Clinical trial NCT03770260
Conditions: Recurrent Multiple Myeloma Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)
Start date: 2020-02-10; Completion date: 2023-07-06
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase Ib trial studies side effects and best dose of pevonedistat when given together with ixazomib in treating patients with multiple myeloma that has come back or does not respond to treatment. Pevonedistat and ixazomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib citrate \[ixazomib\]) in relapsed and/or refractory multiple myeloma (RRMM) patients after more than one previous line of treatment. (Dose-escalation phase) II. Describe the safety profile and tolerability of the combination of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in the proteasome inhibitor (PI)-sensitive and PI-refractory populations. (Dose-expansion phase) III. Determine the anti-tumor activity and overall response rates (ORR) in patients with RRMM with the use of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in combination. (Dose-expansion phase)

SECONDARY OBJECTIVE:

I. Attain pharmacokinetic (PK) characterization of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib) for the purpose of understanding concentration-effect relationships of both agents. (Dose-escalation phase)

EXPLORATORY OBJECTIVE:

I. To correlate and predict disease response using the following tests: NAD(P)H dehydrogenase (quinone) 1 (NQO1) and cystine/glutamate transporter (SLC7A11) (nuclear factor \[erythroid-derived 2\]-like 2 \[NRF2\] target genes): evaluated on whole blood as markers of MLN4924 (pevonedistat) activity.

OUTLINE: This is a dose-escalation study of pevonedistat.

Patients receive ixazomib citrate orally (PO) once daily (QD) on days 1, 8, and 15 of each cycle and pevonedistat intravenously (IV) over 60 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 2-3 months for up to 2 years.

Arms: arm 1: Patients receive ixazomib citrate PO QD on days 1, 8, and 15 of each cycle and pevonedistat IV over 60 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Ixazomib Citrate intervention 2: Pevonedistat
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
ICF_002.pdf: 
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Research Study Informed Consent Document 
 
Study Title for Participants:  Testing the combination of two drugs, MLN9708 
(ixazomib) and MLN4924 (pevonedistat), for relapsed and/or resistant multiple myeloma 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  Protocol 
10249, MLN9708 (Ixazomib) and MLN4924 (Pevonedistat) in Relapsed/Refractory 
Multiple Myeloma Patients:  A Phase 1b Trial (NCT # 03770260) 
 
Overview and Key Information  
 
What am I being asked to do? 
 
We are asking you to take part in a research study. This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services.  We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer. 
 
We are asking you to take part in this research study because you have multiple myeloma that 
has relapsed and/or is resistant to other treatment. 
 
Taking part in this study is your choice.  
 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 
 
Why is this study being done? 
 
This study is being done to answer the following question:  
 
Can we lower the chance of your multiple myeloma growing or spreading by using a new 
combination of drugs? 
 
We are doing this study because we want to find out if this approach is better or worse than the 
usual approach for your multiple myeloma. The usual approach is defined as care most people 
get for multiple myeloma that has relapsed or is resistant to treatment. 
 
 


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What is the usual approach to my multiple myeloma? 
 
The usual approach for patients who are not in a study is treatment with different medications 
that have shown to have anti-myeloma effects, including but not limited to chemotherapy.  Some 
of these agents or combinations of agents are Food and Drug Administration (FDA)-approved 
while others are not.  MLN9708 (ixazomib), when given in combination with lenalidomide and 
dexamethasone, is already FDA approved for your myeloma.  Your doctor can explain which 
treatment may be best for you.  These treatments can reduce symptoms and may stop the tumor 
from growing for a few months or longer. 
 
What are my choices if I decide not to take part in this study? 
 
x You may choose to have the usual approach described above. 
x You may choose to take part in a different research study, if one is available. 
x You may choose not to be treated for cancer. 
x You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
 
What will happen if I decide to take part in this study? 
 
If you decide to take part in this study, you will get MLN9708 (ixazomib) and MLN4924 
(pevonedistat) for as long as your myeloma doesn’t get worse and you don’t have a side effect 
that requires us to stop treatment.  
 
After you finish your study treatment with MLN9708 (ixazomib) and MLN4924 (pevonedistat), 
your doctor will ask you to complete a 30-day safety follow-up visit and continue to follow your 
condition every 2-3 months for up to 2 years. 
 
What are the risks and benefits of taking part in this study? 
 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that MLN9708 (ixazomib) and MLN4924 
(pevonedistat) may not be as good as the usual approach at shrinking or stabilizing your cancer. 
 
There is also a risk that you could have side effects from the MLN9708 (ixazomib) and 
MLN4924 (pevonedistat).  These side effects may be worse and may be different than you would 
get with the usual approach for your cancer.  Tables containing the known common, occasional, 
and rare side effects are presented in the “What risks can I expect from taking part in this study?” 
section. 


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There may be some risks that the study doctors do not yet know about.   
 
Benefits 
 
There is some evidence in living human cells that the combination of MLN9708 (ixazomib) and 
MLN4924 (pevonedistat) can shrink and/or stabilize cancer, but we do not know if this will 
happen in people.  It is unlikely that this drug combination will help you live longer than the 
usual approach alone.   
 
If I decide to take part in this study, can I stop later? 
 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  If you stop, you can decide if you want to keep letting the study doctor know how you 
are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
Are there other reasons why I might stop being in the study? 
 
Yes.  The study doctor may take you off the study if: 
 
x Your health changes and the study is no longer in your best interest. 
x New information becomes available and the study is no longer in your best interest. 
x You do not follow the study rules. 
x For women: You become pregnant while on the study. 
x The study is stopped by the Institutional Review Board (IRB), FDA, or study sponsor 
(National Cancer Institute [NCI]).  The study sponsor is the organization who oversees 
the study.   
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? 
 
The purpose of this study is to test the safety of two drugs called MLN9708 (ixazomib) and 
MLN4924 (pevonedistat).  This drug combination has been tested in animals, but has not been 
tested in people.  This study tests different doses of the drug to see which dose is safer for 
people.  There will be about 66 people taking part in this study. 
 
 
 


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What are the study groups? 
 
There are two parts in this study, a dose escalation part and a dose expansion part.  You are in the 
dose expansion portion. 
 
In the dose expansion part of this study, the highest dose with manageable side effects 
determined in the first part of the study will be given to 24 more people.  This will help study 
doctors better understand the side effects that may happen with this drug. 
 
Treatment schedule: You will get MLN4924 (pevonedistat) through a vein in your arm and 
MLN9708 (ixazomib) as a pill you take by mouth in the clinic on the 1st, 8th, and 15th day of each 
cycle.  Each cycle lasts 28 days.  See the study calendar for more information. 
 
MLN9708 (ixazomib) will be administered at the same time as the MLN4924 (pevonedistat) 
intravenous infusion.  Take MLN9708 (ixazomib) capsule(s) on an empty stomach, 1 hour before 
or 2 hours after food.  Swallow whole capsules with water.  Do not open or break capsules.   
 
You will not be able to get additional doses of the drugs.  MLN9708 (ixazomib) is approved by 
the FDA to treat multiple myeloma.  MLN4924 (pevonedistat) is not approved by the FDA for 
treatment of your disease. 
 
What exams, tests, and procedures are involved in this study? 
 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures. This helps your doctor decide if it is safe for you to take part in the study.  Before 
you begin the study, you will need to have the following extra tests to find out if you can be in 
the study: 
 
x Blood tests 
x A test of the electrical activity of your heart (EKG) 
x An ultrasound of your heart (echocardiogram) 
x A pregnancy test if you are a female of childbearing potential 
x Skeletal survey/CT scan 
 
If you join the study, you will have more exams, tests, and procedures to closely monitor your 
safety and health.  Most of these are included in the usual care you would get even if you were 
not in a study.  
 
Listed below are exams, tests, and procedures that need to be done as part of this study to 
monitor your safety and health, but may not be included in the usual care.  We will use them to 
carefully follow the effects of the study treatment, including preventing and managing side 
effects.  
 
These exams, tests, and procedures to monitor your safety and health include:   
 
 


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x Blood tests every week you receive the study drugs 
x A serum pregnancy test monthly 
x Skeletal survey/CT scan (repeated during treatment to confirm response or disease 
progression) 
 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only.  
 
You will need to have several blood draws for the study.  These blood draws will occur on the 
following days of the study: 
 
x Before you begin the study 
x Day 1 of the 1st cycle 
 
These blood draws will be done to evaluate markers of activity of the study drugs in your system.  
You and your study doctor will not get the results of this testing.   
 
A patient study calendar is attached at the end of this document.  It shows how often these 
exams, tests, and/or procedures will be done. 
 
What risks can I expect from taking part in this study? 
 
General Risks 
 
If you choose to take part in this study, there is a risk that MLN9708 (ixazomib) and MLN4924 
(pevonedistat) may not be as good as the usual approach at shrinking or stabilizing your cancer.  
 
You also may have the following discomforts: 
 
x You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
x You may be asked sensitive or private questions which you normally do not discuss 
x You may not be able to take part in future studies 
x The study drugs may not be better, and could possibly be worse, than the usual approach 
for your cancer. 
 
The study drugs used in this study could be very harmful to an unborn or newborn baby.  There 
may be some risks that doctors do not yet know about. You should not get pregnant, breastfeed, 
or father a baby while in this study and for a minimum of 4 months after the last dose of study 
drug.  It is very important that you check with your study doctor about what types of birth 
control or pregnancy prevention to use during the study and for 4 months after you have 
completed the study. 
 
Women of childbearing potential should practice 1 highly effective method and 1 additional 
(barrier) method of contraception, at the same time during the study and for 4 months after you 
have completed the study.  Or agree to abstain from heterosexual intercourse.  


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Men should practice effective barrier contraception during the study and for 4 months after you 
have completed the study.  Or agree to abstain from heterosexual intercourse. 
 
Blood Draw Risks 
 
You may feel discomfort during some of the tests or procedures during this study or may 
experience some inconveniences.  Some of the risks from drawing blood from your arm may 
include pain, bruising, lightheadedness, and rarely, infection.  Let your study doctor know of any 
questions you have about possible side effects. You can ask the study doctor questions about side 
effects at any time. 
 
Side Effect Risks 
 
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood.  The study doctor will test your blood and let you know if changes 
occur that may affect your health. 
 
There is also a risk that you could have other side effects from the study drugs that could be 
severe or life threatening. 
 
Here are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
3. Some side effects may make it hard for you to have children. 
4. Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 
x Tell your study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
x Your study doctor may be able to treat some side effects. 
x Your study doctor may adjust the study drugs to try to reduce side effects. 
 
Drug Risks 
 
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
 
 
 


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Possible Side Effects of MLN9708 (Ixazomib citrate) 
(Version 2.1, March 26, 2022) 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving MLN9708 (ixazomib citrate), more than 20 and up to 100 may have: 
x 
Diarrhea, nausea, vomiting 
x 
Tiredness 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving MLN9708 (ixazomib citrate), from 4 to 20 may have: 
x 
Anemia which may require blood transfusion 
x 
Pain  
x 
Constipation 
x 
Fever 
x 
Cold symptoms such as stuffy nose, sneezing, sore throat 
x 
Bruising, bleeding 
x 
Loss of appetite 
x 
Headache 
x 
Muscle weakness 
x 
Numbness, tingling or pain of the arms and legs 
x 
Cough, shortness of breath 
x 
Rash 
 
RARE, AND SERIOUS 
In 100 people receiving MLN9708 (ixazomib citrate), 3 or fewer may have: 
x 
Blood clot which may cause confusion, paralysis, seizures and blindness 
x 
Swelling of arms, legs 
x 
Liver damage which may cause yellowing of the eyes and skin 
 
 
Possible Side Effects of MLN4924 (Pevonedistat) 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving MLN4924 (Pevonedistat HCl), more than 20 and up to 100 may have: 
x Diarrhea, nausea, vomiting 
x Tiredness, fever 
x Loss of appetite 
x Pain 
 
 


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OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving MLN4924 (Pevonedistat HCl), from 4 to 20 may have: 
x Anemia which may require blood transfusion 
x Infection, especially when white blood cell count is low which may cause painful 
and frequent urination 
x Bloating, constipation 
x Sores in the mouth which may cause difficulty swallowing 
x Chills 
x Swelling of arms, legs 
x Cold symptoms such as stuffy nose, sneezing, sore throat 
x Bruising, bleeding 
x Dehydration 
x Dizziness, headache 
x Muscle weakness 
x Numbness, tingling or pain of the arms and legs 
x Feeling of “pins and needles” in arms in legs 
x Worry, confusion 
x Difficulty sleeping 
x Cough, shortness of breath, wheezing 
x Nose bleed 
x Fluid around lungs 
x Increased sweating 
x Itching 
x 
Low blood pressure which may cause feeling faint 
 
RARE, AND SERIOUS 
In 100 people receiving MLN4924 (Pevonedistat HCl), 3 or fewer may have: 
x Abnormal heartbeat 
x 
Kidney damage which may cause swelling, may require dialysis 
 
Additional Drug Risks 
 
The study drug could interact with other drugs.  Your study doctor will give you a drug 
information handout and wallet card that lists these possible interactions.  Share this information 
with your family members, caregivers, other health care providers, and pharmacists. 
 
Rarely, there are problems getting enough supplies of the study drug.  If that happens, your 
doctor will talk with you about your options. 
 
Imaging Risks 
 
The skeletal survey/CT scan that you get in this study will expose you to low amounts of 
radiation. Every day, people are exposed to low levels of radiation that come from the sun and 


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the environment around them. This type of radiation is called “background radiation.”  No one 
knows for sure whether exposure to these low amounts of radiation is harmful to your body.  
 
What are my responsibilities in this study? 
 
If you choose to take part in this study you will need to: 
 
x Keep your study appointments. 
x Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
 
For women: Do not get pregnant or breastfeed while taking part in this study.  For men: Do not 
father a baby while taking part in this study.  For all:  Tell your study doctor right away if you 
think that you or your partner have become pregnant during the study or within 4 months after 
your last dose of study drug. 
 
What are the costs of taking part in this study? 
 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
the study, just as you would if you were getting the usual care for your cancer. This includes: 
 
x the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.   
x the costs of CT scans. 
x the costs of the pregnancy tests 
x the costs of getting the study drugs ready and giving them to you. 
x your insurance co-pays and deductibles. 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study. These include:   
 
x The blood draws collected for research purposes. 
x The cost of an echocardiogram 
x The costs of tests of the electrical activity of your heart (EKG). 
 


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You or your insurance provider will not have to pay for the study drugs (MLN9708 [ixazomib] 
and MLN4924 [pevonedistat]) while you take part in this study.  
 
Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat your cancer.  You may: 
 
x Have more travel costs. 
x Need to take more time off work. 
x Have other additional personal costs. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment.    
 
What happens if I am injured because I took part in this study? 
 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options. The study sponsors will not pay 
for medical treatment for injury. Your insurance company may not be willing to pay for a study-
related injury. Ask them if they will pay. If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
 
Your privacy is very important to us. The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law. If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
 
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at or receive copies of some of the information in your 
study records. Your health information in the research database also may be shared with these 
organizations. They must keep your information private, unless required by law to give it to 
another group.   
 
 
 


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Some of these organizations are: 
 
x The study sponsor and any company supporting the study now or in the future.  This 
would include any organization helping the company with the study. 
x The NCI Central IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study. 
x The FDA and the groups it works with to review research.   
x The NCI and the groups it works with to review research. 
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy.  The goal of this 
data sharing is to make more research possible that may improve people’s health.  Your study 
records may be stored and shared for future use in public databases.  However, your name and 
other personal information will not be used.   
 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data with 
older study data.  However, right now we don’t know what research may be done in the future 
using your information.  This means that: 
 
x You will not be asked if you agree to take part in the specific future research studies 
using your health information.   
x You and your study doctor will not be told when or what type of research will be done. 
x You will not get reports or other information about any research that is done using your 
information.  
 
Where can I get more information?   
 
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  Contact the study doctor (*insert name of study doctor[s]*) at 
(*insert telephone number, and email address if appropriate*). 
 
For questions about your rights while in this study, call the (*insert name of organization or 
center*) Institutional Review Board at (*insert telephone number*).  
 
 
 
 


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My signature agreeing to take part in the study 
 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.   
 
 
Participant’s signature 
 
 
 
 
Date of signature 
 
 
 
 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
Date of signature 
 
 
 
 
 


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Attachment A:  Study Calendar for Protocol 10249 Consent Form 
 
Pre- 
Study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
Off Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
MLN9708 (Ixazomib)A 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
MLN4924 (Pevonedistat)B 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Pre-study procedures including 
informed consent, demographics, 
medical history, height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
Physical exam, weight, and general 
well-being 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital signsG 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Blood draws for health status 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
Urine collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Echocardiogram  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X------------------------------------------------------------------------------------------------------------------------------------------------------X 
X 
Pregnancy testC 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Blood draws for scientific study 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Disease assessmentF 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Medical imaging scans (Computed 
Tomography) 
X 
Repeated during treatment if clinically indicated to confirm response or disease progression 
 
A: 
MLN9708 (ixazomib) will be given as assigned on Days 1, 8, and 15 of each 28-day cycle. 
B: 
MLN4924 (pevonedistat) will be given as assigned on Days 1, 8, and 15 of each 28-day cycle. 
C: 
Serum pregnancy test is for women of childbearing potential. 
D: 
Plasma will be collected before treatment beings and approximately 1 hr after treatment begins during the first week of Cycle 1.  Additional collections may occur at 0.5 hrs, 2 hrs, 2.5 hrs, 5 hrs, 
8 hrs, and 21 hrs after treatment during Week 3 of Cycle 1 and Weeks 1 and 3 of Cycle 3.  
F: 
24-hour urine and blood will be collected within 7 days before the study begins, before each cycle (starting with Cycle 2), and at time of study discontinuation.  When clinically indicated, 
 
assessments may also include a physical exam with measurements, CT scan of the chest, abdomen/pelvis, and an ultrasound of the liver/spleen or abdomen. 
G:  Vital signs will be collected at screening, pre-dose on Days 1, 3, and 8 of each cycle, at off study, and as clinical indicated. 
 

Prot_SAP_000.pdf: 
NCI Protocol #:10249 
Version Date:  June 1, 2022 
 
i 
 
DATE: 
June 1, 2022 
 
TO:  
CTEP Protocol and Information Office 
 
FROM:  
Nisha Joseph, MD 
 
SUBJECT: 
Amendment #8 in response to Dr. Wright’s May 27, 2022 request for a 
rapid amendment. 
 
 
SUMMARY OF CHANGES – Protocol 
 
I. 
Response to Dr. Wright’s request for rapid amendment (RRA) for MLN9708 (Ixazomib 
citrate) dated 5/27/22: 
 
# 
Section 
Change 
1. 
Header,  
Title Page Updated protocol version date.  
2. 
10.1.1.1 
Replaced the MLN9708 (Ixazomib citrate) CAEPR with version 2.1, March 26, 2022. 
The following changes were made: 
 
• 
Added New Risk:  
• 
Less Likely: Peripheral sensory neuropathy 
• 
Rare but Serious: Thrombotic thrombocytopenic purpura 
• 
Also Reported on MLN9708 Trials But With Insufficient Evidence for 
Attribution: Bile duct stenosis; Bone pain; Bronchial obstruction; 
Disease progression; Flu like symptoms; Fungemia; Injury, poisoning 
and procedural complications - Other (femoral neck fracture); 
Insomnia; Myocardial infarction; Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - Other (non-Hodgkin’s lymphoma); 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - 
Other (plasma cell myeloma); Pharyngitis; Retinal detachment; Sepsis; 
Shingles; Sinusitis; Spinal fracture; Tumor pain 
 
• 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Also Reported on MLN9708 Trials But 
With Insufficient Evidence for Attribution: Arthralgia; Back pain; 
Dyspnea; Upper respiratory infection 
• 
Decrease in Risk Attribution:  
• 
Changed to Less Likely from Likely: Anorexia; Platelet count 
decreased; Rash maculo-papular 
• 
Changed to Rare but Serious from Less Likely: Edema limbs 
• 
Changed to Also Reported on MLN9708 Trials But With Insufficient 
Evidence for Attribution from Less Likely: Dehydration; Lymphocyte 
count decreased; Pruritus; White blood cell decreased 


NCI Protocol #:10249 
Version Date:  June 1, 2022 
 
ii 
 
 
(continued) 
• 
Deleted Risk: 
• 
Less Likely: Chills; Mucositis oral 
• 
Also Reported on MLN9708 Trials But With Insufficient Evidence for 
Attribution: Alopecia; Blood lactate dehydrogenase increased; Blood 
and lymphatic system disorders - Other (pancytopenia); Dry skin; 
Edema face; Esophageal ulcer; Epistaxis; Erythroderma; Hyperhidrosis; 
Hyperuricemia; Hypophosphatemia; Ileus; Infections and infestations - 
Other (oral herpes); Investigations - Other (C-reactive protein 
increased); Paresthesia; Periorbital edema; Photosensitivity; 
Pneumonitis; Purpura; Pulmonary hypertension; Rash acneiform; Skin 
and subcutaneous tissue disorders - Other (acute febrile neutrophilic 
dermatosis); Skin and subcutaneous tissue disorders -Other (erythema 
nodosum); Skin and subcutaneous tissue disorders - Other (skin 
discoloration); Skin and subcutaneous tissue disorders - Other (skin 
fibrosis); Skin hyperpigmentation; Skin induration; Skin ulceration; 
Urticaria; Vasculitis; Weight loss 
 
 
SUMMARY OF CHANGES – Consent Forms 
 
II. 
Dose Escalation Consent form: 
 
# 
Section 
Change 
1. 
Header 
Updated version date. 
2. 
What risks can I 
expect from taking 
part in this study? 
In response to Dr. Wright’s request for rapid amendment, the following 
changes to the risks of MLN9708 were made: 
• 
Added New Risk: 
• 
Occasional: Cold symptoms such as stuffy nose, sneezing, 
sore throat; shortness of breath 
• 
Rare: Blood clot which may cause confusion, paralysis, 
seizures and blindness 
• 
Decrease in Risk Attribution: 
• 
Changed to Occasional from Common: Bruising, bleeding; 
Loss of appetite; Rash 
• 
Changed to Rare from Occasional: Swelling of arms, legs 
• 
Changed to Also Reported on MLN9708 Trials But With 
Insufficient Evidence for Attribution from Occasional (i.e., 
removed from the Risk Profile): Dehydration; Infection, 
especially when white blood cell count is low; Itching 
 
• 
Deleted Risk: 
• 
Occasional: Chills; Sores in the mouth which may cause 
difficulty swallowing 


NCI Protocol #:10249 
Version Date:  June 1, 2022 
 
iii 
 
 
(continued) 
• 
Provided Further Clarification:  
• 
Pain in belly (under Occasional) is now reported as Pain 
(under Occasional). 
 
III. 
Dose Expansion Consent form: 
 
# 
Section 
Change 
1. 
Header 
Updated version date. 
2. 
What risks can I 
expect from taking 
part in this study? 
In response to Dr. Wright’s request for rapid amendment, the following 
changes to the risks of MLN9708 were made: 
• 
Added New Risk: 
• 
Occasional: Cold symptoms such as stuffy nose, sneezing, 
sore throat; shortness of breath 
• 
Rare: Blood clot which may cause confusion, paralysis, 
seizures and blindness 
• 
Decrease in Risk Attribution: 
• 
Changed to Occasional from Common: Bruising, bleeding; 
Loss of appetite; Rash 
• 
Changed to Rare from Occasional: Swelling of arms, legs 
• 
Changed to Also Reported on MLN9708 Trials But With 
Insufficient Evidence for Attribution from Occasional (i.e., 
removed from the Risk Profile): Dehydration; Infection, 
especially when white blood cell count is low; Itching 
 
• 
Deleted Risk: 
• 
Occasional: Chills; Sores in the mouth which may cause 
difficulty swallowing 
 
• 
Provided Further Clarification:  
• 
Pain in belly (under Occasional) is now reported as Pain 
(under Occasional). 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
1 
NCI Protocol #:  10249 
 
Local Protocol #: 
TBD 
 
ClinicalTrials.gov Identifier:  NCT03770260 
 
TITLE:   MLN9708 (Ixazomib) and MLN4924 (Pevonedistat) in Relapsed/Refractory Multiple 
Myeloma Patients:  A Phase 1b Trial 
 
Corresponding Organization: LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
Nisha Joseph 
 
Emory University 
 
1365B Clifton Road, Suite B400 
 
Atlanta, GA 30322 
 
Telephone: (404)-778-1923 
 
Email: nisha.sara.joseph@emory.edu 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
Statistician: 
 
Study Coordinator: 
 
Zhengjia Chen, PhD 
 
Kathryn Clarke 
 
Room 342, Grace Crum Rollins Building 
Suite 3012  
 
1518 Clifton Road, NE 
1365-C Clifton Rd, NE  
 
Atlanta, GA 30322 
Atlanta, GA 30322 
 
Telephone:  (404)-712-8278 
Telephone:  (404)-778-2227 
 
Fax:  (404)-778-5016 
Fax: (404)-778-4389 
 
Email:  zchen38@emory.edu 
Email: kathryn.clarke@emory.edu  


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
2 
 
Responsible Research Nurse: 
LAO Protocol Liaison: 
 
TBD 
Judy Murray 
 
 
Johns Hopkins University 
 
 
201 N. Broadway, Suite 9130 
 
 
Baltimore, MD 21287 
 
 
Telephone: (410)-955-4044 
 
 
Email: jmurra33@jhmi.edu  
 
NCI-Supplied Agent(s):  MLN4924 (Pevonedistat) (NSC 793435), MLN9708 (Ixazomib) (NSC 
767907) 
 
IND Sponsor:  DCTD, NCI  
 
Protocol Type / Version # / Version Date: 
Original / July 27, 2018 
 
 
 
 
Revision 1 / October 8, 2018 
 
 
 
 
Revision 2 / November 15, 2018 
 
 
 
 
Revision 3 / February 4, 2019 
 
 
 
 
Amendment 1 / April 19, 2019 
 
 
 
 
Amendment 2 / June 24, 2019 
 
 
 
 
Amendment 3 / September 16, 2019 
 
 
 
 
Amendment 4 / November 11, 2019 
 
Amendment 5 / July 13, 2020 
 
Amendment 6 / September 6, 2020 
 
Amendment 7 / August 23, 2021 
 
Amendment 8 / June 1, 2022 
 
 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
3 
 
SCHEMA 
 
 
 
Dose Escalation Schedule 
Dose Level 
Dose 
MLN9708 (Ixazomib) PO QD 
on Days 1, 8, and 15 
MLN4924 (Pevonedistat) IV on 
Days 1, 8, and 15* 
Level -2 
3 mg 
15 mg/m2 
Level -1 
3 or 4 mg# 
15 or 20 mg/m2# 
Level 1 
4 mg 
20 mg/m2 
Level 2 
4 mg 
40 mg/m2 
Level 3 
4 mg 
60 mg/m2 
Level 4 
4 mg 
80 mg/m2 
Level 5 
4 mg 
100 mg/m2 
PO = by mouth, QD = once daily, IV = intravenous 
# Agent attribution for DLT will dictate which drug is dose reduced for dose level -1.  No dose 
reduction below 3 mg for MLN9708 (ixazomib) and 15 mg/m2 for MLN4924 (pevonedistat) 
will be allowed.  Should a DLT occur attributable to either agent at the lowest dose level, the 
trial will be stopped. 
* Dose rounding is allowed as per institutional guidelines. 
Figure 1:  Treatment schema.  MTD = maximum tolerated dose, PI = 
proteasome inhibitor 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
4 
TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Primary Objectives ...................................................................................................6 
1.2 
Secondary Objectives ...............................................................................................6 
1.3 
Exploratory Objectives ............................................................................................6 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease(s).......................................................................................................7 
2.2 
CTEP IND Agents ...................................................................................................7 
2.3 
Rationale ................................................................................................................23 
2.4 
Correlative Studies Background ............................................................................26 
3. 
PATIENT SELECTION ....................................................................................................28 
3.1 
Eligibility Criteria ..................................................................................................28 
3.2 
Exclusion Criteria ..................................................................................................29 
3.3 
Inclusion of Women and Minorities ......................................................................32 
4. 
REGISTRATION PROCEDURES ...................................................................................33 
4.1 
Investigator and Research Associate Registration with CTEP ..............................33 
4.2 
Site Registration .....................................................................................................34 
4.3 
Patient Registration ................................................................................................36 
4.4 
General Guidelines .................................................................................................38 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................39 
5.1 
Biomarker Plan ......................................................................................................39 
5.2 
Integrated Correlative Studies ................................................................................42 
5.3 
Exploratory Correlative Studies .............................................................................45 
6. 
TREATMENT PLAN ........................................................................................................46 
6.1 
Agent Administration .............................................................................................46 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................48 
6.3 
Dose Expansion Cohorts: .......................................................................................49 
6.4 
General Concomitant Medication and Supportive Care Guidelines ......................50 
6.5 
Duration of Therapy ...............................................................................................53 
6.6 
Premature termination of the study ........................................................................54 
6.7 
Duration of Follow Up ...........................................................................................55 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................56 
7.1 
Criteria for Retreatment and Dose Delays .............................................................56 
7.2 
Dose Modifications for Hematologic Toxicities....................................................58 
7.3 
Dose Modifications for Nonhematologic Toxicities..............................................59 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................64 
8.1 
CTEP IND Agents .................................................................................................64 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
5 
9. 
STATISTICAL CONSIDERATIONS...............................................................................70 
9.1 
Study Design/Endpoints.........................................................................................70 
9.2 
Sample Size/Accrual Rate ......................................................................................71 
9.3 
Analysis of Secondary Endpoints ..........................................................................71 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................73 
10.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............73 
10.2 
Adverse Event Characteristics ...............................................................................78 
10.3 
Expedited Adverse Event Reporting ......................................................................79 
10.4 
Routine Adverse Event Reporting .........................................................................81 
10.5 
Pregnancy ...............................................................................................................82 
10.6 
Secondary Malignancy ...........................................................................................82 
10.7 
Second Malignancy ................................................................................................82 
11. 
STUDY CALENDAR .......................................................................................................83 
12. 
MEASUREMENT OF EFFECT........................................................................................80 
12.1 
Antitumor Effect – Hematologic Tumors ..............................................................80 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................89 
13.1 
Study Oversight .....................................................................................................89 
13.2 
Data Reporting .......................................................................................................89 
13.3 
CTEP Multicenter Guidelines ................................................................................91 
13.4 
Collaborative Agreements Language .....................................................................92 
14. 
REFERENCES ..................................................................................................................95 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................90 
APPENDIX B 
PATIENT CLINICAL TRIAL WALLET CARD – 
MLN9708 (IXAZOMIB) ...................................................................................................99 
APPENDIX C 
PATIENT DRUG INTERACTIONS HANDOUT AND 
WALLET CARD – MLN4924 (PEVONEDISTAT) ......................................................100 
APPENDIX D 
NEW YORK HEART ASSOCIATION 
CLASSIFICATION OF CARDIAC DISEASE...............................................................102 
 
 
 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
6 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Dose-escalation phase 
 
1.1.1.1 
Determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) 
of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib) in relapsed 
and/or refractory multiple myeloma (RRMM) patients after more than one previous 
line of treatment. 
 
1.1.2 Dose-expansion phase 
 
1.1.2.1 
Describe the safety profile and tolerability of the combination of MLN9708 
(ixazomib) and MLN4924 (pevonedistat) in the proteasome inhibitor (PI)-sensitive 
and PI-refractory populations. 
 
1.1.2.2 
Determine the anti-tumor activity and overall response rates (ORR) in patients with 
RRMM with the use of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in 
combination. 
 
1.2 
Secondary Objectives 
 
1.2.1 Dose-escalation phase 
 
1.2.1.1 
Attain pharmacokinetic (PK) characterization of MLN4924 (pevonedistat) in 
combination with MLN9708 (ixazomib) for the purpose of understanding 
concentration-effect relationships of both agents. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To correlate and predict disease response using the following tests: 
 
• NAD(P)H dehydrogenase (quinone) 1 (NQO1) and cystine/glutamate transporter 
(SLC7A11) (nuclear factor [erythroid-derived 2]-like 2 [NRF2] target genes):  evaluated 
on whole blood as markers of MLN4924 (pevonedistat) activity. 
 
 
 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
7 
2. 
BACKGROUND 
 
2.1 
Study Disease(s) 
 
Multiple Myeloma (MM) is the third most common hematologic malignancy with over 30,000 
new diagnoses annually and an estimated 12,770 deaths to occur in 2018 (Noone et al., 2018).  
Though median overall survival (OS) has improved markedly in recent years due to improved 
therapies, the median progression-free survival (PFS) and OS in PI- and immunomodulatory 
drug (IMiD)-refractory patients with prior exposure to alkylating agents is 5 and 15 months, 
respectively (Kumar et al., 2017).  Therefore, there is a continued need for effective agents in the 
relapsed setting. 
 
2.2 
CTEP IND Agents 
 
2.2.1 MLN9708 (Ixazomib Citrate) 
 
MLN9708 (ixazomib citrate) (also known as NINLARO®, herein referred to as MLN9708 
[ixazomib]), which rapidly hydrolyzes to the biologically active boronic acid MLN9708 
(ixazomib) under physiological conditions, is a PI that potently, reversibly, and selectively 
inhibits the β5 site of the 20S catalytic subunit of the 26S proteasome (Ixazomib Investigator's 
Brochure, 2017).  Proteasome inhibition results in the accumulation of polyubiquitinated 
substrates, such as cyclin-dependent kinase inhibitors, tumor protein p53 (p53), and the nuclear 
factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitory protein (I- κB), within 
cells (Dalton, 2004; Chauhan et al., 2011).  This subsequently leads to increased apoptosis and 
decreased cell growth and survival, particularly in cancer cells. 
 
2.2.1.1 
Nonclinical Experience 
 
MLN9708 (ixazomib) potently inhibits chymotrypsin-like (β5) 20S proteasome activity, with a 
half-maximal inhibitory concentration (IC50) of 3.4 nM (Kupperman et al., 2010).  Compared to 
the β5 site, MLN9708 (ixazomib) potency was reduced roughly 10-fold toward the caspase-like 
β1 proteolytic site, and ≥1000-fold toward the trypsin-like β2 site.  Consistent with its potent 
inhibition of the proteasome, MLN9708 (ixazomib) induced apoptosis and inhibited the viability 
of human MM cell lines and patient-derived MM cells in a dose-dependent manner (Chauhan et 
al., 2011).  MLN9708 (ixazomib) was shown to affect cell types found in the bone marrow 
microenvironment, inhibiting the in vitro formation and function of osteoclasts, promoting those 
of bone-forming osteoblasts, and providing benefit in tumor burden control and bone loss 
prevention in vivo (Garcia-Gomez et al., 2014).  MLN9708 (ixazomib) has demonstrated activity 
in a range of xenograft models of MM, lymphoma, and solid tumors grown in 
immunocompromised mice, as well as in transgenic mouse models of plasma cell malignancy 
(PCM) (Ixazomib Investigator's Brochure, 2017). 
 
Company-sponsored PK studies in rats, rabbits, dogs, and monkeys after intravenous (IV) dosing 
demonstrated that MLN9708 (ixazomib) had a very low blood clearance, a steep initial 
distribution phase, and a terminal half-life (t1/2) >24 hours (Ixazomib Investigator's Brochure, 
2017).  MLN9708 (ixazomib) had a higher plasma clearance than in blood, largely because of 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
8 
extensive concentration-dependent red blood cell partitioning.  Metabolism via hydrolysis, 
hydroxylation, dehydrogenation, and N-dealkylation appear to be major routes of MLN9708 
(ixazomib) elimination. 
 
Oral (PO) dosing studies in rats and dogs showed that the MLN9708 (ixazomib) plasma 
concentration increased in an approximately dose-proportional or less than dose-proportional 
manner, with slight accumulation after repeat dosing (Ixazomib Investigator's Brochure, 2017).  
Dose-limiting toxicity (DLT) was primarily related to gastrointestinal (GI) and lymphoid 
systems.  Alterations in leukocyte and coagulation parameters consistent with an inflammatory 
response were also seen at doses below those associated with DLT.  Neuronal degeneration of 
the sympathetic, dorsal root, and end organ ganglia was seen mainly in dogs (probably as a result 
of higher exposure).  In general, the effects seen in the PO toxicology studies in both rats and 
dogs at tolerated doses were reversible or reversing.  The effects seen in IV studies were largely 
consistent with those of the PO-dosing studies. 
 
2.2.1.2 
Clinical Experience 
 
MLN9708 (ixazomib) is the first investigational PO PI to receive regulatory approval (Ixazomib 
Investigator's Brochure, 2017).  The MLN9708 (ixazomib) clinical development program has 
included both IV and PO formulations.  Please refer to the MLN9708 (ixazomib) Investigator’s 
Brochure for details on the IV formulation.  Only the PO formulation is commercially available 
and will be used for clinical trials going forward.  As of March 27, 2017, exposure and safety 
data are available from 779 patients with hematologic and nonhematologic malignancies who 
have received at least one dose of PO MLN9708 (ixazomib) in phase 1, 1/2, or 2 trials.  In 
addition, serious adverse event (SAE) and death data are available from 2,682 patients enrolled 
in ongoing phase 3 clinical trials with PO MLN9708 (ixazomib). 
 
2.2.1.2.1 
Clinical Pharmacology 
 
After either once- or twice-weekly (QW and BIW, respectively) PO dosing, MLN9708 
(ixazomib) is rapidly absorbed with a median first time of maximum observed plasma 
concentration (Tmax) of approximately 1 hour post dose (Ixazomib Investigator's Brochure, 
2017).  The plasma exposure (area under the concentration-time curve [AUC]) of MLN9708 
(ixazomib) increases in a dose proportional manner over a dose range of 0.2-10.6 mg based on a 
population PK analysis performed using data from patients treated with either IV or PO 
MLN9708 (ixazomib).  The population PK analysis also estimated the absolute PO 
bioavailability for MLN9708 (ixazomib) to be 58%, the steady state volume of distribution to be 
543 L, and the geometric mean terminal t1/2 as 9.5 days.  Based on measured PK parameters and 
the population PK model, it can be inferred that MLN9708 (ixazomib) is a low clearance drug, 
with an apparent plasma oral clearance (CL/F) of 3.21 L/hour.  Population PK analyses 
demonstrated that MLN9708 (ixazomib) can be administered as a fixed dose rather than using 
body surface area (BSA)-based dosing because there was no significant effect of BSA on 
MLN9708 (ixazomib) clearance. 
 
MLN9708 (ixazomib) has been classified, according to the Food and Drug Administration 
(FDA) Biopharmaceutical Classification System (BSC), as a Class 3 compound (i.e., high 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
9 
solubility, low permeability) (Ixazomib Investigator's Brochure, 2017).  A high-fat meal reduced 
the MLN9708 (ixazomib) maximum observed plasma concentration (Cmax) by 69% and the AUC 
from time 0 to 216 hours post dose by 28%.  Therefore, MLN9708 (ixazomib) should be taken at 
least 1 hour before or at least 2 hours after food.  Metabolism by multiple cytochrome P450 
(CYP) enzymes and non-CYP proteins is expected to be the major clearance mechanism for 
MLN9708 (ixazomib).  Analysis of clinical data indicates that the PK properties of MLN9708 
(ixazomib) are not affected by co-administration of either strong CYP3A or CYP1A2 inhibitors.  
At clinically relevant concentrations of MLN9708 (ixazomib), minimal CYP-mediated drug-drug 
interactions (DDIs) with a selective CYP inhibitor are expected.  Similarly, the potential for 
MLN9708 (ixazomib) to produce DDIs via CYP isozyme induction or inhibition is low.  
However, reported data from a clinical DDI study with rifampin showed that MLN9708 
(ixazomib) Cmax and AUC from time 0 to the time of the last quantifiable concentration were 
reduced in the presence of rifampin by approximately 54% and 74%, respectively (NINLARO® 
Package Insert, 2015).  As a result, the co-administration of strong CYP3A inducers with 
MLN9708 (ixazomib) should be avoided (Gupta et al., 2015).  MLN9708 (ixazomib) is unlikely 
to cause or be susceptible to clinical DDIs with substrates or inhibitors of clinically relevant drug 
transporters (Ixazomib Investigator's Brochure, 2017).  PK parameters for MLN9708 (ixazomib) 
co-administered with lenalidomide plus dexamethasone (LenDex) appear to be similar to those 
observed when MLN9708 (ixazomib) is administered as a single agent.  
 
Mild or moderate renal impairment (creatinine clearance [CrCL] ≥30 mL/min) and mild hepatic 
impairment (total bilirubin <1.5 times the upper limit of normal [ULN]) did not alter the PK of 
MLN9708 (ixazomib) based on the results of a population PK analysis (Ixazomib Investigator's 
Brochure, 2017).  As a result, no dose adjustment is required for these patients.  However, a 
reduced starting dose of MLN9708 (ixazomib) is recommended in patients with severe renal 
impairment, end-stage renal disease requiring dialysis, moderate hepatic impairment, or severe 
hepatic impairment.  A pooled analysis of data from four phase 1 clinical trials indicates that the 
pro-arrhythmic risk associated with MLN9708 (ixazomib) is low, with no impact of clinically-
relevant MLN9708 (ixazomib) dose or exposure on the corrected time between the start of the Q-
wave and end of the T-wave (QTc) prolongation. 
 
2.2.1.2.2 
Clinical Safety 
 
Preliminary clinical data are available as of March 27, 2017 for a total of 3,623 patients across 
26 studies, 24 of which administered PO MLN9708 (ixazomib) (Ixazomib Investigator's 
Brochure, 2017).  The emerging safety profile indicates that MLN9708 (ixazomib) 
administration can lead to adverse events (AEs) that are generally manageable and reversible 
with dose reduction and supportive care.  Overall, the observed AEs are generally consistent with 
the class-based effects of proteasome inhibition.  Based on clinical experience from phase 1 
studies, the dose recommended for phase 3 studies is 4 mg PO given QW for 3 weeks in a 28-day 
cycle.  Common DLTs included vomiting, nausea, diarrhea, neutropenia, and thrombocytopenia. 
 
As of March 27, 2017, data for the PO formulation of MLN9708 (ixazomib) (administered as 
monotherapy or in combination with other agents) are available for 779 patients treated in phase 
1, 1/2, and 2 trials (Ixazomib Investigator’s Brochure, 2017).  The most common (>20% of 
patients) AEs across PO MLN9708 (ixazomib) trials were nausea (43%), diarrhea (43%), fatigue 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
10 
(39%), vomiting (33%), thrombocytopenia (27%), constipation (25%), decreased appetite (22%), 
and anemia (23%). 
 
Study drug-related AEs were reported for 84% of patients in the PO formulation studies, and 
49% of patients experienced a study drug-related AE of Grade 3 or higher (Ixazomib 
Investigator's Brochure, 2017).  Most of these AEs were in the SOCs of GI disorders (59% any 
Grade, 10% Grade ≥3), general disorders (43% any Grade, 8% Grade ≥3), blood and lymphatic 
system disorders (38% any Grade, 27% Grade ≥3), or nervous system disorders (37% any Grade, 
4% Grade ≥3).  The most common preferred terms included nausea (35% overall, 3% Grade ≥3), 
diarrhea (32% overall, 6% Grade ≥3), fatigue (28% overall, 6% Grade ≥3), vomiting (25% 
overall, 3% Grade ≥3), and thrombocytopenia (24% overall, 16% Grade ≥3). 
 
As of March 27, 2017, out of the overall safety population in monotherapy and combination 
studies with oral MLN9708 (ixazomib) (N = 3447), 625 patients reported at least one AE that 
resulted in discontinuation of at least one of the drugs in the study drug regimen (Ixazomib 
Investigator's Brochure, 2017).  The most common of these events were peripheral neuropathies 
asthenic conditions, thrombocytopenia, pneumonia, diarrhea, acute kidney injury, neutropenia, 
septic shock, general physical health deterioration, maculopapular rash, insomnia, anemia, and 
plasma cell myeloma.  As of March 27, 2017, at least one SAE has been reported for 1482 of 
3607 (41%) patients in the safety populations across all company-sponsored clinical studies.  The 
most common SAEs include pneumonia, pyrexia, diarrhea, acute kidney injury, pulmonary 
embolism, thrombocytopenia, back pain, atrial fibrillation, anemia, and bronchitis.  Of the 
reported 167 deaths that occurred on PO MLN9708 (ixazomib) studies, 23 were considered at 
least possibly related to study treatment (though not necessarily related to MLN9708 
[ixazomib]). 
 
Clinical data regarding the AEs experienced during single-agent PO MLN9708 (ixazomib) 
therapy are available from studies in RRMM, relapsed and/or refractory systemic light-chain 
amyloidosis (RRAL), and non-Hodgkin lymphoma (NHL) (Ixazomib Investigator's Brochure, 
2017).  Overall, the most common AE frequencies were fairly similar between the four trials, 
though rash was more common with BIW dosing than with QW dosing. 
 
As of March 27, 2017, the most common SAEs reported across six MLN9708 (ixazomib) single-
agent trials varied (Ixazomib Investigator's Brochure, 2017).  In RRMM trials, the most common 
SAEs regardless of causality were pneumonia, pyrexia, diarrhea, thrombocytopenia, and 
dehydration.  In newly diagnosed MM patients receiving MLN9708 (ixazomib) or placebo, the 
most common SAEs included pneumonia, pyrexia, herpes zoster, plasma cell myeloma, 
influenza, lower respiratory tract infection, back pain, diarrhea, acute kidney injury, and 
plasmacytoma.  In a single-agent MLN9708 (ixazomib) trial conducted in patients with RRAL, 
the most common SAEs were pleural effusion, atrial fibrillation, and congestive cardiac failure.  
The most common SAEs in a single-agent trial in NHL were asthenia, diarrhea, vomiting, and 
bronchopulmonary aspergillosis. 
 
MLN9708 (ixazomib) has been tested in the following combinations:  1) with LenDex, 2) with 
cyclophosphamide plus dexamethasone, 3) with dexamethasone alone, and 4) with melphalan 
plus prednisone (Ixazomib Investigator's Brochure, 2017).  All but the melphalan plus 


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prednisone combination have been investigated in phase 2 or 3 trials.  As of March 27, 2017, 
SAE data is available from completed or ongoing trials of all four combinations.  Pneumonia was 
consistently the most common SAE.  The AEs in the combination studies were consistent with 
the safety profile of the individual agents in the combination regimen (e.g., myelosuppression 
was common in regimens containing melphalan and rash was common in regimens containing 
lenalidomide).  While some of these potential toxicities may be severe, they can be managed by 
clinical monitoring and standard medical intervention. 
 
As of March 27, 2017, treatment-emergent AE data are available for two phase 1/2 and one 
phase 3 company-sponsored trials combining MLN9708 (ixazomib) with LenDex to treat 
patients with RRMM or newly-diagnosed MM (Ixazomib Investigator's Brochure, 2017).  On 
each trial, the most common AEs included diarrhea, constipation, fatigue, nausea, and edema 
peripheral.  The most common Grade ≥3 AEs varied across trials, and included neutropenia, 
thrombocytopenia, diarrhea, fatigue, lymphopenia, hyperglycemia, hyponatremia.  In the phase 3 
study in RRMM patients, the incidence of herpes zoster reactivation was 8% in the MLN9708 
(ixazomib) plus LenDex regimen and 3% in the placebo plus LenDex regimen for patients who 
did not receive antiviral prophylaxis; this was compared to <1% for either regimen with antiviral 
prophylaxis. 
 
As of March 27, 2017, at least 1 Grade ≥3 AE was reported for (67%) patients on a trial 
combining MLN9708 (ixazomib) with cyclophosphamide and dexamethasone to treat patients 
with newly-diagnosed MM who were ineligible for high-dose therapy followed by autologous 
stem cell transplantation (Ixazomib Investigator's Brochure, 2017).  The most common of these 
events included neutropenia (20%), anemia (13%), and thrombocytopenia (12%).  Grade 3 or 
greater skin toxicities for the rash AEs of special interest included rash macular, rash 
maculopapular, petechiae, drug eruption, erythema, pruritus allergic, and rash erythematous.  
Grade 3 or greater peripheral neuropathies were reported in 2 patients (both with events of 
peripheral sensory neuropathy). 
 
2.2.1.2.3 
Clinical Efficacy 
 
The clinical efficacy of MLN9708 (ixazomib)-based induction regimens followed by single-
agent MLN9708 (ixazomib) maintenance therapy was evaluated in an integrated analysis of four 
phase 2 trials conducted in patients with newly-diagnosed MM (Dimopoulos et al., 2017).  The 
combined ORR was 93% after induction and 94% after maintenance.  The best response rate of 
complete response (CR) plus very good partial response (VGPR) was 57% (22% CR), which 
increased to 63% (35% CR/stable CR) after maintenance. 
 
MLN9708 (ixazomib) is currently undergoing phase 3 study in RRMM, newly-diagnosed MM, 
and RRAL (Ixazomib Investigator's Brochure, 2017).  Compared to a placebo-controlled LenDex 
regimen, MLN9708 (ixazomib) in combination with LenDex significantly improved the PFS of 
RRMM patients in a pivotal global study (PFS:  20.6 months versus 14.7 months; P=0.01), as 
well as in a study of advanced RRMM in China (PFS:  6.7 months versus 4.0 months; P=0.035) 
(Moreau et al., 2016; Hou et al., 2017).  At the time of analysis, there was a significant 
(P=0.001) 139% improvement in OS with MLN9708 (ixazomib) in the Chinese study; OS 
benefit was not yet demonstrated in the global study. 


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2.2.2 MLN4924 (Pevonedistat) 
 
2.2.2.1 
Background 
 
MLN4924 (also known as TAK 924 and pevonedistat; hereinafter referred to as MLN4924 
[pevonedistat]) is a first-in-class, small molecule inhibitor of NEDD8-activating enzyme (NAE) 
under development for the treatment of malignancies (Pevonedistat Investigator's Brochure, 
2017).  The NEDD8 conjugation (neddylation) pathway is responsible for much of the regulated 
protein turnover in the cell, which is similar to the ubiquitin-proteasome pathway (UPP) (Podust 
et al., 2000; Read et al., 2000).  However, UPP is known to regulate a myriad of processes in 
eukaryotic cells, whereas only a limited number of neddylation substrates have been described to 
date.  VELCADE® (bortezomib) for Injection, a drug that acts by inhibiting the 26S proteasome, 
has proven utility in the treatment of MM and mantle cell lymphoma (VELCADE Package 
Insert, 2015).  Therefore, it is anticipated that other compounds directed against different 
components of the UPP and/or the NEDD8 conjugation pathway may prove useful in the 
treatment of malignancies. 
 
NAE, an E1 ligase, is an essential component of the NEDD8 conjugation pathway, which 
initiates the neddylation to protein substrates (Pevonedistat Investigator's Brochure, 2017).  
Specifically, NEDD8 conjugation to cullin dependent ubiquitin E3 ligases (CDLs) is necessary 
for their activity.  The ligases in the NEDD8 conjugation pathway control the timely neddylation 
of many substrate proteins with important roles in cell cycle progression and signal transduction.  
The ubiquitination/neddylation of proteins targets them for proteasomal degradation.  These 
cellular processes are relevant to tumor cell growth, proliferation, and survival; as such, 
inhibitors of NAE activity may be of therapeutic value in the treatment of various cancers by 
inhibiting the degradation of a subset of proteins that are regulated by the proteasome.  In 
nonclinical studies, treatment of cells with MLN4924 (pevonedistat) results in the accumulation 
of CDL substrates, followed by a DNA damage response and cell death.  MLN4924 
(pevonedistat) treatment results in tumor growth inhibition (TGI) in mouse tumor xenograft 
models of solid tumors, lymphoma, and acute myeloid leukemia (AML). 
 
2.2.2.2 
Preclinical Experience with MLN4924 (Pevonedistat) 
 
2.2.2.2.1 
Target pharmacology 
 
MLN4924 (pevonedistat) is a potent and selective inhibitor of NAE activity (MLN4924 
[pevonedistat] was at least 300- and 1800-fold more selective for NAE than for the closely 
related ubiquitin activating enzyme and sumo activating enzyme, respectively) (Pevonedistat 
Investigator's Brochure, 2017).  MLN4924 (pevonedistat) treatment of cultured tumor cells 
resulted in growth inhibition of a wide variety of cell lines derived from acute leukemias, 
lymphomas, MM, and a range of solid tumor types.  Changes in protein levels observed in 
cultured cells treated with MLN4924 (pevonedistat) were consistent with the inhibition of NAE, 
in particular, a decrease in NEDD8-cullin levels and a reciprocal increase in the levels of known 
CDL substrates, including nuclear factor, erythroid 2 (NFE2)-related factor 2 (NRF2) and 
chromatin-licensing and DNA-replication factor-1 (Cdt-1).  In most cell lines evaluated, NAE 


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inhibition by MLN4924 (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 (Soucy et al., 2009; Lin et al., 2010; Milhollen et al., 2011).  When administered in 
combination with hypomethylating agents azacitidine and decitabine, MLN4924 (pevonedistat) 
demonstrated synergistic activity in AML cell lines. 
 
MLN4924 (pevonedistat) demonstrated pharmacodynamic and antitumor activity in solid tumor 
(HCT-116 colon and Calu-6 lung), lymphoma (OCI-Ly10, OCI-Ly19, and PHTX-22L), and 
AML (HL-60) xenograft models when administered to immunocompromised mice by the 
subcutaneous (SC) route (Pevonedistat Investigator's Brochure, 2017).  Antitumor activity of 
MLN4924 (pevonedistat) in mice bearing HL-60 and THP-1 tumor xenografts was enhanced by 
combination treatment with azacitidine.  Combination treatment with MLN4924 (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 MLN4924 (pevonedistat) and carboplatin in both 
NCI-H69 human small cell lung cancer (SCLC) xenografts and LU1143 primary sqNSCLC 
xenografts resulted in significant antitumor activity. 
 
2.2.2.2.2 
Safety pharmacology 
 
In vitro assay results indicated a low risk for human ether-à-go-go related gene (hERG) channel 
inhibition by MLN4924 (pevonedistat)  (inhibitory constant [Ki]=17.3 mcM) or its three major 
circulating metabolites (Pevonedistat Investigator's Brochure, 2017). 
 
A non-Good Laboratory Practices (GLP)-compliant PO toxicity study was performed in Sprague 
Dawley rats dosed with 150 mg/kg MLN4924 (pevonedistat) on Days 1, 3, and 5 (Pevonedistat 
Investigator's Brochure, 2017).  Minimal to mild pulmonary artery adventitial hyperplasia and 
correlative increases in pulmonary artery pressure were observed at 24 hours post dose.  
However, no correlation was observed between severity of the microscopic lesions and increases 
in pulmonary artery pressure.  This finding was not observed in rats dosed IV or SC in studies up 
to 3 months in duration, so the relevance of this finding to clinical safety is not known. 
 
In a GLP-compliant cardiovascular safety pharmacology assessment in male beagle dogs dosed 
via IV infusion at 15, 30, or 40 mg/kg (300, 600, or 800 mg/m2, respectively), MLN4924 
(pevonedistat) was not well tolerated at doses ≥30 mg/kg (≥600 mg/m2) (Pevonedistat 
Investigator's Brochure, 2017).  Mortality and/or moribundity were observed within 24 hours 
post dose as a result of GI 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. 
 
2.2.2.2.3 
Toxicology 
 
The systemic toxicity of MLN4924 (pevonedistat) was assessed in GLP-compliant repeat-dose 
studies in rats and dogs (Pevonedistat Investigator's Brochure, 2017).  MLN4924 (pevonedistat) 
was administered via a 30-minute IV infusion or by SC injection for two cycles (5 days of dosing 
followed by a 14-day nondosing period) or for five cycles (4 doses administered every other day 


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followed by a 14-day nondosing period).  The DLTs in the 2-cycle studies for both species were 
GI toxicity and bone marrow and lymphoid tissue depletion.  In tolerated doses in both species, 
AEs included GI tract injury with emesis (dogs only) and abnormal excreta, hematologic 
alterations, and an acute phase response (increased fibrinogen and decreased albumin).  
Increased new trabecular bone formation was observed in the 2-cycle study, while decreased 
trabecular bone formation was observed in the 5-cycle study and was considered an adverse 
finding.  Microscopic observations in both species included karyomegaly, apoptosis, and 
increased mitotic figures occurring in rapidly dividing tissues, including the intestinal tract and 
bone marrow.  Most AEs were resolving or had resolved after a 2-week recovery period. 
 
MLN4924 (pevonedistat) did not result in lethality in either of the 5-cycle studies (Pevonedistat 
Investigator's Brochure, 2017).  The primary adverse test article-related effects in IV dosed dogs 
included an acute phase response (increased body temperature, decreased albumin, increased 
globulin, increased monocytes and neutrophils, and increased fibrinogen levels); neutrophilic 
infiltrates in multiple tissues (liver, intestines, spleen, trachea, Peyer patches, and gallbladder); 
and in males, vacuolation and degeneration of the seminiferous epithelium of the testes.  Most 
AEs were reversing or had reversed after a 2-week recovery period in both rats and dogs.  
MLN4924 (pevonedistat) did not induce any local tissue response when administered by IV 
infusion to rats or dogs.  MLN4924 (pevonedistat) was not mutagenic in the bacterial reverse 
mutation assay (Ames assay). 
 
Microscopic changes were observed in male and female reproductive organs in the GLP 
compliant repeat-dose toxicology studies in both dogs and rats, therefore MLN4924 
(pevonedistat) likely represents a substantial reproductive and developmental hazard 
(Pevonedistat Investigator's Brochure, 2017). 
 
2.2.2.2.4 
Nonclinical pharmacokinetics 
 
MLN4924 (pevonedistat) was extensively partitioned into red blood cells (RBCs) in mice, rats, 
dogs, monkeys, and humans, most likely as a result of the binding to carbonic anhydrase (CA) in 
the RBCs (Pevonedistat Investigator's Brochure, 2017).  The partitioning was species dependent, 
concentration dependent, and saturable.  MLN4924 (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, MLN4924 (pevonedistat) is predominantly metabolized by the 
CYP isozyme 3A4.  There is potential for DDIs if MLN4924 (pevonedistat) is co-administered 
with drugs that are CYP3A inhibitors or inducers.  MLN4924 (pevonedistat) is neither an 
inhibitor of CYP1A2, 2C9, 2C19, 2D6, or 3A4/5 (IC50 >100 mcM and Ki >50 mcM) nor an 
inducer of CYP1A2, 2B6, or 3A4/5 (at concentrations up to 30 mcM), but is a weak inhibitor of 
CYP2B6 and 2C8 (IC50 = 97.6 and 23.1 mcM, respectively).  The major elimination pathway of 
MLN4924 (pevonedistat) in animals is through the hepatic route.  MLN4924 (pevonedistat) is a 
substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug 
resistance protein 2 (MRP2) in Caco-2 cells.  MLN4924 (pevonedistat) is also a weak inhibitor 
of P-gp (IC50 = 41.2 to 56.0 mcM) and BCRP (IC50 = 6.3 mcM), but not of MRP2 (IC50 >200 
mcM).  Additionally, MLN4924 (pevonedistat) is not a substrate for organic anion-transporting 
proteins (OATPs). 
 


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Detailed information regarding the nonclinical pharmacology and toxicology is provided in the 
Pevonedistat Investigator’s Brochure. 
 
2.2.2.3 
Clinical Experience with MLN4924 (Pevonedistat) 
 
The clinical development program of MLN4924 (pevonedistat) began with four phase 1 studies 
of single agent MLN4924 (pevonedistat) at doses ranging from 25 to 278 mg/m2: 
 
• Study C15001 in patients with solid tumors (Sarantopoulos et al., 2016); 
• Study C15002 in patients with lymphoma or multiple myeloma (Shah et al., 2016);  
• Study C15003 in patients with AML, high-grade myelodysplastic syndrome (MDS), or 
acute lymphoblastic leukemia (ALL) (Swords et al., 2015); 
• Study C15005 in patients with melanoma (Bhatia et al., 2016). 
 
In these studies, toxicity involving multiorgan failure on Cycle 1, Day 1, including SAEs of 
renal, hepatic, and cardiac failure, some with a fatal outcome, was identified at doses equal to or 
above 110 mg/m2 (Pevonedistat Investigator's Brochure, 2017).  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 MLN4924 (pevonedistat) program in October 2012.  The current 
understanding of the renal toxicity observed with MLN4924 (pevonedistat) suggests that it is not 
a primary event but is likely secondary to hemodynamic changes occurring in the setting of a 
type of acute phase response.  Results from an investigational toxicity study performed to model 
the Cycle 1, Day 1 findings in rats suggested that an existing pro-inflammatory state in rats 
driven by administration of a single dose of tumor necrosis factor alpha (TNF) followed by a 
single dose of MLN4924 (pevonedistat) was associated with a more robust sepsis-like response.  
These rats exhibited a robust toxicity that was evidenced by the exacerbation of TNF- or 
MLN4924 (pevonedistat) induced microscopic changes in the liver, kidney, heart, and intestine 
(large and small).  Rats dosed with the combination also displayed a profound increase in 
circulating cytokines and chemokines that correlated with microscopic changes.  Overall, this 
investigational study suggests a potential synergy between inflammatory state and administration 
of MLN4924 (pevonedistat)-. 
 
As of January 2017, approximately 240 additional patients have been treated with MLN4924 
(pevonedistat) in single agent and combination studies, and no Cycle 1, Day 1 SAEs as described 
above have been observed (Pevonedistat Investigator's Brochure, 2017).  The Days 1, 3, and 5 
schedule for MLN4924 (pevonedistat) infusion was chosen for further studies.  The MTD for 
that schedule for patients with AML in Study C15003 was determined to be 59 mg/m2, and the 
MTD for patients with solid tumors in Study C15001 was determined to be 67 mg/m2.  Current 
development is focused on MLN4924 (pevonedistat) in combination with standard clinically 
available therapies in hematologic malignancies and solid tumors.  Ongoing studies are as 
follows: 
 
• Study C15009 (phase 1b) is evaluating the MTD of MLN4924 (pevonedistat) on Days 1, 
3, and 5 in combination with 75 mg/m2 azacitidine (administered on a 5-on/2-off 


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[weekend]/2-on schedule) in a 28-day treatment cycle in elderly patients with treatment-
naïve AML (Swords R.T., 2014). 
• Study C15010 (phase 1b) is evaluating the MTD of MLN4924 (pevonedistat) plus 
docetaxel, gemcitabine, or the combination of carboplatin and paclitaxel, in patients with 
solid tumors (Lockhart C.A., 2015; Bauer T.M., 2016). 
• Study C15011 (phase 1) is evaluating the effects of CYP3A-mediated inhibition of 
MLN4924 (pevonedistat) in patients with solid tumors (DDI assessment; Part A).  After 
completion of the DDI assessment portion of the study, patients had the opportunity to 
continue in the study by participating in Part B (MLN4924 [pevonedistat] plus docetaxel 
or the combination of carboplatin and paclitaxel). 
• Pevonedistat-2001 (phase 2) is evaluating the efficacy and safety of MLN4924 
(pevonedistat) plus azacitidine versus single-agent azacitidine in patients with higher-risk 
MDS (HR MDS), chronic myelomonocytic leukemia, and low-blast AML. 
• Pevonedistat-1012 (phase 1) is investigating MLN4924 (pevonedistat) as a single agent 
and in combination with azacitidine in adult East Asian patients with AML or MDS.  
 
The cumulative enrollment in all clinical studies through January 22, 2017, is approximately 451 
patients (237 for hematological indications and 214 for solid tumor indications), defined as 
having received at least 1 dose of study drug (Pevonedistat Investigator's Brochure, 2017). 
 
2.2.2.3.1 
Clinical Pharmacokinetics 
 
The clinical PK of MLN4924 (pevonedistat) have been evaluated in four monotherapy phase 1 
studies in 96 patients with solid tumors (C15001 and C15005) and 109 patients with hematologic 
malignancies (C15002 and C15003) (Pevonedistat Investigator's Brochure, 2017).  These studies 
have evaluated the single- and multiple-dose PK of MLN4924 (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 MLN4924 (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 (Pevonedistat Investigator's Brochure, 
2017).  Mean terminal elimination half-life (t1/2z) was estimated to be approximately 10 hours 
(range 7.7-15.2) across doses and schedules.  Consistent with in vitro data, MLN4924 
(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.  
MLN4924 (pevonedistat) generally exhibited linear PK over the dose range studied.  Observed 
interindividual variability was generally moderate with 18% to 41% coefficient of variation (CV) 
for Cmax, 12% to 56% CV for AUC from time 0 to 24 hours post dose (AUC0-24), and 15% to 
33% CV for the AUC from time zero to the end of the dosing interval when MLN4924 
(pevonedistat) was administered on Days 1, 3, and 5.  Body size influences MLN4924 
(pevonedistat) systemic clearance and volume of distribution, thus supporting BSA-normalized 
dosing to reduce variation in systemic exposure of MLN4924 (pevonedistat) in cancer patients.  
MLN4924 (pevonedistat) clearance (CL) 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 CrCL >30 mL/min) on MLN4924 (pevonedistat) PK.  


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A population PK analysis was conducted using data from MLN4924 (pevonedistat) single-agent 
studies and MLN4924 (pevonedistat) in combination with standard-of-care chemotherapy in 
patients with solid tumor or hematological malignancies (Pevonedistat Investigator's Brochure, 
2017).  MLN4924 (pevonedistat) plasma concentration-time profiles were well described by a 2-
compartment model with linear elimination.  BSA was an important predictor of CL, 
intercompartmental clearance (Q), and both central compartment volume of distribution (Vc) and 
peripheral compartment volume of distribution (Vp).  For a typical patient with a BSA of 1.73 
m2, an alpha half-life of 1.27 hours and a beta (elimination) half-life of 7.85 hours are estimated.  
Concurrent administration of carboplatin and paclitaxel decreased the CL of MLN4924 
(pevonedistat)- by approximately 44%, translating to an approximately 80% higher TAK-924 
exposure (AUC) during co-administration with carboplatin and paclitaxel.  Co-administration 
with azacitidine, gemcitabine, or docetaxel did not appear to affect the CL of MLN4924 
(pevonedistat).  Race, sex, age, tumor type (hematologic vs. solid), mild or moderate renal 
impairment (CrCL ≥30 mL/min), or mildly impaired liver function, to the extent represented in 
this dataset, had no impact on MLN4924 (pevonedistat) PK. 
 
Additionally, evaluation of MLN4924 (pevonedistat) PK is ongoing for two studies of MLN4924 
(pevonedistat) in combination with different standard-of-care therapies, and for a DDI study 
evaluating the effects of CYP3A-mediated inhibition on MLN4924 (pevonedistat) (Pevonedistat 
Investigator's Brochure, 2017).  MLN4924 (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 MLN4924 (pevonedistat) in the presence of docetaxel or gemcitabine have been 
observed, whereas a trend towards increasing plasma concentrations of MLN4924 (pevonedistat) 
in the presence of carboplatin plus paclitaxel was evident (Lockhart C.A., 2015; Bauer T.M., 
2016).  This apparent drug interaction effect, which cannot be explained at this time, warrants 
further understanding of the disposition properties of MLN4924 (pevonedistat) in humans. 
 
In the DDI study, preliminary PK evaluations from 26 patients with advanced solid tumors 
(MLN4924 [pevonedistat] 8 mg/m2 [13 patients on fluconazole, 13 patients on itraconazole]) 
indicated that multiple-dose fluconazole appeared to have a minimal effect on MLN4924 
(pevonedistat) PK (13% increased AUC from 0 to infinity [AUC] on average), while systemic 
exposure of MLN4924 (pevonedistat) appeared to increase by 23% on average in the presence of 
itraconazole (Pevonedistat Investigator's Brochure, 2017).  MLN4924 (pevonedistat) was found 
to extensively partition in human blood, with a mean blood-to-plasma concentration ratio of 
about 65, which remained constant throughout the 24-hour sampling period, indicative of rapid 
equilibrium. 
 
Additional data from 11 patients who completed protocol specified dosing and PK evaluations 
indicated that MLN4924 (pevonedistat)- systemic exposures following IV administration at 20 
mg/m2 in the presence of itraconazole were similar to those in the absence of itraconazole 
(Pevonedistat Investigator's Brochure, 2017).  On the basis of these results, moderate and strong 
CYP3A inhibitors and P-gp inhibitors can be used in patients receiving MLN4924 
(pevonedistat).   For individual studies in the MLN4924 (pevonedistat) clinical program, 
reference should be made to the respective protocols for specific information relating to excluded 
and permitted medications. 


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For detailed information please consult the current Pevonedistat Investigator’s Brochure. 
 
2.2.2.3.2 
Pharmacodynamics 
 
Preliminary data provide evidence of pathway inhibition downstream of NAE and biological 
activity of MLN4924 (pevonedistat) in skin and tumor tissue (solid tumor or AML bone marrow 
derived blasts) at all doses tested in pharmacodynamic assays (Pevonedistat Investigator's 
Brochure, 2017).  These doses range from 25 to 261 mg/m2 across the various single-agent, 
phase 1 MLN4924 (pevonedistat) trials. 
 
For detailed information please consult the current Pevonedistat Investigator’s Brochure. 
 
2.2.2.3.3 
Summary of Safety and Efficacy Data Findings Available on Takeda-Sponsored 
Trials 
 
For detailed information please consult the current Pevonedistat Investigator’s Brochure. 
 
Phase 1 Monotherapy Studies 
 
Overall, 99 patients with advanced solid tumors or melanoma in Study C15001 and Study 
C15005 were treated with single-agent MLN4924 (pevonedistat) at doses ranging from 25 to 278 
mg/m2 (Pevonedistat Investigator's Brochure, 2017).  Common AEs (reported by ≥25% of 
patients in either study) were fatigue, nausea, anemia, decreased appetite, vomiting, diarrhea, 
myalgia, constipation, arthralgia, dizziness, and peripheral neuropathy.  DLTs included increased 
enzymes upon liver function tests (LFTs), increased creatinine, acute renal failure and acute 
hepatic failure, hypophosphatemia, and myocarditis.  Acute renal failure occurred in three 
patients:  two patients on Study C15001 at 196 mg/m2 (one patient also reported acute hepatic 
failure); and one patient on Study C15005 at 157 mg/m2, who also reported myocarditis and 
hyperbilirubinemia.  Deaths on study that were considered related to study treatment included 
multi-organ failure (at 61 mg/m2 once daily [QD] for 5 consecutive days and 196 mg/m2 in Study 
C15001), disease progression (at 83 mg/m2 in Study C15001), and renal failure acute (at 209 
mg/m2 in Study C15005). 
 
A total of 128 patients with hematologic malignancies (lymphoma, MM, AML, MDS, or ALL) 
in Study C15002 and Study C15003 were treated with single-agent MLN4924 (pevonedistat) at 
doses ranging from 25 to 261 mg/m2 (Pevonedistat Investigator's Brochure, 2017).  Common 
AEs (reported by ≥25% of patients in either study) were alanine aminotransferase (ALT) 
increased, anemia, aspartate aminotransferase (AST) increased, chills, constipation, decreased 
appetite, diarrhea, dizziness, dyspnea, fatigue, febrile neutropenia, headache, muscle spasms, 
myalgia, nausea, peripheral edema, pyrexia, and vomiting.  DLTs included increased LFTs, 
febrile neutropenia, muscle spasms, thrombocytopenia, acute renal failure, orthostatic 
hypotension, cardiac failure, rash morbilliform, GI necrosis, hypotension, lactic acidosis, and 
myocardial ischemia.  Deaths on study that were considered related to study treatment (all in 
Study C15003) included two deaths from multiorgan failure (at 110 and 147 mg/m2), one from 
sepsis (at 78 mg/m2), and one from cardiopulmonary failure (at 45 mg/m2).  


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The primary aims of the phase 1 monotherapy studies were to establish the safety profile and to 
determine the MTDs of MLN4924 (pevonedistat) administered by several different dose 
schedules in both hematologic and solid tumor settings (Pevonedistat Investigator's Brochure, 
2017).  While safety, PK, and pharmacodynamic objectives were the primary focus of these 
studies, disease response was also assessed.  A total of 12 patients experienced partial responses 
(PRs) or better in the phase 1 monotherapy studies. 
 
In Study C15003, responses (CRs and PRs) were observed in a variety of patient settings, 
including postallogeneic transplant, therapy-related AML, and primary refractory AML 
(Milhollen et al., 2011).  Although some of the responses were of relatively short duration, one 
patient each in the 44 mg/m2 cohort of Schedule A (dosed on Days 1, 3, and 5), the 83 mg/m2 
MTD cohort of Schedule B (dosed on Days 1, 4, 8, and 11), and the 25 mg/m2 cohort of Schedule 
A achieved a remission for 12.3, 10.1, and 5.1 months, respectively (Pevonedistat Investigator's 
Brochure, 2017).  Another patient had stable disease (SD) for 8 cycles, then a PR, followed by a 
CR for a total of 2.7 months.  All 13 patients who received treatment for 5 or more cycles 
achieved SD or better, ranging from 2.56 to 13.44 months.  The duration of SD or better was 
considered clinically meaningful if the patient had SD or better at Cycle 4, Day 21 and 
proceeded to Cycle 5. 
 
Phase 1 Combination Studies 
 
Study C15009 is a phase 1b study evaluating the MTD of MLN4924 (pevonedistat) on Days 1, 3, 
and 5 in combination with 75 mg/m2 azacitidine (administered on a 5-on/2-off [weekend]/2-on 
schedule) in a 28-day treatment cycle in patients 60 years of age or older with treatment-naïve 
AML who are unlikely to benefit from standard induction therapy (Pevonedistat Investigator's 
Brochure, 2017).  As of January 22, 2017, enrollment had completed and 4 patients remained on 
study.  As of January 22, 2017, preliminary data are available for 64 patients enrolled in the 
study who received at least one dose of MLN4924 (pevonedistat) in combination with 
azacitidine; these patients had completed a total of approximately 441 cycles, with a median of 
four cycles of treatment.  In the dose escalation cohorts, six patients received 20 mg/m2 
MLN4924 (pevonedistat), and three patients received 30 mg/m2.  The most common events 
(reported by ≥25% of patients) were constipation (48%), nausea (42%), fatigue (39%), anemia 
(39%), febrile neutropenia (31%), decreased appetite (30%), thrombocytopenia (28%), and 
pyrexia (25%).  The MTD in this study was determined to be 20 mg/m2 MLN4924 
(pevonedistat) given on Days 1, 3, and 5, in combination with 75 mg/m2 azacitidine given on 
Days 1 through 5, 8, and 9, in 28-day treatment cycles.  A total of 45 (70%) patients experienced 
at least one SAE.  A total of 13 SAEs were reported for more than one patient, including: febrile 
neutropenia (17 patients); pneumonia (9 patients); AML (6 patients); pyrexia (4 patients); sepsis 
(3 patients); and acute myocardial infarction, cellulitis, diverticulitis, dyspnea, embolism, 
hypoxia, mental status changes, multi-organ failure, and transaminase increased (2 patients 
each).  A total of 21 patients treated with MLN4924 (pevonedistat) (either 20 mg/m2 or 30 
mg/m2) discontinued from study participation because of neutropenia.  No other events leading 
to discontinuation were assessed by study investigators as at least possibly related to study drug 
treatment.  Seventeen on-study deaths were reported (within 30 days of the last dose of study 
drug); none were assessed as related to study treatment.  A total of 31 patients (60%) 


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experienced PR or better.  Nineteen patients (37%) had a best response of CR, 5 patients (10%) 
had a best response of complete remission with incomplete blood count recovery (CRi), and 7 
patients (13%) had a best response of PR.  One patient in the 30 mg/m2 dose level group 
achieved a CR; all other responses occurred in patients treated with 20 mg/m2. 
 
Study C15010 is a phase 1b study evaluating the MTD of MLN4924 (pevonedistat) plus 
docetaxel, gemcitabine, or a combination of carboplatin and paclitaxel, in patients with solid 
tumors (Pevonedistat Investigator's Brochure, 2017).  As of January 22, 2017, enrollment has 
completed; 2 patients remained on study.  The treatment arms are:  
 
• Arm 1:  MLN4924 (pevonedistat) dosing on Days 1, 3, and 5 with 75 mg/m2 docetaxel 
dosing on Day 1 in a 21-day cycle. 
• Arm 2 Lead-in:  MLN4924 (pevonedistat) dosing on Days 1, 3, and 5 with AUC6 
carboplatin dosing on Day 1 in a 21-day cycle. 
• Arm 2:  MLN4924 (pevonedistat) dosing on Days 1, 3, and 5 with 175 mg/m2 paclitaxel 
dosing on Day 1 and AUC5 carboplatin dosing on Day 1 in a 21-day cycle (based on the 
DLTs in the Arm 2 Lead-in cohort). 
• Arm 3:  MLN4924 (pevonedistat) dosing on Days 1, 8, and 15 with 1000 mg/m2 
gemcitabine dosing on Days 1, 8, and 15 in a 28-day cycle. 
 
As of January 22, 2017, preliminary data are available for 64 patients enrolled who received at 
least one dose of MLN4924 (pevonedistat) in combination with standard of care; these patients 
had completed a total of approximately 366 cycles, with medians ranging from 2 to 6 cycles of 
treatment across the four treatment groups (Pevonedistat Investigator's Brochure, 2017).  The 
starting dose levels for dose escalation and determination of MLN4924 (pevonedistat) MTD 
were 15 mg/m2 for Arm 1 and Arm 2, and 25 mg/m2 for Arm 3.  Overall, the most common AEs 
(occurring in ≥25% of patients) were fatigue (58%), nausea (50%), anemia (41%), diarrhea 
(34%), constipation (34%), AST increased (31%), ALT increased (28%), and alopecia (27%). 
 
Per the data cut off, 15 patients experienced Cycle 1 DLTs in Study C15010.  Increased ALT or 
AST (or both) accounted for DLTs in 11 patients, febrile neutropenia was reported for 3 patients, 
and 1 patient experienced thrombocytopenia (Pevonedistat Investigator's Brochure, 2017).  In 
Arm 3, one event of febrile neutropenia worsened from Grade 3 to Grade 5. 
 
The MTD for Arm 1 was determined to be 25 mg/m2 MLN4924 (pevonedistat) (dosing on Days 
1, 3, and 5 with 75 mg/m2 docetaxel dosing on Day 1 in a 21-day cycle) (Pevonedistat 
Investigator's Brochure, 2017).  No MTD was determined for the Arm 2 Lead-in per protocol, 
but these DLTs informed the dose selection for paclitaxel and carboplatin in Arm 2:  paclitaxel 
dose 175 mg/m2 and a reduced dose for carboplatin of AUC5.  The MTD for Arm 2 was 
determined to be 20 mg/m2 MLN4924 (pevonedistat) (dosing on Days 1, 3, and 5 with 175 
mg/m2 paclitaxel and AUC5 carboplatin dosing on Day 1 in a 21-day cycle).  The gemcitabine 
combination arm (Arm 3) was closed to enrollment due to lack of tolerability (MTD was not 
determined).  A total of 26 (41%) patients experienced at least one SAE.  Febrile neutropenia 
was the only event reported for at least one patient in each of the four treatment arms (reported 
for 2 of 26 patients in Arm 2 and 2 of 10 patients in Arm 3).  Dyspnea was reported for 3 of the 
22 patients in Arm 1 and for 1 patient in Arm 3.  Abdominal pain was reported for one patient 


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each in Arm 1 and Arm 3 and pneumonia was reported for two patients in Arm 1; all other 
events were reported for only one patient across the treatment arms.  Eighteen patients 
discontinued the study because of treatment-emergent AEs (TEAEs).  Events that resulted in 
study discontinuation that were assessed at least possibly related to study drug treatment 
included ALT and AST increased, blood bilirubin increased, and blood creatinine increased (one 
patient each in Arm 1); platelet count decreased (one patient in Arm 2), peripheral neuropathy 
(two patients in Arm 2); neutropenia (one patient in Arm 2), thrombocytopenia (one patient in 
Arm 2), leukopenia, lymphopenia, and pneumonitis (one patient each in Arm 3), and febrile 
neutropenia (two patients in Arm 3).  Six on-study deaths (within 30 days of the last dose of 
study drug) were reported with one death (Arm 3; due to febrile neutropenia) assessed as related 
to study treatment (MLN4924 [pevonedistat] and gemcitabine).  
 
Twelve patients (22%) on Study C15010 had achieved PR or better (Pevonedistat Investigator's 
Brochure, 2017).  Two (9%) patients in Arm 2 achieved a CR; three (16%) patients in Arm 1, 
one (17%) patient in the Arm 2 Lead-in, and six (26%) patients in Arm 2 achieved a PR. 
 
In Part A of Study C15011, patients receive a single dose of MLN4924 (pevonedistat) given as 
an IV infusion on Day 1 and Day 8, and either concomitant oral fluconazole or itraconazole on 
Day 4 through Day 10 (Pevonedistat Investigator's Brochure, 2017).  Patients are assessed for 
eligibility to continue in Part B (optional) after completion of Part A during a 2- to 8-week 
washout period.  As of January 22, 2017, enrollment is completed.  Thirty-six of the 51 patients 
enrolled in Study C15011 continued into Part B of the study with 4 ongoing as of January 2017; 
these 36 patients received a total of approximately 203 cycles of MLN4924 (pevonedistat) in 
combination with either docetaxel (n=23; median 4 cycles; range 2-10) or the combination of 
carboplatin and paclitaxel (n=13; median 5 cycles; range 2-27).  Overall, the most common AEs 
(occurring in ≥30% of patients in Part A or Part B) were fatigue (45%, 53%), vomiting (45%, 
50%), nausea (41%, 50%), decreased appetite (41%, 39%), dehydration (35%, 44%), 
constipation (33%, 39%), anemia (35%, 33%), stomatitis (Part B, 33%), diarrhea (31%, 39%), 
headache (Part B, 36%), and hypokalemia (Part B, 31%). 
 
A total of 30/51 (59%) patients experienced at least one SAE.  Most SAEs (inclusive of Part A 
and Part B) were reported for 1 patient only; events reported for 3 or more patients included 
dyspnea (6 patients); pneumonia (5 patients); abdominal pain, abdominal pain upper, nausea, 
vomiting, failure to thrive, aspiration pneumonia, hypotension (4 patients each); small intestinal 
obstruction, and hyperkalemia (3 patients each) (Pevonedistat Investigator's Brochure, 2017).  
Further details can be found in the current Pevonedistat Investigator’s Brochure.  Seventeen 
patients had discontinued the study because of a TEAE, only 1 assessed as related to study 
treatment in Part A. 
 
As of January 22, 2017, 18 on study deaths (within 30 days after the last dose of study drug) had 
been reported in Study C15011 as an outcome of an AE (Pevonedistat Investigator's Brochure, 
2017).  One death (due to respiratory failure) was assessed by the investigator as related to 
treatment with docetaxel.  None of the other deaths were considered related to study treatment. 
 
As of January 22, 2017, 4 patients achieved a PR in Part B of the study.  Two patients (breast, 
mixed ductal/lobular carcinoma; adenocarcinoma of vulva) received MLN4924 (pevonedistat) 


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with docetaxel; both patients previously received taxane (Pevonedistat Investigator's Brochure, 
2017).  Two patients (thyroid cancer; thymic cancer) who received MLN4924 (pevonedistat) 
with carboplatin/paclitaxel had also received carboplatin plus paclitaxel as part of their prior 
therapy.  Five additional patients achieved durable SD (at least five cycles of on-study 
treatment), including a patient with thymoma who received 29 cycles of treatment with 
MLN4924 (pevonedistat) plus carboplatin/paclitaxel, with a best response of SD. 
 
In the phase 1 Study Pevonedistat-1012, patients are enrolled in one of four treatment arms: 
 
• Cohort S1 (MLN4924 [pevonedistat] 25 mg/m2). 
• Cohort S2 (MLN4924 [pevonedistat] 44 mg/m2). 
• Cohort C1 (MLN4924 [pevonedistat] 10 mg/m2 plus azacitidine 75 mg/m2). 
• Cohort C2 (MLN4924 [pevonedistat] 20 mg/m2 plus azacitidine 75 mg/m2). 
 
Patients in Cohorts S1 and S2 received MLN4924 (pevonedistat) on Days 1, 3, and 5 in a 21-day 
cycle (Pevonedistat Investigator's Brochure, 2017).  In the combination treatment cohorts, C1 
and C2, patients received MLN4924 (pevonedistat) on Days 1, 3, and 5 with 75 mg/m2 
azacitidine dosing on Days 1 through 5, 8, and 9 in a 28-day cycle. 
 
As of January 22, 2017, 10 patients had received therapy (mean, 7.7 doses; median, 6.0 doses) 
for a total of 27 treatment cycles (mean, 2.7 cycles; median, 2.0 cycles) (Pevonedistat 
Investigator's Brochure, 2017). 
 
Preliminary data indicates that five patients discontinued (Pevonedistat Investigator's Brochure, 
2017).  The most common TEAEs (two patients each) were fatigue, dizziness, and febrile 
neutropenia.  Five (50%) patients reported an SAE during the study, with no event reported in 
more than one patient.  Three deaths occurred and were assessed as not related to the study 
treatment. 
  
Pevonedistat-2001, a phase 2 study, is evaluating the efficacy and safety of MLN4924 
(pevonedistat) plus azacitidine versus single-agent azacitidine in patients (aged 18 years and 
older) with HR MDS, chronic myelomonocytic leukemia (CMML), and low blast AML 
(Pevonedistat Investigator's Brochure, 2017).  With a 28-day treatment cycle, MLN4924 
(pevonedistat) is administered on Days 1, 3, and 5 at a starting dose of 20 mg/m2, with 
azacitidine at a starting dose of 75 mg/m2 administered on Days 1 through 5, 8, and 9.  As of 
January 22, 2017, 33 patients were treated with the combination of MLN4924 (pevonedistat) 
plus azacitidine, and 34 patients received azacitidine alone. 
 
As of January 22, 2017, preliminary data are available for the 65 patients enrolled in the study 
and 61 patients remain on the study (Pevonedistat Investigator's Brochure, 2017).  The most 
common TEAE was nausea, reported by 16 patients (25%).  Eighteen (28%) patients reported an 
SAE.  The only SAEs experienced by more than 1 patient in either treatment group were febrile 
neutropenia (3 patients in the azacitidine treatment group and 1 patient in the MLN4924 
(pevonedistat) plus azacitidine treatment group) and pyrexia (2 patients in the MLN4924 
[pevonedistat] plus azacitidine treatment group).  Two patients were discontinued from the 
study/study drug because of TEAEs; these events were not considered related to the study 


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treatment.  No deaths occurred in the MLN4924 (pevonedistat) plus azacitidine treatment group.  
Seven deaths occurred in the azacitidine treatment group; only febrile neutropenia was 
considered related to treatment. 
 
2.3 
Rationale 
 
MLN9708 (ixazomib) is the first orally available PI and has shown more potent 
pharmacodynamic effects as compared to bortezomib (Kupperman et al., 2010).  MLN9708 
(ixazomib) binds and inhibits the chymotrypsin-like site of the 20S proteasome, subsequently 
interfering with the function of the UPP and leading to accumulation of intracellular proteins and 
cellular stress.  MLN9708 (ixazomib) was approved in 2015 for the treatment of RRMM patients 
after one prior line of therapy in combination with lenalidomide and dexamethasone following a 
phase 3 clinical trial that demonstrated an improved PFS over lenalidomide and dexamethasone 
alone (20.6 months vs. 14.7 months, P=0.01) (Moreau et al., 2016).  In the aforementioned 
TOURMALINE-MM1 study, MLN9708 (ixazomib) was dosed 4 mg weekly on Days 1, 8, and 
15 of a 28-day cycle.  In a phase 1 study, Richardson et al. evaluated twice weekly dosing of 
MLN9708 (ixazomib), dosed on Days 1, 4, 8, and 11 of a 21-day cycle, and found this dosing 
schedule to also be well tolerated with durable and prolonged disease responses, with a 
maximum tolerated dose of 2 mg/m2 (Richardson et al., 2014).  
 
The clinical efficacy of PIs in the treatment of myeloma has confirmed the therapeutic strategy 
of targeting the ubiquitin-proteasome pathway and led to attempts to identify targets at different 
levels of this pathway.  MLN4924 (pevonedistat) is a novel small-molecule inhibitor of NAE 
that regulates protein ubiquitination upstream of the proteasome.  NAE catalyzes the initial step 
in the neddylation pathway, covalent attachment of NEDD8 to cullin-ring ligases (CRLs), the 
largest family of the E3 ubiquitin ligases.  This step is required for activation of CRLs, which 
then ubiquitinate target proteins for degradation. 
 
MLN4924 (pevonedistat) has demonstrated both in vitro and in vivo activity in preclinical 
models.  In vitro treatment of myeloma cell lines showed a dose- and time-dependent decrease in 
cell growth (Figure 2) (McMillin et al., 2012; Gu et al., 2014).  This response was preserved 
even when co-cultured with osteoclasts and bone marrow stromal cells, supporting the efficacy 
of NEDD8 inhibition despite the bone marrow microenvironment.  Additionally, MLN4924 
(pevonedistat) demonstrated activity in bortezomib-resistant ANBL-6-V5R myeloma cells, with 
no increased resistance as compared with the parental cell line (ANBL-6).  In vivo, 
administration of MLN4924 (pevonedistat) in immunocompromised mice led to a significant 
reduction in tumor burden (McMillin et al., 2012). 
 


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Figure 2:  Human myeloma cell lines treated with MLN4924 (pevonedistat) for 48 or 72 hours 
(Gu et al., 2014). 
 
Preclinical data have also demonstrated increased cytotoxicity utilizing the combination of 
bortezomib and MLN4924 (pevonedistat), which is dependent upon REDD1 expression, 
subsequently leading to the down-regulation of the phosphatidylinositol-4,5-bisphosphate 3-
kinase (PI3K)/ mechanistic target of rapamycin (mTOR) pathway.  REDD1 is a CRL substrate 
that modulates mTOR pathway signaling.  Using quantitative reverse transcription polymerase 
chain reaction (RT-qPCR), REDD1 mRNA levels have been shown to increase rapidly following 
exposure to MLN4924 (pevonedistat) in MM.1R myeloma cells (Figure 3) (Gu et al., 2014). 
 
 
Furthermore, when small interfering RNA (siRNA) is used to silence REDD1 expression, there 
is increased phosphorylation of mTOR, protein kinase B (AKT), eukaryotic translation initiation 
factor 4E-binding protein 1 (4EBP1), and p70 ribosomal S6 kinase (p70S6K), proteins involved 
in the PI3K/mTOR pathway, suggesting suppression of this pathway is in fact dependent upon 
REDD1 (Figure 4) (Gu et al., 2014).  Bortezomib is known to affect mTOR signaling, and the 
Figure 3:  REDD1 mRNA levels measured by RT-qPCR in MM.1R 
cells treated with pevonedistat (MLN4924) at 2 hours, 4 hours, 8 
hours, and 24 hours (Gu et al., 2014). 


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combination of MLN4924 (pevonedistat) with bortezomib not only results in increased 
cytotoxicity (Figure 5), but western blot analysis demonstrated marked suppression of the 
PI3K/mTOR pathway with the combination versus either agent alone in both myeloma cell lines 
and primary human myeloma cells (Figure 6).  Again, silencing of REDD1 led to decreased 
growth inhibition when MLN4924 (pevonedistat) and bortezomib were used in combination, 
supporting the important role REDD1 plays both on the single-agent activity of MLN4924 
(pevonedistat), and when used in combination with a PI.  
 
In a phase 1 study of MLN4924 (pevonedistat), Shah et al. treated 17 patients with RRMM after 
≥2 prior lines of therapy (Shah et al., 2016).  MLN4924 (pevonedistat) was dosed on either Days 
1, 2, 8, and 9 (Schedule A) or Days 1, 4, 8, and 11 (Schedule B) of 21-day cycles.  The starting 
dose for both schedules was 25 mg/m2 with dose escalations 1.33 times the prior dose.  The 
predominant DLTs were febrile neutropenia, transaminitis, and muscle cramps on Schedule A, 
and thrombocytopenia on Schedule B.  The MTD was 110 mg/m2 on Schedule A and 196 mg/m2 
on Schedule B.  The most common AEs included fatigue and nausea.  Grade ≥3 AEs were 
limited to anemia (19%, Schedule A), neutropenia (12%, Schedule B), and pneumonia (12%, 
Schedule B).  Thirteen of the seventeen patients, all of whom had previously been exposed to 
bortezomib, achieved SD. 
Figure 6:  Primary human myeloma cells 
treated with pevonedistat, bortezomib, and the 
combination leading to increased inhibition of 
PI3K/mTOR pathway (Gu et al., 2014). 
Figure 5:  siRNA silencing of REDD1 leads to 
increased PI3K/mTOR pathway signaling (Gu 
et al., 2014). 
Figure 4:  Cell viability of MM.1R cells treated with pevonedistat, bortezomib, or 
both (Gu et al., 2014). 


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The aim of this study is to improve upon the single-agent activity of MLN9708 (ixazomib) with 
the addition of MLN4924 (pevonedistat) without significant cumulative toxicity, as well as to 
assess which patient populations are more susceptible to this therapeutic approach (PI-sensitive 
versus PI-refractory).  If antitumor activity is shown, the authors would consider moving forward 
in the identified population(s) of interest (PI-sensitive and/or PI-refractory) with a Simon’s 2-
stage design phase 2 study. 
 
The hypotheses for this study are: 
 
• The combination of MLN9708 (ixazomib) and MLN4924 (pevonedistat) will be 
synergistic resulting in improved efficacy in patients with RRMM compared to historical 
data of treatment with MLN9708 (ixazomib) alone. 
• The MTD/RP2D of MLN4924 (pevonedistat) when administered in combination with 
MLN9708 (ixazomib) will be able to be determined. 
• Collected correlative and PK and pharmacodynamics will recapitulate pre-clinical data. 
 
2.4 
Correlative Studies Background 
 
2.4.1 MLN4924 (Pevonedistat) PK Profile 
 
MLN4924 (pevonedistat) PK values will be obtained to assess dose-exposure-effect relationships 
with AEs, pharmacodynamic markers, and, potentially, response.  The concentrations of 
MLN4924 (pevonedistat) that demonstrated activity with bortezomib in vitro (2.5 mcM or 
higher) are achievable with the doses to be utilized in this trial.  The full metabolic fate of 
MLN4924 (pevonedistat) is still to be determined, and patient level variables that impact 
disposition are being globally investigated.  Within this combination trial with MLN9708 
(ixazomib), Cycle 1, Day 1 MLN4924 (pevonedistat) PK profiles will be obtained at each dose 
level for the purpose of relating exposure to clinical and pharmacodynamic outcomes, with the 
expectation that Day 1 exposures are equivalent to subsequent exposures due to prior data on 
clearance rates, known PK of MLN9708 (ixazomib), and weekly dosing interval. 
 
2.4.2 NQO1 and SLC7A11 (NRF2 Target Genes) Expression 
 
NAE activates the ubiquitin-like protein NEDD8 for conjugation to CRLs and, therefore, 
regulates the proteasomal destruction of CRL substrate proteins (Walker et al., 2011).  NAE 
inhibition prevents degradation of CRL substrates (e.g., NRF2, CDT1), leading to their 
accumulation.  To develop a pharmacodynamic assay, Walker et al. (2011) developed a RT-
PCR-based assay using blood samples from multiple healthy volunteers that were treated ex vivo 
with a range of MLN4924 (pevonedistat) concentrations.  Eight genes (including the NRF2-
regulated genes NQO1 and SLC7A11) displayed a robust induction (>3-fold) in whole blood.  
This assay is aimed at assessing whether MLN4924 (pevonedistat) target engagement, as 
measured by increased NRF2-regulated NQO1 and SLC7A11 gene expression in whole blood by 
RT-PCR, is a biomarker of MLN4924 (pevonedistat) activity.   
 


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2.4.3 MLN9708 (Ixazomib) Limited PK Profile 
 
MLN9708 (ixazomib) PK sampling will be obtained on Days 1 and 15 in Cycles 1 and 3 to 
assess peak concentrations and accumulation effects.  These values will be assessed in the 
context of MLN4924 (pevonedistat) PK, pharmacodynamic markers, response data, and AE data.  
 
 
 
 


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3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have RRMM with measurable disease, as defined by at least one of the 
following: 
• Serum monoclonal protein ≥0.5 g/dL 
• Urinary monoclonal protein excretion of ≥200 mg/24 hours 
• Kappa or lambda light chain level ≥10 mg/dL with an abnormal free light chain 
ratio 
 
3.1.2 At least two prior lines of therapy and all patients should have at least been exposed to a 
proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 
antibody. 
• For proteasome-sensitive expansion cohort: Patients with MM who relapsed or 
are refractory to a prior line of therapy not including a proteasome inhibitor 
• For proteasome-relapsed/refractory expansion cohort: Patients with MM who 
have relapsed after prior PI exposure or are PI-refractory, defined as 
nonresponsive to treatment or progresses within 60 days of last exposure to a PI 
 
3.1.3 Age ≥18 years.  
 
Because no dosing or AE data are currently available on the use of MLN4924 
(pevonedistat) in combination with MLN9708 (ixazomib) in patients <18 years of age, 
and as this disease is exceptionally uncommon in this age group, children are excluded 
from this study.  
 
3.1.4 Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%, 
see Appendix A). 
 
3.1.5 Patients must have adequate organ and marrow function as defined below: 
 
− 
Leukocytes 
 
≥3,000/mcL 
− 
Absolute Neutrophil Count  
≥1,000/mcL 
− 
Platelets  
 
≥75,000/mcL 
− 
Bilirubin  
 
≤ institutional upper limit of normal (ULN).  
− 
Patients with Gilbert’s syndrome may enroll if 
direct bilirubin ≤1.5 × ULN 
− 
AST(SGOT)/ALT(SGPT) 
 
≤3.0 × institutional ULN 
− 
CrCl by Cockcroft-Gault 
 
≥30 mL/min 
3.1.6 Known HIV positive patients who meet the following criteria will be considered eligible: 
 
• CD 4 count >350 cells/mm3 
• Undetectable viral load 


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• Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents 
(e.g. excluding ritonavir) 
• No history of Acquired Immune Deficiency Syndrome (AIDS)-defining opportunistic 
infections 
 
3.1.7 The effects of MLN4924 (pevonedistat) and MLN9708 (ixazomib) on the developing 
human fetus are unknown.  For this reason and because NAE inhibitory agents are known 
to be teratogenic, women of child-bearing potential and men must meet the following 
criteria:  
 
Female patients who are: 
• Postmenopausal for at least one year before the screening visit, OR 
• Surgically sterile, OR 
• If of childbearing potential, agree to practice 1 highly effective method and 1 
additional (barrier) method of contraception, at the same time, from the time of 
signing the informed consent until 4 months after the last dose of the ixazomib and 
pevonedistat (female and male condoms should not be used together), or agree to 
abstain from heterosexual intercourse, 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.) 
 
Male patients, even if surgically sterilized, who: 
• Agree to practice effective barrier contraception during the entire time enrolled on 
study through 4 months after completion of ixazomib and pevonedistat administration 
(female and male condoms should not be used together), OR 
• Agree to abstain from heterosexual intercourse, 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.) 
 
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.   
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document.  
Participants with impaired decision-making capacity (IDMC) who have a legally-
authorized representative (LAR) and/or family member available will also be eligible.  
 
3.2 
Exclusion Criteria 
 
3.2.1 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 non-melanoma skin cancer or carcinoma in situ of any type are not 


NCI Protocol #:  10249 
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30 
excluded if they have undergone resection. 
 
3.2.2 Patients who are receiving any other investigational agents, within 30 days of the start of 
this trial and throughout the duration of this trial. 
 
3.2.3 Patients with known central nervous system involvement should be excluded from this 
clinical trial because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other AEs. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MLN4924 (pevonedistat) or MLN9708 (ixazomib) (including boron or 
boron-containing products). 
 
3.2.5 Patients with uncontrolled intercurrent illness.  
 
3.2.6 Pregnant women are excluded from this study because MLN4924 (pevonedistat) is an 
NAE inhibitory agent with the potential for teratogenic or abortifacient effects.  Because 
there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with MLN4924 (pevonedistat), breastfeeding should be discontinued if the 
mother is treated with MLN4924 (pevonedistat).  These potential risks may also apply to 
the use of MLN9708 (ixazomib) in this study.   
 
3.2.7 Major surgery within 14 days before the first dose of any study drug or a scheduled 
surgery during study period. 
 
3.2.8 Patients with uncontrolled coagulopathy or bleeding disorder. 
 
3.2.9 Known hepatic impairment as defined by known hepatic cirrhosis, 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. 
 
3.2.10 Known cardiopulmonary disease defined as: 
• Unstable angina;  
• Congestive heart failure (New York Heart Association [NYHA] Class III or IV; 
see Appendix D); 
• Myocardial infarction within 6 months prior to first dose (patients who had 
ischemic heart disease such as acute coronary syndrome [ACS], myocardial 
infarction, and/or revascularization greater than 6 months before screening and 
who are without cardiac symptoms may enroll); 
• Symptomatic cardiomyopathy 
• Clinically significant arrhythmia: 
1. History of polymorphic ventricular fibrillation or torsade de pointes, 


NCI Protocol #:  10249 
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31 
2. Permanent atrial fibrillation, defined as continuous atrial fibrillation for ≥6 
months, 
3. Persistent atrial fibrillation, defined as sustained atrial fibrillation lasting 
>7 days and/or requiring cardioversion in the 4 weeks before screening, 
4. Grade 3 atrial fibrillation defined as symptomatic and incompletely 
controlled medically, or controlled with device (e.g., pacemaker), or 
ablation in the past 6 months and 
5. Patients with paroxysmal atrial fibrillation or Grade <3 atrial fibrillation 
for period of at least 6 months are permitted to enroll provided that their 
rate is controlled on a stable regimen. 
• Clinically significant pulmonary hypertension requiring pharmacologic therapy 
 
3.2.11 Uncontrolled high blood pressure (i.e., systolic blood pressure >180 mmHg, diastolic 
blood pressure >95 mmHg). 
 
3.2.12 Prolonged rate corrected QT (QTc) interval ≥500 msec, calculated according to 
institutional guidelines. 
 
3.2.13 Left ventricular ejection fraction (LVEF) <50% as assessed by echocardiogram. 
 
3.2.14 Known moderate to severe chronic obstructive pulmonary disease, interstitial lung 
disease, and pulmonary fibrosis. 
 
3.2.15 Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of MLN9708 (ixazomib), including difficulty swallowing. 
 
3.2.16 Peripheral neuropathy that is Grade ≥3, or Grade 2 with pain on clinical examination 
during the screening period. 
 
3.2.17 Patients that have previously been treated with MLN9708 (ixazomib). 
 
3.2.18 Systemic treatment, within 14 days before the first dose of MLN9708 (ixazomib), with 
strong CYP3A inducers (rifampin, rifapentine, rifabutin, ritonavir, carbamazepine, 
phenytoin, phenobarbital), or use of St. John’s wort.  Clinically significant metabolic 
enzyme inducers are not permitted during this study. 
 
3.2.19 Radiotherapy within 14 days before enrollment.  If the involved field is small, 7 days will 
be considered a sufficient interval between treatment and administration of the MLN9708 
(ixazomib). 
 
3.2.20 Female patients who intend to donate eggs (ova) during the course of this study or 4 
months after receiving their last dose of study drug(s). 
 
3.2.21 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). 
 


NCI Protocol #:  10249 
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32 
3.3 
Inclusion of Women and Minorities 
 
National Institute of Health (NIH) policy requires that women and members of minority groups 
and their subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale and 
justification establishes to the satisfaction of the funding Institute & Center (IC) Director that 
inclusion is inappropriate with respect to the health of the patients or the purpose of the research.  
Exclusion under other circumstances must be designated by the Director, NIH, upon the 
recommendation of an IC Director based on a compelling rationale and justification.  Cost is not 
an acceptable reason for exclusion except when the study would duplicate data from other 
sources.  Women of childbearing potential should not be routinely excluded from participation in 
clinical research.  Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
All eligible patients regardless of sex/gender, race, or ethnicity will have the opportunity to 
enroll.  The expected distribution of sex, race, and ethnicity will reflect the general population of 
our institution.  Further details on planned distribution can be found in the table in Section 9.2. 
 
 
 


NCI Protocol #:  10249 
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33 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to Oncology Patient Enrollment Network (OPEN), Rave, or acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• IVR:  MD, DO, or international equivalent, 
• NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
• AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System [RUMS], OPEN, Rave,), 
• Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required 
IV
R 
NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 
• Addition to a site roster, 


NCI Protocol #:  10249 
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34 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance).  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov.  
 
4.2 
Site Registration 
 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 


NCI Protocol #:  10249 
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35 
 
 
4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment.  To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Participating 
Organization on the protocol.  
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-MD017, 
and protocol number 10249, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided.  (Note:  For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU as described above.)  
 
4.2.2 Requirements For 10249 Site Registration 
 
•  Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU.  However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com, Theradex phone: 609-799-7580). 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website → 
Regulatory → Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
36 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site’s registration status on the members’ side of the CTSU website.  
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration  
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined above.  It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
 
Requirements for OPEN access:   
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar.  
Registrars must hold a minimum of an AP registration type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar task on 
the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
37 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on 
the protocol is available to the patient.  Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study.  
 
Special Instructions for Patient Enrollment 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
 
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
• The system is accessed through special Rave user roles:  “CRA Specimen Tracking” for 
data entry at the treating institutions and “Biorepository” for users receiving the 
specimens for processing and storage at reference labs and the Biorepository.   
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website under the Rave/DQP tab. 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
 
 
4.3.2 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11.  This link to the Theradex website is also on the CTSU website OPEN 
tab.  For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
38 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 30 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
39 
 
5. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Biomarker Plan  
 
List of Biomarker Assays in Order of Priority  
 
Priority 
Biomarker 
Name 
Biomarker 
Assay 
Biomarker 
Type and 
Purpose 
M/O 
Timing 
Specimen 
Quantity 
Needed 
Laboratory 
1 
MLN4924 
(pevonedistat
) PK profile 
LC/MS/MS 
Integrated 
 
PK analysis 
M 
Cycle 1, Day 
1 pre-dose, 
and at the 
following 
time points 
after 
initiation of 
infusion: 0.5 
hr ±10 min, 1 
hr ±10 min, 2 
hrs ±10 min, 
2.5 hrs ±10 
min, 5 hrs, 
±30 min, 8 
hrs ±45 min, 
and 21 hrs ±2 
hrsin the dose 
escalation 
portion only  
Plasma 
3 mL in 
EDTA 
tubes at 
each time 
point 
QPS, LLC 
2 
NQO1 and 
SLC7A11 
(NRF2 target 
genes) 
qRT-PCR 
Integrated 
 
Hypothesis 
generation to 
develop response 
predictors 
M 
Pre-
treatment, 
and 4 hours 
post-
MLN4924 
(pevonedistat
) completion 
on C1D1 
Blood 
2.5 mL  
Asuragen 
 
Deepa 
Eveleigh 
 
develeigh@as
uragen.com 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
40 
Priority 
Biomarker 
Name 
Biomarker 
Assay 
Biomarker 
Type and 
Purpose 
M/O 
Timing 
Specimen 
Quantity 
Needed 
Laboratory 
3 
MLN9708 
(ixazomib) 
limited PK 
profile 
LC/MS/MS 
Integrated 
 
PK analysis 
M 
C1D1, 
C1D15, 
C3D1, and 
C3D15 at the 
following 
timepoints:  
pre-dose and 
1 hr ±10 min 
after dosing 
in the dose 
escalation 
portion only 
Plasma 
3 mL at 
each time 
point 
QPS, LLC 
2 
ATF3, B2M, 
GCLM, GSR, 
MAG1, 
RPLP0, 
SRXN1, 
TXNRD1, and 
UBC 
RT-PCR 
 
Exploratory 
 
Hypothesis 
generation to 
develop response 
predictors 
M 
Pre-treatment 
and 4 hours 
post-
MLN4924 
(pevonedistat
) completion 
on C1D1 
Blood 
N/A (Same 
collection 
as NQO1 
and 
SLC7A11 
Biomarker) 
Asuragen 
 
Deepa 
Eveleigh 
 
develeigh@as
uragen.com 
M = Mandatory, PK = Pharmacokinetics, LC/MS/MS = Liquid chromatography/tandem mass spectrometry, EDTA = Ethylenediaminetetraacetic acid, PBMC = 
Peripheral blood mononuclear cell, Na = Sodium, NQO1 = NAD(P)H dehydrogenase (quinone) 1, SLC7A11 = Cystine/glutamate transporter, NRF2 = Nuclear 
factor (erythroid-derived 2)-like 2, qRT-PCR = Quantitative reverse transcription polymerase chain reaction 
  
 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
41 
Specimen Collection Schedule 
 
Specimen Type 
Baseline 
(Pre-
treatment) 
Cycle 1, 
Day 1 
Cycle 1, 
Day 15 
Cycle 3, 
Day 1 
Cycle 3, 
Day 15 
End of 
Study 
Plasmac 
 
Xa,b 
Xb 
Xb 
Xb 
 
Blood (PBMC isolation) 
X 
 
 
 
 
 
Blood 
X 
 
 
 
 
X 
 
PMBC = Peripheral blood mononuclear cell 
a: 
Plasma for MLN4924 (pevonedistat) and MLN9708 (ixazomib) PK profiles.  Time points to be collected for MLN9708 (ixazomib) and MLN4924 
(pevonedistat) PK profiles are:  pre-dose and 1 hr ±10 min after initiation of infusion.  Additional time points to be collected for only MLN4924 (pevonedistat) 
PK profile are:  0.5 hr ±10 min, 2 hr ±10 min, 2.5 hr ±10 min, 5 hrs ±30 min, 8 hr ±45 min, and 21 hrs ±2 hrs after initiation of infusion. 
b:  
Plasma for MLN9708 (ixazomib) PK profile.  Time points to be collected are:  pre-dose and 1 hr ±10 min after initiation of infusion. 
c: 
Plasma will only be collected during the dose escalation phase. 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
42 
 
5.2 
Integrated Correlative Studies 
 
5.2.1 MLN4924 (Pevonedistat) PK Profile 
 
5.2.1.1 
Collection of Specimen(s) 
 
Blood samples (3 mL) will be collected in chilled lavender top K2EDTA Vacutainer tube for 
plasma analysis on Cycle 1, Day 1 pre-dose and at the following time points after initiation of 
infusion:  pre-dose, 0.5 hour ±10 min, 1 hour ±10 min, 2 hours ±10 min, 2.5 hours ±10 min, 5 
hours, ±30 min, 8 hours ±45 min, and 21 hours ±2 hours.  This study will only be performed 
during the dose escalation portion. 
 
Legibly write the subject’s initials and subject identification number clearly using a blue or black 
pen only (no markers) on the blood collection tubes.  Cryovial labels must include the protocol 
number, subject identification number, and the sample identification code shown below.  The 
(nominal time) may be the scheduled visit and/or time point. 
 
• a. Plasma PK Pevo (nominal time) Set1 
• b. Plasma PK Pevo (nominal time) Set2 
 
5.2.1.2 
Handling of Specimens(s) 
 
1. Gently invert the Vacutainer 8 to 10 times to mix the additive with the collected blood 
prior to centrifugation and place immediately on ice.  
2. Centrifuge the Vacutainers for 10 minutes at approximately 1100 to 1300 × g (RCF) at 
approximately 4°C in a refrigerated centrifuge.  Note:  if using a collection device other 
than Becton-Dickinson, refer to manufacturer’s instruction for proper centrifugation force 
and time.  
3. Immediately following centrifugation, gently remove plasma from the packed cells and 
transfer into 2 appropriately labeled 2.0 mL cryogenic vials.  To ensure a more 
homogeneous sample, transfer all plasma into one cryovial.  From there, split the plasma 
evenly between the 2 aliquots.  A minimum of 0.6 mL needs to be obtained for each 
aliquot.  
4. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -70°C or lower.  If a -70°C freezer is not available, freeze and store 
samples at -20°C.  No more than 45 minutes will elapse between blood collection and 
freezing the plasma sample.  
5. Store samples frozen at approximately -70°C or lower until shipment.  If a -70°C freezer 
is not available, samples can be stored in a -20°C freezer for up to 30 days.  
 
5.2.1.3 
Shipping of Specimen(s) 
 
1. All samples to be shipped to below address. 
2. Primary and backups of same sample should not be shipped together. 
3. Each shipment should include a Sample Inventory. 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
43 
4. Please notify QPS of the shipment with sample inventory copy via email (email address 
below) ahead of time, or at the latest on the day of shipment. 
5. Samples will be packed in styrofoam shipping containers with a sufficient amount of dry 
ice to maintain frozen conditions for at least 72 hours (3 days), or up to the expected 
delivery date, whichever is longer. 
 
QPS Sample Receipt Address: 
 
Attn: Sample Coordination Team 
QPS, LLC 
3 Innovation Way 
Suite 240 
Newark, DE, 19711 
Phone: +1 302 369 5120 
Email: sample@qps.com 
 
5.2.1.4 
Site(s) Performing Correlative Study 
 
QPS, LLC will analyze plasma for MLN4924 (pevonedistat) and MLN9708 (ixazomib) PK.   
 
5.2.2 NQO1 and SLC7A11 (NRF2 Target Genes) Expression 
 
5.2.2.1 
Collection of Specimen(s) 
 
Blood (2.5 mL) will be collected prior to treatment and 4 hours after MLN4924 (pevonedistat) 
completion on Cycle 1, Day 1. 
 
Instructions for Processing Samples 
 
1. Ensure that the PAXgene Blood RNA Tube is at room temperature prior to use and properly 
labeled with the protocol number, whether pre- or post-study, and the patient study ID. 
2. If the PAXgene Blood RNA Tube is the only tube to be drawn, a small amount of blood 
should be drawn into a discard tube prior to drawing blood into the PAXgene Blood RNA 
Tube.  Otherwise, the PAXgene Blood RNA Tube should be the last tube drawn in the 
phlebotomy procedure. 
3. Using a BD Vacutainer Safety-Lok Blood Collection Set (or equivalent), collect 2.5 mL of 
blood into the PAXgene Blood RNA Tube using the local institution’s recommended 
standard procedure for phlebotomy.  Samples from a central venous catheter are also 
acceptable and should be obtained using the local institution’s recommended procedures.  
Note that the PAXgene tube is a standard sized 10 mL blood draw tube with 7.5 mL of RNA 
stabilizing agent in it, so 2.5 mL of blood is drawn in, for a total of 10 mL. 
4. Hold the PAXgene Blood RNA Tube vertically and below the patient’s arm during blood 
collection. 
5. Allow at least 10 seconds for a complete blood draw to take place.  Ensure that the blood has 
stopped flowing into the tube before removing the tube from the holder. 
 


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5.2.2.2 
Handling of Specimens(s) 
 
1. Gently invert the PAXgene Blood RNA Tube 8-10 times. 
2. Freeze PAXgene Blood RNA Tubes at -20°C until ready to ship. 
 
5.2.2.3 
Shipping of Specimen(s) 
 
The PAXgene tubes can be batched and shipped on dry ice same day or overnight to Asuragen.  
Please reference either the trial ID or Asuragen project code on the package and any shipping 
manifest provided.  Shipping manifests with detailed sample information should be sent to:  
develeigh@asuragen.com. 
 
Ship samples to: 
Asuragen 
2150 Woodward St., Suite 100 
Austin, TX 78744 
 
5.2.2.4 
Site(s) Performing Correlative Study   
 
The test will be performed at Asuragen. 
 
5.2.3 MLN9708 (ixazomib) Limited PK Profile 
 
5.2.3.1 
Collection of Specimen(s) 
 
Blood samples (3 mL) will be collected in appropriately labeled chilled lavender top K2EDTA 
Vacutainer tube for plasma analysis on Cycle 1, Day 1; Cycle 1, Day 15; Cycle 3, Day 1; and 
Cycle 3, Day 15 at the following time points:  pre-dose and 1 hour ±10 minutes after dosing.  
This study will only be performed during the dose escalation portion. 
 
5.2.3.2 
Handling of Specimens(s) 
 
1. Immediately mix the blood with the anticoagulant by gently inverting the tube 8-10 times 
to thoroughly mix the blood with the anticoagulant (do not shake), and immediately place 
the blood collection tube on wet ice 
• NOTE: Wet ice is defined as a mixture of ice and water. 
2. Within 10 minutes of blood collection, centrifuge the blood samples for 10 minutes at 
1600 × g at 4°C in a refrigerated centrifuge. 
3. Immediately following centrifugation, gently remove the plasma and aliquot into two pre-
labeled transfer vials filled with lyophilized citric acid. Each aliquot should contain 0.5 
mL of plasma. 
• NOTE:  If <0.5 mL plasma is obtained post centrifugation, do not process or store 
split1 or split2, record split1:  ISV (Insufficient Sample Volume), split2:  ISV. 
4. Securely cap the tube and freeze the samples immediately at -70°C. 
5. No more than 30 minutes should elapse between blood collection and freezing the plasma 
samples.  Keep samples frozen at -70°C or lower until shipment.  


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5.2.3.3 
Shipping of Specimen(s) 
 
6. All samples to be shipped to below address. 
7. Primary and backups of same sample should not be shipped together. 
8. Each shipment should include a Sample Inventory. 
9. Please notify QPS of the shipment with sample inventory copy via email (email address 
below) ahead of time, or at the latest on the day of shipment. 
10. Samples will be packed in styrofoam shipping containers with a sufficient amount of dry 
ice to maintain frozen conditions for at least 72 hours (3 days), or up to the expected 
delivery date, whichever is longer. 
 
QPS Sample Receipt Address: 
 
Attn: Sample Coordination Team 
QPS, LLC 
3 Innovation Way 
Suite 240 
Newark, DE, 19711 
Phone: +1 302 369 5120 
Email: sample@qps.com 
 
5.2.3.4 
Site(s) Performing Correlative Study   
 
QPS, LLC will analyze plasma for MLN4924 (pevonedistat) and MLN9708 (ixazomib) PK.   
 
5.3 Exploratory Correlative Studies 
 
5.3.1 ATF3, B2M, GCLM, GSR, MAG1, RPLP0, SRXN1, TXNRD1, and UBC 
 
5.3.1.1 
Collection of Specimen(s) 
 
This study will use the sample collected in Section 5.2.3.1. 
 
5.3.1.2 
Handling of Specimens(s) 
 
See Section 5.2.3.1 for information on the handling of this specimen. 
 
5.3.1.3 
Shipping of Specimen(s) 
 
See Section 5.2.3.3 for information on the shipping of this specimen. 
 
5.3.1.4 
Site(s) Performing Correlative Study   
 
This study will be performed by Asuragen.   


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6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported AEs and potential risks are 
described in Section 10.  Appropriate dose modifications are described in Section 7.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
This is a phase 1 clinical trial of MLN9708 (ixazomib) in combination with MLN4924 
(pevonedistat) in RRMM patients.  This clinical trial will use a 3+3 dose escalation design to 
determine the MTD for the combination of MLN9708 (ixazomib) and MLN4924 (pevonedistat) 
to target a DLT rate of less than 33% in myeloma patients regardless of status of PI sensitivity.  
MLN9708 (ixazomib) will be given on Days 1, 8, and 15 of a 28-day cycle.  MLN4924 
(pevonedistat) will be given concurrently on Days 1, 8, and 15 of a 28-day cycle.  The trial will 
start from dose level 1.  If no patient experiences a DLT in a 3-patient cohort at a given dose 
level, then the dose will be escalated to the next higher level.  If a DLT occurs in 1 of 3 patients 
at a dose level, the cohort will be expanded to 6 patients.  If the incidence of DLT among those 6 
patients is 1 in 6, then the next cohort of 3 patients is treated at the next higher dose.  If 2 or more 
patients experience a DLT in a 3-patient or 6-patient cohort at a given dose level, then the MTD 
has been exceeded, dose escalation will be stopped, and up to 3 additional patients will be 
enrolled at the next lower dose (unless 6 patients have already been treated at that prior dose).  
The MTD will be the highest dose at which 1 or fewer of six patients experience a DLT.  In the 
expansion phase, a total of 24 patients will be enrolled at the MTD of MLN4924 (pevonedistat) 
defined in the dose escalation phase in 2 cohorts:  PI-sensitive and PI-refractory.  Refractoriness 
will be defined as per the 2011 International Myeloma Working Group (IMWG) definition, 
disease that is nonresponsive to treatment or progresses within 60 days of last exposure to a PI. 
 
Dose Escalation Schedule 
Dose Level 
Dose 
MLN9708 (Ixazomib) PO QD 
on Days 1, 8, and 15 
MLN4924 (Pevonedistat) IV on 
days 1, 8, and 15* 
Level -2 
3 mg 
15 mg/m2 
Level -1 
3 or 4 mg# 
15 or 20 mg/m2# 
Level 1 
4 mg 
20 mg/m2 
Level 2 
4 mg 
40 mg/m2 
Level 3 
4 mg 
60 mg/m2 
Level 4 
4 mg 
80 mg/m2 
Level 5 
4 mg 
100 mg/m2 
PO = by mouth, QD = once daily, IV = intravenous 
# Agent attribution for DLT will dictate which drug is dose reduced for dose level -1.  No dose 
reduction below 3 mg for MLN9708 (ixazomib) and 15 mg/m2 for MLN4924 (pevonedistat) 


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will be allowed.  Should a DLT occur attributable to either agent at the lowest dose level, the 
trial will be stopped.  
* Dose rounding is allowed as per institutional guidelines. 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
MLN9708 
(Ixazomib) 
N/A 
** 
PO (To be 
given 
concurrently 
with MLN4924 
[Pevonedistat]) 
Days 1, 8, 
and 15 
28 days 
(4 weeks) 
MLN4924 
(Pevonedistat) 
N/A 
** 
IV (Infuse over 
60 minutes [±10 
minutes]) 
Days 1, 8, 
and 15 
PO = by mouth, IV = intravenous 
**Doses as appropriate for assigned dose level. 
 
6.1.1 MLN9708 (Ixazomib) 
 
Patients should be instructed to swallow MLN9708 (ixazomib) capsules whole, with water, and 
not to break, chew, or open the capsules.  MLN9708 (ixazomib) should be taken on an empty 
stomach (no food or drink) at least 1 hour before or at least 2 hours after food.  Each capsule 
should be swallowed separately with water.  A total of approximately 8 ounces (240 mL) of 
water should be taken with the capsules.  MLN9708 (ixazomib) should be given concurrently 
with MLN4924 (pevonedistat). 
 
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 72 
hours or more away.  A double dose should not be taken to make up for a missed dose.  If the 
patient vomits after taking a dose, the patient should not repeat the dose but should resume 
dosing at the time of the next scheduled dose. 
 
Fluid deficit should be corrected before initiation of treatment and during treatment. 
 
Prophylaxis against risk of reactivation of herpes infection:  Investigators should consider the use 
of antiviral prophylaxis for patients being treated with MLN9708 (ixazomib), as patients may be 
at an increased risk of infection, including reactivation of herpes zoster and herpes simplex 
viruses.  Antiviral therapy such as acyclovir, valacyclovir, or other antivirals may be initiated as 
clinically indicated.  Other antivirals are also acceptable. 
 
6.1.2 MLN4924 (Pevonedistat) 
 
All protocol-specific criteria for administration of study drug must be met and documented prior 
to drug administration.  Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s). 


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If MLN4924 (pevonedistat) dosing is delayed, a minimum of 1 full calendar day between any 2 
doses should be maintained.  In each cycle, a maximum of 3 doses of MLN4924 (pevonedistat) 
should not be exceeded.  
 
The dose will be calculated based on BSA using actual body weight.  Re-calculate dose if there 
is a change in body weight of ≥5%.   
 
Infuse over 60 minutes (±10 minutes) through central or peripheral venous access.  The IV infusion 
can be slowed or stopped and restarted for any associated infusion-related reactions.  The total time 
from the IV preparation to end of IV infusion must not exceed 6 hours.  MLN4924 (pevonedistat) 
should be given concurrently with MLN9708 (ixazomib). 
 
6.2 
Definition of Dose-Limiting Toxicity 
 
DLT will be defined as any of the following events that are considered by the investigator to be 
related to therapy with MLN4924 (pevonedistat): 
• Grade 3 or greater prothrombin time (PT) or activated partial thromboplastin time (aPTT) 
elevation in the absence of anticoagulation therapy.  
• Grade 2 or greater elevation of the PT or aPTT that is associated with clinically 
significant bleeding (CNS, GI, etc.).  
• Grade 3 or greater nausea and/or emesis despite use of optimal anti-emetic prophylaxis.  
Optimal anti-emetic prophylaxis is defined as an anti-emetic regimen that employs a 5-
hydroxytryptamine 3 serotonin receptor antagonist given in standard doses and according 
to standard schedules.  
• Grade 3 or greater diarrhea that occurs despite maximal supportive therapy. 
• Grade 3 arthralgia/myalgia despite the use of optimal analgesia.  
• Any other Grade 3 or greater non-hematologic toxicities (e.g. nausea, vomiting, diarrhea, 
etc.) despite optimal medical management, with the following exception: 
• Grade 3 hypophosphatemia  
• Persistent elevations of one of the 2 transaminases or bilirubin above Grade 2 beyond 
2 days between doses. 
• Other MLN4924 (pevonedistat)-related non-hematologic toxicities Grade 2 or greater 
that, in the opinion of the investigator, require a dose reduction or discontinuation of 
therapy with MLN4924 (pevonedistat).  
• A delay in the initiation of Cycle 2 due to a lack of adequate recovery from treatment-
related toxicity (recovery to Grade ≤1 or to patient’s baseline values): 
• Of more than 4 weeks due to hematologic toxicity believed not related to 
leukemic infiltration.  Bone marrow evaluation may be required. 
• Of more than 2 weeks due to nonhematologic toxicities. 
• Grade 3 fatigue >1 week 
• Grade ≥3 electrolyte abnormalities Grade 4 neutropenia (ANC 500 cells/mm3) lasting 
more than 7 consecutive days. 


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49 
• Grade 3 neutropenia with fever and/or infection, where fever is defined as 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. 
• A platelet count 10,000/mm3 at any time. 
• Grade 4 anemia not attributable to underlying disease process. 
Grade 3 events lasting <1 week will not be considered a DLT.  Although DLTs may occur at any 
point during treatment, only DLTs occurring during Cycle 1 of treatment will necessarily 
influence decisions regarding dose escalation, expansion of a dose level, or evaluation of 
intermediate dose levels.  Patients will be monitored through all cycles of therapy for treatment 
related- toxicities. 
Management and dose modifications associated with the above AEs are outlined in Section 7. 
 
Dose escalation will proceed within each cohort according to the following scheme.  DLT is 
defined above.   
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose.  At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
6.3 
Dose Expansion Cohorts: 
 
Once the RP2D is reached, an additional 24 patients will be treated at this dose.  For the 


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expansion cohort, patients will continue to be monitored for occurrence of DLTs as in the table 
below.  If the number of DLTs warrant stopping of the trial for toxicity, the Principal 
Investigator will discuss with all study investigators and with CTEP whether further addition of 
patients is needed to re-assess the RP2D.  Monitoring of all safety and toxicity data is done by 
the Principal Investigator and the Corresponding Organization on a real-time basis as data are 
entered into Medidata Rave using the Web Reporting Module.  All participating sites are 
expected to notify the Principal Investigator when a DLT has occurred. 
 
The pre-stopping rule in the Table below is generated based on the cumulative distribution 
function (CDF) of the binomial distribution, given the number of successes, the number of trials, 
and the probability of a successful outcome occurring.  The trial will be pre-stopped when the 
CDF is greater than 95% based on 33% DLT. 
 
Total number of 
treated patients 
Number of DLTs to stop the trial for 
toxicity 
3 
≥2 
4 
≥3 
5 
≥3 
6 
≥4 
7 
≥4 
8 
≥5 
9 
≥5 
10 
≥6 
11 
≥6 
12 
≥7 
13 
≥7 
14 
≥8 
15 
≥8 
16 
≥8 
17 
≥9 
18 
≥9 
19 
≥10 
20 
≥10 
21 
≥11 
22 
≥11 
23 
≥11 
24 
≥12 
 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of MLN9708 (ixazomib) and/or MLN4924 
(pevonedistat) with other concomitantly administered drugs that require CYP450 enzyme and 
transport protein, the case report form must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies.  The Principal Investigator should be alerted if 
the patient is taking drugs that are moderate/strong inducers of CYP3A4, or moderate/strong 


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inhibitors/inducers of P-gp, BCRP, and MRP2.  The study team should check a frequently-
updated medical reference for a list of drugs to avoid or minimize use of.  Appendix B and 
Appendix C (Patient Drug Information Handout and Wallet Card) should be provided to patients 
if available. 
 
6.4.1 MLN9708 (Ixazomib) 
 
6.4.1.1 
Excluded Concomitant Medications and Procedures 
 
Strong CYP3A4/5 inducers decrease MLN9708 (ixazomib) exposure; thus, avoid concomitant 
use of strong CYP3A4/5 inducers (e.g., rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, phenobarbital, and St. John’s Wort) with MLN9708 (ixazomib). 
 
The following medicinal products and procedures are prohibited during the study: 
• St. John’s Wort.  
• Any antineoplastic treatment with activity against MM, other than study drugs. 
• Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression). 
• Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days 
prior to study drug dosing for any dosing day. 
• Acetaminophen and acetaminophen-containing products 2 g per day are not allowed 
during MLN4924 (pevonedistat) and MLN9708 (ixazomib) treatment schedules. 
 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal function 
given reported NSAID-induced renal failure in patients with decreased renal function. 
 
6.4.1.2 
Permitted Concomitant Medications and Procedures 
 
The following medications and procedures are permitted during the study: 
• Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the 
discretion of the investigator and as per institutional policy and guidelines. 
• Loperamide or other antidiarrheal should be used for symptomatic diarrhea at discretion 
of the investigator.  The dose and regimen will be according to institutional guidelines. 
IV fluids should be given to prevent volume depletion. 
• Growth factors (e.g., granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], and recombinant erythropoietin) are 
permitted.  Their use should follow published guidelines and/or institutional practice; 
however, alternative usage may be reviewed with the study sponsor.  Erythropoietin will 
be allowed in this study.  Its use should follow published guidelines and/or institutional 
practice. 
• Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
• Concomitant treatment with bisphosphonates will be permitted, as appropriate. 
• Patients who experience worsening neuropathy from baseline may be observed for 
recovery and have dose reductions/delays as indicated in the protocol, and any supportive 


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therapy or intervention may be initiated as appropriate at the discretion of the 
investigator. 
• Supportive measures consistent with optimal patient care may be given throughout the 
study. 
 
6.4.2 MLN4924 (Pevonedistat) 
 
MLN4924 (pevonedistat) is metabolized mainly by CYP3A4 and may be affected by drugs that 
are moderate or strong inducers of CYP3A4.  MLN4924 (pevonedistat) (in vitro) is also a 
substrate of P-gp, BCRP, and MRP2.  The tables below list concomitant medications that are 
permitted and excluded, and those whose use should be avoided while taking MLN4924 
(pevonedistat). 
 
6.4.2.1 
Excluded Concomitant Medications and Procedures 
 
Concomitant Medications Excluded During the Study 
Therapy 
Comment/Exceptions 
Acetaminophen and 
acetaminophen-containing 
products 
For patients in the dose-escalation phase of a clinical study, agents such as 
acetaminophen and acetaminophen-containing products should not be 
administered 24 hours before, on the day of, and 24 hours after dosing with 
pevonedistat.  For patients not in dose escalation, agents such as 
acetaminophen and acetaminophen-containing compounds may be used 
judiciously and should not exceed a dose of 2 g of acetaminophen in a 24-
hour period. 
 
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/mcL 
while on study treatment.  The dosing of hydroxyurea and changes to 
dosing of hydroxyurea must be recorded. 
Clinically significant metabolic 
enzyme inducers  
Exclude carbamazepine, phenytoin, phenobarbital, primidone, rifabutin, 
rifampin, ritonavir, rifapentine and St. John’s Wort. 
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 MLN4924 (pevonedistat) dose until 72 hours 
before the next MLN4924 (pevonedistat) dose.  For example, if a patient 
receives MLN4924 (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 MLN4924 (pevonedistat) 
For example, androgens, supraphysiologic doses of corticosteroids, 
erythropoietin, eltrombopag (Promacta), or romiplostim (Nplate) are 
excluded. 
BCRP=breast cancer resistance protein 
 
 
 
 


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6.4.2.2 
Permitted Concomitant Medications and Procedures 
 
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 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/mcL) 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/mcL in the absence of clinical bleeding).  
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, 
CR=complete response, CRi=complete remission with incomplete blood count recovery, ANC=absolute 
neutrophil count. 
 
6.5 
Duration of Therapy 
 
In the absence of treatment delays due to AE(s), treatment may continue until one of the 
following criteria applies: 
 
• Disease progression as defined by the IMWG response criteria:  
o ≥25% increase or absolute increase ≥0.5 g/dL in serum M-protein. 
o ≥25% increase or absolute increase ≥200 mg/24 hours in urine M-protein. 
o For patients without measurable M-protein in the serum or urine, ≥25% increase 
in the kappa to lambda free light chain (FLC) ratio or an absolute increase >10 
mg/dL.  
o For patient without measurable M-protein or involved FLC, ≥25% increase in 
bone marrow plasma cell percentage or an absolute increase must be ≥10%. 
o ≥50% increase in the size or development of new bone lesions or soft tissue 
plasmacytomas.  
Or one of the following attributable to underlying myeloma:  serum calcium 
>11.5 mg/dL, decrease in hemoglobin of ≥2 g/dL, rise in serum creatinine ≥2 mg/dL, or 
hyperviscosity. 
 
• Intercurrent illness that prevents further administration of treatment 


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54 
 
• Unacceptable AE(s) 
 
• Patient decides to withdraw from the study 
 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
• Clinical progression 
 
• Patient non-compliance 
 
• Pregnancy 
 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
• Termination of the study by sponsor 
 
• The drug manufacturer can no longer provide the study agent 
 
• Initiation of hematopoietic stem cell transplant 
 
• Subsequent anti-cancer therapy 
 
• The patient loses the capacity to freely consent to participate in the study due to 
psychiatric illness, incarceration, or other reasons. 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.6 Premature termination of the study 
 
This study may be suspended or prematurely terminated if there is sufficient cause. Written 
notification, documenting the reason for study suspension or termination will be provided by the 
suspending or terminating party to the investigator, funding agency, the IND sponsor, and 
regulatory authorities. If the study is prematurely terminated or suspended, the PI will promptly 
inform the IRB and will provide the reason(s) for the termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
• Determination of unexpected, significant, or unacceptable risk to participants 


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• Demonstration of efficacy that would warrant stopping  
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination of futility 
 
6.7 
Duration of Follow Up 
 
Patients will be followed every 2-3 months for 2 years after removal from study or until death, 
whichever occurs first.  Patients removed from study for unacceptable AE(s) will be followed 
until resolution or stabilization of the AE. 
 
 


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7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose Escalation Schedule 
Dose Level 
Dose 
MLN9708 (Ixazomib) PO QD 
on Days 1, 8, and 15 
MLN4924 (Pevonedistat) IV on 
days 1, 8, and 15 
Level -2 
3 mg 
15 mg/m2 
Level -1 
3 or 4 mg# 
15 or 20 mg/m2# 
Level 1 
4 mg 
20 mg/m2 
Level 2 
4 mg 
40 mg/m2 
Level 3 
4 mg 
60 mg/m2 
Level 4 
4 mg 
80 mg/m2 
Level 5 
4 mg 
100 mg/m2 
PO = by mouth, QD = once daily, IV = intravenous 
#Agent attribution for DLT will dictate which drug is dose reduced for dose level -1.  No dose 
reduction below 3 mg for MLN9708 (ixazomib) and 15 mg/m2 for MLN4924 (pevonedistat) will 
be allowed.  Should a DLT occur attributable to either agent at the lowest dose level, the trial 
will be stopped. 
 
7.1 
Criteria for Retreatment and Dose Delays 
 
7.1.1 MLN9708 (Ixazomib) 
 
MLN9708 (ixazomib) dose modifications are permitted on this study according to the dose 
modifications below.  Once MLN9708 (ixazomib) is reduced for any toxicity, the dose may not 
be re-escalated. 
 
Treatment with MLN9708 (ixazomib) will use a cycle length of 28 days.  For a new cycle of 
treatment to begin, the patient must meet the following criteria: 
 
• ANC must be ≥1,000/mcL. 
• Platelet count must be ≥75,000/mcL. 
• All other non-hematologic toxicity (except for alopecia) must have resolved to Grade ≤1 
or to the patient’s baseline condition. 
 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of treatment, 
dosing should be delayed for 1 week.  At the end of that time, the patient should be re-evaluated 
to determine whether the criteria have been met.  If the patient continues to fail to meet the 
above-cited criteria, delay therapy and continue to re-evaluate.  The maximum delay before 
treatment should be discontinued will be 3 weeks or at the discretion of the Principal 
Investigator. 
 


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For dosing recommendations upon recovery, refer to Sections 7.2 and 7.3. 
 
7.1.2 MLN4924 (Pevonedistat) 
 
7.1.2.1 
Retreatment within a Cycle 
 
If dosing of either drug is delayed for safety reasons, retreatment may be resumed upon 
resolution of the safety condition.  For MLN4924 (pevonedistat), a minimum of one full calendar 
day between any two doses should be maintained.  A maximum of three doses of MLN4924 
(pevonedistat) per cycle should not be exceeded. 
 
If dosing is interrupted within a cycle because of drug-related toxicity, and if the sponsor 
investigator (or designee) agrees that it is in the patient’s interest to continue therapy with the 
study drug(s), then after recovery of the toxicity or toxicities in question to Grade ≤1 or to the 
patient’s baseline values, the dose of study drug may be reduced in the next cycle.  For toxicity 
not related to drug (e.g., disease-related toxicity), although a similar dose reduction is permitted, 
in general it is discouraged.  If the reduced dose is well tolerated and the toxicity leading to dose 
reduction was Grade ≤3, has resolved, and does not reoccur, the dose may resume at the original 
dose level in the next cycle after endorsement by the sponsor investigator (or designee). 
 
7.1.2.2 
Initiation of a New Cycle 
 
Treatment with study drugs will be repeated every cycle.  For therapy to resume, toxicity 
considered related to treatment with study drugs must have resolved to Grade 1, to the patient’s 
baseline values, or to a level considered acceptable by the sponsor investigator. 
 
If a patient fails to meet the criteria for retreatment, initiation of the next cycle of treatment may 
be delayed for up to 2 weeks.  At the end of that time, the patient should be reevaluated to 
determine whether the criteria for retreatment have been met.  A dose reduction would be 
triggered if treatment is delayed for >2 weeks because of incomplete recovery from treatment 
related toxicity.  If the reduced dose is well tolerated and the toxicity leading to dose reduction 
was Grade ≤3, has resolved, and does not reoccur, the dose may resume at the original dose level 
in the next cycle after endorsement by the sponsor investigator (or designee). 
 
For toxicity not related to drug (e.g., disease-related toxicity), although a similar dose reduction 
is permitted, in general it is discouraged.  If the dose is well tolerated and the toxicity leading to 
dose reduction was Grade ≤3, has resolved, and does not reoccur, the dose may resume at the 
original dose level in the next cycle. 
 
For hematologic toxicity, a delay in the initiation of a cycle by 3 weeks or greater because of 
lack of recovery from treatment-related hematologic toxicity (resolved to Grade 1, to patient’s 
baseline values, or to a level considered acceptable by the sponsor investigator) that is not related 
to leukemic infiltration will trigger discontinuation of treatment.  If indicated, bone marrow 
evaluation will be performed to establish whether continued myelosuppression is related to 
persistent or progressing leukemic infiltration.  The MLN4924 (pevonedistat) dose should be 
reduced by at least one dose level.  


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7.2 
Dose Modifications for Hematologic Toxicities 
 
7.2.1 MLN9708 (Ixazomib) 
 
The following tables provide AE management and MLN9708 (ixazomib) dose modification 
recommendations for hematologic toxicities. 
 
ANC:  absolute neutrophil count; CBC:  complete blood count. 
 
7.2.2 MLN4924 (Pevonedistat) 
 
It is not anticipated that pevonedistat dose modifications would be necessary due to 
myelosuppression.  However, if clinically indicated in the opinion of the investigator, the 
MLN9708 (Ixazomib) Dose Adjustments for Hematologic Toxicities 
Criteria 
Action 
Within-Cycle Dose Modifications 
 
• 
If platelet count ≤30  109/L or ANC ≤0.50  
109/L on an MLN9708 (ixazomib) dosing day 
(other than Day 1) 
• 
MLN9708 (ixazomib) dose should be withheld.   
• 
CBC with differential should be repeated at least 
every other day until the ANC and/or platelet 
counts have exceeded the prespecified values 
(see Section 7.1.1) on at least 2 occasions.   
• 
Upon recovery, MLN9708 (ixazomib) may be 
reinitiated with 1 dose level reduction.  
Dose Modifications for Subsequent Treatment Cycles 
 
• 
Delay of >2 weeks in the start of a subsequent 
cycle due to lack of toxicity recovery as 
defined above 
• 
ANC < 1.0  109/L, platelet count < 75  109/L 
• 
Hold MLN9708 (ixazomib) until resolution as 
per criteria Section 7.1.1. 
• 
Upon recovery, reduce MLN9708 (ixazomib) 1 
dose level. 
• 
The maximum delay before treatment should be 
discontinued will be 3 weeks or at the discretion 
of the Principal Investigator. 
Dose Modifications for Subsequent Treatment Cycles 
 
• 
All hematologic toxicities 
• 
For hematologic toxicity that occurs during a 
cycle but recover in time for the start of the 
next cycle: 
o 
 If dose was reduced within the 
cycle, start the next cycle at that 
same dose. 
o 
If due to toxicity timing, i.e., after 
Day 15 dosing thus a dose 
reduction was not required at that 
point in the cycle, reduce 
MLN9708 (ixazomib) by 1 dose 
level at the start of that cycle. 
o 
Do not reduce the dose both within 
a cycle and at the start of the cycle 
for the same most severe toxicity. 


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MLN4924 (pevonedistat) dose may be reduced one dose level.  The MLN4924 (pevonedistat) 
dose may be re-escalated at the next cycle, if the toxicity has recovered to Grade ≤1 or the 
patient’s baseline.   
 
7.3 
Dose Modifications for Nonhematologic Toxicities 
 
7.3.1 MLN9708 (Ixazomib) 
 
MLN9708 (Ixazomib) Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity)* 
Action on Study Drug 
Further Considerations 
Peripheral Neuropathy: 
Grade 1 peripheral neuropathy 
 
• No action 
 
Grade 1 signs and symptoms:  
asymptomatic; without pain or loss 
of function; clinical or diagnostic 
observations only 
 
 
New or worsening Grade 1 
peripheral neuropathy with pain or 
Grade 2 
• Hold study drug until 
resolution to Grade ≤1 or 
baseline 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental ADL 
 
 
New or worsening Grade 2 
peripheral neuropathy with pain or 
Grade 3 
• Hold study drug until 
resolution to Grade ≤1 or 
baseline 
• Reduce study drug to next 
lower dose upon recovery 
 
Grade 3 signs and symptoms:  
severe symptoms; limiting self-
care ADL; assistive device 
indicated 
New or worsening Grade 4 
peripheral neuropathy 
• Discontinue study drug 
 
 
Grade 2 Rash 
• 
Symptomatic 
recommendations as per 
Section 7.3.1.3 
The investigator and project 
clinician may discuss 
considerations for dose 
modifications and symptom 
management. 
Grade 3 non-hematologic toxicity 
judged to be related to study drug 
• Hold study drug until 
resolution to Grade <1 or 
baseline 
Symptomatic recommendations 
noted later in this Section. 
If not recovered to Grade 
<1 or baseline within 4 
weeks 
 
• Reduce study drug 1 to next 
lower dose upon return to 
Grade <1 or baseline 
 


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MLN9708 (Ixazomib) Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity)* 
Action on Study Drug 
Further Considerations 
Subsequent recurrence 
Grade 3 that does not 
recover to Grade <1 or 
baseline within 4 weeks 
• Hold study drug until 
resolution to Grade <1 or 
baseline 
• Reduce study drug to next 
lower dose  
Monitor closely, take appropriate 
medical precautions, and provide 
appropriate symptomatic care 
Grade 4 non-hematologic toxicities 
judged to be related to study drug 
• Consider permanently 
discontinuing study drug 
Exceptions are cases in which the 
investigator determines the patient 
is obtaining a clinical benefit  
*Grade is defined according to the Common Terminology Criteria for Adverse Events (CTCAE). 
ADL = activities of daily living 
 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and rash 
have been associated with MLN9708 (ixazomib) treatment.  Management guidelines regarding 
these events are outlined below.   
 
7.3.1.1 
Nausea and/or Vomiting 
 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics may 
also be considered at the physician’s discretion.  Dexamethasone should not be administered as 
an anti-emetic.  Fluid deficit should be corrected before initiation of study drug and during 
treatment. 
 
7.3.1.2 
Diarrhea 
 
Prophylactic antidiarrheals will not be used in this protocol.  However, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals once 
infectious causes are excluded.  Fluid intake should be maintained to avoid dehydration.  Fluid 
deficit should be corrected before initiation of treatment and during treatment. 
 
7.3.1.3 
Erythematous Rash with or without Pruritus 
 
As with bortezomib, rash with or without pruritus has been reported with MLN9708 (ixazomib), 
primarily at the higher doses tested and when given with agents where rash is an overlapping 
toxicity.  The rash may range from limited erythematous areas, macular and/or small papular 
bumps that may or may not be pruritic over a few areas of the body, to a more generalized 
eruption that is predominately on the trunk or extremities.  Rash has been most commonly 
characterized as maculopapular or macular.  To date, when it does occur, rash is most commonly 
reported within the first 3 cycles of therapy.  The rash is often transient, self-limiting, and is 
typically Grade 1 to 2 in severity. 
 
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles.  The 


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61 
use of a topical, IV, or oral steroid (e.g., prednisone ≤10 mg per day or equivalent) is permitted.  
Management of a Grade 3 rash may require intravenous antihistamines or corticosteroids.  
Administration of MLN9708 (ixazomib) should be modified and re-initiated at a reduced level 
from where rash was noted. 
 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any 
SAE involving rash is recommended.  Prophylactic measures should also be considered if a 
patient has previously developed a rash (e.g., using a thick, alcohol-free emollient cream on dry 
areas of the body or oral or topical antihistamines).  A rare risk is Stevens-Johnson Syndrome, a 
severe and potentially life-threatening rash with skin peeling and mouth sores, which should be 
managed symptomatically according to standard medical practice.  Punch biopsies for 
histopathological analysis are encouraged at the discretion of the investigator.  Study 
medications should be discontinued in the event of severe, potentially life-threatening rash. 
 
7.3.1.4 
Thrombocytopenia 
 
Blood counts should be monitored regularly with additional testing obtained according to 
standard clinical practice.  Thrombocytopenia may be severe but has been manageable with 
platelet transfusions according to standard clinical practice.  MLN9708 (ixazomib) 
administration should be modified as noted as per dose modification recommendations when 
thrombocytopenia occurs.  Therapy can be reinitiated at a reduced level upon recovery of platelet 
counts. A rare risk is thrombotic thrombocytopenic purpura (TTP), a rare blood disorder where 
blood clots form in small blood vessels throughout the body characterized by thrombocytopenia, 
petechiae, fever, or possibly more serious signs and symptoms.  TTP should be managed 
symptomatically according to standard medical practice. 
 
7.3.1.5 
Neutropenia 
 
Blood counts should be monitored regularly with additional testing obtained according to 
standard clinical practice.  Neutropenia may be severe but has been manageable.  Growth factor 
support is not required but may be considered according to standard clinical practice.  MLN9708 
(ixazomib) administration should be modified as noted as per dose modification 
recommendations when neutropenia occurs.  Therapy can be reinitiated at a reduced level upon 
recovery of ANCs. 
 
7.3.1.6 
Fluid Deficit 
 
Dehydration should be avoided since MLN9708 (ixazomib) may cause vomiting, diarrhea, and 
dehydration.  Acute renal failure has been reported in patients treated with MLN9708 
(ixazomib), commonly in the setting of the previously noted gastrointestinal toxicities and 
dehydration.  Fluid deficit should be corrected before initiation of study drug and as needed 
during treatment to avoid dehydration. 
 
7.3.1.7 
Hypotension 
 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 


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reported with MLN9708 (ixazomib).  Blood pressure should be closely monitored while the 
patient is on study treatment and fluid deficit should be corrected as needed, especially in the 
setting of concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia.  Patients 
taking medications and/or diuretics to manage their blood pressure (for either hypo- or 
hypertension) should be managed according to standard clinical practice, including 
considerations for dose adjustments of their concomitant medications during the course of the 
trial.  Fluid deficit should be corrected before initiation of study drug and as needed during 
treatment to avoid dehydration.   
 
7.3.1.8 
Posterior Reversible Encephalopathy Syndrome 
 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has been 
reported with MLN9708 (ixazomib).  This condition is characterized by headache, seizures, and 
visual loss, as well as abrupt increase in blood pressure.  Diagnosis may be confirmed by 
magnetic resonance imaging (MRI).  If the syndrome is diagnosed or suspected, symptom-
directed treatment should be maintained until the condition is reversed by control of 
hypertension or other instigating factors. 
 
7.3.1.9 
Progressive Multifocal Leukoencephalopathy (PML) 
 
PML, which may be fatal, has occurred in less than 1% of oncology patients receiving MLN9708 
(ixazomib) in combination with other cancer therapies.  It is not known whether MLN9708 
(ixazomib) causes PML; however, the possibility that MLN9708 (ixazomib) may have 
contributed to PML cannot be excluded.  In the event of occurrence of PML, MLN9708 
(ixazomib) should be discontinued and supportive care provided as needed. 
 
7.3.1.10 Transverse Myelitis 
 
Transverse myelitis has also been reported with MLN9708 (ixazomib).  It is not known if 
MLN9708 (ixazomib) causes transverse myelitis; however, because it happened to a patient 
receiving MLN9708 (ixazomib), the possibility that MLN9708 (ixazomib) may have contributed 
to transverse myelitis cannot be excluded. 
 
7.3.2 MLN4924 (Pevonedistat) 
 
7.3.2.1 
MLN4924 (Pevonedistat) Dose Adjustment Based on Serum Transaminases and 
Total Bilirubin 
 
ALT, AST and bilirubin grading will be determined by CTCAE v5.0 in times per ULN, 
irrespective of baseline levels. 
 
It is anticipated that LFTs (AST, ALT, and occasionally bilirubin) may be elevated for 
approximately 48 hours following the end of MLN4924 (pevonedistat) infusion on Cycle 1, Day 
1.  For elevated LFTs of Grade 2 or 3 that occur on or after Cycle 1, Day 3, MLN4924 
(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, MLN4924 (pevonedistat) 


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dose may be resumed.  For MLN4924 (pevonedistat), a minimum of one full calendar day 
between any two doses should be maintained, and a maximum of three doses of MLN4924 
(pevonedistat) within the cycle must not be exceeded.  
 
For elevated LFTs of Grade 4 that occur on or after Cycle 1 Day 3, the MLN4924 (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 MLN4924 
(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, MLN4924 (pevonedistat) may be re-escalated. 
 
7.3.2.2 
MLN4924 (Pevonedistat) Dose Adjustment Based on Hypophosphatemia 
 
If hypophosphatemia is Grade ≥3, study drug treatment should not be resumed until the 
hypophosphatemia is Grade ≤2.  Hypophosphatemia should be evaluated (including severity and 
etiology), monitored, and treated according to institutional guidelines. 
 
7.3.2.3 
MLN4924 (Pevonedistat) Dose Adjustment for Other Toxicities 
 
For other Grade ≥2 nonhematologic toxicities potentially related to MLN4924 (pevonedistat), the 
MLN4924 (pevonedistat) dose may be reduced at the discretion of the sponsor investigator as 
clinically indicated.  If the toxicity returns to Grade ≤1 or the patient’s baseline status, MLN4924 
(pevonedistat) may be re-escalated at the next cycle. 
 
 


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8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agents 
 
8.1.1 MLN9708 (Ixazomib citrate) (NSC 767907) 
 
Chemical Name: 
 1,3,2-Dioxaborolane-4,4-diacetic acid, 2-[(1R)-1-[[2-[(2,5-
dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo 
 
Classification:   
Proteasome inhibitor 
 
Other Names:  
 Ixazomib ML0070120, MLN2238 citrate ester, Ninlaro® 
 
CAS Registry Number:  1239908-20-3 
 
Molecular Formula: C20H23BCl2N2O9 
M.W.: 517.12 g/mol (ixazomib citrate) 
 
Description:  In its solid state, MLN9708 is a white to off-white powder.  Under 
physiologic conditions, ixazomib citrate rapidly hydrolyzes to the biologically active 
form, ixazomib, the boronic acid form of ixazomib citrate.  
 
Mode of Action:  MLN9708 is a reversible proteasome inhibitor.  MLN9708 
preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of 
the 20S proteasome.  It induced apoptosis of multiple myeloma cell lines in vitro.  
 
How Supplied: Takeda supplies and Pharmaceutical Management Branch (PMB), CTEP, 
Division of Cancer Treatment and Diagnosis (DCTD) distributes MLN9708 as 3 mg and 4 
mg capsule strengths (expressed as boronic acid equivalent).  The capsule strengths are 
unique colors and packaged as 3 capsules per blister pack.  
 
The hard-capsule formulation consists of ixazomib citrate and the following excipients:  
microcrystalline cellulose, talc, and magnesium stearate. 
 
Storage:  Do not store MLN9708 above 30ºC (or not above 86ºF).  Do not freeze. 
 
If a storage temperature excursion is identified, promptly return MLN9708 to not above 
30ºC (or not above 86ºF) and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Stability studies are ongoing. 
 
 
Route(s) of Administration:  PO 


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Method of Administration:  Take capsule(s) on an empty stomach, 1 hour before or 2 
hours after food.  Swallow whole capsules with water.  Do not open or break capsules.   
 
Missed or delayed dose can be taken only if the next scheduled dose is ≥72 hours away.  A 
missed dose should not be taken within 72 hours of the next scheduled dose.  If vomiting 
occurs after taking a dose, the patient should not repeat the dose.  Resume dosing at the time 
of the next scheduled dose. 
 
Potential Drug Interactions:  MLN9708 is metabolized by CYP3A4 (42.3%), 1A2 
(26.1%), 2B6 (16%), 2C8 (6%), 2D6 (4.8%), 2C19 (4.8%), and 2C9 (<1%).  Co-
administration of MLN9708 with clarithromycin did not result in a clinically significant 
change in the systemic exposure of MLN9708.  Co-administration of MLN9708 with 
rifampin decreased MLN9708 Cmax by 54% and AUC by 74%.  Therefore, avoid 
concomitant administration of MLN9708 with strong CYP3A4 inducers (such as 
rifampin, phenytoin, carbamazepine, and St. John’s Wort). 
 
MLN9708 is neither a time-dependent nor a reversible inhibitor of CYP1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, or 3A4/5.  MLN9708 (ixazomib) did not induce CYP1A2, CYP2B6, and 
CYP3A4/5 activity or corresponding immunoreactive protein levels.  MLN9708 is not 
expected to produce drug-drug interactions via CYP inhibition or induction. 
 
MLN9708 is a low affinity substrate of P-gp.  MLN9708 is not a substrate of BCRP, 
MRP2, or hepatic OATPs.  MLN9708 (ixazomib) is not an inhibitor of P-gp, BCRP, 
MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K.  Hence, 
MLN9708 is not expected to cause transporter-mediated drug-drug interactions. 
 
Patient Implications:  There are no human data available regarding the potential effect 
of MLN9708 on pregnancy or development of the embryo or fetus.  Based on clinical 
data, MLN9708 caused embryo-fetal toxicity in pregnant rats and rabbits at doses 
resulting in exposures that were slightly higher than those observed in patients receiving 
the recommended dose.  Women should avoid becoming pregnant while being treated 
with MLN9708.  Male and female patients of childbearing potential must use effective 
contraceptive measures during and for 90 days following treatment. 
 
It is not known whether MLN9708 or its metabolites are present in human milk.  Many 
drugs are present in human milk and as a result, there could be a potential for adverse 
events in nursing infants.  Women should discontinue nursing while receiving MLN9708. 
 
Availability 
 
MLN9708 (ixazomib)is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
MLN9708 (ixazomib)is provided to the NCI under a Collaborative Agreement between 
the Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.4). 


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66 
 
8.1.2 MLN4924 (Pevonedistat HCl) (NSC 793435) 
 
Chemical Name: ((1S,2S,4R)-4-{(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d] 
pyrimidin-7-yl}-2-hydroxycyclopentyl) methyl sulfamate hydrochloride 
 
Classification:  NEDD8-activating enzyme (NAE) inhibitor 
 
Other Names:  Pevonedistat, TAK924/MLN4924; MLN4924-003 (hydrochloride salt); 
MLN4924-001 (free base); ML00644807; ML644507 
 
CAS Registry Number:  905579-51-3 (free base); 1160295-21-5 (hydrochloride salt) 
 
Molecular Formula:  C21H26CIN5O4S 
 
M.W.:  443.52 (free base); 479.98 (hydrochloride salt) 
 
Mode of Action:  MLN4924 is an inhibitor of neural precursor cell expressed development 
down-regulated 8 (NEDD8)-activating enzyme or NAE.  NAE is essential in the NEDD8-
conjugation pathway to control the activity of a subset of multiprotein complexes that 
transfer NEDD8 molecules to protein substrates by E3 ligases.  NAE inhibitors stop the 
degradations of a subset of proteins that regulated by the proteasomes.  
 
Description:  White to off-white solid with an assay value of 96.0% to 103.0% (w/w) on an 
anhydrous basis.  Acid dissociation constants of pKa1 = 5.16 and pKa2 = 8.81. 
 
How Supplied:  Takeda supplies and PMB distributes MLN4924 (Pevonedistat HCl) 
formulated as 10 mg/mL Concentrate for Solution for Infusion. Each single-use vial 
contains either 50 mg (5 mL) or 44 mg (4.4 mL) free base equivalent  
 
                                              . The sterile solution is packaged in USP Type I glass vials with 
rubber stoppers (latex free), aluminum seals with plastic caps.  
 
The current supply is 50 mg (5 mL) with 0.3 mL overfill volume. At a future date, the 44 
mg (4.4 mL) vial configuration will replace the 50 mg (5 mL) vial configuration. The 44 mg 
(4.4 mL) vial contains 0.3 mL overfill volume. 
 
Preparation:  
Before use, bring MLN4924 (Pevonedistat HCl) vials to ambient room temperature (15⁰ – 
30⁰ C / 59⁰ – 86⁰ F) for 15 minutes.  Do not use a water bath to warm up the vials. Return 
vials to 2⁰ – 8⁰ C (36⁰ – 46⁰ F) storage if not used within 6 hours.  
 
- 
Use a 250 mL prefilled 5% Dextrose (D5W) or 0.9% Normal Saline (NS) IV bag: 
o Remove excess volume from 250 mL D5W or NS prefilled IV bag 
o Add the calculated dose (mL) of pevonedistat 
o Final volume (250 mL) = drug + D5W or NS 


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67 
o Do not shake; gently mix the IV solution by inverting the IV bag several times 
o Inspect the IV solution to ensure it is clear and free of visible particles 
 
- 
Alternatively, a 250 mL empty IV bag can be used: 
o Add the required volume of D5W or NS into the empty IV bag  
o Add the calculated dose (mL) of pevonedistat 
o Final volume (250 mL) = Drug + D5W or NS 
o Do not shake; gently mix the IV solution by inverting the IV bag several times 
o Inspect the IV solution to ensure it is clear and free of visible particles 
 
Materials:  PVC or Polyolefin bags; non-DEHP IV bag is preferred but not required. 
 
Storage:   
Store MLN4924 (Pevonedistat HCl) refrigerated at 2⁰ – 8⁰ C (36⁰ – 46⁰ F) in its original 
carton to protect from light. 
 
If a storage temperature excursion is identified, promptly return MLN4924 
(Pevonedistat HCl) to 2⁰ – 8⁰ C (36⁰ – 46⁰ F) and quarantine the supplies.  Provide 
a detailed report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
Stability:   
Stability studies of the intact vials are ongoing. 
 
o Once MLN4924 (Pevonedistat) prepared IV solution is complete, the 
prepared IV solution must be used within 6 hours when stored at ambient 
room temperature. Discard the IV bag if it cannot be used within 6 hours.  
o Alternatively, the prepared IV solution is stable up to 18 hours when stored at 
2⁰ - 8⁰ C (36⁰ – 46⁰ F), after which the IV bag can be used within 3 hours upon 
removal from          2⁰ - 8⁰ C storage.  The prepared IV solution must be 
brought up to ambient room temperature before administering to patient.  If 
cannot used within 3 hours, the prepared IV solution must be discarded. 
 
Route of Administration:  Intravenous  
 
Method of Administration:  Infuse over 60 minutes (±10 minutes) through peripheral IV-
line, midline or central venous access.  The IV infusion can be slowed or stopped and 
restarted for any associated infusion-related reactions.  The total time from the IV 
preparation to end of IV infusion must not exceed 6 hours.  Infusion line can be flushed with 
5% Dextrose in Water or 0.9% Normal Saline immediately after IV administration is 
complete. Protecting IV bag from light during IV infusion is not required. 
 
Potential Drug Interactions:  In vitro, MLN4924 is metabolized mainly by hepatic 
CYP3A4/5 and to some extent by CYP2D6 (3%).  CYP1A1 and 2J2 appear to be involved 
in extrahepatic metabolism, which may explain the lack of drug-drug interaction with 
CY3A4/5 inhibitors.  This was demonstrated in an in vivo PK study where a moderate 


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68 
CYP3A inhibitor (e.g., fluconazole) and a strong CYP3A4 inhibitor (e.g., itraconazole, 
which is also a strong P-gp inhibitor) did not result in interactions when administered with 
MLN4924.  Therefore, drugs that are CYP3A/P-gp inhibitors can be used in patients 
receiving MLN4924.  Use of strong CYP3A inducers (e.g., rifampin, phenytoin, St. 
John’s wort) with MLN4924 is prohibited.   
 
In vitro, MLN4924 is not an inhibitor of CYP1A2, 2C9, 2C19, 2D6, or 3A4/5 (IC50 >100 
mcM and Ki >50 mcM) but is a weak inhibitor of CYP2B6 and 2C8 (IC50 = 97.6 and 23.1 
mcM, respectively).  MLN4924 causes concentration-dependent decreases in CYP1A2, 
2B6, and 3A4/5 mRNA expression and/or activities but is not expected to affect the PK of 
CYP1A2, 2B6 or 3A4/5 substrates.  
 
MLN4924 is a substrate of P-gp and BCRP, and a weak inhibitor of P-gp, OATP, and 
BCRP-mediated transport.  MLN4924 is unlikely to affect the PK of known P-gp, BCRP, or 
OATP substrates.  Co-administration of BCRP inhibitors (e.g., cyclosporine) is not allowed; 
consult the protocol document if no suitable alternative exists for the patient.  
 
Because the metabolic and excretion pathways of MLN4924 remain to be fully 
characterized in humans, the risk of drug-drug interactions between MLN4924 and 
concomitantly administered drugs are currently informed by available nonclinical and 
clinical data.  As a general precaution, patients receiving concomitant medications, 
particularly those with narrow therapeutic indices, should be carefully monitored. 
 
Availability 
 
MLN4924 (pevonedistat) is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI.  MLN4924 (pevonedistat) is 
provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13.4). 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 
 
Confirmation of patient enrollment onto study is required for initial supply. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 


NCI Protocol #:  10249 
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69 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
8.1.3.2 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
8.1.4 Investigator Brochure Availability 
The current versions of the Investigator’s Brochures for the agents will be accessible to site 
investigators and research staff through the PMB OAOP application.  Access to OAOP requires 
the establishment of a CTEP IAM account and the maintenance of an “active” account status, a 
“current” password and active person registration status.  Questions about Investigator’s 
Brochures access may be directed to the PMB Investigator’s Brochures Coordinator via email. 
 
8.1.5 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• Investigator’s Brochures Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
 


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70 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
This is a multicenter phase 1b, open-label study to assess the safety and tolerability of MLN4924 
(pevonedistat) and MLN9708 (ixazomib) in patients with RRMM, and to determine the 
MTD/tentative RP2D of the combination. 
 
Primary Endpoints: 
• Safety of MLN4924 (pevonedistat) and MLN9708 (ixazomib) given in combination 
• Determine the MTD of the combination 
 
Secondary Endpoints: 
• PK characterization of MLN4924 (pevonedistat) in combination with MLN9708 
(ixazomib) 
• Information on correlative pharmacodynamic measures (NRF2 target genes) in both PI-
sensitive and PI-refractory patients 
 
All patients who receive any amount of the study drug will be evaluable for toxicity.  The DLT-
evaluable period will be during Cycle 1, although toxicity will be monitored throughout the 
course of treatment.  The primary analysis will occur after all patients have either discontinued 
the study or completed at least 6 months of treatment. 
 
Descriptive statistics will be provided for selected demographic, safety, PK, and 
pharmacodynamic data by dose and time as appropriate.  Descriptive statistics on continuous 
data will include means, medians, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages.  Graphical summaries of the data may be 
presented.  
 
Efficacy analysis will be performed for all patients in the dose escalation and dose expansion 
part (MTD of the combination in PI-sensitive and PI-refractory patients) of the study.  
Parameters assessed will include stringent complete response (sCR), CR, VGPR, PR, and SD per 
IMWG Uniform Response criteria and minor response (MR) per European Group for Blood and 
Marrow Transplantation (EBMT) criteria.  In addition, overall response rate (defined as greater 
than or equal to PR across all cycles of treatment), response duration, time-to-response (TTR), 
PFS, and OS will be assessed. 
 
Best overall response categories will be tabulated by dose cohort and overall for the IMWG 
categories of sCR, CR, VGPR, PR, SD, PD, and relapse and the EBMT category of MR.  A two-
sided 95% exact binominal confidence intervals (CI) will be calculated for each category.  The 
myeloma response rate (responses ≥PR) will also be tabulated by dose cohort and overall.  The 
myeloma response rate and each of the best overall response categories will be compared 
between dose cohorts with Chi-square test.  Survival analyses will be done using Kaplan-Meier 
method, log-rank test, and Cox model.  The endpoints of time to event analyses will include 
TTR, duration of response, PFS, and OS, as data allow.  If there is not enough data for survival 
analyses, the data will be summarized by descriptive statistics. 


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71 
 
9.2 
Sample Size/Accrual Rate 
 
The dose escalation part of this study consists of 7 dose levels including at least 3 and up to 6 
patients for a minimum of 18 patients if no DLT is reached, or a maximum of 42 patients.  An 
exploratory expansion phase including 24 patients at the RP2D is also planned for a total of 42-
66 patients in total.  Based on prior phase 1 and 2 studies at Emory targeting a similar patient 
population, we estimate 2 patients will be accrued every month, suggesting that 21-33 months 
will be needed to meet the total sample size.  Please note this assumes no interruption in accrual. 
 
For the expansion cohort, 24 patients will be enrolled, 12 each with PI-sensitive and 
PI-refractory disease.  In the PI-sensitive group, success will be defined as >6 patients having a 
PR or better at the RP2D.  In the PI refractory population, >2 patients with PR or better will 
define success. 
 
For a maximum of 66 patients, we would estimate 50% male and 50% female.  Per institutional 
experience, we would expect ~30% African Americans and ~5% Hispanic or Latino.  
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
Black or African 
American 
9 
9 
1 
1 
20 
White 
22 
22 
1 
1 
46 
Total 
31 
31 
2 
2 
66 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
 
OMB No. 0925-0001/0002 
 
9.3 
Analysis of Secondary Endpoints 
 
A full PK profile of MLN4924 (pevonedistat) will be examined to assess exposure-response 
relationships with various pharmacodynamic endpoints (i.e., changes, toxicity, and efficacy).  
MLN4924 (pevonedistat) concentrations in these samples will be quantitatively measured using 
a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method in place at Covance 
under contract with Takeda.  For MLN4924 (pevonedistat), the individual PK parameters from a 
single dose will be estimated for Cmax, AUC, t1/2, apparent CL/F, and apparent volume of 
distribution (V/F) using non-compartmental or compartmental PK methods with the software 
WinNonlin.  Advanced population PK methods may be employed to assess the link between 
drug exposure and biological effects and efficacy.  The PK variables and changes in 
pharmacodynamic markers will be tabulated and descriptive statistics (e.g., geometric means and 


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72 
CV) calculated for each dose level.  A more limited PK analysis will be performed for MLN9708 
(ixazomib) to assess accumulation, with blood samples (3 mL) to be taken predose (within 1 
hour) and 1 hour ±10 min postdose on Days 1 and 15 of Cycles 1 and 3.  Plasma MLN9708 
(ixazomib) concentrations will be measured using a validated LC/MS/MS method. 
 
PK parameters (i.e., t1/2, CL, and AUC) changes will be compared across dose levels using the 
parametric General Linear Model (GLM) or nonparametric Kruskal-Wallis test, depending on 
the distribution of data.  Exploratory correlative studies with pharmacodynamic (biological 
endpoints, toxicity, and efficacy) will be analyzed using Pearson or Spearman’s correlation 
coefficient and tested with Wald’s test.  Significance for comparisons will be at the P<0.05 level.   
 
For the biomarker study of NQO1 and SLC7A11, descriptive statistics will first be used to 
summarize their gene expression in whole blood by RT-PCR.  Biomarker data will also be 
displayed graphically, where appropriate.  Depending on whether data is normally distributed, 
Person or Spearman’s correlation coefficient will be used to measure the correlations of NQO1 
and SLC7A11 with the dosage of MLN4924 (pevonedistat), and then tested with Wald’s test.  
GLM will be used to compare each of the biomarkers (NQO1 and SLC7A11) between different 
dose levels of MLN4924 (pevonedistat) with and without adjusting for other factors.  Logistics 
regression model will be further employed to test the adjusted effect of each biomarkers (NQO1 
and SLC7A11) on the response rate after adjusting for dosage of MLN4924 (pevonedistat) as 
well as other factors.  
 
 


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73 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
AE monitoring and reporting is a routine part of every clinical trial.  The following list of AEs 
(Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 10.3) will determine 
whether the event requires expedited reporting via the CTEP Adverse Event Reporting System 
(CTEP-AERS) in addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential AE associated with an agent using a uniform presentation of events by 
body system.  In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text.  This subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
 
NOTE:  Report AEs on the SPEER ONLY IF they exceed the Grade noted in parentheses next 
to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the Grades to 
determine if expedited reporting is required.  
 
10.1.1 CAEPRs for CTEP IND Agents 
 
10.1.1.1 CAEPR for MLN9708 (ixazomib) 
 
Frequency is provided based on 1122 patients. Below is the CAEPR for MLN9708 (Ixazomib 
citrate). 
 
Version 2.1, March 26, 20221 
 
 Adverse Events with Possible  
 Relationship to MLN9708 (Ixazomib citrate) 
 (CTCAE 5.0 Term) 
[n= 1122] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
 
 
Thrombotic thrombocytopenic 
purpura 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 


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74 
 
 Adverse Events with Possible  
 Relationship to MLN9708 (Ixazomib citrate) 
 (CTCAE 5.0 Term) 
[n= 1122] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
 
Edema limbs 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(hepatotoxicity)2 
  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory infection 
 
 Upper respiratory infection 
(Gr 2) 
INVESTIGATIONS 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
(Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 
2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Headache 
 
  
 
Nervous system disorders - 
Other (peripheral neuropathies 
NEC, peripheral neuropathy, 
peripheral motor neuropathy) 
 
 Nervous system disorders - 
Other (peripheral 
neuropathies NEC, peripheral 
neuropathy, peripheral motor 
neuropathy) (Gr 2) 
 
Peripheral sensory neuropathy  
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity 
have each been reported in <1% of patients treated with MLN9708. Events of liver impairment have been 
reported. Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms.  
 
Adverse events reported on MLN9708 (Ixazomib citrate) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MLN9708 (Ixazomib citrate) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 


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75 
CARDIAC DISORDERS - Myocardial infarction 
EYE DISORDERS - Blurred vision; Retinal detachment 
GASTROINTESTINAL DISORDERS - Enterocolitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Disease progression; Flu like 
symptoms; Malaise 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
INFECTIONS AND INFESTATIONS - Bronchial infection; Fungemia; Infections and infestations - Other 
(Parainfluenza Infection); Lung infection; Pharyngitis; Sepsis; Shingles; Sinusitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (femoral neck fracture); Spinal fracture 
INVESTIGATIONS - Aspartate aminotransferase increased; Lymphocyte count decreased; White blood 
cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle weakness lower 
limb; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (non-Hodgkin’s lymphoma); Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (plasma cell myeloma); Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchial obstruction 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Hypotension 
 
Note: MLN9708 (Ixazomib citrate) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
10.1.1.2 CAEPR for MLN4924 (Pevonedistat) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer to 
the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguideli
nes.pdf for further clarification. Frequency is provided based on 474 patients. 
Below is the CAEPR for MLN4924 (Pevonedistat HCl). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade 
noted in parentheses next to the AE in the SPEER. If this CAEPR is part 
of a combination protocol using multiple investigational agents and has 
an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
 
 
 


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76 
Version 2.3, July 10, 20201 
 
 Adverse Events with Possible  
 Relationship to MLN4924 (Pevonedistat HCl) 
 (CTCAE 5.0 Term) 
[n= 474] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Sinus tachycardia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
Fever 
 
 
 Fever (Gr 2) 
 
Pain 
 
 Pain (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Lung infection 
 
 Lung infection (Gr 2) 
 
Upper respiratory infection 
 
  
 
Urinary tract infection 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
 Bruising (Gr 2) 
INVESTIGATIONS 
  
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase 
increased (Gr 2) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Creatinine increased 
 
  
 
GGT increased 
 
  
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
 
Hypercalcemia 
 
  
 
Hyperglycemia 
 
  
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
 Hypokalemia (Gr 2) 
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
  


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77 
 
 Adverse Events with Possible  
 Relationship to MLN4924 (Pevonedistat HCl) 
 (CTCAE 5.0 Term) 
[n= 474] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
Myalgia 
 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
Nervous system disorders - 
Other (neuropathy peripheral, 
peripheral neuropathy) 
 
  
 
Paresthesia 
 
  
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Confusion 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
  
 
Hypoxia 
 
  
 
Pleural effusion 
 
  
 
Productive cough 
 
  
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(rales) 
 
  
 
Wheezing 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
Pruritus 
 
  
 
Purpura 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
 Hypotension (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
Adverse events reported on MLN4924 (Pevonedistat HCl) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that MLN4924 
(Pevonedistat HCl) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 


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78 
(pancytopenia); Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocarditis 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Ascites; Dyspepsia; Gastrointestinal disorders - Other 
(gastrointestinal necrosis); Gastrointestinal disorders - Other (gastrointestinal hemorrhage); Ileus; Small 
intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Generalized edema; Multi-organ 
failure; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Bacteremia; Sepsis; Sinusitis; Skin infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall 
INVESTIGATIONS - Investigations - Other (brain natriuretic peptide increased); Neutrophil count 
decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hyperuricemia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Spinal cord compression 
PSYCHIATRIC DISORDERS - Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Dysuria; Renal and urinary disorders - Other (renal impairment); 
Urinary retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Nasal congestion; Oropharyngeal pain; Respiratory failure; Rhinorrhea 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Rash maculo-papular 
VASCULAR DISORDERS - Hypertension; Phlebitis; Thromboembolic event 
 
Note: MLN4924 (Pevonedistat HCl) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
10.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and Grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
Grade is above the Grade provided in the SPEER. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 


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79 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 RAVE-CTEP-AERS Integration 
 
The Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) integration enables evaluation of post-baseline AEs entered in 
Rave to determine whether they require expedited reporting, and facilitates entry 
in CTEP-AERS for those AEs requiring expedited reporting.    
 
All AEs that occur after baseline are collected in Medidata Rave using the 
Adverse Event form, which is available for entry at each treatment or reporting 
period, and used to collect AEs that start during the period or persist from the 
previous reporting period.  The Clinical Research Associate (CRA) will enter AEs 
that occur prior to the start of treatment on a baseline form that is not included in 
the Rave-CTEP-AERS integration.  AEs that occur prior to enrollment must begin 
and end on the baseline Adverse Event form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been 
an increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify 
the following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-
free (fields added to the form during study build do not need to be query-
free for the integration call with CTEP-AERS to be a success). 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If 
the CRA modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for 
rules evaluation by completing the Expedited Reporting Evaluation form.  Both 
NCI and protocol-specific reporting rules evaluate the AEs submitted for 
expedited reporting.  A report is initiated in CTEP-AERS using information 
entered in Medidata Rave for AEs that meet reporting requirements.  The CRA 
completes the report by accessing CTEP-AERS via a direct link on the Medidata 
Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is 
restored, the 24-hour notification that was phoned in must be entered immediately 
into CTEP-AERS using the deep link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the 
CTSU website: 
 


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80 
• Study specific documents:  Protocols > Documents > Education and 
Promotion, and   
• Expedited Safety Reporting Rules Evaluation user guide:  Resources > 
CTSU Operations Information > User Guides. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements 
is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf. 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “General disorders and administration site conditions.”  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
 
 


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81 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 


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82 
 
 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine AE 
reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
Myelodysplastic syndrome (MDS)  
Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 


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83 
11. STUDY CALENDAR 
 
Schedules shown in the Study Calendar below are provided as an example and should be 
modified as appropriate. 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.


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84 
 
 
Pre- 
Study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
Off 
Studya 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5* 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9* 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13* 
Wk 
14 
Wk 
15 
Wk 
16 
MLN9708 (ixazomib) 
 
A 
A 
A 
 
A 
A 
A 
 
A 
A 
A 
 
A 
A 
A 
 
 
MLN4924 
(Pevonedistat) 
 
B 
B 
B 
 
B 
B 
B 
 
B 
B 
B 
 
B 
B 
B 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital signsh, i 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, platelets 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
Chemistry Panelb 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Echocardiogram  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X---------------------------------------------------------------------------------------------------------X 
X 
Serum B-HCG 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Urinalysis and 
coagulation (including 
PT and aPTT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma collection for 
MLN4924 
(pevonedistat) and 
MLN9708 (ixazomib) 
PKj 
 
Xc 
 
Xd 
 
 
 
 
 
Xd 
 
Xd 
 
 
 
 
 
 
Blood collection for 
NRF2 target gene 
studies 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Myeloma laboratory 
testing assessmentsf 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Extramedullary disease 
assessmentg 
X 
 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
Xf 


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85 
 
Pre- 
Study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
Off 
Studya 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5* 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9* 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13* 
Wk 
14 
Wk 
15 
Wk 
16 
Skeletal survey/CT scan 
X 
Repeated during treatment if clinically indicated to confirm response or PD 
 
Bone marrow aspiratek 
X 
 
 
*Assessments are treatments on D1 of each subsequent cycle after C1 can be done in a ±2 day window  
A: 
MLN9708 (ixazomib):  Dose as assigned on Days 1, 8, and 15 of each 28-day cycle. 
B: 
MLN4924 (pevonedistat):  Dose as assigned on Days 1, 8, and 15 of each 28-day cycle. 
a: 
Off-study evaluation.   
b: 
Chemistry panel will include the following:  BUN, creatinine, sodium, potassium, chloride, carbon dioxide, glucose, bilirubin, alkaline phosphatase (ALP), LDH, AST, 
ALT, total protein, albumin, magnesium, phosphate, urate, direct bilirubin, and calcium.  ALP, ALT, AST, and total bilirubin assessments must be performed and read 
prior to dosing MLN4924 (pevonedistat). 
c:  
Plasma for MLN4924 (pevonedistat) and MLN9708 (ixazomib) PK profiles.  Time points to be collected for PK profiles are:  pre-dose and 1 hr ±10 min after initiation 
of infusion.  Additional time points to be collected for MLN4924 (pevonedistat) PK profile are:  0.5 hr ±10 min, 2 hr ±10 min, 2.5 hr ±10 min, 5 hrs ±30 min, 8 hr ±45 
min, and 21 hrs ±2 hrs after initiation of infusion. 
d:  
Plasma for MLN9708 (ixazomib) PK profile.  Time points to be collected are:  pre-dose and 1 hr ±10 min after initiation of infusion. 
e:  
To be collected 4 hours after completion of pevonedistat infusion on Cycle 1, Day 1. 
f:  
M-protein quantification by SPEP and UPEP, Serum Free Light Chain Assay, 24-hour urine collection, and immunofixation of serum and urine are to be performed   
at baseline within 7 days prior to study, prior to each cycle thereafter and at time of study discontinuation (if last tests were >4 weeks).  Repeat MM labs on Day 1 of 
Cycle 1 if screening done >7 days prior to study entry. 
g:  
Only when clinically indicated or with known history, prior to study (28 days) and every cycle (with known history) or upon clinical suspicion of progressive disease.  
This may include physical exam with measurements, CT scan of the chest, abdomen/pelvis, ultrasound of the liver/spleen or abdomen.  
h:  
Vital signs are to be taken with the patient in the supine or sitting position. 
i:  
To include blood pressure, heart rate, and temperature taken at Screening; Day 1 and Day 8 of each cycle; at off study; and as clinically indicated. 
j:  
PK samples will only be collected during the dose escalation portion. 
k;      Bone marrow aspirate and biopsy is optional at screening.  
 
 


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86 
12. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drugs has not yet been established, the intent of offering 
this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability.  Patients 
with measurable disease will be assessed by standard criteria.  For the purposes of this study, 
patients should be re-evaluated every 4 weeks.  In addition to a baseline scan, confirmatory scans 
will also be obtained 4 weeks following initial documentation of an objective response. 
 
12.1 
Antitumor Effect – Hematologic Tumors 
 
Responses will be evaluated utilizing the IMWG Response Criteria as per the table below. 
 
Response 
IMWG criteria 
Stringent 
Complete 
Response 
(sCR) 
CR as defined below plus:  
• 
Normal free light chain (FLC) ratio, and  
• 
absence of clonal cells in bone marrow by immunohistochemistry or 
2–4 color flow cytometry. 
Complete 
Response 
(CR) 
• 
Negative immunofixation on the serum and urine,  
• 
disappearance of any soft tissue plasmacytomas, and  
• 
<5% plasma cells in bone marrow.   
• 
In patients with only FLC disease, a normal FLC ratio of 0.26–1.65 is 
required.  
Very Good 
Partial 
Response 
(VGPR) 
• 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis, or 
• 
>90% reduction in serum M-protein plus urine M-protein level 
<100 mg/24 hours.   
• 
In patients with only FLC disease, >90% decrease in the difference 
between involved and uninvolved FLC levels is required. 
Partial 
Response 
(PR) 
• 
50% reduction of serum M-protein and reduction in 24 hour urinary 
M-protein by >90% or to <200 mg/24 hours. 
• 
If the serum and urine M-protein are unmeasurable, a >50% decrease 
in the difference between involved and uninvolved FLC levels is 
required in place of the M-protein criteria. 


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87 
• 
If serum and urine M-protein are not measurable, and serum free 
light assay is also not measurable, >50% reduction in plasma cells is 
required in place of M-protein, provided baseline bone marrow 
plasma cell percentage was >30%. 
• 
In addition to the above listed criteria, if present at baseline, a >50% 
reduction in the size of soft tissue plasmacytomas is also required. 
Stable 
Disease (SD) 
• 
Not meeting criteria for CR, VGPR, PR or progressive disease 
Minimal 
Response 
(MR) 
• 
25% but < 49% reduction of serum M protein and reduction in 24 
hour urine M-protein by 50 to 89% which still exceeds 200 mg/24 
hours. 
• 
In addition to the above criteria, if present at baseline, 25-49% 
reduction in the size of soft tissue plasmacytomas is also required. 
• 
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response). 
Progressive 
disease 
Increase of >25% from lowest response value in any one of the following: 
• 
Serum M-component (the absolute increase must be >0.5 g/dL), 
and/or  
• 
Urine M-component (the absolute increase must be >200 mg/24 
hours), and/or  
• 
Only in patients without measurable serum and urine M-protein, the 
difference between involved and uninvolved FLC levels.  The 
absolute increase must be >10 mg/dL. 
• 
Only in patients without measurable serum and urine M-protein and 
without measurable disease by FLC levels, bone marrow plasma cell 
percentage (absolute percentage must be ≥10%).  
• 
Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas. 
• 
Development of hypercalcemia (corrected serum calcium >11.5 
mg/dL) that can be attributed solely to the plasma cell proliferative 
disorder. 
 
Adapted from Durie et al. (2006).  All response categories (CR, sCR, VGPR, and PD) require two consecutive 
assessments made at any time before the institution of any new therapy; complete response and PR and SD 
categories also require no known evidence of progressive or new bone lesions if radiographic studies were 
performed.  VGPR and CR categories require serum and urine studies regardless of whether disease at baseline was 


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88 
measurable in serum, urine both or either.  Radiographic studies are not required to satisfy these response 
requirements.  Bone marrow assessments need not be confirmed.  For progressive disease, serum M-component 
increases of ≥1 gm/dL are sufficient to define response if starting M-component is ≥5g/dL.     
 
IMWG clarification for coding PD:  Clarified that Bone marrow criteria for PD are to be used only in patients 
without measurable disease by M protein and by FLC levels.  Clarified that 25% increase refers to M protein, FLC, 
and bone marrow results and does not refer to bone lesions, soft tissue plasmacytomas or hypercalcemia.  Note the 
lowest response value does not need to be a confirmed value. 
 
 
 


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89 
14. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
AE lists, guidelines, and instructions for AE reporting can be found in Section 10 (Adverse 
Events:  List and Reporting Requirements). 
 
14.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
14.2 
Data Reporting 
 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  To access Rave via iMedidata: 
 
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site:  Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 


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90 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
14.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
▪ Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the Principal Investigator(s) at the site to ensure that 
all investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 


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91 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the Investigational Drug Branch 
(IDB), CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching goal of 
ensuring the integrity of data generated from NCI-sponsored clinical trials, as described in the 
ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and 
CTSU websites. 
 
An End of Study CRF is to be completed by the Principal Investigator and is to include a 
summary of study endpoints not otherwise captured in the database, such as (for phase 1 trials) 
the recommended phase 2 dose (RP2D) and a description of any DLTs.  CTMS will utilize a core 
set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) compliant 
(http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 
unique study requirements.  The Principal Investigator is encouraged to review the eCRFs, 
working closely with CTMS to ensure prospectively that all required items are appropriately 
captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs with built-in edit 
checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
14.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports.  Review the DQP modules on a regular basis to manage specified 


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92 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note:  Some Rave protocols may not have delinquent form details or reports specified on the 
DQP.  A protocol must have the Calendar functionality implemented in Rave by the Lead 
Protocol Organization (LPO) for delinquent form details and reports to be available on the 
DQP.  Site staff should contact the LPO Data Manager for their protocol regarding questions 
about Rave Calendaring functionality. 
 
14.4 
CTEP Multicenter Guidelines 
 
N/A 
 
14.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 


NCI Protocol #:  10249 
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93 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human patients, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or Principal Investigator for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 


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15. REFERENCES 
 
Bauer T.M., D.R.H., C.B. Lee, et al.  (2016).  Investigational NEDD8-activating enzyme 
inhibitor pevonedistat plus chemotherapy in patients with solid tumors (phase 1b study): Activity 
of pevonedistat plus carboplatin/paclitaxel.  J Clin Oncol.  34:2580. 
 
Bhatia, S., A.C. Pavlick, P. Boasberg, et al.  (2016).  A phase I study of the investigational 
NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with 
metastatic melanoma.  Invest New Drugs.  34:439-449. 
 
Chauhan, D., Z. Tian, B. Zhou, et al.  (2011).  In vitro and in vivo selective antitumor activity of 
a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells.  Clin 
Cancer Res.  17:5311-5321. 
 
Dalton, W.S.  (2004).  The proteasome.  Semin Oncol.  31:3-9; discussion 33. 
 
Dimopoulos, M.A., J. Laubach, M.A. Echeveste Gutierrez, et al.  (2017).  Efficacy and safety of 
long-term ixazomib maintenance therapy in patients (pts) with newly diagnosed multiple 
myeloma (NDMM) not undergoing transplant: An integrated analysis of four phase 1/2 studies.  
Blood.  130:A902. 
 
Durie, B.G., J.L. Harousseau, J.S. Miguel, et al.  (2006).  International uniform response criteria 
for multiple myeloma.  Leukemia.  20:1467-1473. 
 
Garcia-Gomez, A., D. Quwaider, M. Canavese, et al.  (2014).  Preclinical activity of the oral 
proteasome inhibitor MLN9708 in Myeloma bone disease.  Clin Cancer Res.  20:1542-1554. 
 
Gu, Y., J.L. Kaufman, L. Bernal, et al.  (2014).  MLN4924, an NAE inhibitor, suppresses AKT 
and mTOR signaling via upregulation of REDD1 in human myeloma cells.  Blood.  123:3269-
3276. 
 
Gupta, N., M.J. Hanley, K. Venkatakrishnan, et al.  (2015).  Abstract B147:  A phase 1 drug-
drug interaction study between ixazomib, an oral proteasome inhibitor, and rifampin in patients 
(pts) with advanced solid tumors.  Mol Cancer Ther.  14:Abstract B147: 
 
Hou, J., J. Jin, Y. Xu, et al.  (2017).  Improved PFS and OS with ixazomib plus lenalidomide-
dexamethasone (IRd) vs plascebo-Rd in patients (pts) with relapsed/refractory multiple myeloma 
(RRMM): Final data from the phase 3 china continuation of TOURMALINE-MM1.  Clin 
Lymphoma Myeloma Leuk.  17:e67. 
 
Ixazomib Investigator's Brochure.  (2017).  Millennium Pharmaceuticals, Inc.  Edition 11, July 
27, 2017. 
 
Kumar, S.K., M.A. Dimopoulos, E. Kastritis, et al.  (2017).  Natural history of relapsed 
myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter 
IMWG study.  Leukemia.  31:2443-2448. 


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Kupperman, E., E.C. Lee, Y. Cao, et al.  (2010).  Evaluation of the proteasome inhibitor 
MLN9708 in preclinical models of human cancer.  Cancer Res.  70:1970-1980. 
 
Lin, J.J., M.A. Milhollen, P.G. Smith, et al.  (2010).  NEDD8 targeting drug MLN4924 elicits 
DNA re-replication by stabilizing Cdt1 in S Phase, triggering checkpoint activation, apoptosis 
and senescence in cancer cells.  Cancer research.  70:10310-10320. 
 
Lockhart C.A., T.M.B., D. Harvey, et al.  (2015).  Phase 1b trial of investigational NEDD8-
activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in combination with 
docetaxel, paclitaxel/carboplatin, or gemcitabine in patients with solid tumors.  Mol Cancer 
Ther.  14:B26. 
 
McMillin, D.W., H.M. Jacobs, J.E. Delmore, et al.  (2012).  Molecular and cellular effects of 
NEDD8-activating enzyme inhibition in myeloma.  Mol Cancer Ther.  11:942-951. 
 
Milhollen, M.A., U. Narayanan, T.A. Soucy, et al.  (2011).  Inhibition of NEDD8-activating 
enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating 
CDT1 turnover.  Cancer Res.  71:3042-3051. 
 
Moreau, P., T. Masszi, N. Grzasko, et al.  (2016).  Oral ixazomib, lenalidomide, and 
dexamethasone for multiple myeloma.  N Engl J Med.  374:1621-1634. 
 
Noone, A.M., N. Howlader, M. Krapcho, et al.  (2018).  SEER Cancer Statistics Review, 1975-
2015, National Cancer Institute. Bethesda, MD.  Based on November 2017 SEER data 
submission, posted to the SEER web site, April 2018.   
 
Package Insert.  (2015).  NINLARO® (ixazomib) capsules, for oral use.  Millennium 
Pharmaceuticals, Inc., Cambridge, MA. 
 
Package Insert.  (2015).  VELCADE (bortezomib) for injection.  Millennium Pharmaceuticals, 
Inc., Cambridge, MA. 
 
Pevonedistat Investigator's Brochure.  (2017).  Millennium Pharmaceuticals, Inc.  Edition 9, 
August 10, 2017. 
 
Podust, V.N., J.E. Brownell, T.B. Gladysheva, et al.  (2000).  A Nedd8 conjugation pathway is 
essential for proteolytic targeting of p27(Kip1) by ubiquitination.  PNAS.  97:4579-4584. 
 
Read, M.A., J.E. Brownell, T.B. Gladysheva, et al.  (2000).  Nedd8 modification of cul-1 
activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha.  Mol Cell Biol.  20:2326-
2333. 
 
Richardson, P.G., R. Baz, M. Wang, et al.  (2014).  Phase 1 study of twice-weekly ixazomib, an 
oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients.  Blood.  124:1038-
1046. 


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Sarantopoulos, J., G.I. Shapiro, R.B. Cohen, et al.  (2016).  Phase I Study of the Investigational 
NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with 
Advanced Solid Tumors.  Clin Cancer Res.  22:847-857. 
 
Shah, J.J., A.J. Jakubowiak, O.A. O'Connor, et al.  (2016).  Phase I Study of the Novel 
Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with 
Relapsed/Refractory Multiple Myeloma or Lymphoma.  Clin Cancer Res.  22:34-43. 
 
Soucy, T.A., P.G. Smith, M.A. Milhollen, et al.  (2009).  An inhibitor of NEDD8-activating 
enzyme as a new approach to treat cancer.  Nature.  458:732. 
 
Swords R.T., M.R.S., M.B. Maris, et al.  (2014).  Pevonedistat (MLN4924), an investigational, 
first-in-class NAE inhibitor, in combination with azacitidine in elderly patients with acute 
myeloid leukemia (AML) considered unfit for conventional chemotherapy: Updated results from 
the phase 1 C15009 trial.  Blood.  124:2313. 
 
Swords, R.T., H.P. Erba, D.J. DeAngelo, et al.  (2015).  Pevonedistat (MLN4924), a First-in-
Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and 
myelodysplastic syndromes: a phase 1 study.  Br J Haematol.  169:534-543. 
 
Walker, R.M., E. Koenig, G. Mulligan, et al.  (2011)  Development, validation, and clinical 
implementation of a peripheral blood RT-PCR pharmacodynamic assay for MLN4924, an 
investigational small molecule inhibitor of NEDD8-activating enzyme (NAE).  Proceedings of 
the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 
2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR.  Mol Cancer Ther.  10(11 
Suppl):A196. 
 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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APPENDIX B 
PATIENT CLINICAL TRIAL WALLET CARD – MLN9708 
(IXAZOMIB) 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:  10249 
Study Drug(S):  MLN9708 (Ixazomib) 
 
 
 
Version FEB/2019 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
 
 
 


NCI Protocol #:  10249 
Version Date:  June 1, 2022 
 
100 
APPENDIX C 
PATIENT DRUG INTERACTIONS HANDOUT AND WALLET 
CARD – MLN4924 (PEVONEDISTAT) 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
10249 
Study 
Doctor: 
      
Study Doctor 
Phone #:  
      
Study 
Drug(s): 
MLN4924 
(Pevonedistat) 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse practitioners, 
pharmacists), and tell them you are taking part in a clinical trial sponsored by the National Cancer 
Institute.  
 
These are the things that your healthcare providers need to know: 
MLN4924 (pevonedistat) interacts with certain specific enzyme in your liver or other tissue like the gut 
and certain transport proteins that help move drugs in and out of cell. 
 
 
Explanation 
CYP 
isoenzymes 
The enzymes in question are CYP3A4/5.  MLN4924 (pevonedistat) is broken down 
by CYP3A4/5 and may be affected by drugs that are moderate or strong inducers of 
CYP3A4/5.  Use of CYP3A4 inducers (e.g., St. Jon’s Wort, rifampin, phenytoin) is 
not allowed while taking MLN4924. 
 
Transport 
proteins 
The transporter enzymes and proteins in question are P-glycoprotein (P-gp), OATP and 
BCRP.  MLN4924 is moved in and out of cells/organs by P-gp and BCRP.  Use caution 
with concomitant drugs that are inhibitors of P-gp.  Concurrent use of drugs that are 
BCRP inhibitors (e.g., cyclosporine) is not allowed.  MLN4924 may affect the ability 
of other drugs to be moved in and out of cells by inhibiting P-gp, OATP and BCRP.  
Use substrates of these transport proteins with caution. 
 
These are the things that you need to know: 
The study drug MLN4924 (pevonedistat), may interact with other drugs which can cause side effects. For 
this reason, it is very important to tell your doctors about all your medicines, including: (a) medicines you 
are taking before this clinical trial, (b) medicines you start or stop taking during this study, (c) medicines 
you buy without a prescription (over-the-counter remedy), (d) herbals or supplements (e.g. St. John’s 
Wort). It is helpful to bring your medication bottles or an updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care 
providers to review any medicines and herbal supplements that are considered moderate or strong 
inhibitors or inducers of CYP3A4/5, P-gp, OATP and BCRP. 
 
• 
Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects. Avoid ingesting grapefruit and grapefruit juice. 
• 
Make sure your doctor knows to avoid certain prescription medications.  
• 
Your regular health care provider should check a frequently updated medical reference or call 
your study doctor before prescribing any new medicine or discontinuing any medicine.   
Version JAN/2019 


NCI Protocol #:  10249 
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101 
PATIENT DRUG INTERACTION WALLET CARD  
 
 
 
 
 
 
EMERGENCY 
INFORMATION 
 
DRUG INTERACTIONS  
Show this card to all of your 
healthcare providers. Keep it 
with you in case you go to the 
emergency room. 
Tell your doctors before you start or 
stop any medicines. 
Check with your doctor or 
pharmacist if you need to use an 
over-the-counter medicine or herbal 
supplement! 
Carry this card with you at all times   
MLN4924 (pevonedistat) interacts with enzymes in your liver or other tissue like 
the gut, transport proteins that help move drugs in and out of cells and must be 
used very carefully with other medicines. 
Patient Name:       
Use caution and avoid the 
following drugs if possible:  
 
St. John’s Wort, grapefruit or 
grapefruit juice 
 
Your healthcare providers should be aware of any medicines that are strong 
inhibitors/inducers of CYP3A4/5, P-gp and OATP.  Drugs that are CYP3A4/5 
inducers (e.g., rifampin, St. John’s Wort), or BCRP inhibitors (e.g., cyclosporine) 
ae not allowed.  
Diagnosis:       
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #: 10249 
Before prescribing new medicines, your health care provider should check a 
frequently-updated medical reference for a list of drugs to avoid or contact 
your study doctor. 
Study Drug(S): MLN4924 
(pevonedistat) 
 
 
Version JAN/2019 
For more information: 1-800-4-CANCER 
For more information: 1-800-4-CANCER 
For more information: 1-800-4-CANCER 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
 
 
 


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102 
APPENDIX D 
NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
CARDIAC DISEASE 
 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure 
or the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 

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Page 1 of 13 
Research Study Informed Consent Document 
 
Study Title for Participants:  Testing the combination of two drugs, MLN9708 
(ixazomib) and MLN4924 (pevonedistat), for relapsed and/or resistant multiple myeloma 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  Protocol 
10249, MLN9708 (Ixazomib) and MLN4924 (Pevonedistat) in Relapsed/Refractory 
Multiple Myeloma Patients:  A Phase 1b Trial (NCT # 03770260) 
 
Overview and Key Information  
 
What am I being asked to do? 
 
We are asking you to take part in a research study.  This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services.  We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer. 
 
We are asking you to take part in this research study because you have multiple myeloma that 
has relapsed and/or is resistant to other treatment. 
 
Taking part in this study is your choice.  
 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice.  Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 
 
Why is this study being done? 
 
This study is being done to answer the following question:  
 
Can we lower the chance of your multiple myeloma growing or spreading by using a new 
combination of drugs? 
 
We are doing this study because we want to find out if this approach is better or worse than the 
usual approach for your multiple myeloma.  The usual approach is defined as care most people 
get for multiple myeloma that has relapsed or is resistant to treatment. 
 
 


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Page 2 of 13 
What is the usual approach to my multiple myeloma? 
 
The usual approach for patients who are not in a study is treatment with different medications 
that have shown to have anti-myeloma effects, including but not limited to chemotherapy.  Some 
of these agents or combinations of agents are Food and Drug Administration (FDA)-approved 
while others are not.  MLN9708 (ixazomib), when given in combination with lenalidomide and 
dexamethasone, is already FDA approved for your myeloma.  Your doctor can explain which 
treatment may be best for you.  These treatments can reduce symptoms and may stop the tumor 
from growing for a few months or longer. 
 
What are my choices if I decide not to take part in this study? 
 
x You may choose to have the usual approach described above. 
x You may choose to take part in a different research study, if one is available. 
x You may choose not to be treated for cancer. 
x You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
 
What will happen if I decide to take part in this study? 
 
If you decide to take part in this study, you will get MLN9708 (ixazomib) and MLN4924 
(pevonedistat) for as long as your myeloma doesn’t get worse and you don’t have a side effect 
that requires us to stop treatment.  
 
After you finish your study treatment with MLN9708 (ixazomib) and MLN4924 (pevonedistat), 
your doctor will ask you to complete a 30-day safety follow-up visit and continue to follow your 
condition every 2-3 months for up to 2 years. 
 
What are the risks and benefits of taking part in this study? 
 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that MLN9708 (ixazomib) and MLN4924 
(pevonedistat) may not be as good as the usual approach at shrinking or stabilizing your cancer. 
 
There is also a risk that you could have side effects from the MLN9708 (ixazomib) and 
MLN4924 (pevonedistat).  These side effects may be worse and may be different than you would 
get with the usual approach for your cancer.  Tables containing the known common, occasional, 
and rare side effects are presented in the “What risks can I expect from taking part in this study?” 
section. 


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Page 3 of 13 
There may be some risks that the study doctors do not yet know about.   
 
Benefits 
 
There is some evidence in living human cells that the combination of MLN9708 (ixazomib) and 
MLN4924 (pevonedistat) can shrink and/or stabilize cancer, but we do not know if this will 
happen in people. It is unlikely that this drug combination will help you live longer than the 
usual approach alone. This study may help the study doctors learn things that may help other 
people in the future. 
 
If I decide to take part in this study, can I stop later? 
 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  If you stop, you can decide if you want to keep letting the study doctor know how you 
are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
Are there other reasons why I might stop being in the study? 
 
Yes.  The study doctor may take you off the study if: 
 
x Your health changes and the study is no longer in your best interest. 
x New information becomes available and the study is no longer in your best interest. 
x You do not follow the study rules. 
x For women: You become pregnant while on the study. 
x The study is stopped by the Institutional Review Board (IRB), FDA, or study sponsor 
(National Cancer Institute [NCI]).  The study sponsor is the organization who oversees 
the study.   
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document.  If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? 
 
The purpose of this study is to test the safety of two drugs called MLN9708 (ixazomib) and 
MLN4924 (pevonedistat).  This drug combination has been tested in animals, but has not been 
tested in people.  This study tests different doses of the drug to see which dose is safer for 
people.  There will be about 66 people taking part in this study. 
 
 


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What are the study groups? 
 
There are two parts in this study, a dose escalation part and a dose expansion part.  You are in the 
dose escalation part. 
 
In the dose escalation part of this study, different people will get different doses of the study 
drugs MLN9708 (ixazomib) and MLN4924 (pevonedistat). 
 
The first 3 people taking part in this study will get the beginning dose.  If the drug does not cause 
serious side effects, the next group of people in the study will get a higher dose.  The study 
doctor will watch each group carefully as they increase the dose.  The doses will continue to 
increase for every new group until people have serious side effects that require the dose to be 
lower.  Once this dose is found, the dose escalation is stopped.  
 
Treatment schedule: You will get MLN4924 (pevonedistat) through a vein in your arm and 
MLN9708 (ixazomib) as a pill you take by mouth in the clinic on the 1st, 8th, and 15th day of each 
cycle.  Each cycle lasts 28 days.  See the study calendar for more information. 
 
MLN9708 (ixazomib) will be administered at the same time as the MLN4924 (pevonedistat) 
intravenous infusion. Take MLN9708 (ixazomib) capsule(s) on an empty stomach, 1 hour before or 
2 hours after food. Swallow whole capsules with water. Do not open or break capsules.   
 
You will not be able to get additional doses of the drugs.  MLN9708 (ixazomib) is approved by 
the FDA to treat multiple myeloma.  MLN4924 (pevonedistat) is not approved by the FDA for 
treatment of your disease. 
 
What exams, tests, and procedures are involved in this study? 
 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures. This helps your doctor decide if it is safe for you to take part in the study. Before 
you begin the study, you will need to have the following extra tests to find out if you can be in 
the study: 
 
x Blood tests 
x A test of the electrical activity of your heart (EKG) 
x An ultrasound of your heart (echocardiogram) 
x A pregnancy test if you are a female of childbearing potential 
x Skeletal survey/CT scan 
 
If you join the study, you will have more exams, tests, and procedures to closely monitor your 
safety and health. Most of these are included in the usual care you would get even if you were 
not in a study.  
 
Listed below are exams, tests, and procedures that need to be done as part of this study to 
monitor your safety and health, but may not be included in the usual care. We will use them to 
carefully follow the effects of the study treatment, including preventing and managing side 


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effects.  
 
These exams, tests, and procedures to monitor your safety and health include:   
 
x Blood tests every week you receive the study drugs 
x A serum pregnancy test monthly 
x Skeletal survey/CT scan (repeated during treatment to confirm response or disease 
progression) 
 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only.  
 
You will need to have several blood draws for the study.  These blood draws will occur on the 
following days of the study: 
 
x Before you begin the study 
x Day 1 of the 1st cycle 
x Day 9 of the 1st cycle 
x Day 15 of the 1st cycle 
x Day 1 of the 3rd cycle 
x Day 15 of the 3rd cycle 
 
These blood draws will be done to evaluate markers of activity of the study drugs in your system.  
You and your study doctor will not get the results of this testing.   
 
A patient study calendar is attached at the end of this document.  It shows how often these 
exams, tests, and/or procedures will be done. 
 
What risks can I expect from taking part in this study? 
 
General Risks 
 
If you choose to take part in this study, there is a risk that MLN9708 (ixazomib) and MLN4924 
(pevonedistat) may not be as good as the usual approach at shrinking or stabilizing your cancer.  
 
You also may have the following discomforts: 
 
x You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
x You may be asked sensitive or private questions which you normally do not discuss 
x You may not be able to take part in future studies 
x The study drugs may not be better, and could possibly be worse, than the usual approach 
for your cancer. 
 
The study drugs used in this study could be very harmful to an unborn or newborn baby.  There 


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may be some risks that doctors do not yet know about. You should not get pregnant, breastfeed, 
or father a baby while in this study and for a minimum of 4 months after the last dose of study 
drug.  It is very important that you check with your study doctor about what types of birth 
control or pregnancy prevention to use during the study and for 4 months after you have 
completed the study. 
 
Women of childbearing potential should practice 1 highly effective method and 1 additional 
(barrier) method of contraception, at the same time during the study and for 4 months after you 
have completed the study. Or agree to abstain from heterosexual intercourse.  
 
Men should practice effective barrier contraception during the study and for 4 months after you 
have completed the study. Or agree to abstain from heterosexual intercourse. 
 
Blood Draw Risks 
 
You may feel discomfort during some of the tests or procedures during this study or may 
experience some inconveniences.  Some of the risks from drawing blood from your arm may 
include pain, bruising, lightheadedness, and rarely, infection.  Let your study doctor know of any 
questions you have about possible side effects.  You can ask the study doctor questions about 
side effects at any time. 
 
Side Effect Risks 
 
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood.  The study doctor will test your blood and let you know if changes 
occur that may affect your health. 
 
There is also a risk that you could have other side effects from the study drugs that could be 
severe or life threatening. 
 
Here are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
3. Some side effects may make it hard for you to have children. 
4. Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 
x Tell your study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
x Your study doctor may be able to treat some side effects. 
x Your study doctor may adjust the study drugs to try to reduce side effects. 


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Drug Risks 
 
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
Possible Side Effects of MLN9708 (Ixazomib citrate) 
(version 2.1, March 26, 2022) 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving MLN9708 (ixazomib citrate), more than 20 and up to 100 may have: 
x 
Diarrhea, nausea, vomiting 
x 
Tiredness 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving MLN9708 (ixazomib citrate), from 4 to 20 may have: 
x 
Anemia which may require blood transfusion 
x 
Pain  
x 
Constipation 
x 
Fever 
x 
 
x 
Cold symptoms such as stuffy nose, sneezing, sore throat 
x 
Bruising, bleeding 
x 
Loss of appetite 
x 
Headache 
x 
Muscle weakness 
x 
Numbness, tingling or pain of the arms and legs 
x 
Cough, shortness of breath 
x 
Rash 
 
RARE, AND SERIOUS 
In 100 people receiving MLN9708 (ixazomib citrate), 3 or fewer may have: 
x 
Blood clot which may cause confusion, paralysis, seizures and blindness 
x 
Swelling of arms, legs 
x 
Liver damage which may cause yellowing of the eyes and skin 
 
 
 
 
 
 
 
 
 


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Possible Side Effects of MLN4924 (Pevonedistat) 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving MLN4924 (Pevonedistat HCl), more than 20 and up to 100 may have: 
x Diarrhea, nausea, vomiting 
x Tiredness, fever 
x Loss of appetite 
x Pain 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving MLN4924 (Pevonedistat HCl), from 4 to 20 may have: 
x Anemia which may require blood transfusion 
x Infection, especially when white blood cell count is low which may cause painful 
and frequent urination 
x Bloating, constipation 
x Sores in the mouth which may cause difficulty swallowing 
x Chills 
x Swelling of arms, legs 
x Cold symptoms such as stuffy nose, sneezing, sore throat 
x Bruising, bleeding 
x Dehydration 
x Dizziness, headache 
x Muscle weakness 
x Numbness, tingling or pain of the arms and legs 
x Feeling of “pins and needles” in arms and legs 
x Worry, confusion 
x Difficulty sleeping 
x Cough, shortness of breath, wheezing 
x Nose bleed 
x Fluid around lungs 
x Increased sweating 
x Itching 
x Low blood pressure which may cause feeling faint 
 
RARE, AND SERIOUS 
In 100 people receiving MLN4924 (Pevonedistat HCl), 3 or fewer may have: 
x Abnormal heartbeat 
x Kidney damage which may cause swelling, may require dialysis 
 
 
 


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Additional Drug Risks 
 
The study drug could interact with other drugs.  Your study doctor will give you a drug 
information handout and wallet card that lists these possible interactions.  Share this information 
with your family members, caregivers, other health care providers, and pharmacists. 
 
Rarely, there are problems getting enough supplies of the study drug.  If that happens, your 
doctor will talk with you about your options. 
 
Imaging Risks 
 
The skeletal survey/CT scan that you get in this study will expose you to low amounts of 
radiation.  Every day, people are exposed to low levels of radiation that come from the sun and 
the environment around them.  This type of radiation is called “background radiation.”  No one 
knows for sure whether exposure to these low amounts of radiation is harmful to your body.  
 
What are my responsibilities in this study? 
 
If you choose to take part in this study you will need to: 
 
x Keep your study appointments. 
x Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
 
For women: Do not get pregnant or breastfeed while taking part in this study.  For men: Do not 
father a baby while taking part in this study.  For all:  Tell your study doctor right away if you 
think that you or your partner have become pregnant during the study or within 4 months after 
your last dose of study drug. 
 
What are the costs of taking part in this study? 
 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
the study, just as you would if you were getting the usual care for your cancer.  This includes: 
 
x the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.   
x the costs of CT scans. 
x the costs of the pregnancy tests 
x the costs of getting the study drugs ready and giving them to you. 
x your insurance co-pays and deductibles. 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 


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approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study.  These include:   
 
x The blood draws collected for research purposes. 
x the costs of tests of the electrical activity of your heart (EKG). 
x The cost of an echocardiogram.  
You or your insurance provider will not have to pay for the study drugs (MLN9708 [ixazomib] 
and MLN4924 [pevonedistat]) while you take part in this study.  
 
Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat your cancer.  You may: 
 
x Have more travel costs. 
x Need to take more time off work. 
x Have other additional personal costs. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment.    
 
What happens if I am injured because I took part in this study? 
 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for a study-
related injury. Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
 
Your privacy is very important to us. The study doctors will make every effort to protect it. The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.   
If this should happen, the study doctors will do their best to make sure that any information that 
goes out to others will not identify who you are.  
 
Some of your health information, such as your response to cancer treatment, results of study 


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tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at or receive copies of some of the information in your 
study records. Your health information in the research database also may be shared with these 
organizations. They must keep your information private, unless required by law to give it to 
another group.   
 
Some of these organizations are: 
 
x The study sponsor and any company supporting the study now or in the future.  This 
would include any organization helping the company with the study. 
x The NCI Central IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study. 
x The FDA and the groups it works with to review research.   
x The NCI and the groups it works with to review research. 
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy. The goal of this data 
sharing is to make more research possible that may improve people’s health. Your study records 
may be stored and shared for future use in public databases.  However, your name and other 
personal information will not be used.   
 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data with 
older study data.  However, right now we don’t know what research may be done in the future 
using your information.  This means that: 
 
x You will not be asked if you agree to take part in the specific future research studies 
using your health information.   
x You and your study doctor will not be told when or what type of research will be done. 
x You will not get reports or other information about any research that is done using your 
information.  
 
Where can I get more information?   
 
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results. You can search this Web site at any time. 
 


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You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  Contact the study doctor (*insert name of study doctor[s]*) at 
(*insert telephone number, and email address if appropriate*). 
 
For questions about your rights while in this study, call the (*insert name of organization or 
center*) Institutional Review Board at (*insert telephone number*).  
 
My signature agreeing to take part in the study 
 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.   
 
 
Participant’s signature 
 
 
 
 
Date of signature 
 
 
 
 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
Date of signature 
 
 


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Attachment A:  Study Calendar for Protocol 10249 Consent Form 
 
Pre- 
Study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
Off Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
MLN9708 (Ixazomib)A 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
MLN4924 (Pevonedistat)B 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Pre-study procedures including 
informed consent, demographics, 
medical history, height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
Physical exam, weight, and general 
well-being 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital signsG 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Blood draws for health status 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
Urine collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Echocardiogram  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X------------------------------------------------------------------------------------------------------------------------------------------------------X 
X 
Pregnancy testC 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Plasma collection to study what 
your body does to the drugsD 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
Blood draws for scientific study 
X 
 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Disease assessmentF 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Medical imaging scans (Computed 
Tomography) 
X 
Repeated during treatment if clinically indicated to confirm response or disease progression 
 
A: 
MLN9708 (ixazomib) will be given as assigned on Days 1, 8, and 15 of each 28-day cycle. 
B: 
MLN4924 (pevonedistat) will be given as assigned on Days 1, 8, and 15 of each 28-day cycle. 
C: 
Serum pregnancy test is for women of childbearing potential. 
D: 
Plasma will be collected before treatment beings and approximately 1 hr after treatment begins during the first week of Cycle 1.  Additional collections may occur at 0.5 hrs, 2 hrs, 2.5 hrs, 5 hrs, 
8 hrs, and 21 hrs after treatment during Week 3 of Cycle 1 and Weeks 1 and 3 of Cycle 3.  
E: 
Collected on Day 9 of Cycle 1 approximately 4 hours after treatment. 
F: 
24-hour urine and blood will be collected within 7 days before the study begins, before each cycle (starting with Cycle 2), and at time of study discontinuation.  When clinically indicated, 
 
assessments may also include a physical exam with measurements, CT scan of the chest, abdomen/pelvis, and an ultrasound of the liver/spleen or abdomen. 
G:  Vital signs will be collected at screening, pre-dose on Days 1, 3, and 8 of each cycle, at off study, and as clinical indicated.