedistat administration) will be performed with a window of +/- 3 
days. 
1 Within 14 days of starting therapy, except for CT scan which can be within 28 days. 
2 Includes electrolytes, BUN/creatinine, sodium, potassium, chloride, carbon dioxide, glucose, 
urate, total bilirubin, direct bilirubin, ALP, LDH, AST, ALT, albumin, magnesium, phosphate and 
calcium. 
3 Includes BUN, creatinine, phosphate, total bilirubin, albumin, ALP, AST, and ALT 
4 ECG to be performed after infusion 
5 Patients who have not had this performed within 1 year 
6 Urinalysis will include assessments of turbidity and color, pH, specific gravity, protein, ketones, 
bilirubin, occult blood, nitrite, glucose, and leukocyte esterase. Urine microscopic analysis will 
include erythrocytes, leukocytes, bacteria, casts, and crystals. 
6 CT scan will be performed at the completion of every 2 cycles (i.e. every 6 weeks). 
8 Patients will receive up to 6 cycles of pemetrexed/cisplatin + pevonedistat, and following that will 
be treated with pevonedistat alone (maintenance therapy) until progression. 
9 PK draws: It is recommended that samples should be taken right after each infusion of 
pevonedistat before the infusion pump is turned off. However, there is a ± 10 minute window for 
Cycle 1 Day 1 PK draws and a ±2 hour window for Cycle 1 Day 2 and Day 3 PK draws. Samples 
should be collected in polypropylene nunc tubes. Please follow dosing schedule as outlined below: 
 
 
Pharmacokinetics  Schedule 
Cycle and Day 
Time point 
Cycle 1 Day 1 
Pre-dose 
End of 
infusion 
1 hour 
post- 
infusion 
2 hour 
post- 
infusion 
4 hour 
post- 
infusion 
6 hour 
post- 
infusion 
Cycle 1 Day 2 
24 hours 
post- 
infusion 
Cycle 1 day 3 
48 hours 
post- 
infusion 
 
 
Correlative Studies: We will obtain on-treatment core biopsies from the first 10 patients in 
cohort 1 one to two weeks after starting therapy to obtain tissue for confirmation of expected 
drug effects. Levels of NEDD8-Cullin, YAP, and P-YAP will be measured by Western blot. 
Nuclearly localized (active) and cytoplasmic (inactive) YAP and TAZ will be assessed by 
immunohistochemistry in collaboration with Filipo Giancotti. 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
NCI Common Te rminology Criteria (CTC): This study will utilize the most recent version 
of the Common Terminology Criteria (CTC) version for toxicity and adverse event 
reporting (currently 4.0). A copy of the CTC can be downloaded from the CTEP home 
page (http://ctep.info.nih.gov). All treatment areas have access to a copy of the CTC. 
 
Possible toxicities side e ffects 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 31 of 52 
 
 
 
 
 
Pevonedistat 
 
COMMON: 
 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
• 
Fever 
• 
Abnormal liver function tests 
• 
Myalgias 
• 
Musculoskeletal pain 
 
 
 
OCCASIONAL 
 
• 
Tachycardia 
• 
Dehydration 
• 
Electrolyte imbalance 
• 
Myelosuppression 
RARE AND SERIOUS 
• 
Multi-organ failure 
• 
Cardiac arrhythmia 
• 
Kidney Failure 
• 
Acute Phase response 
Cisplatin (Group 2 only) 
COMMON: 
• 
Leukopenia 
• 
Thrombocytopenia 
• 
Anemia 
• 
Mild hearing loss 
• 
Hair loss 
• 
Nausea, vomiting, constipation, or diarrhea 
• 
Loss of appetite 
• 
Changes in blood pressure 
• 
Fatigue 
OCCASIONAL 
• 
Allergic reactions 
• 
Kidney damage 
• 
Neurologic abnormalities 
• 
Peripheral neuropathy 


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IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 32 of 52 
 
 
 
 
 
• 
Liver irritation 
• 
High blood pressure 
• 
Weight loss 
• 
Rash, skin changes 
• 
Dehydration 
• 
Electrolyte abnormalities 
• 
Dyspnea or pneumonitis 
• 
Mucositis 
• 
Peripheral edema 
RARE AND SERIOUS 
• 
Thrombosis 
• 
Vision changes 
• 
Development of leukemia 
Pemetrexed (Group 2 only) 
COMMON: 
• 
Leukopenia 
• 
Thrombocytopenia 
• 
Anemia 
• 
Changes in blood pressure 
• 
Temporary abnormalities in liver function tests 
• 
Nausea, vomiting, constipation, or diarrhea 
• 
Loss of appetite 
• 
Fatigue 
OCCASIONAL 
• 
Allergic reactions 
• 
Kidney damage 
• 
Fever 
• 
Weight loss 
• 
Rash, skin changes 
• 
Dehydration 
• 
Electrolyte abnormalities 
• 
Dyspnea 
• 
Mucositis 
• 
Peripheral edema 
RARE AND SERIOUS 
• 
Hemorrhage due to thrombocytopenia 
• 
Severe anemia 
• 
Kidney failure 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 33 of 52 
 
 
 
 
 
 
 
Dose De lays and Modifications for Hematologic Toxicities 
 
Hematologic Toxicity 
Modification instructions 
On day 1 of treatment: 
ANC < 1000/L but ≥ 
500/L 
Or 
Platelet count < 100/L but 
≥ 50/L 
Hold treatment and recheck CBC weekly. Cohort 1: 
Resume pevonedistat at full dose once recovered. 
Cohort 2: Resume pevonedistat and 
pemetrexed/cisplatin at full dose. Add peg-filgrastim 
as per discretion of treating physician. 
On day 1 of treatment: 
ANC < 500/L 
Or 
Platelet count < 50/L 
Hold treatment and recheck CBC weekly. Cohort 1: 
Resume pevonedistat at next lower dose level once 
recovered. 
Cohort 2: Resume pevonedistat at next lower dose 
level once recovered. Administer pemetrexed at 
400mg/m2. Continue cisplatin at full dose 75 mg/m2. 
Add peg-filgrastim as per discretion of treating 
physician. 
Episode of febrile neutropenia 
at any time during last cycle 
Hold treatment until resolution. 
Cohort 1: Resume pevonedistat at next lower dose 
level 
Cohort 2: Resume pevonedistat at next lower dose 
level once recovered. Administer pemetrexed at 
400mg/m2. Administer cisplatin at 60 mg/m2. Add peg- 
filgrastim as per discretion of treating physician. 
 
 
Dose De lays and Modifications for Nausea/Vomiting 
 
Nausea/vomiting Grade 
Modification instructions 
At any time during the cycle: 
Grade 1 
Both Cohorts: Maximize supportive care measures, 
e.g. ondansetron, lorazepam, dexamethasone, 
hydration. Proceed with full-dose treatment. 
At any time during the cycle: 
Grade 2 
Both cohorts: Hold treatment until improvement to 
grade 1. Maximize supportive care measures, e.g. 
ondansetron, lorazepam, dexamethasone, hydration. 
Continue with full dose of treatment. 
At any time during the cycle: 
Grade 3 
Hold treatment until recovered to grade 1. Maximize 
supportive care measures, e.g. ondansetron, 
lorazepam, dexamethasone, hydration. 
Cohort 1: Resume pevonedistat at next lower dose 
level once recovered. 
Cohort 2: Resume pevonedistat at next lower dose 
level once recovered. Administer pemetrexed at full 
dose 500mg/m2. Reduce dose of cisplatin to 60 
mg/m2. 
 
 
Dose De lays and Modifications for Peripheral Neuropathy or Ototoxicity (Cohort 2 
only) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 34 of 52 
 
 
 
 
 
Neuropathy/Ototoxicity Grade 
Modification instructions 
Grade 1 
Proceed with full-dose treatment of all agents. 
Grade 2 
Proceed with full-dose treatment of pevonedistat and 
pemetrexed. Reduce dose of cisplatin to 60 mg/m2. 
≥ Grade 3 
Proceed with full-dose treatment of pevonedistat and 
pemetrexed. Discontinue cisplatin. 
 
 
Dose De lays and Modifications for All Other Non-Hematologic Toxicities, 
 
Toxicity Grade 
Modification instructions 
Grade 1 - 2 
Proceed with full-dose treatment of all agents. 
Grade 3 
Hold treatment until recovery to grade 1 or 2. Cohort 
1: Proceed with treatment with pevonedistat at next 
lower dose. 
Cohort 2: Proceed with treatment with pevonedistat at 
next lower dose. 
Lower pemetrexed to 400 mg/m2 and cisplatin to 60 
mg/m2. 
Grade 4 
Hold treatment until recovery to grade 1 or 2. Resume 
treatment with dose reductions of all agents only at 
the discretion of the Principal Investigator. 
 
 
De finition of dose limiting toxicity (Cohort 2 only) 
 
All toxicity will be graded according to the National Cancer Institute (NCI) Common Toxicity 
Criteria, version 4.0. The grade of toxicity should be that seen despite maximal medical 
management. Attempts will be made as best as possible to determine whether the toxicity 
is related to pemetrexed, cisplatin, pevonedistat, or the combination. 
 
Hematologic dose-limiting toxicity is defined as any: 
 
• 
Grade 4 neutropenia lasting more than 7 consecutive days 
• 
Grade 3 neutropenia with fever and/or infection where fever is an oral temperature 
>38.5˚C 
• 
Grade 4 thrombocytopenia(platelets < 25,000/mm3 but > 10,000/mm3) lasting more 
than 7 consecutive days 
• 
Grade 3 thrombocytopenia with bleeding 
• 
Platelet count <10,000/mm3 at any time 
 
No n-Hematologic dose-limiting toxicity is defined as: 
 
• 
A delay in the initiation of Cycle 2 due to a lack of adequate recovery fromtreatment- 
related toxicity (recovery to ≤ Grade 1 or to patients baseline values): 
o Of more than 4 weeks due to nonhematologic toxicities. 
• 
Grade 3 or greater PT or aPTT elevation in the absence of anticoagulation 
• 
Grade 2 or greater elevation of the PT or aPTT that is associated with clinically 
significant bleeding (CNS, GI, etc.) 


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IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 35 of 52 
 
 
 
 
 
• 
Grade 3 or greater nausea and/or emesis despite use of optimal anti-emetic 
treatment. Optimal anti-emetic prophylaxis is defined as an anti-emetic regimen that 
employs a 5-hydroxytryptamine 3 serotonin receptor antagonist given in standard 
doses and according to standard schedules. 
• 
Grade 3 or greater diarrhea that occurs despite maximal supportive therapy 
• 
Grade 3 arthralgia/myalgia despite use of optimal analgesia 
• 
Patients experiencing concomitantLFT (≥3xULN) and bilirubin (≥2xULN) elevations 
without cholestasis and in  absence of potential alternative cause (per Hy’s Law) 
• 
Other pevonedistat-related non-hematologic toxicities Grade 2 or greater that, in the 
opinion of the investigator, require a dose reeducation or discontinuation of therapy 
with pevonedistat. 
• 
Any other grade 3 or greater non-hematologic toxicity deemed at least possibly 
related to therapy by the investigator with the following exceptions: 
o Brief (<1 week) grade 3 fatigue 
o Grade 3 hypophosphatemia 
 
Although DLTs may occur at any point during treatment, only DLTs occurring during Cycle 
1 of treatment will necessarily influence decisions regarding dose escalation, expansion of 
a dose level, or evaluation of intermediate dose levels. Patients will be monitored through 
all cycle of therapy for treatment-related toxicities. 
 
Dosing Modifications for Nonhematologic Toxicities 
 
Pe v onedistat Dose Adjustment Based on Se rum Transaminases and Total Bilirubin 
 
It is anticipated that LFTs (AST, ALT, and occasionally bilirubin) may be elevated for 
approximately 48 hours following the end of pevonedistat infusion on Cycle 1 Day 1. 
For elevated LFTs of Grade 2 or 3 that occur on or after Cycle 1 Day 3, pevonedistat 
should be held; once the elevated AST or ALT returns to ≤Grade 1, and/or elevated 
bilirubin returns to ≤1.5×ULN or the patient’s baseline level, pevonedistat dose may be 
resumed. For pevonedistat, a minimum of 1 full calendar day between any 2 doses should 
be maintained, and a maximum of 3 doses of pevonedistat within the cycle must not be 
exceeded. 
 
For elevated LFTs of Grade 4 that occur on or after Cycle 1 Day 3, the pevonedistat dose 
should be held for the remainder of the cycle; if the elevated AST or ALT returns to 
≤Grade 1, and/or elevated bilirubin returns to ≤1.5×ULN or the patient’s baseline level, 
then pevonedistat may be restarted at the next cycle at a reduced dose. If the toxicity 
returns to ≤Grade 1 or the patient’s baseline status, pevonedistat may be re-escalated. 
Dosing Guidelines for Hypophosphatemia 
 
If hypophosphatemia is ≥Grade 3, study drug treatment should not be resumed 
until the hypophosphatemia is ≤Grade 2. Hypophosphatemia should be evaluated 
(including severity and etiology), monitored, and treated according to institutional 
guidelines. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-361 A(5) 
Approval date: 16-Apr-2019 
Page 36 of 52 
 
 
 
 
 
Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study: 
Table 
Concomitant Medications Excluded During the Study 
Therapy 
Comment/Exceptions 
Acetaminophen and acetaminophen- 
containing products 
May be used judiciously but should not exceed a 
dose of 2 g in 24 hours. 
Systemic antineoplastic therapy, 
except for hydroxyurea 
Hydroxyurea dosing during the study treatment 
phase may be adjusted to control the level of 
circulating blast counts to no lower than 10,000/µL 
while on study treatment. The dosing of 
hydroxyurea and changes to dosing of hydroxyurea 
must be recorded. 
Clinically significant metabolic 
enzyme inducers 
Excluded 
Known BCRP inhibitors (i.e., 
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. 
Any investigational agent other than 
pevonedistat, including but not limited 
to androgens, supraphysiologic doses 
of corticosteroids, erythropoietin, 
eltrombopag [Promacta], or 
romiplostim [Nplate] 
BCRP=breast cancer resistance protein, CYP=cytochrome P450, 
 
 
Permitted Concomitant Medications and Procedures 
 
Table 
Concomitant Medications and Procedures Permitted 
During the Study 
Therapy 
Comment 
Anti-platelet agents (e.g., aspirin, 
clopidogrel) and anticoagulants 
May be used in patients who have controlled 
coagulopathy at baseline, as well as those who 
develop a coagulopathy on study. Note that patients 
with active uncontrolled coagulopathy are excluded 
from enrollment. 
Myeloid growth factors (e.g., G-CSF, 
GM-CSF) 
In general, the use of myeloid growth factors is 
discouraged and should be restricted. For patients 
in CR, CRi, or marrow CR, growth factors may be 
used in specific circumstances after discussion with 


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Table 
Concomitant Medications and Procedures Permitted 
During the Study 
Therapy 
Comment 
the project clinician or designee. Use of growth 
factors may also be used in patients with Grade 3 or 
Grade 4 febrile neutropenia after discussion and 
agreement with the project clinician or designee. 
Additionally to avoid dose delays, patients who 
experience Grade 4 neutropenia (ANC <500/µL) 
with or without fever may receive granulocyte 
colony-stimulating factor (G-CSF) or granulocyte 
macrophage colony-stimulating factor (GM-CSF) 
between days 28-42 days of azacitidine 
monotherapy or combination after discussion and 
agreement with the sponsor investigator (or 
designee). 
Patients who receive myeloid growth factors will not 
be included in assessment of neutrophil response. 
Platelet transfusion 
Permitted as medically necessary per institutional 
guidelines (e.g., for platelets <10,000/µL in the 
absence of clinical bleeding); see Section 6.9 
Red blood cell transfusion 
To be considered for all patients with anemia, 
especially those with hemoglobin values ≤8 g/dL. 
G-CSF=granulocyte colony-stimulating factor, GM-CSF=granulocyte macrophage colony- 
stimulating factor. 
 
 
Precautions and Restrictions 
Pre gnancy 
It is not known what effects pevonedistat has on human pregnancy or development of the 
embryo or fetus. Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner. 
Nonsterilized female patients of reproductive age group and male patients should use 
highly effective methods of contraception (see Appendix) through defined periods during 
and after study treatment as specified below. 
Female patients must meet 1 of the following: 
 
• 
Postmenopausal (See Appendix) for at least 1 year before the Screening visit, or 
 
• 
Surgically sterile, or 
 
• 
If they are of childbearing potential, agree to practice 1 highly effective method and  
1 additional effective (barrier) method of contraception, at the same time, from     
the time of signing the informed consent through 4 months after the last dose of 
study drug, or 


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• 
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, postovulation methods] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.) 
 
• 
Female patients must agree to not donate eggs (ova) during the course of this 
study or 4 months after receiving their last dose of study drug(s). 
 
Male patients, even if surgically sterilized (i.ee, status post vasectomy), must agree to 1 of 
the following: 
• 
Practice highly effective barrier contraception during the entire study treatment 
period and through 4 months after the last dose of study drug, or 
 
• 
Practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods for the female partner] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.) 
 
Male patients must agree to not donate sperm during the course of this study or 4 months 
after receiving their last dose of study drug(s). 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The Modified Response Evaluation Criteria in Solid Tumors Group (Modified RECIST) 
criteria will be used to evaluate the response to treatment.23 
 
Target Lesions: 
 
Change in disease will be assessed by measuring the tumor thickness perpendicular to the 
chest wall or mediastinum in up to three involved areas of pleural rind at least 2 cm apart 
on computed tomography scan, at baseline, and every other cycle (at least one 
measurement must be >1.5 cm). 
 
Complete Response (CR): Complete absence of all signs of disease without any new 
lesions or disease-related symptoms. 
 
Partial Response (PR): A reduction of at least 30%. 
 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as references the smallest sum LD since the treatment started. 
Progressive Disease (PD): An increase of 20% over the nadir measurement is defined as 
progressive disease. 
No n-Target Lesions 


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All other lesions (or sites of disease) not included in the “target lesions,” including small 
lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT 
scan) and truly non-measurable lesions, should be identified as non-target lesions and 
recorded at baseline. Measurements are not required and these lesions should be followed 
as defined below. 
Lesions that are considered non-measurable include bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusion, abdominal masses that are not confirmed and followed 
by imaging techniques, and cystic lesions. 
Complete response: Disappearance of all non-target lesions. 
 
Non-complete response/Non-progression: Persistence of one or more non-target lesion. 
 
Progression: Appearance of one or more new lesions. Unequivocal progression of existing 
non-target lesions. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).In general, the patient’sbest response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
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. 
 
Conditions that may define early death include patients that have died without 
documentation of disease progression and before it was time to conduct the first tumor 
reassessment. Inevaluable patients have received protocol treatment and did not have any 
follow-up assessment completed before initiation of alternative treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease fromnormal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
Guidelines for Evaluation of Measurable Disease 


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All patients in this study will be getting a CT scan to include the target lesion. 
Confirmation Measurement/Duration of Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR/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). 
 
Duration of 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. 
 
 
 
 
13.1 
CRITERIA FOR REM OVAL FROM STUDY 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
 
o Disease progression 
o Intercurrent illness that prevents further administration of treatment 
o Unacceptable adverse event(s) 
o Patient decides to withdraw from the study 
o General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
o Inability of subject to comply with study requirements 
 
For patients who stop the treatment before 4 cycles, every effort will be made to have a CT 
scan at 18 weeks after treatment start, so that they can be have a standard evaluation of 
the primary objective. If a CT scan evaluation is not available, patients will not be replaced 
and they will be considered as not having clinical benefit. 
 
 
 
14.0 
BIOSTATISTICS 
 
The primary objective of this study is to investigate pevonedistat as a single agent and in 
combination with chemotherapy in patients with MM with the use of two separate cohorts 
that will enroll patients concurrently. Cohort 1 will determine the efficacy of single agent 
pevonedistat in patients with previously treated MM and possess NF2 mutation; cohort 2 
will examine the safety of pevonedistat in combination with pemetrexed/cisplatin in 
patients with previously untreated MM to establish the recommended phase II dose. 
 
Cohort 1: Efficacy cohort 
 
We chose clinical benefit rate (CBR = CR + PR + SD) at 18 weeks post initiation of treatment 
as the primary endpoint for this cohort based on the preclinical data showing growth 
inhibition with pevonedistat. We base the sample size calculation on the estimated 20% 


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clinical benefit as a benchmark, which we derive from the placebo arm of a phase III trial, 
and our own institutional data.2,24 We consider an increase to 40% CBR as promising. A 
two-stage Simon’s minimax design will be employed to the test the hypothesis that the true 
CBR is ≤20% versus the alternative hypothesis that the true CBR is at least 40% with type 
I and II error of 0.05 and 0.2, respectively. In the first stage, we will accrue 18 patients. If 4 
or fewer show clinical benefit, then subject enrollment will be terminated and study declared 
negative. If at least 5 patients show clinical benefit in the first stage, we will request 
permission from the sponsor to enroll an additional 15 patients in the second stage. At the 
end of the study, if ≥11 patients out of total of 33 enrolled patients show clinical benefit, then 
further investigation of pevonedistat will be considered worthwhile. The study enrollment of 
the 19th patient will be suspended until the determination of the first-stage results, unless 
the benchmark of 5 patients with clinical benefit is achieved by then. All patients will be 
included in the primary analysis of clinical benefit, even if there are major protocol 
deviations. Patients are considered non-responses (no clinical benefit) if  they are not 
evaluable (including if CT scan evaluation not available) or died during the study. If patients 
terminate treatment prior to 6 cycles, every effort will be made to have a CT scan at 18 
weeks post treatment initiation so that they can contribute to the primary analysis. This study 
requires accrual of a minimum of 18 patients and up to a maximum of 33 patients if the 
cohort is expanded to the second stage. The accrual time is estimated to be between 10-24 
months at the rate of 2 patients/month and a likely planned 4 months suspension between 
the first and second stages. 
The CBR is defined as the proportion of patients CR, PR or SD at 18 weeks based on 
RECIST criteria. The CBR and corresponding exact 95% CI will be reported. Progression- 
free survival will be measured from the start of treatment until the documentation of disease 
progression or death due to any cause, whichever occurs first, and censored on the date of 
last tumor assessment document absence of tumor progression for patients who are still 
alive prior to data cutoff, dropout, or the initiation of alternate anticancer treatment. Overall 
survival will be determined as the time from the start of pevonedistat treatment to death, 
and censored on the last follow-up date. PFS and OS will be evaluated using the Kaplan- 
Meier method.25 A sensitivity analysis will also be conducted for PFS and OS where early 
dropout patients will be considered as events. 
 
All recorded toxicity data and adverse events of pevonedistat will be listed and tabulated by 
system organ class, preferred term and treatment. Any significant vital signs and clinical 
laboratory test results will be listed and summarized. Any significant physical examination 
findings and clinical laboratory results will be listed. 
 
As a secondary objective, we explore downstream mechanistic biomarkers of pevonedistat 
activity such NEDD8-Cullin4 adduct, phosphorylated YAP and TAZ from on treatment core 
biopsies. These biomarkers will be measured by western blot, and qPCR. These methods 
have been previously reported in the literature {Hansen Cell Res 2015}; however, the data 
on reproducibility, repeatability have not been established. In this study, we will perform 
reproducibility testing (3 sites from the obtained biopsy specimen) and repeatability testing 
(perform test 3 times) of each assay to determine the coefficient of variation of each test. If 
the coefficient of variation is less than 15%, we will move forward in testing these correlative 


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biomarkers in a randomized phase II trial. Using histogramplots, we will graph the biomarker 
distribution of the assays performed on on-treatment biopsies. 
 
Cohort 2: Safety cohort 
 
In this 3-by-3 dose escalation design, we investigate the maximum tolerated dose (MTD) of 
pevonedistat in combination with the full dose of pemetrexed/cisplatin. Pevonedistat will be 
administered at the dose levels of 50%, 75% and 100% of the recommended single agent 
dose (see section 9.0). If none of the initial cohort of 3 has a dose-limited toxicity (DLT, as 
defined in Section 11.0), the dose level will be escalated. If one has a DLT that dose level 
will be expanded with 3 more patients. Dose escalation will stop if ≥2 DLTs are seen at a 
dose level. The MTD is defined as the highest dose level at which no more than 1 of the 6 
patients at that level has a DLT. If no patient in the 3-patient cohort has a DLT and the dose 
level is under final consideration of the MTD, an additional three patients will be treated at 
that level for confirmation. Three dose levels plus a “-1” dose level are planned for this study. 
The maximum sample size is 24 patients for this dose escalation design. The probability of 
escalation is as follows: 
 
True DLT rate 
5% 
10% 
15% 
20% 
25% 
30% 
40% 
50% 
Probability of 
escalation 
0.97 
0.91 
0.81 
0.71 
0.60 
0.49 
0.31 
0.17 
 
 
Adverse events will be graded according to the CTCAE version 4.0, with patients being 
assess weekly while on the treatment. Proportion of clinical benefit (CR+PR+SD) and 
response (CR+PR) will be summarized among patients treated at MTD. 
 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOM IZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. Study 
staff are responsible for ensuring that all institutional requirements necessary to enroll a 
participant to the study have been completed. See related Clinical Research Policy and 
Procedure #401 (Protocol Participant Registration). 
 
 
15.3 
Randomization 
 
Not applicable 
 
16.1 
DATA MANAGEM ENT ISSUES 


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A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA will include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate the 
activities of the protocol study team. The data collected for this study will be entered into a 
secure database (Medidata). Source documentation will be available to support the 
computerized patient record. The principal investigator will maintain ultimate responsibility 
for the clinical trial. 
 
16.2 
Quality Assurance 
 
Routine data quality reports will be generated to assess missing data and inconsistencies. 
Accrual rates and extent and accuracy of evaluation and follow-up will be monitored 
periodically throughout the study period and potential problems will be brought to the 
attention of the principal investigator for discussion and action.  Random-sample data 
quality and protocol compliance audits will be conducted by the study team, at a minimum 
of two times per year, more frequently if indicated. 
 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address 
the policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.  The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data 
and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality.  There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the activities 
of our clinical trials programs.  The committees: Data and Safety Monitoring Committee 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board  
(DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 
 
 
 
16.4 
Regulatory Documentation 


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Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol 
document.. 
 
The site that is conducting specimen analysis must submit the following documents to 
MSK before specimens can be shipped to the site: 
• 
Participating Site 1572 
• 
Conflict of Interest forms for Participating Site Investigators on the 1572 
 
 
The site conducting data/specimen analysis should submit this protocol to its IRB 
according to local guidelines. Copies of any site IRB correspondence should be forwarded 
to MSK. 


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17.1 
PROTECTION OF HUM AN SUBJECTS 
 
Human Subjects Involvement, Characteristics, and Design 
 
This project involves the treatment of human subjects with pevonedistat on a phase I/II 
protocol. 
 
The subject population will include patients, age 18 or over, with advanced malignant pleural 
or peritoneal mesothelioma. Patients must have a Karnofsky Performance Status ≥70%. 
Other inclusion and exclusion criteria is specified at the beginning of this document to ensure 
enrollment of patients with adequate hematologic and biochemical function, and no other 
serious medical conditions. Patients who are pregnant or lactating are excluded, and all 
patients must use appropriate methods of contraception. About 42 patients will be enrolled. 
 
Vulnerable populations will not be included in the research. 
This study will be conducted only at MSKCC. 
Sources of Materials 
 
The data collected from patients on the study will include demographics, medical history, 
medication records, toxicities, radiologic responses, and outcomes such as time to 
progression and survival. 
 
Archived tissue samples as well as fresh biopsy samples will be collected for correlative 
studies to elucidate the mechanism of drug action. 
The data collected for this study will be entered into a secure database (Medidata) at 
Memorial Sloan Kettering Cancer Center. Source documentation will be available to support 
the computerized patient record. 
 
The use and disclosure of protected health information will be limited to the individuals 
described in the Research Authorization form. A Research Authorization form must be 
completed by the Principal Investigator and approved by the IRB and Privacy Board 
(IRB/PB). 
 
Potential Risks of Pevonedistat 
 
There are potential risks in the pevonedistat program that require monitoring. While these 
toxicities may be severe or life threatening, it is anticipated that they can be managedby clinical 
monitoring and intervention. Patients will be monitored for these potential toxicities and for 
unanticipated toxicities when they receive pevonedistatfor at least 30 days after their last dose. 
 
For detailed information please consult the current IB. 
Adequacy of Protection Against Risks 


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Recruitment and Informed Consent: Potential research subjects will be identified by a 
member of the patient’s treatment team, the protocol investigator, or research team at 
MSKCC.  If the investigator is a member of the treatment team, s/he will screen their  
patient’s medical records and discuss the study and their potential for enrolling in the 
research study.  Potential subjects contacted by their treating physician will be referred to the 
investigator/research staff of the study. 
 
Subject participation is voluntary. The proposed study does not include patients under 18 
years old. All patients will be required to sign a statement of informed consent that conforms 
to IRB guidelines. Informed consent will be documented by the use of a written consent form 
which has been approved by the IRB. Before protocol specified procedures are carried out, a 
study investigator or their staff explains the full details of the protocol and study procedures, 
as well as the risks involved to patients prior to their inclusion in the trial. Patients will also be 
informed that they are free to withdraw from the study at any time. The patient must be aware 
of the neoplastic nature of his/her disease and willingly consent after being informed of        
the procedures to be followed, the experimental nature of the therapy, alternatives,    
potential benefits, side effects, risks and discomforts. This consent is obtained in the clinic by 
one of the physician investigators whose name is indicated on the face page of the protocol. 
All patients must read, discuss with consenting physician, and sign an IRB approved consent 
form indicating their consent to participate. This consent form conforms to the applicable 
requirements of 21 CFR 50.25 elements of informed consent. Written consent will be 
obtained by either the principal investigator, co-principal investigators, or participating 
investigators. The original signed consent forms will become part of the patient's medical 
record. Each patient will receive a copy of the signed consent form. There is absolutely no 
waiver of the consent. Consent must be documented in the medical record of each patient. 
Protections Against Risk: Procedures for protecting against and minimizing risks to treatment 
and other clinical interventions is described within the text of the protocol. This includes 
toxicity monitoring, dose modification guidelines, and indications for removing patients from 
the study. 
 
Potential Benefits of the Proposed Research to Human Subjects and Others 
 
The potential benefits of the research to the subjects are not known and there may be no 
benefit to the research subject. Administration of pevonedistat will potentially cause disease 
regression. The potential benefits of the research to others are not known, but may include 
development of new therapies. 
 
The risks to subjects are reasonable in relation to the anticipated benefits to the subjects and 
others based on the preclinical and clinical data derived on the study drug to date. 
Importance of the Knowledge to be Gained 
 
The treatment of MM is an important unmet need that could impact thousands of potential 
patients. This approach would also provide a proof of concept for targeting this pathway in 
other patients with tumors resulting from NF2 loss. 


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The risks to subjects are reasonable in relation to the anticipated benefits to the subjects and 
others given the broad potential of this therapy for NF2 related malignancies and the impact 
on possible future therapies. 
 
 
 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (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. 
 
No te: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All other 
reports should be sent to saemskind@mskcc.org. 


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Regardless of expectedness or causality, all SAEs must also be reported in English to 
Millennium Pharmacovigilance or designee: 
 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
 
All other serious (non-fatal/non life threatening) events within 4 calendar days of 
the sponsor-investigator’s observation or awareness of the event 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
The CRDB SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
 
Follow-up information on the SAE may be requested by Millennium Pharmacovigilance (or 
designee). 
 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure 
that the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-investigator 
so that the sponsor-investigator can meet his/her foregoing reporting obligations to the 
required regulatory agencies and to Millennium Pharmacovigilance, unless otherwise agreed 
between the sponsor-investigator and sub-investigator(s). 


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Relationship to all study drugs for each SAE will be determined by the investigator or sub- 
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
 
 
 
 
17.2.1 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study drug. 
The sponsor-investigator must fax a completed Pregnancy Form to the Millennium 
Pharmacovigilance or designee immediately (see Section 8.2). The pregnancy must be 
followed for the final pregnancy outcome (i.e., delivery, still birth, miscarriage) and Millennium 
Pharmacovigilance or designee will request this information from the sponsor-investigator. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation 
in this study and MSKCC is notified, the sponsor-investigator will provide the external 
sponsor the information for their further action via  faxing a completed Pregnancy Form to the 
Millennium Pharmacovigilance or designee (see Section 8.2).  MSKCC will not be involved in 
the consent or data oversight of that pregnant individual. 
 
Product Complaints 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately contact Millennium (see 
below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a 
Millennium Quality representative. 
 
 
 
For Product Complaints, call 
Phone 1-844-ONC-TKDA (1-844-662-8532) 
Email: GlobalOncologyMedinfo@takeda.com 
Fax: 1-800-881-6092, Hours Mon-Fri, 9 a.m.- 7 p.m. ET 
US and Canada 
Toll-Free Fax #: 1-800-963-6290 
E-mail: TakedaOncoCases@cognizant.com All 
other countries (Rest of World) 
Fax #: 1-202-315-3560 
E-mail: TakedaOncoCases@cognizant.com 


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Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed and sent to Millennium Pharmacovigilance 
 
18.1 
INFORM ED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain   
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
REFERENCES 
 
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2. 
Zauderer MG, Kass SL, Woo K, et al: Vinorelbine and gemcitabine as second- or 
third-line therapy for malignant pleural mesothelioma. Lung Cancer, 2014 
3. 
Ladanyi M, Zauderer MG, Krug LM, et al: New strategies in pleural mesothelioma: 
BAP1 and NF2 as novel targets for therapeutic development and risk assessment. 
Clin Cancer Res 18:4485-90, 2012 
4. 
Testa JR, Cheung M, Pei J, et al: Germline BAP1 mutations predispose to malignant 
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Li W, Cooper J, Karajannis MA, et al: Merlin: a tumour suppressor with functions at 
the cell cortex and in the nucleus. EMBO Rep 13:204-15, 2012 
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Okada T, Lopez-Lago M, Giancotti FG: Merlin/NF-2 mediates contact inhibition of 
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Li W, You L, Cooper J, et al: Merlin/NF2 suppresses tumorigenesis by inhibiting the 
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Approval date: 16-Apr-2019 
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9. 
Angers S, Li T, Yi X, et al: Molecular architecture and assembly of the DDB1-CUL4A 
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Harper JW, Elledge SJ: The DNA damage response: ten years after. Molecular Cell 
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Li W, Cooper J, Zhou L, et al: Merlin/NF2 loss-driven tumorigenesis linked to 
CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the 
nucleus. Cancer Cell 26:48-60, 2014 
12. 
Bott M, Brevet M, Taylor BS, et al: The nuclear deubiquitinase BAP1 is commonly 
inactivated by somatic mutations and 3p21.1 losses in malignant pleural 
mesothelioma. Nature Genetics 43:668-72, 2011 
13. 
Lopez-Rios F, Chuai S, Flores R, et al: Global gene expression profiling of pleural 
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Ou SH, Moon J, Garland LL, et al: SWOG S0722: Phase II Study of mTOR Inhibitor 
Everolimus (RAD001) in Advanced Malignant Pleural Mesothelioma (MPM). J Thorac 
Oncol 10:387-91, 2015 
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Dolly SO, Krug LM, Wagner AJ, et al: Phase I study of apitolisib (GDC_0980), Dual 
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patients with advanced solid tumors. Clin Cancer Res 2016 Jan 19 epub ahead of 
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Zoncu R, Efeyan A, Sabatini DM: mTOR: from growth signal integration to cancer, 
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Petroski MD, Deshaies RJ: Function and regulation of cullin-RING ubiquitin ligases. 
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Soucy TA, Smith PG, Milhollen MA, et al: An inhibitor of NEDD8-activating enzyme as 
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Lallemand D, Manent J, Couvelard A, et al: Merlin regulates transmembrane receptor 
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cells and in human schwannomas. Oncogene 28:854-65, 2009 
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Lopez-Lago MA, Okada T, Murillo MM, et al: Loss of the tumor suppressor gene NF2, 
encoding merlin, constitutively activates integrin-dependent mTORC1 signaling. Mol 
Cell Biol 29:4235-49, 2009 
21. 
Bott M, Brevet M, Taylor BS, et al: The nuclear deubiquitinase BAP1 is commonly 
inactivated by somatic mutations and 3p21.1 losses in malignant pleural 
mesothelioma. Nat Genet 43:668-72, 2011 
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Nawrocki ST, Griffin P, Kelly KR, et al: MLN4924: a novel first-in-class inhibitor of 
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Byrne MJ, Nowak AK: Modified RECIST criteria for assessment of response in 
malignant pleural mesothelioma. Ann Oncol 15:257-60, 2004 
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Krug LM, Kindler HK, Calvert H, et al: Vorinostat in Patients with Advanced Malignant 
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20.0 
APPENDICES 
 
Lab Manual.