Conditions: Acute Myeloid Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This phase Ib/II trial studies the side effects and best dose of pinometostat and how well it works with standard chemotherapy in treating patients with newly diagnosed acute myeloid leukemia and a type of genetic mutation called MLL gene rearrangement. Pinometostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in standard chemotherapy, such as daunorubicin hydrochloride and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pinometostat with standard chemotherapy may work better at treating acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine a safe and tolerable schedule of pinometostat continuous intravenous infusion in combination with daunorubicin hydrochloride (daunorubicin) and cytarabine in patients with untreated, newly diagnosed acute myeloid leukemia harboring MLL rearrangement.

II. Determine the rate of complete remission (complete remission \[CR\], CR with incomplete hematologic recovery \[CRi\]) in patients with newly diagnosed acute myeloid leukemia harboring MLL rearrangement after treatment with pinometostat in combination with daunorubicin and cytarabine.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. Estimate biologic activity of 7 day window treatment of pinometostat monotherapy.

III. Estimate the toxicity profile of pinometostat alone (week 1) and in combination with daunorubicin and cytarabine.

IV. Estimate event free and overall survival of patients with MLL rearranged acute myeloid leukemia after combination treatment with pinometostat, daunorubicin, and cytarabine.

V. Estimate the early death rate (death =\< 30 days) of pinometostat, daunorubicin, and cytarabine.

VI. Determine the rate of minimal residual disease (MRD) negativity by clinical flow cytometry on post-treatment recovery bone marrow.

OUTLINE: This is a phase I, dose-escalation study of pinometostat followed by a phase II study. Patients are assigned to 1 of 2 cohorts.

COHORT I: Patients receive higher dose pinometostat intravenously (IV) continuously on days 1-7 and lower dose pinometostrat IV continuously on days 8-35. Patients also receive daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously on days 8-14. Cycles repeat every 35 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve CR/CRi after treatment receive pinometostat IV continuously on days 1-28, daunorubicin hydrochloride IV over 10-30 minutes on days 1 and 2 and cytarabine IV continuously on days 1-5 in the absence of disease progression or unacceptable toxicity.

COHORT II: Patients receive higher dose pinometostat IV continuously on days 1-35. Patients also receive daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously on days 8-14. Cycles repeat every 35 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve CR/CRi after treatment receive pinometostat IV continuously on days 1-28, daunorubicin hydrochloride IV over 10-30 minutes on days 1 and 2 and cytarabine IV continuously on days 1-5 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up monthly for 1 year, then every 3 months for up to 4 years.

Arms:
arm 1: Patients receive higher dose pinometostat IV continuously on days 1-7 and lower dose pinometostrat IV continuously on days 8-35. Patients also receive daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously on days 8-14. Cycles repeat every 35 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve CR/CRi after treatment receive pinometostat IV continuously on days 1-28, daunorubicin hydrochloride IV over 10-30 minutes on days 1 and 2 and cytarabine IV continuously on days 1-5 in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive higher dose pinometostat intravenously (IV) continuously on days 1-35. Patients also receive daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously on days 8-14. Cycles repeat every 35 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve CR/CRi after treatment receive pinometostat IV continuously on days 1-28, daunorubicin hydrochloride IV over 10-30 minutes on days 1 and 2 and cytarabine IV continuously on days 1-5 in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cytarabine intervention 2: Daunorubicin intervention 3: Daunorubicin Hydrochloride intervention 4: Pinometostat
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV

Protocol document:
ICF_002.pdf: 
Protocol Version Date 03/26/2019 
 
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Page i of ii 
 
 
SUMMARY OF CHANGES 
 
NCI Protocol #:         10212 
Local Protocol #: 
OSU 18296 
 
NCI Version Date: March 26, 2019 
Protocol Date: March 26, 2019 
 
I. NCI Rapid Request Amendment (RRA), Dated 03/25/2019 
 
# 
Section 
Page(s) 
Change 
1.  
Header 
All 
Updated Header Version Date to match updated 
protocol version 
 
2. 
What risks can I 
expect from taking 
part in this study? 
 
6-8 
In response to the Request for Rapid Amendment 
from CTEP dated 03/25/2019, some of the risk 
information for pinometostat has been updated: 
 
If you choose to take part in this study, there is a risk 
that the pinometostat (EPZ-5676) may not be as good 
as the usual approach for your cancer or condition at 
shrinking or stabilizing your cancer 
 
The pinometostat (EPZ-5676) used in this study may 
affect how different parts of your body work such as 
your liver, kidneys, heart, and blood.   
 
There is also a risk that you could have side effects 
from the study drug(s)/study approach. 
 
Some side effects may make it hard for you to have 
children. 
 
Updated condensed risk profile for pinometastat per 
revised CAEPR (Version 1.1,  January 7,2019: 
 
 
 
 


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Page ii of ii 
 
 
 
 
 
x Added New Risk:  
x Possible: Diarrhea; Electrocardiogram QT 
corrected interval prolonged; Fatigue; 
Hypocalcemia; Lymphocyte count decreased; 
Nausea; Neutrophil count decreased; Rash 
maculo-papular; Vomiting; White blood cell 
decreased 
x Also Reported on Pinometostat Trials But With 
Insufficient Evidence for Attribution: Alkaline 
phosphatase increased; Alopecia; Anorexia; 
Apnea; Cough; Creatinine increased; Dry skin; 
Dysgeusia; Edema face; Folliculitis; Headache; 
Hyperkalemia; Hypermagnesemia; 
Hypernatremia; Hypertension; Hyperuricemia; 
Hypoalbuminemia; Hypokalemia; 
Hypomagnesemia; INR increased; 
Investigations - Other (ejection fraction 
increased); Irritability; Localized edema; 
Mucositis oral; Periorbital edema; Pruritus; 
Respiratory, thoracic and mediastinal disorders 
- Other (tachypnea); Sore throat; Thrush 
 
x Increase in Risk Attribution:  
x Changed to Possible from Also Reported on 
Pinometostat Trials But With Insufficient 
Evidence for Attribution: Anemia; 
Hypophosphatemia; Platelet count decreased 
 
x Decrease in Risk Attribution:  
x Changed to Also Reported on Pinometostat 
Trials But With Insufficient Evidence for 
Attribution from Possible: Constipation; 
Intracranial hemorrhage; Lung infection; Sepsis 


Protocol Version Date 03/26/2019 
 
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Page 1 of 16 
 
 
Research Study Informed Consent Document 
 
Study Title for Participants: Testing the addition of a new anti-cancer drug, pinometostat, 
to the usual chemotherapy treatment (cytarabine and daunorubicin) in patients with Acute 
Myeloid Leukemia 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: “NCI-
10212: A Phase 1b/2 study of Pinometostat in combination with standard induction 
chemotherapy in newly diagnosed Acute Myeloid Leukemia with MLL rearrangement,” 
(NCT#PENDING) 
 
 
Overview and Key Information  
 
What am I being asked to do? 
 
We are asking you to take part in a research study.  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 Acute Myeloid Leukemia 
(AML), and your cancer has a change in the gene called MLL (lysine methyltransferase 2A).   
 
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 increase the chance of better treating AML by adding a new drug to the usual 
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 AML. The usual approach is defined as care most people get for AML. 


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What is the usual approach to my Acute Myeloid Leukemia? 
 
The usual approach for patients who are not in a study is treatment with chemotherapy drugs 
(Cytarabine and Daunorubicin) approved by the Food and Drug Administration (FDA).   
 
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 pinometostat for up to 35 days, in 
combination with standard intensive induction chemotherapy.  
 
After you finish your 35 days of pinometostat your doctor will continue to follow your condition 
and watch you for side effects.. The follow up will occur either until your AML comes back or 
worsens, or until you get a different treatment for your AML. The follow up will occur during 
regular clinic visits with your hematologist at least every month. 
 
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 the pinometostat along with the regular 
chemotherapy may not be as good as using the regular chemotherapy alone at treating your 
cancer.  
 
There is also a risk that you could have side effects from the pinometostat. These side effects 
may be worse and may be different than you would get with the usual approach for your cancer.   
 
Some of the most common side effects that the study doctors know about are: 
x Low red blood cell counts 
x Low or High white blood cell counts 


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x Low platelets 
x Heart Failure 
x High liver enzymes 
x Low phosphate electrolyte 
 
There may be some risks that the study doctors do not yet know about.   
 
Benefits 
 
This study drug has shrunk or stabilized your type of cancer in a limited number of people with 
your type of cancer. It is unlikely that it will work in everyone with your type of cancer or help 
you live longer.  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), Food and Drug 
Administration (FDA), or study sponsor (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? 
 


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One purpose of this study is to test the safety of a drug called pinometostat, when given in 
combination with standard chemotherapy for acute myeloid leukemia, at different doses. “Dose” 
is defined as the amount of drug you get, and there are three possible doses you may receive. 
Another purpose of this study is to test the good and bad effects of pinometostat, when added to 
a standard of care treatment for new acute myeloid leukemia. Pinometostat could shrink your 
cancer, but it could also cause side effects, which are described in the risks section below.  The 
study tests different doses of the drug and doctors hope to see which dose is safer for people and 
learn if the study drug will remove some or all of the cancer cells from your blood and bone 
marrow.   
 
There will be about 6-37 people taking part in this study. 
 
 
What are the study groups? 
 
This study has a screening step.  The purpose of this step is to test your tumor to find out if it has 
a specific gene change. If it does and you meet all the study requirements, then we can assign 
you to treatment based on these changes. If we find that your blood does not have the genetic 
changes that are needed for this study, then your doctor will discuss other options for your care.   
 
In the first part of this study (called the “safety run-in phase”), different people will receive 
different doses of the study drug pinometostat, in combination with a standard of care treatment 
for acute myeloid leukemia. In the later part of this study (called the “dose expansion phase”), 
everyone will receive the same dose of pinometostat. 
 
Treatment schedule: You will get pinometostat through a vein in your arm continuously for 35 
days. Beginning on the 8th day, you will receive daunorubicin through a vein in your arm daily 
for 3 days. Also beginning on the 8th day, you will receive cytarabine through a vein in your arm 
continuously for 7 days. 
 
In the safety run-in phase of this study, there are 2 study groups. 
 
x Group 1  
 
If you are in this group, you will get pinometostat at a higher dose for 7 days, then you 
will get pinometstat at a lower dose for another 28 days, while you receive the standard 
of care treatment of daunorubicin and cytarabine. 
 
There will be about 3-6 people in this group. 
 
x Group 2  
 
If you are in this group, you will get the same dose of pinometostat for 35 days. You will 
only be put in this group if the higher dose given to the people in group 1 does not cause 
serious side effects. After the first seven days, you will also receive the standard of care 


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treatment of daunorubicin and cytarabine.
There will be about 3-6 people in this group.
The study doctor will watch each group carefully. 
In the dose expansion phase of this study, all participants will receive the same doses of 
pinometostat as either group 1, or group 2, depending on which was safer. Patients in this group 
will also receive the same standard of care combination of daunorubicin and cytarabine 
described above as in the safety run-in phase. There will be up to 25 people in this group.
You will not be able to get additional doses of the drug.  This drug is not approved by the FDA
for treatment of your disease.
Another way to find out what will happen to you during this study is to read the chart below. 
Start reading at the left side and read across to the right following the lines and arrows. There are 
two diagrams, one for the early part of the study (the safety run-in phase), where 2 doses are 
tested, and one for the latter part of the study (the dose-expansion phase), which will study only 
one dose that was confirmed safe in the first part of the study.
If you participate in the first part of the study:
If you participate in the latter part of the study:
You will be assigned to 
a group that says what 
dose of pinometostat 
you will be on
Group 2
You will be put in this group 
if the higher dose of 
pinometostat given to patients 
in group 1 did not cause 
serious side effects.
You agree to take 
part in the study 
and sign this 
consent form.
Group 1
You will be put in this 
group if you are one of the 
first 6 patients enrolled
You will be treated with 
pinometostat for up to 35 
days along with the usual 
chemotherapy for your 
disease
You agree to take 
part in the study 
and sign this 
consent form.


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Regardless of which group you will be assigned, your study doctor may treat you again for 
another 28 days if your disease has not responded to study treatment:  This is called re-induction.  
During re-induction, you will receive pinometostat on days 1-28, daunorubicin on days 1 and 2, 
and cytarabine on days 1-5.    
   
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.  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.  
 
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 have a bone marrow aspiration and biopsy at screening.  If you consent to have optional 
research specimens collected, then an optional bone marrow aspiration and biopsy will be 
performed after you have finished 7 days of pinometstat.  This optional bone marrow biopsy 
takes small pieces of bone marrow from your body.  This is like the biopsy you had that helped 
diagnose your cancer. This optional bone marrow aspiration and biopsy will help the study 
researchers find out how pinometostat is working to treat your cancer. You and your study doctor 
will get the results of this testing.  If you agree to take part in the study, you may need to sign a 
separate consent form for the study biopsy at the hospital or clinic where the biopsy is done. 
 
Fourteen days after starting chemotherapy (21 days after starting pinometostat, the study drug) 
you will have a bone marrow biopsy to see if all the leukemia is gone. If it is not, your doctors 
will recommend repeating chemotherapy, but at a smaller dose. This is called “re-induction”. 
 
A bone marrow aspiration will be performed at week 5 to examine your blood counts.  
 
Also, if there is relapse in your disease, another bone marrow aspirate will be performed.   
 
What risks can I expect from taking part in this study? 
 
General Risks 
 
A test result will be used to determine patient eligibility in the study. Because of this, risks 
include: 
x The possibility of incorrectly being found eligible, or 
x Receiving an incorrect assignment due to an error in the test, and thus possibly not 
receiving the best treatment option.   
 


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If you choose to take part in this study, there is a risk that the pinometostat (EPZ-5676) may not 
be as good as the usual approach for your cancer or condition at shrinking or stabilizing your 
cancer. 
You also may have the following discomforts: 
 
x Spend more time in the hospital or doctor’s office. 
x Be asked sensitive or private questions about things you normally do not discuss. 
x May not be able to take part in future studies.  
 
The study drug 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.  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 after you have completed the study medication. Women must use acceptable birth 
control for 4 weeks after the last dose of study treatment. Men must use a barrier method of birth 
control for 90 days (3 months) after the last dose of study treatment.  
 
Genetic Testing Risks 
 
As part of this study, we are also studying a study required genetic test that will be performed in 
the hospital’s molecular diagnostics lab. The test is designed to find out if your tumor has the 
genetic changes that are needed for this study.  If it does, we will assign you to a study group 
based on the genetic changes in your tumor.  
Because this genetic test is still being studied, there is a risk that the test results may be wrong.  
If the test results are wrong, you may be included in this study even though it may not offer the 
best treatment option for you.  Or, you may not be included in this study even though it may 
offer a good treatment option for you 
 
Bone Marrow Biopsy Risks 
 
Common side effects of a biopsy are a small amount of bleeding at the time of the procedure, 
bruising, and pain at the biopsy site.  Rarely, an infection can occur.  You may sign a separate 
consent form for the study biopsy that describes the risks in more detail.   
 
Side Effect Risks 
 
The pinometostat (EPZ-5676) 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 side effects from the study drug(s)/study approach. 
Here are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 


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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 If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
x Your study doctor will work with you to treat your side effects. 
x Your study doctor may adjust the study drugs to try to reduce side effects. 
 
This study is looking at a combination of the usual drugs used to treat this type of cancer plus a 
study drug.  This different combination of drugs may increase your side effects or may cause 
new 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. 
 
Possible side effects of Pinometostat are listed in the tables below. This drug is the experimental 
part of the study. 
 
POSSIBLE RISKS, SOME MAY BE SERIOUS 
x 
Anemia which may require blood transfusion 
x 
Infection, especially when white blood cell count is low 
x 
Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
x 
Diarrhea, nausea, vomiting 
x 
Tiredness 
x 
Change in the heart rhythm 
x 
Bruising, bleeding 
x 
Rash 
 
 
 


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Possible side effects of Cytarabine and Daunorubicin are listed in the tables below.  These drugs 
are part of the usual approach for treating this type of cancer: 
 
Possible Side Effects of Cytarabine 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cytarabine, more than 20 and up to 100 may have: 
x Blood clot 
x Rash 
x Swelling in the rectum which may cause rectal pain 
x Diarrhea, loss of appetite, nausea, vomiting 
x Sores in mouth which may cause difficulty swallowing 
x Anemia which may cause tiredness, or may require blood transfusions 
x Fever 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cytarabine, from 4 to 20 may have: 
x Infection, especially when white blood cell count is low 
x Bruising, bleeding 
x Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
x Numbness and tingling of the arms and legs 
x Severe blood infection 
x Kidney damage which may cause swelling, may require dialysis 
x Headache 
x Dizziness 
x Chest pain 
x Hair loss 
x Liver damage which may cause yellowing of skin or eyes 
x Swelling and redness of the eye 
 
RARE, AND SERIOUS 
In 100 people receiving Cytarabine, 3 or fewer may have: 
x Coma 
 
Possible Side Effects of Daunorubicin 
 


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COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Daunorubicin, more than 20 and up to 100 may have: 
x Pink or red colored urine, sweat, or saliva 
x Nausea, vomiting 
x Hair loss 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Daunorubicin, from 4 to 20 may have: 
x Damage to the heart which may cause shortness of breath, tiredness 
x Infection, especially when white blood cell count is low 
x Bruising, bleeding 
x Anemia which may require transfusion 
x Pain and sores in mouth and throat 
x Diarrhea  
x Redness and pain at the site of previous radiation 
x Swelling and redness at the site of injection 
x Loss of nails 
x Dark discoloration of the nail, skin 
 
RARE, AND SERIOUS 
In 100 people receiving Daunorubicin, 3 or fewer may have: 
x Cancer of the bone marrow (leukemia) caused by chemotherapy 
x Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
 
Additional Drug Risks 
 
The study drug could interact with other drugs and food. However, these are unknown at this 
point because the drug is so new.  
 
Rarely, there are problems getting enough supplies of the study drug.  If that happens, your 
doctor will talk with you about your options. 
 
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  


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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 weeks for 
women and 90 days (3 months) for men 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 AML. 
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 daunorubicin and cytarabine 
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 Bone marrow aspiration and biopsy done before treatment 
x Bone marrow aspiration and biopsy done at relapse (if applicable) 
x Bone marrow aspiration on day 8, and the genetic and chemical tests done on this 
specimen 
x Bone marrow aspiration and biopsy on day 21 
x Bone marrow aspiration and biopsy at week 5 
 
You or your insurance provider will not have to pay for the pinometostat while you take part in 
this study: it is provided free of cost to study participants. The preparation and administration of 
pinometostat is also provided free of cost to study participants.  
 
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? 
 


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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 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 drug company supporting the study 
x The 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. 
x The NCI’s National Clinical Trials Network and the groups it works with to conduct 
research 
 
Your study records also will be stored for future use.  However, your name and other personal 
information will not be used.  Some types of future research may include looking at your records 
and those of other patients to see who had side effects across many studies or comparing new 
study data with older study data.  However, 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. 


Protocol Version Date 03/26/2019 
 
10212 
 
 
Page 13 of 16 
 
 
x You will not get reports or other information about any research that is done using your 
information.  
 
There are laws that protect your genetic information.  However, there is a risk that someone 
could get access to your genetic information and identify you by name.  In some cases, 
employers could use your genetic information to decide whether to hire or fire you.  The study 
doctors believe the risk of this happening is very small.  However, the risk may increase in the 
future as people find new ways of tracing information.  For more information about the laws that 
protect you, ask your study doctor.  
 
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                              at                              .                            
 
For questions about your rights as a participant in this study or to discuss other study-related 
concerns or complaints with someone who is not part of the research team, you may contact  
                                    at                              .  
 
Optional studies that you can choose to take part in 
 
This part of the consent form is about optional studies that you can choose to take part in.  They 
are separate from the main study described above.  These optional studies will not benefit your 
health.  The researchers leading these optional studies hope the results will help other people 
with your condition in the future.  The results will not be added to your medical records and you 
or your study doctor may not know the results. 
 
Taking part in these optional studies is your choice.  You can still take part in the main study 
even if you say “no” to any or all of these studies.  There is no penalty for saying “no.” You and 
your insurance company will not be billed for these optional studies. If you sign up for, but 
cannot complete any of these studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
Optional sample collections for known laboratory studies and/or storage for possible 
future studies 
 


Protocol Version Date 03/26/2019 
 
10212 
 
 
Page 14 of 16 
 
 
Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
 
Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 
are found in you and your family.  Examples of traits are the color of your eyes, having curly or 
straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
Known future studies 
 
If you choose to take part in this optional study, researchers will collect bone marrow for 
research on AML.  
 
The researched will look at the white blood cells in your bone marrow to see how your AML 
responded to the study drug and the white blood cells changed from AML cells to normal white 
blood cells. The researchers will also look to see if the genes and the mechanisms that control the 
genes in your white blood cells in your bone marrow changed because of the study drug. The 
researchers will also look at the DNA of your white blood cells to see if certain mutations are 
there to see how your blood responded to the study drug.  
 
What is involved in this optional sample collection? 
 
If you agree to take part, here is what will happen next: 
 
1. A sample of tissue and extra aspirate will be collected from an optional biopsy (the same 
biopsy that is done after getting pinometostat for 7 days). 
2. A small amount of blood will be collected at times when you are already receiving a 
blood draw for your clinical care 
3. Some of your genetic and health information may be placed in central databases for 
researchers to use.  The databases will not include your name or contact information. The 
researchers do not believe there will be enough genetic information to identify you.    
 
 
What are the risks in this optional sample collection? 
 
 
x Because blood will be drawn at times you are getting blood drawn for your clinical care, 
no extra risk to you is expected 
x Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace information 
in a database back to you.  They could use that information in a way that could harm you.  
Researchers believe the chance that someone could access and misuse your information is 


Protocol Version Date 03/26/2019 
 
10212 
 
 
Page 15 of 16 
 
 
very small.  However, the risk may increase in the future as people find new ways of 
tracing information.  
x In some cases, this information could be used to make it harder for you to get or keep a 
job and get or keep health insurance.   
x However, the researchers do not plan to generate the type of data (“Whole genome” or 
“Whole exome”) for which this is typically a risk. 
 
How will information about me be kept private? 
 
Your privacy is very important to the study researchers and biobank.  They will make every 
effort to protect it.  Here are just a few of the steps they will take: 
 
1. They will remove identifiers, such as your initials, from your sample and information.   
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information.  
2. Researchers who study your sample and information will not know who you are.   They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  
4. If research results are published, your name and other personal information will not be 
used. 
 
What are the benefits to taking part in this optional sample collection? 
 
You will not benefit from taking part.  
 
The researchers, using the samples from you and others, might make discoveries that could help 
people in the future. 
 
Are there any costs or payments to this optional sample collection? 
 
There are no costs to you or your insurance.  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 if I change my mind about this optional sample collection? 
 
If you decide you no longer want your samples to be used, you can call the study doctor, Dr. 
James S. Blachly at 614-685-5667. This will not apply to any samples or related health 
information that have already been given to or used by researchers. 
 
What if I have questions about this optional sample collection? 
 
If you have questions about the use of your samples for research, contact the study doctor, Dr. 
James S. Blachly at 614-685-5667.  
 


Protocol Version Date 03/26/2019 
 
10212 
 
 
Page 16 of 16 
 
 
Please circle your answer below to show if you would or would not like to take part in each 
optional study: 
 
Samples for known future studies: 
 
I agree that my samples and related health information may be used for the laboratory studies 
described above. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
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. I also agree to take part in any additional studies where I circled 
“yes”. 
 
 
Participant’s signature 
 
 
 
 
Date of signature 
 
 
 
 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
Date of signature 
  
 
 

Prot_SAP_000.pdf: 
NCI Protocol #:10212 
Version 1 Date: 2019.03.26 
i 
 
 
SUMMARY OF CHANGES 
 
NCI Protocol #:         10212 
Local Protocol #: 
OSU 18296 
 
NCI Version Date: March 26, 2019 
Protocol Date: March 26, 2019 
 
I. NCI Rapid Request Amendment (RRA) 03/26/2019 
 
# 
Section 
Page(s) 
Change 
1.  
Header 
All 
Updated Header Version Date 
 
2. 
Title Page 
1 
Updated amendment number and version date 
3. 
CAEPR for 
pinometostat 
 
48-50 
Updated CAEPR for pinometastat  (Version 1.1,  
January 7,2019: 
 
• Added New Risk:  
• Possible: Diarrhea; Electrocardiogram QT 
corrected interval prolonged; Fatigue; 
Hypocalcemia; Lymphocyte count decreased; 
Nausea; Neutrophil count decreased; Rash 
maculo-papular; Vomiting; White blood cell 
decreased 
• Also Reported on Pinometostat Trials But With 
Insufficient Evidence for Attribution: Alkaline 
phosphatase increased; Alopecia; Anorexia; 
Apnea; Cough; Creatinine increased; Dry skin; 
Dysgeusia; Edema face; Folliculitis; Headache; 
Hyperkalemia; Hypermagnesemia; 
Hypernatremia; Hypertension; Hyperuricemia; 
Hypoalbuminemia; Hypokalemia; 
Hypomagnesemia; INR increased; Investigations 
- Other (ejection fraction increased); Irritability; 
Localized edema; Mucositis oral; Periorbital 
edema; Pruritus; Respiratory, thoracic and 
mediastinal disorders - Other (tachypnea); Sore 
throat; Thrush 
 
• Increase in Risk Attribution:  
• Changed to Possible from Also Reported on 
Pinometostat Trials But With Insufficient 
Evidence for Attribution: Anemia; 
Hypophosphatemia; Platelet count decreased 
 
 


NCI Protocol #:10212 
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ii 
 
 
 
• Decrease in Risk Attribution:  
• 
Changed to Also Reported on Pinometostat 
Trials But With Insufficient Evidence for 
Attribution from Possible: Constipation; 
Intracranial hemorrhage; Lung infection; 
Sepsis 
 
 
 
 


NCI Protocol #:10212 
Version 1 Date: 2019.03.26 
1 
 
 
 
NCI Protocol #: 
10212 
 
Local Protocol #: 
TBD 
 
ClinicalTrials.gov Identifier: TBD 
 
TITLE: A Phase 1b/2 study of Pinometostat in Combination with standard induction 
chemotherapy in newly diagnosed Acute Myeloid Leukemia with MLL 
rearrangement. 
 
Corresponding Organization: LAO-OH007 / Ohio State University Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
James S Blachly, MD 
The Ohio State University, Comprehensive Cancer Center 
B304 Starling-Loving Hall 
320 W. 10th Ave 
Columbus, OH 43210, USA 
614-685-5667 (phone) 
614-293-7526 (fax) 
James.Blachly@osumc.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 


NCI Protocol #:10212 
Version 1 Date: 2019-03-26 
2 
 
 
Statistician: 
Study Coordinator: TBD 
Lai Wei 
(if applicable) 
320H Lincoln Tower 
Name 
1800 Cannon Drive 
Address 
Columbus, OH 43210, USA 
Address 
614-293-6449 (phone) 
Telephone 
614-688-6600 (fax) 
Fax 
Lai.Wei@osumc.edu 
e-mail address 
 
Responsible Research Nurse: TBD 
Responsible Data Manager TBD 
Name 
Name 
Address 
Address 
Address 
Address 
Telephone 
Telephone 
Fax 
Fax 
e-m ail address 
e-mail address 
 
 
NCI-Supplied Agent: Pinometostat (NSC# 795144) 
Other Agent(s): Daunorubicin (NSC# 82151), Cytarabine (NSC# 287459) 
Supplier: Commercial 
 
IND #: TBD 
IND Sponsor: DCTD, NCI 
 
 
Protocol Type / Version # / Version Date: Original / Version 1 / 14 September 2018 
Revised / Version 1 / 12 December 2018 
Revised / Version 1 / 19 December 2018 
Revised / Version 1 / 14 January 2019 
Amendment #1 / Version 1 / 26 March 2019 


NCI Protocol #:10212 
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3 
 
 
SUMMARY FACTS 
 
Diagnosis: Acute Myeloid Leukemia with MLL (KMT2A) rearrangement 
Line of treatment: Previously untreated 
Target population: Ages 14+ 
Performance status: ECOG 0-2 
Abnormal organ function permitted: 
- 
Total bilirubin 
≤ 1.5 × institutional ULN, unless elevated due to 
Gilbert syndrome, hemolysis, or leukemia 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional ULN, unless due to leukemia in 
which case < 5 × ULN 
- 
Creatinine 
≤ 1.5 × institutional ULN 
OR 
− 
Glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
 
Agents: 
Pinometostat*, CIVI days 1-35 
Daunorubicin, daily, days 8-10 
(part of “7+3” standard of care) 
Cytarabine, CIVI days 8-14 
(part of “7+3” standard of care) 
 
*Investigational agent 
 
Treatment plan: Pinometostat will be given IV starting on day 1 at one of two doses in the 
phase 1b portion, and at a single defined dose (RP2D) in the phase 2 portion. Pinometostat will 
continue as a continuous IV infusion through day 35. A bone marrow biopsy will be performed 
on day 8 to assess the single agent activity. On day 8, standard of care 7+3 with cytarabine and 
daunorubicin will be initiated. One re-induction attempt is permitted if no CR or CRi is achieved 
by day 21 (day 14 of 7+3). No further study treatments (e.g. consolidation or maintenance) are 
planned, and patients should be consolidated as per standard of care. 
 
Phase: 1b, 2 


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SCHEMA 
This study is a multi-site phase 1b/2 study designed to confirm a safe and tolerable dose of 
pinometostat and to gauge preliminary evidence of efficacy when given as lead-in prior to and 
contemporaneous with standard intensive induction therapy for newly diagnosed AML with 
MLL rearrangement. There will be a brief safety run-in phase exploring two dosing schemes, 
followed by a phase 2 efficacy expansion. The phase 2 expansion will use the higher dose-level 
of the two schedules if tolerated (see definitions below), otherwise, the lower dose-level if 
tolerated. The phase 1b/safety run-in portion will have a primary endpoint of Dose-limiting 
Toxicity (DLT; defined below), while the phase 2 portion will have a primary endpoint of 
complete remission attainment, and will gather additional laboratory correlative data. 
 
 
Figure 1: Abbreviated Trial Schema (Depicting Initial Induction. Re-induction resets calendar; see details) 
 
Phase 1b/safety run-in phase 
The phase 1b portion will operate according to Figure 1. Up to two cohorts will be accrued in 
order to identify a maximum tolerated dose for expansion. Dose escalation will occur in the 
standard cohorts-of-3/3+3 design. With only two cohorts (dose levels), escalation stops after 
cohort 2; if 2-3/3 DLT are observed at dose level 1 (cohort 1), a safety review will be initiated to 
decide whether dose level reductions below the starting dose should be considered. 
Phase 2/expansion phase 
The phase 2 portion will use the maximum tolerated dose/schedule and accrue additional patients 
to gather preliminary evidence of efficacy. Patients will be treated in the same manner as in the 
phase 1b portion above, with the exception that only a single dose level/cohort will be expanded. 
Re-induction 
Patients not achieving CR/CRi by day 21 may undergo a second induction; see details. 


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TABLE OF CONTENTS 
SUMMARY FACTS ....................................................................................................................... 3 
SCHEMA ......................................................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................. 5 
1. 
OBJECTIVES ...................................................................................................................... 7 
1.1 
Primary Objectives ................................................................................................... 7 
1.2 
Secondary Objectives ............................................................................................... 7 
2. 
BACKGROUND ................................................................................................................. 7 
2.1 
Acute Myeloid Leukemia ........................................................................................ 7 
2.2 
Pinometostat ............................................................................................................. 8 
2.3 
Cytarabine and Daunorubicin .................................................................................. 9 
2.4 
Rationale ................................................................................................................ 10 
2.5 
Correlative Studies Background ............................................................................ 11 
3. 
PATIENT SELECTION .................................................................................................... 12 
3.1 
Eligibility Criteria .................................................................................................. 12 
3.2 
Exclusion Criteria .................................................................................................. 13 
3.3 
Inclusion of Women and Minorities ...................................................................... 15 
4. 
REGISTRATION PROCEDURES ................................................................................... 15 
4.1 
Investigator and Research Associate Registration with CTEP .............................. 15 
4.2 
Site Registration ..................................................................................................... 16 
4.3 
Patient Registration ................................................................................................ 18 
4.4 
General Guidelines ................................................................................................. 21 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES......................................... 21 
5.1 
Biomarker Plan ...................................................................................................... 21 
5.2 
Integral Laboratory Studies .................................................................................... 24 
5.3 
Exploratory/Ancillary Correlative Studies ............................................................. 25 
6. 
TREATMENT PLAN ........................................................................................................ 29 
6.1 
Agent Administration ............................................................................................. 29 
6.2 
Definition of Dose-Limiting Toxicity .................................................................... 33 
6.3 
Monitoring ............................................................................................................. 34 
6.4 
General Concomitant Medication and Supportive Care Guidelines ...................... 34 
6.5 
Duration of Therapy ............................................................................................... 35 
6.6 
Duration of Follow Up ........................................................................................... 35 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................ 35 
8. 
PHARMACEUTICAL INFORMATION .......................................................................... 36 


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8.1 
CTEP IND Agent ................................................................................................... 36 
8.2 
Commercial Agents ............................................................................................... 39 
9. 
STATISTICAL CONSIDERATIONS ............................................................................... 40 
9.1 
Study Design/Endpoints ......................................................................................... 40 
9.2 
Sample Size/Accrual Rate ...................................................................................... 44 
9.3 
Analysis of Secondary Endpoints .......................................................................... 46 
9.4 
Phase 2 portion: Reporting and Exclusions ........................................................... 47 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................ 47 
10.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ............... 48 
10.2 
Adverse Event Characteristics ............................................................................... 50 
10.3 
Expedited Adverse Event Reporting ...................................................................... 50 
10.4 
Routine Adverse Event Reporting ......................................................................... 53 
10.5 
Pregnancy ............................................................................................................... 53 
10.6 
Secondary Malignancy ........................................................................................... 53 
10.7 
Second Malignancy ................................................................................................ 54 
11. 
STUDY CALENDAR ....................................................................................................... 54 
12. 
MEASUREMENT OF EFFECT ........................................................................................ 57 
12.1 
Antitumor Effect – Hematologic Tumors .............................................................. 57 
12.2 
Other Response Parameters ................................................................................... 58 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ............................................................................................................. 58 
13.1 
Study Oversight...................................................................................................... 58 
13.2 
Data Reporting ....................................................................................................... 59 
13.3 
Data and Safety Monitoring ................................................................................... 61 
13.4 
Collaborative Agreements Language ..................................................................... 61 
13.5 
Genomic Data Sharing Plan ................................................................................... 63 
13.6 
Incidental/Secondary Findings Disclosure Procedure ........................................... 64 
14. 
REFERENCES .................................................................................................................. 65 
APPENDIX A 
PERFORMANCE STATUS CRITERIA .................................................. 68 
APPENDIX B 
CTEP MULTICENTER GUIDELINES .................................................... 69 
APPENDIX C 
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD ............................................................................................................... 70 
APPENDIX D 
BIOASSAY TEMPLATES ....................................................................... 71 
APPENDIX E 
COLLECTION OF SPECIMENS ............................................................... 0 


NCI Protocol #:10212 
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7 
 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 
Determine a safe and tolerable schedule of pinometostat continuous intravenous infusion 
in combination with daunorubicin and cytarabine in patients with untreated, newly 
diagnosed acute myeloid leukemia harboring MLL rearrangement 
 
1.1.2 
Determine the rate of complete remission (CR, CRi) in patients with newly diagnosed 
acute myeloid leukemia harboring MLL rearrangement after treatment with pinometostat 
in combination with daunorubicin and cytarabine 
 
1.2 
Secondary Objectives 
 
1.2.1 
To observe and record anti-tumor activity. Although the clinical benefit of pinometostat 
has not been fully 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 
 
1.2.2 
Estimate biologic activity of 7 day window treatment of pinometostat monotherapy 
 
1.2.3 
Estimate the toxicity profile of pinometostat alone (week 1) and in combination with 
daunorubicin and cytarabine 
 
1.2.4 
Estimate event free and overall survival of patients with MLL rearranged acute myeloid 
leukemia after combination treatment with pinometostat, daunorubicin, and cytarabine 
 
1.2.5 
Estimate the early death rate (death ≤ 30 days) of pinometostat, daunorubicin, and 
cytarabine 
 
1.2.6 
Determine the rate of MRD negativity by clinical flow cytometry on post-treatment 
recovery bone marrow 
 
2. 
BACKGROUND 
 
2.1 
Acute Myeloid Leukemia 
 
Acute myeloid leukemia (AML) is a cancer of developing hematopoietic progenitors in which a 
differentiation block causes the accumulation of nonfunctional precursor cells with the functional 
consequence of rapid progression to severe and ultimately fatal compilations such as 
dysfunctional immunity, myelophthisic and/or immune cytopenias (with attendant 
consequences), or hyperviscosity. The standard therapy for younger, fit patients includes 
intensive induction chemotherapy over the course of a week with combination of an 
anthracycline (typically daunorubicin) and nucleoside analogue (cytarabine; the combination 
being called “7+3”), a prolonged hospitalization and peripheral blood count recovery, and for all 
but very good risk patients, consolidation with an allogenic stem cell transplant, if a donor is 


NCI Protocol #:10212 
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8 
 
 
available. About 60-80% of younger patients can achieve a complete remission, but despite this 
only about a third are ultimately cured.1 Older patients or those who are not fit for high intensity 
induction chemotherapy may be treated with hypomethylating agents (azacitidine and decitabine) 
with varying levels of remission induction rates and improvement in progression free survival, 
but not cure.2 
 
Many clinical and molecular prognostic factors have been identified in AML. These include 
specific abnormalities identified by karyotype analysis, specific abnormalities identified with 
fluorescent in-situ hybridization (FISH), and somatic point mutations. Cytogenetic abnormalities, 
or gross changes in the chromsomes (deletions, insertions, inversions, translocations, etc.) were 
the first molecular factors identified to carry prognostic value in AML. Some cytogenetic 
abnormalities, like the translocation t(8;21) leading to the fusion gene RUNX1-RUNX1T1 
portend well for patients, while others, like the loss of chromosome 7 portend very poorly.3,4 In 
general, each chromosomal abnormality drives specific gene expression programs, and a variety 
of recurrent cytogenetic abnormalities have been identified to co-associate with specific genetic 
mutations or mutations in specific cellular pathways.5–8 The current World Health Organization 
classification system defines specific recurrent cytogenetic abnormalities as distinct subtypes of 
AML, although apart from withholding upfront bone marrow transplant in very good risk groups 
like t(8;21) and inv(16)/t(16;16), or giving all-trans retinoic acid in Acute Promeylocytic 
Leukemia, the individual cytogenetic and molecular groups of AML are treated similarly. In the 
future, it is likely that individual subtypes will be treated distinctly as we understand more about 
the functional consequences of their molecular underpinnings. 
 
One interesting exception to this co-association of cytogenetic abnormalities with specific driver 
mutations is AML harboring rearrangement of the locus containing the lysine methyltransferase 
KMT2A, more commonly known as “MLL”. Rearrangement involving this locus (11q23) results 
in the creation of an oncogenic fusion protein including the N-terminus of KMT2A with more 
than 50 possible other fusion partners conferring hyperactivity and/or aberrant genome targeting, 
and is an adverse risk factor.9–11 It is believed that the paucity of mutations in MLL-rearranged 
AML is because the dysregulated epigenome induced by KMT2A fusions is sufficient on its own 
to confer a leukemic transformation.12 Thus, in this setting, unlike direct targeting of 
transforming mutant enzymes (e.g. IDH) or signal transduction proteins (e.g. FLT3), a primary 
epigenetic targeting approach may be most viable. 
 
2.2 
Pinometostat 
 
2.2.1 
Summary 
 
Pinometostat (EPZ-5676) is a small molecule inhibitor of the histone H3 methyltransferase 
DOT1L and available as an investigational drug product for IV injection. Pinometostat is a 
potent, competitive, and specific inhibitor of DOT1L enzyme activity, but does not substantially 
inhibit activity of other histone methyltransferases. In vitro, pinometostat treatment induces 
widespread demethylation at H3K79 without substantial effect of methylation at other histone 
methyl sites. As could be expected from an epigenetic therapy, inducing cell death upon 
treatment with pinometostat takes several days, as the leukemic transcriptional program mediated 
by aberrant H3K79 methylation takes several days to reset. Readouts for reversal of the MLL 


NCI Protocol #:10212 
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9 
 
 
mediated gene expression program upon treatment with pinometostat include decreases in 
HOXA9 and MEIS1 transcripts.13 Treatment-emergent mechanisms of resistance in cell lines 
include both increases in drug efflux transporter P-glycoprotein (MDR1; ABCB1) as well as 
potential other transcriptional mechanisms that are currently unclear.14 
 
2.2.2 
Pharmacokinetics 
 
Pinometostat pharmacokinetics (PK) studies in humans indicate a very short half-life of about 
2.5 hours, and consequently the chosen treatment strategy is a continuous IV infusion (CIVI) to 
maintain plasma levels long enough to effect histone demethylation in target cell populations. 
The metabolism of pinometostat in humans is mostly cytochrome P450-mediated. While the 
major route of elimination of pinometostat in humans has not been formally determined, in 
animal studies of rats and dogs, the major route of elimination was fecal excretion.15 
 
2.2.3 Clinical studies 
 
A peer reviewed-manuscript for the adult Phase 1 trial of pinometostat has been published by 
Stein et al. in Blood in 2018.16 This study enrolled adult patients with relapsed or refractory 
leukemia (including AML as well as acute lymphoblastic leukemia), myelodysplastic syndrome, 
myeloproliferative neoplasm, or chronic myeloid leukemia. An expansion cohort was restricted 
to MLL-r (including MLL-partial tandem duplication), and these patients received either a 90 
mg/m2 (n = 17) or 54 mg/m2 (n = 6) dose of pinometostat. A total of 49 patients are reported. 
Grade ≥ 3 adverse events (non-hematologic) included hypophosphatemia (n=1), decreased 
ejection fraction (n=3), and elevated transaminases (n=1). Leukocytosis was reported in nine 
patients, suggesting that pinometostat may be differentiating agent. The median days of 
treatment was 35 days (with a broad range from 3-189 days). Reported objective responses 
included 1 each morphologic CR and cytogenetic CR (in a patient negative for MLL-r by FISH), 
1 PR, and 3 patients with resolution of leukemia cutis. Correlative studies demonstrated HOXA9 
and MEIS1 reduction in all patients analyzed in the 90mg/m2 cohort (n=9). 
 
Pinometostat has also been studied in the pediatric population. From 2014 to 2016, study EPZ- 
5676-12-002 enrolled 18 pediatric patients ranging from < 1 year of age to 18 years, with 
relapsed or refractory MLL rearranged acute leukemia (AML and ALL) into cohorts comprising 
3 dose levels: 45 mg/m2/day, 70 mg/m2/day, and 90 mg/m2/day. Dose limiting toxicity occurred 
in 4 patients, and included Grade 3 ALT increase, Grade 3 urinary tract infection, Grade 4 
thrombocytopenia, Grade 3 hypophosphatemia, and Grade 4 unwitnessed apnea. Pinometostat 
was administered via uninterrupted continuous IV infusion. The median treatment duration was 
26 days (range 7-53 days). There were no objective responses in this study. Because of the 
responses observed after single-agent in adults with relapsed disease, and the poor prognosis of 
children with MLL rearranged AML, this agent is being combined with the standard of care 
induction treatment for adolescents with AML. 
 
 
2.3 
Cytarabine and Daunorubicin 
 
Patients will be treated with the standard of care for AML with 7 days of Cytarabine 100 mg/m2 


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by continuous intravenous infusion and 3 days of Daunorubicin 60 mg/m2 daily (“7+3”). This is 
a standard of care AML remission induction regimen for younger, fit patients. 17–19 This 
combination of medications has been the most successful induction regimen for AML to date.18 
Per NCCN guidelines, the dose of Cytarabine should be 100 mg/m2, as stated above, and the 
dose of daunorubicin should be 60-90 mg/m2. Daunorubicin will be dosed at 60 mg/m2 in this 
study. These doses will stay constant and not be escalated in our study, as is standard of care. 
Common side effects of cytarabine include increased risk for blood clots, rash, diarrhea, 
anorexia, nausea and vomiting, mouth sores, and anemia. Common side effects of daunorubicin 
are nausea, vomiting, and hair loss. These side effects with be treated with supportive care, 
transfusions, and further treated medically as needed. 
 
2.4 
Rationale 
 
MLL-r AML occurs more commonly in younger AML patients (15% among patients less than 
age 60) compared to older patients (only about 2% among patients aged greater than 60 years) 
and as a high-risk disease subset is typically treated with 7 + 3 induction, 0-1 cycles of 
consolidation (depending on donor status), and then allogeneic stem cell transplant. Patients who 
relapse, or patients who were primary refractory, have leukemias enriched for mutations in 
pathways (e.g. RAS/ERK, or PTPN11/STAT) that render the cells insensitive to inhibition of 
Syk signaling or epigenetic silencing by DOT1L inhibition. Accordingly, we have observed a 
higher response rate among front line patients compared to relapsed or refractory patients in 
response to SYK inhibition (unpublished observation), and would anticipate a similar scenario 
with DOT1L inhibition. Overall, relapsed and refractory patients represent a small heterogeneous 
population with induction failure or relapse after transplant, in both cases likely enriched for 
mutations conferring resistance to targeted therapies, and do not represent an ideal population in 
which to administer a targeted therapy due to the risk of missing an agent with up-front activity. 
For any agent, the heterogeneous and poorly understood relapsed/relapsed population represents 
a very challenging drug development and registration strategy, whereas development could 
potentially be pursued more systematically and rationally in newly diagnosed patients. 
 
To further understand newly diagnosed MLL-r patients, we examined records from 118 
historical cases of MLL-r AML treated on CALGB/Alliance cooperative group clinical trials. 
Patients less than age 60 have only a 64% CR rate with 7+3 induction/5+2 re-induction (if 
necessary; Mims et al: publication in preparation). This CR rate is significantly below what can 
be achieved by other subgroups, and patients who fail to achieve CR are less likely to move to 
transplant and overall are more likely to die sooner of their disease. Therefore, there is a 
significant opportunity to show clinical benefit in this previously untreated patient population by 
adding another agent to 7+3 chemotherapy. 
 
In AML, MLL rearrangement (MLL-r) is a strong driving factor on its own and consequently 
carries no associated primary driving co-mutation (NPM1, DNMT3a, TET2, TP53, JAK2), but 
can have secondary mutations (RAS, FLT3, PTPN11, etc).7,20 It is thought that the lack of other 
drivers in this subtype of AML is because MLL rearranged leukemias are driven by widespread 
aberrant activation of genes, including HOX genes, leading to the leukemia phenotype, mediated 
by aberrant histone methylation (H3K79me2) due to an interaction of the MLL fusion gene and 
DOT1L and consequent hyperactive methyltransferase activity.21 Genetic and pharmacologic 


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studies support the notion that MLL-r transcriptional activation is mediated by DOT1L 
recruitment, as knockdown or inhibition reverses the overexpression of target genes like HOXA9 
and MEIS1, and ultimately lead to cell death. 
 
2.5 
Correlative Studies Background 
 
2.5.1 
Detection of Hematopoietic Differentiation by Mass Cytometry 
 
In the EPZ-5676-012-001 study, a leukocytosis with increased numbers of polymorphonuclear 
cells (PMNs; neutrophils) was seen after treatment with pinometostat. In at least some cases, 
these PMNs were demonstrated to have MLL rearrangement by FISH, suggesting that 
pinometostat may act as a differentiating agent. 
 
We plan to investigate qualitative and quantitative differences in the overall composition of 
hematopoietic progenitors and mature cells after 7 days of pinometostat (as a single agent) 
compared to pre-treatment to understand whether this agent acts through differentiation in 
addition to direct cytotoxicity. 
 
Pinometostat removes active histone marks (and thereby silencers transcription) from genes 
involved in an aberrant stem-cell program and differentiation block including HOX family 
genes. Experimental silencing of these genes in other contexts has led to a differentiation 
phenotype. In the phase 1 study of pinometostat in relapsed or refractory AML, nine patients 
experienced leukocytosis manifest as increase in granulocytes and monocytes. Clinically, this is 
similar to the differentiation seen with treatment with all-trans retinoic acid in acute 
promyelocytic leukemia or IDH inhibitors in IDH1 or IDH2 mutant AML. An alternative, but 
less likely explanation, is that it could represent a drug-induced demargination of existing cells. 
Profiling the bone marrow aspirate for all stages of differentiation by mass cytometry can help 
make this distinction by detecting differences that can be too subtle to be picked up by 
morphology, or even conventional flow cytometry. These correlative studies will shed further 
light on the mechanism of action of pinometostat (or DOT1L inhibition in general) and may lead 
to more rational novel-novel combinations in the future. 
 
 
2.5.2 
Studies of Recurrently Mutated Genes by Targeted Capture Panel DNA Sequencing 
 
In a hypothesis generating way, we plan to investigate the mutational profile of study entrants at 
baseline and any relationship to outcomes, and differential mutational profile of study 
participants at study entry and relapse (if applicable), or off-study if refractory. 
 
MLL rearranged AML is a disease harboring few mutations at diagnosis and generally lacks 
notable driver mutations. However, subsets of MLL rearranged AML do have either at diagnosis 
or acquire as a mechanism of resistance mutations in RAS pathway and STAT pathways. 
Further, there may be passenger mutations or specific ensembles of passenger mutations at 
diagnosis that predict for better or worse response. It is important to be able to detect even small 
clones in order to find mediators of resistance prior to treatment that may expand in evolutionary 
selection during treatment. This type of discovery could lead to better combination therapies or 


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specific guidelines for monitoring emergence of resistance mutations (with potential mitigation 
strategies). 
 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 
Patients must have histologically confirmed Acute Myeloid Leukemia by World Health 
Organization (WHO) criteria. Patients with treatment-related acute leukemia are eligible 
if they do not exceed lifetime anthracycline doses as outlined below. 
 
3.1.2 
Presence of a cytogenetic rearrangement of KMT2A (MLL) by interphase Fluorescent in- 
situ Hybridization (FISH). 
 
3.1.3 
Patients must have previously untreated (with exception of hydroxyurea for count 
control, or ATRA for acute promyelocytic leukemia (APML) that was initially suspected 
but later ruled out) AML by World Health Organization (WHO) criteria. Treatment with 
hydroxyurea for count-control of hyperproliferative disease is permitted before and 
during treatment with pinometostat and chemotherapy. 
 
3.1.4 
Age ≥14 years at time of screening, although individual sites may further restrict age 
eligibility in accordance with local IRB and hospital policy. 
 
3.1.5 
ECOG performance status ≤2 (Karnofsky ≥60%; see Appendix A). 
 
3.1.6 
Patients must have adequate organ function at the time of eligibility screening as defined 
below: 
 
- 
Total bilirubin 
≤ 1.5 × institutional ULN, unless elevated due to 
Gilbert syndrome, hemolysis, or leukemia 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional ULN, unless due to leukemia in 
which case < 5 × ULN 
- 
Creatinine 
≤ 1.5 × institutional ULN 
OR 
− 
Glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
− 
Coagulation: PT and aPTT 
≤ 1.5 × ULN (both) 
 
− 
Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral 
therapy with undetectable viral load within 6 months are eligible for this trial. 
− 
If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be 
undetectable on suppressive therapy if indicated. 
− 
If history of hepatitis C virus (HCV) infection, must be treated with undetectable 
HCV viral load. 


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− 
For pediatric patients, a serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum Creatinine 
(mg/dL) 
Male 
Female 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
 
The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR 
(Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC. 
 
3.1.7 
Be medically fit, in the opinion of the investigator, for intensive (7+3) induction 
chemotherapy. 
 
3.1.8 
Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or 
MUGA, AND no symptoms of congestive heart failure exceeding NYHA Class II 
 
3.1.9 
Willingness to comply with all study procedures, including scheduled visits, 
investigational and standard of care drug administration plans, imaging studies, 
laboratory tests (including all biomarkers), procedures, and study- and disease-related 
restrictions. 
 
3.1.10 The effects of pinometostat on the developing human fetus are unknown. For this reason 
and because other small molecule inhibitors as well as other therapeutic agents used in 
this trial are known to be teratogenic, women of child-bearing potential must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry for the duration of study participation, and for 4 weeks after the last dose of 
study treatment. 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. Men treated or enrolled on this protocol must also agree to use adequate 
barrier contraception prior to the study, for the duration of study participation, and for 90 
days after completion of pinomatostat administration. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent document, 
or, for patients with impaired decision-making capacity, the consent of a close legal 
guardian who is readily available. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Acute promyelocytic leukemia with t(15;17)(q22;q12) and/or PML-RARA molecular 
rearrangement, or other atypical RARA translocation partner. 


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3.2.2 
Patients who have received prior chemotherapy for AML, excluding hydroxyurea for 
count control, or ATRA for APML that was initially suspected but later ruled out. 
 
3.2.3 
Patients who have received any prior investigational agent for acute myeloid leukemia 
 
3.2.4 
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study 
 
3.2.5 
Patients who have a cumulative lifetime exposure (prior to study entry) of greater than 
300 mg/m2 doxorubicin equivalent anthracycline. 
 
3.2.6 
Patients who have received chest radiation (unless organ-sparing) and who have a 
cumulative lifetime exposure (prior to study entry) of greater than 240 mg/m2 
doxorubicin equivalent anthracycline. 
 
3.2.7 
Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1) with the exception of alopecia, or peripheral 
neuropathy (up to Grade 2 is permitted) 
 
3.2.8 
Patients who are receiving any other investigational agents. 
 
3.2.9 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to pinometostat or other agents used in study. 
 
3.2.10 Patients receiving any medications or substances that are strong inhibitors or inducers of 
CYP3A4 are ineligible unless the offending medication can be safely stopped prior to 
enrollment. Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical reference. As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product. 
 
3.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring antibiotics (with exception; see below), symptomatic congestive heart failure, 
unstable angina pectoris, unstable cardiac arrhythmia not controllable with medications, 
eletrocardiographic evidence of ischemia, or psychiatric illness/social situations that 
would limit compliance with study requirements. Patients receiving an anti-microbial 
agent may be eligible if the patient remains afebrile and hemodynamically stable for 72 
hours. 
 
3.2.12 Patients with an active bleeding diathesis.. 


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3.2.13 Pregnant women are excluded from this study because pinometostat is a small molecule 
inhibitor with the potential for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with pinometostat, breastfeeding should be discontinued if the mother is 
treated with pinometostat. These potential risks may also apply to other agents used in 
this study. 
 
3.2.14 Subjects with known symptomatic leukemia of the central nervous system including 
leptomeningeal leukemic involvement 
 
3.2.15 History of active other malignancy that limits survival to less than 1 year 
 
3.2.16 Ongoing viral or drug induced liver injury, including active chronic HCV, chronic active 
hepatitis B, clinically known alcoholic liver disease, non alcoholic steatohepatitis, non 
alcoholic fatty liver disease, primary biliary cirrhosis, other cirrhosis of the liver, history 
of hepatic encephalopathy, or portal hypertension 
 
3.2.17 Any other prior condition that could, in the opinion of the investigator, compromise 
patient safety or evaluation of the primary outcome 
 
3.3 
Inclusion of Women and Minorities 
 
The target population is all adults aged 14 or greater with MLL (KMT2A) rearranged AML 
(subject to additional inclusion and exclusion criteria for reasons of medical safety). We will 
make every effort to enroll women and minority patients. 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH- 
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research. Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification. Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources. Women of 
childbearing potential should not be routinely excluded from participation in clinical research. 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
Planned enrollment targets are provided in tables in section 9.2. 
 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 


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investigators. NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually. To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE or acting as 
a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation 
requirements per registration type are outlined in the table below. 
 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 


Financial Disclosure Form 



NCI Biosketch (education, training, employment, 
license, and certification) 



HSP/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 CTSU (Cancer Trials Support Unit) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
 
Additional information can be found 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). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 


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protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following: 
 An active Federal Wide Assurance (FWA) number 
 An active roster affiliation with the Lead Network or a participating organization 
 A valid IRB approval 
 Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
 Active registration status 
 The IRB number of the site IRB of record listed on their Form FDA 1572 
 An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally. 
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office. In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 
Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the NCI#10212 protocol page located on 
the CTSU Web site. Permission to view and download this protocol is restricted and is 
based on person and site roster data housed in the CTSU RSS. To participate, 
Investigators and Associates must be associated with the Corresponding or Participating 
protocol organization in the RSS. 
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen. 
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-OH007, 
and protocol #10212. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided. (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 
Requirements For NCI #10212 Site Registration 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 


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documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
 
4.2.3 
Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab 
→Regulatory Submission 
When applicable, original documents should be mailed to: 
 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
 
4.2.4 
Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website. 
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements as outlined by the Lead 
Network. 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 


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4.3.1 
OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available to users on a 24/7 basis. It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 
 
4.3.2 
OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations: Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type. 
• To approve slot reservations or access cohort management: Be identified to 
Theradex as the “Client Admin” for the study. 
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. 
• If applicable, all patients have signed an appropriate consent form and Health 
Insurance Portability and Accountability Act (HIPAA) authorization form. 
 
4.3.3 
Patient Enrollment Instructions 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment initiation 
to check slot availability. Registration staff should ensure that a slot is available and secured for 
the patient before completing an enrollment. OSU will register all patients, including subsite 
patients, using IWRS. 
 
The OPEN system will provide the site with a printable confirmation of registration and treatment 
information. Please print this confirmation for your records. 
 
Patients will be registered after meeting all entry requirements, clearance by the Protocol 
Coordinator, and signing of the informed consent. 
 
OSU patients will be registered by the OSU research coordinator, as per their standard practice. 


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Subsite patients will have eligibility verified and will be entered on study centrally at the Ohio 
State University by the Multi-Institution Program Coordinator. All subsites must email the 
Multi-Institution Program Coordinator to verify slot availabilities prior to consenting patients. 
The required forms, including Eligibility Criteria Checklist and Registration Form, can be 
found in the Supplemental Forms Document. 
 
To register a subsite patient, the following documents must be completed by the subsite research 
team and faxed or securely e-mailed to the Multi-Institution Program Coordinator: 
• 
Copy of all baseline tests required per the protocol calendar. Tests must be within 
the specified window. 
• 
Signed Patient Consent Form 
• 
Signed Patient HIPAA Authorization Form 
• 
Consent Documentation Note 
• 
Completed & Signed Eligibility Checklist (refer to Supplemental Forms Document) 
• 
Registration Form (refer to Supplemental Forms Document) 
• 
Source documents verifying every inclusion & exclusion criteria 
o Note: every inclusion and exclusion criteria must be documented in the patient’s 
medical record 
 
Upon receipt of registration documents, the Multi-Institution Program Coordinator will send an 
email confirmation of receipt. If confirmation of receipt is not received within 1 hour of 
submission, please call or page the Multi-Institution Program Coordinator. 
 
Upon receipt of all required registration documents and upon verification the subsite patient 
meets all eligibility criteria, the Multi-Institution Program Coordinator will: 
• 
Assign the patient a study sequence ID 
• 
Register the patient on the study 
• 
Fax and/or e-mail to the subsite the completed Registration Form with the assigned 
study sequence ID as confirmation of patient registration 
 
Each participating institution will order study agents directly. Agents may be ordered by a 
participating site only after the initial IRB approval for the site has been forwarded to the 
Multi- Institution Program Coordinator. 
 
Patient sequence IDs will be assigned in the following fashion: 
• 
A-BCD 
o A = CTEP Site ID 
o BCD = sequential numbers by order of enrollment 


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4.3.4 
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. 
 
 
 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment as rapidly as possible, but in no 
more than 7 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. 
 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Biomarker Plan 


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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 
Differentiation 
analysis 
(CyTOF) 
CyTOF (mass 
cytometry) 
Exploratory 
Understand 
mechanism of action 
and identify potential 
new biomarkers 
CyTOF mass 
cytometry will be used 
to evaluate whether 
treatment with 
pinometostat removes 
the differentiation 
block in leukemia 
blasts and increases 
populations of mature 
myeloid cells; it will 
also be used to 
examine the 
relationship (if any) of 
immune effector 
subsets to response 
O 
Initial 
screening 
and day 8, 
and relapse 
(if applicable) 
Bone marrow 
aspirate and 
peripheral 
blood 
3-5 mL 
bone 
marrow 
aspirate 
4-6 mL of 
peripheral 
blood 
Laboratory of 
Gregory 
Behbehani, MD, 
PhD at 
The Ohio State 
University 
2 
Differentiation 
analysis 
(morphology) 
Morphology 
differential 
(Wright-Giemsa 
Exploratory 
Understand 
mechanism of action 
and identify potential 
new treatment dosing 
strategies 
O 
Initial 
screening 
and day 8, 
and relapse 
(if 
applicable). 
Bone marrow 
aspirate and 
peripheral 
blood 
1 mL bone 
marrow 
aspirate (as 
slides) 
1 mL PB 
(as slides) 
Local site CLIA 
lab 
3 
Comprehensive 
mutational 
profile 
Targeted panel 
DNA sequencing 
Exploratory 
Understand pre- and 
post-treatment 
mechanisms of 
resistance and 
identify potential new 
biomarkers 
This panel is much 
more comprehensive 
than the CLIA panel 
performed for patient 
care 
O 
Initial 
screening 
and relapse 
(if applicable) 
Bone marrow 
aspirate 
4 mL bone 
marrow 
aspirate 
6 mL of 
peripheral 
blood, if 
blasts > 1 x 
109/L 
Laboratory of 
James S 
Blachly, MD at 
The Ohio State 
University 


23 
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Specimen Collection Schedule 
 
Specimen Type 
Baseline 
(Pre- 
treatment) 
Day 8 of 
treatment 
Relapse (if 
applicable) 
Serum samples from 
peripheral blood 
X 
X 
Bone Marrow biopsy and 
aspirate 
X 
X 
X 


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5.2 
Integral Laboratory Studies 
 
All integral laboratory studies (metaphase karyotype, KMT2A rearrangement by FISH, and 
multiparameter flow cytometry) are standard of care and required to establish diagnosis and 
eligibility. These will be done at the site and are considered standard of care for management of 
AML patients. 
 
5.2.1 
MLL (KMT2A) translocation by metaphase karyotype and FISH 
 
Background: MLL rearrangement creates a fusion protein consisting of the N terminal end of 
MLL and a variable number of exons from the C terminal end of a fusion partner gene. This 
results in the loss of MLL’s SET domain (responsible for H3K4 methylation), but acquisition of 
additional gene-targeting activity through the fusion partner gene. Many fusion partner genes 
appear to activate DOT1L and thereby increase H3K79 methylation. A phase I study of the 
DOT1L inhibitor pinometostat has demonstrated single-agent activity in the setting of MLL 
rearranged relapsed/refractory acute myeloid leukemia, consistent with the pathobiology of MLL 
rearrangement and the drug’s mechanism of action. This study is restricted to patients with MLL 
(KMT2A) rearrangements as detected by metaphase cytogenetics (karyotype) or FISH 
(preferred). 
 
Method: This test which is required to establish eligibility will be performed on-site at each 
participating institution in a cytogenetics lab accredited by the College of American Pathologists 
in Clinical Cytogenetics and supervised by a cytogeneticist boarded by the American Board of 
Medical Genetics and Genomics in Clinical Cytogenetics. 
 
Analysis: Details of analysis as perfomed at the lead institution are provided in supplementary 
appendices. 
 
5.2.1.1 
Collection of Specimen 
4.0 mL of bone marrow aspirate should be collected in a sodium heparin tube. A single specimen 
tube for both metaphase cytogenetics and FISH is acceptable. 
 
5.2.1.2 
Handling of Specimen 
Invert tube 3 times after collection. Specimen can be sent to the cytogenetics laboratory at room 
temperature, but should be processed on the same day. 
 
5.2.1.3 
Shipping of Specimen 
Not applicable. 
 
5.2.1.4 
Site(s) Performing Correlative Study 
This integral biomarker is required to establish study eligibility, and will be performed 
individually at each site. 


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5.2.2 
Immunophenotyping by multiparameter flow cytometry 
 
Background: Acute myeloid leukemia requires several criteria for diagnosis, including a blast 
percentage greater than or equal to 20%. Blasts can be sensitively distinguished by 
multiparameter flow cytometry, and individual blast populations (e.g., regenerative; leukemic) 
can be distinguished on the basis of a number of surface markers, both normal and aberrant. 
Evaluation of immunophenotype aids in (1) diagnosis (2) discrimination of regenerative marrow 
from persistent disease and (3) evaluation for minimal residual disease 
 
Method: This test is a standard of care test that aids in the diagnosis and management of AML 
will be performed on-site at each participating institution in a flow cytometry lab accredited by 
the College of American Pathologists and/or certified according to the Clinical Laboratory 
Improvements Amendment (CLIA) and supervised by a pathologist boarded by the American 
Board of Pathology with specialization in flow cytometry. 
 
Analysis: Detailed analysis methods as performed at the lead institution are provided in 
supplementary appendices. 
 
5.2.2.1 
Collection of Specimen(s) 
3.0-5.0 mL of bone marrow aspirate should be collected in a sodium heparin tube. 
4.0-6.0 mL of peripheral blood should be collected in a sodium heparin tube. 
 
5.2.2.2 
Handling of Specimens(s) 
Invert tubes 3 times after collection. Specimen can be sent to the flow cytometry laboratory at 
room temperature, but should be processed on the same day. 
 
5.2.2.3 
Shipping of Specimen(s) 
Not applicable. 
 
5.2.2.4 
Site(s) Performing Correlative Study 
This integral biomarker is required to establish study eligibility, and will be performed 
individually at each site. 
 
 
5.3 
Exploratory/Ancillary Correlative Studies 
 
 
5.3.1 
Detection of Hematopoietic Differentiation by Mass Cytometry 
 
CyTOF (mass cytometry) will be used to evaluate whether treatment with Pinometostat removes 
the differentiation block in leukemia blasts and increases population proportions of mature 
myeloid cells; it will also be used to examine the relationship (if any) of immune effector subsets 
to response. These studies will be performed by Gregory Behbehani, MD, PhD. Briefly, bone 
marrow aspirates from screening and day 8 (prior to initiation of 7+3) will be fixed, 
permeablized, and stained with a validated custom cocktail of metal conjugated antibodies 
against a variety of cell surface and intracellular proteins and phospho-proteins, and run on a 


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Fluidigm 3rd Generation Helios Mass Cytometer in Dr. Behbehani’s laboratory. High 
dimensional single-cell data will be preprocessed and clustered, and visualized with SPADE and 
ViSNE using Cytobank platform. 
 
5.3.1.1 
Hypothesis and Rationale as it relates to future development. 
 
We hypothesize that pinometostat will remove the differentiation block from certain subtypes of 
AML with a concomitant increase in the proportion of intermediate and mature myeloid cells 
compared to pretreatment. If this is borne out, it may suggest that certain genetically selected 
subsets of AML patients may be able to forego intensive induction therapy for longer or in total, 
or suggest that it could be justified to combine pinometostat with other complementary agents. 
 
5.3.1.2 
Intended use 
 
These data will be exploratory in nature only 
 
5.3.1.3 
Preclinical in vitro and in vivo data, and clinical results 
 
We are not aware of current CyTOF data in the setting of pinometostat treatment 
 
5.3.1.4 
Appropriateness 
 
CyTOF is an ideal tool to study simultaneously all hematopoietic and immune subsets in a bone 
marrow aspirate sample, and this use is well-supported in the scientific literature. CyTOF is 
capable of detecting shifts in differentiation that are not yet evident by morphology, or 
conventional flow cytometry. As it is unknown what degree of differentiation may be present 
after 7 days, the most sensitive assay is favored. 
 
5.3.1.5 
Fit for purpose and clinical qualification 
See the separate biomarker review committee submission sheet. 
 
5.3.1.6 
Collection of Specimen(s) 
3.0-5.0 mL of bone marrow aspirate should be collected in a sodium heparin tube. 
 
5.3.1.7 
Handling of Specimens(s) 
 
Tubes should be inverted gently at least 3 times. 
Tubes may be kept at ambient temperature after collection and during shipment. 
 
5.3.1.8 
Shipping of Specimen(s) 
 
Specimens should be shipped by overnight (but not shipped on a Friday or Saturday) express 
courier to: 
Experimental Hematology Laboratory 
Attn.: NCI-10212 
410 West 12th Ave. Room 417 


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Columbus, OH 43210 
Phone: 614-685-5667 
 
5.3.1.9 
Site(s) Performing Correlative Study: 
LAO-OH007 (Ohio State University) 
 
 
5.3.2 
Studies of Recurrently Mutated Genes by Targeted Capture Panel DNA Sequencing 
 
Upon arrival to OSU, bone marrow blasts from screening, bone marrow at time of count 
recovery, relapse (if applicable), and off-study (if refractory) aspirate will undergo 
immunomagnetic selection for CD34+ blasts, which will be snap frozen for later processing. 
Bone marrow and peripheral blood mononuclear cells from day 8 will also be collected with 
gradient density centrifugation and snap frozen for later processing. At the time of processing, 
DNA will be isolated in the standard fashion. If there is evidence of differentiation from other 
correlative studies, DNA from the day 8 PBMCs will also be prepared for evaluation of mutation 
variant allele frequency in blasts and non-blasts. We will use the Kapa HyperPLUS prep kit 
including enzymatic fragmentation and then ligate custom Illumina compatible forked adapters 
featuring both UMI and 2-sided non-redundant 96x96 sample indexing to the fragmented DNA. 
Indexed DNA will then be pooled and a custom panel of IDT xGen lockdown probes covering 
the entire coding region of 90 genes relevant to AML will be used to capture DNA. Captured 
libraries will be sequenced on an Illumina Hiseq 4000 targeting an average per locus depth of > 
1000X. 
 
5.3.2.1 
Hypothesis and Rationale as it relates to future development 
 
MLL (KMT2A) rearranged acute leukemias are recognized as having fewer driver somatic gene 
mutations compared to other acute leukemia subtypes8,20, likely because the epigenetic influence 
of the MLL fusion has sufficient oncogenic activity. However, there are a subset of cases with 
driver gene alterations, particularly in RAS and STAT pathways. Relapsed and primary 
refractory (to conventional therapy) patients may be enriched for mutations compared to MLL 
rearranged patients with less poor outcomes. Understanding the relationship of potential driver 
mutations present at diagnosis (especially if in small subclones that have expanded at the time of 
relapse or off-study) will help improve patient selection and maximize patient benefit should 
development of pinometostat proceed. 
 
Overall, this biomarker study is anticipated to be hypothesis-generating, rather than testing a 
specific hypothesis and is therefore exploratory. 
 
5.3.2.2 
Intended use 
 
Mutation profiles and temporally differential mutation profiles as they relate to outcome will be 
used to guide effective patient selection and eligibility in future studies of pinometostat to 
maximize patient benefit by enrolling patients who are most likely to benefit and conversely 


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guiding patients who are most likely to be refractory to alternative clinical trials, and to assist in 
the design of alternative combination strategies to overcome resistance 
 
5.3.2.3 
Preclinical in vitro and in vivo data, and clinical results 
Not applicable 
5.3.2.4 
Appropriateness 
 
Mutation-profile-directed therapy is supplanting the all-comers approach to oncology drug 
development, even in the early phase setting. Collection of this data is a necessary prerequisite to 
future rational development of pinometostat in the context of AML. 
 
5.3.2.5 
Fit for purpose and clinical qualification 
 
The OSU Experimental Hematology Lab targeted AML panel has been deployed in the context 
of numerous published studies. See supplementary appendices. 
 
5.3.2.6 
Collection of Specimen(s) 
 
4.0 mL of bone marrow aspirate should be collected in a sodium heparin tube. 
6.0 mL of peripheral blood should be collected in an ACD-A tube. 
 
5.3.2.7 
Handling of Specimens(s) 
 
Tubes should be inverted gently at least 3 times. 
Tubes may be kept at ambient temperature after collection and during shipment. 
 
5.3.2.8 
Shipping of Specimen(s) 
 
Specimens should be shipped by overnight (but not shipped on a Friday or Saturday) express 
courier to: 
Experimental Hematology Laboratory 
Attn.: NCI-10212 
410 West 12th Ave. Room 417 
Columbus, OH 43210 
Phone: 614-685-5667 
 
5.3.2.9 
Site(s) Performing Correlative Study 
LAO-OH007 (Ohio State University) 


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6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an inpatient basis.  Reported adverse events and potential 
risks are described in Section 10. Appropriate dose modifications are described in Section 6. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
A second induction (“reinduction”), if necessary, may be administered and is described in 
separate table below. 
 
6.1.1 
Phase 1b - Safety-Run in Phase 
 
Regimen Description - Cohort 1 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Pinometostat 
Premedications: 
ondansetron, 
dexamethasone 
90 mg/m2/day 
in NS to a final 
concentration 
between 0.54 
mg/ml and 
5.63 mg/ml 
Continuous 
IV infusion 
Days 1-7, 
week 1 
35 days 
(5 weeks) 
Pinometostat 
Premedications: 
ondansetron, 
dexamethasone 
60 mg/m2/day 
in NS to a final 
concentration 
between 0.54 
mg/ml and 
5.63 mg/ml 
Continuous 
IV infusion 
Days 8-35, 
weeks 2-5 
Daunorubicin 
(as “7+3”) 
Premedications: 
ondansetron, 
dexamethasone 
60 mg/m2 in 
50-100 mL NS 
IV over 10-30 
minutes 
Daily, days 
8-10 
Cytarabine 
(as “7+3”) 
Premedications: 
ondansetron, 
dexamethasone 
100 mg/m2/day 
in 1,000 mL 
NS (per day) 
Continuous 
IV infusion at 
rate to 
achieve 
100mg/m2 in 
24 hours 
Days 8-14, 
week 2 
 
Regimen Description - Cohort 2 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Pinometostat 
Premedications: 
90 mg/m2/day 
Continuous 
Days 1-35, 
35 days 


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ondansetron, 
dexamethasone 
in NS to a final 
concentration 
between 0.54 
mg/ml and 
5.63 mg/ml 
IV infusion 
weeks 1-5 
(5 weeks) 
Daunorubicin 
(as “7+3”) 
Premedications: 
ondansetron, 
dexamethasone 
60 mg/m2 in 
50-100 mL NS 
IV over 10-30 
minutes 
Daily, days 
8-10 
Cytarabine 
(as “7+3”) 
Premedications: 
ondansetron, 
dexamethasone 
100 mg/m2/day 
in 1,000 mL 
NS (per day) 
Continuous 
IV infusion at 
rate to 
achieve 
100mg/m2 in 
24 hours 
Days 8-14, 
week 2 
 
6.1.2 
Phase 2 - Expansion Phase 
 
Regimen Description 
Agent 
Premedications 
; Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Pinometostat 
Premedications: 
ondansetron, 
dexamethasone 
Maximum 
tolerated dose 
schedule from 
either Cohort 1 
or Cohort 2 
from Phase 1b 
above 
2 
Continuous 
IV infusion 
Days 1-35, 
weeks 1-5 
35 days 
(5 weeks) 
Daunorubicin 
(as “7+3”) 
Premedications: 
ondansetron, 
dexamethasone 
60 mg/m in 
50-100 mL NS 
IV over 10- 
30 minutes 
Daily, days 
8-10 
Cytarabine 
(as “7+3”) 
Premedications: 
ondansetron, 
dexamethasone 
100 mg/m2/day 
in 1,000 mL 
NS (per day) 
Continuous 
IV infusion 
at rate to 
achieve 
100mg/m2 
in 24 hours 
Days 8-14, 
week 2 
 
6.1.3 
Re-induction in either Safety Run-in Phase or Expansion Phase 
 
If a patient in either phase (Phase 1b Safety Run-in, or Phase 2 Expansion) requires re-induction 
due to not achieving a CR/CRi, they will be treated according to the following schedule. Day 
numbers below refer to a reset calendar where day 1 refers to the first day of re-induction 
chemotherapy. The study treatment then continues for a total of 28 days. 


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Regimen Description 
Agent 
Premedications 
; Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Pinometostat 
Premedications: 
ondansetron, 
dexamethasone 
90 mg/m2/day, 
unless 60 
mg/m2/day has 
been 
previously 
identified as 
the maximum 
tolerated dose 
after 
completion of 
the Safety Run- 
in Phase 
Continuous 
IV infusion 
Days 1-28, 
weeks 1-4 
28 days 
(4 weeks) 
Daunorubicin 
(as “5+2”) 
Premedications: 
ondansetron, 
dexamethasone 
60 mg/m2 in 
50-100 mL NS 
IV over 10- 
30 minutes 
Daily, days 
1, 2 
Cytarabine 
(as “5+2”) 
Premedications: 
ondansetron, 
dexamethasone 
100 mg/m2/day 
in 1,000 mL 
NS (per day) 
Continuous 
IV infusion 
at rate to 
achieve 
100mg/m2 
in 24 hours 
Days 1-5 
 
 
6.1.4 
Pinometostat (CTEP IND Agent) 
 
There are no known prophylactic or supportive care regimens required for pinometostat. 
There are no special precautions or relevant warnings associated with pinometostat. 
Pinometostat is given as IV continuous infusion administered at a constant flow rate for 
up to 90 hours. Pinometostat must be diluted in 0.9% sodium chloride to a final 
concentration between 0.54 mg/ml and 5.63 mg/ml prior to administration. Refer to 
section 8.1 for compatible IV infusion bags and sets. 


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6.1.5 
Daunorubicin and Cytarabine 
 
Supportive care for both cytarabine and daunorubicin involves administering oral 
ondansetron 16 mg every 24 hours for the full 7 days (5 days if in re-induction) of 
treatment, as well as oral dexamethasone 8 mg every 24 hours for the first 3 days (2 days 
if in re-induction) of treatment. For prophylactic treatment patients are given anti-fungal 
prophylaxis with oral posaconazole delayed release tablet beginning after the completion 
of daunorubicin and at a dose of 300 mg twice daily as a loading dose on the starting day, 
followed by 300 mg daily thereafter. Azole prophylaxis should be discontinued temporarily 
(i.e., not to overlap with anthracycline) in the event of re-induction. 
 
Daunorubicin has Y-site intravenous incompatibility with cefepime hydrochloride, 
dexamethasone 
sodium 
phosphate, 
furosemide, 
heparin 
sodium, 
levofloxacin, 
pantoprazole, 
Piperacillin 
sodium-tazobactam 
sodium, 
and 
Sulfamethoxazole- 
trimethoprim among others. Daunorubicin has admixture intravenous incompatibility with 
dexamethasone sodium phosphate and heparin sodium. Cytarabine has Y-site intravenous 
incompatibility with allopurinol sodium, amiodarione, amphotericin B conventional 
colloidal, and daptomycin among others. Cytarabine has admixture intravenous 
incompatibility with heparin sodium, and regular insulin among others. 
 
Daunorubicin should be prepared by injecting the calculated patient dose into 50-100 mL 
of 0.9% (normal) saline, and should be administered over 10-30 minutes in a free-flowing 
IV. The IV push route is not recommended. 
 
Cytarabine should be prepared by diluting the calculated patient daily (24 hour) dose in a 
1,000 mL bag of 0.9% (normal) saline, and administered by continuous IV infusion at a 
rate sufficient to achieve 100 mg/m2 in 24 hours. 
 
6.1.6 
Body Surface Area (BSA) calculation and dose adjustments 
 
BSA should be calculated according to local site standards. If none exists, the widely- 
used formula of Du Bois and Du Bois is suggested: 
 
BSA = 0.007184 x W0.425 x H0.725 
 
Calculation of the BSA should be performed with a height and weight obtained within the 
past 24 hours prior to the start of chemotherapy, but need not be recalculated 
continuously for agents given by continuous infusion, unless weight has changed more 
than 10%. In the case of re-induction treatment, a new calculation should be made. 
 
Doses of chemotherapy agents may be rounded +/- 5%, or less as defined by institutional 
policy, in order to accommodate standard vial sizes and reduce waste. 


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6.1.7 
No lumbar punctures are mandated, and institutional practices and standards of care 
should be followed. Intrathecal chemotherapy given prophylactically should be given 
after platelet recovery from induction therapy. Intrathecal chemotherapy given for 
documented CNS disease may be given at any time at treating physician discretion. 
 
6.1.8 
If, during the pinometostat run-in phase (days 1-7) the disease is uncontrollable (either in 
terms of proliferation, or life-threatening organ dysfunction resulting from disease 
burden) with hydroxyurea in addition to the study agent, 7+3 induction therapy may be 
started early, if in the opinion of the treating physician-investigator that this is necessary 
to save the life of the patient. This decision will be up to the treating physician, but the 
study chair should be informed. 
 
6.2 
Definition of Dose-Limiting Toxicity 
 
DLT Period. DLTs will be evaluated only in the Phase 1b – Safety Run-in Period. The period 
defined for evaluation of DLT is from the first day of pinometostat administration (day 1) to day 
42 after induction, or if a re-induction was attempted, day 42 after re-induction. 
Non Hematologic DLT will be determined based on non-hematologic Grade ≥3 toxicity related 
to the study drug alone or the study drug in combination with chemotherapy that occurs within 
first cycle of the combination. Severity of AEs will be graded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) v5. With the following 
exceptions: Grade 3 fatigue < 7 days; correctable electrolyte abnormalities within 72 hours; 
isolated, asymptomatic AST or ALT (<Grade 4) in the absence of significant bilirubin elevation 
(<Grade 3) that resolves within 7 days of drug hold; isolated, asymptomatic amylase elevation 
(<Grade 4) in the absence of lipase elevation (<Grade 3) that resolves within 7 days of drug hold. 
Pinometostat may be re-initiated in these patients at 60 mg/m2 (no matter whether the patient was 
receiving 90 mg/m2 or 60 mg/m2), and re-escalated (if patient was previously on 90 mg/m2; 
otherwise not applicable) if it does not recur; Grade 3 diarrhea that resolved to ≤ Grade 1 or 
baseline in a week after receiving the maximal supportive therapy based on standard practice Grade 
3 nausea and/ or vomiting (excluding need for TPN) that resolved to ≤ Grade 1 or baseline in a 
week after the use of an optimal antiemetic regimen based on standard practice. 
Hematologic DLT will be provisionally defined as an absolute neutrophil count (ANC) < 500/µL 
by day 42 (of first or second induction if applicable) in patients with < 5% blasts in the bone 
marrow, absence of myelodysplastic changes, and/or absence of evidence of disease by flow 
cytometry in the bone marrow. Neupogen in this setting may be administered. If persistent 
cytogenetic 
abnormalities 
or 
immunophenotypic 
evidence 
of 
leukemia 
is 
present, 
myelosuppression would be considered secondary to leukemia even if morphology shows < 5% 
blasts. Beyond the provisional assignment by day 42, patients who meet above hematologic DLT 
criteria and continue to have neutrophil < 500/µL shall have repeat bone marrow biopsy by day 
56. During this additional 2 week period, patients who continue to meet the hematologic DLT 
criteria shall be DLTs; patients who have evidence of count recovery will not be DLTs. 
For patients with > 5% blasts, myelodysplastic changes, or evidence of disease by flow 
cytometry/cytogenetics, failure to recover neutrophil or platelet count may not be considered DLT 
as this could be the result of persistent disease. 


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Also to be considered as DLT: 1) Failure to administer ≥75% of planned doses (including in the 
denominator days needed for re-induction, if any) of the study drug due to therapy related or 
possibly related non-hematologic toxicities during the defined DLT period. 2) Other related Grade 
2 or greater non-hematological toxicities that, in the opinion of the investigator, require a dose 
reduction or discontinuation of therapy with pinometostat. 
 
All AEs and laboratory toxicities will be graded using the CTCAE version 5. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
Dose escalation will proceed within each cohort according to the following scheme. Dose-limiting 
toxicity (DLT) is defined above. 
Dose escalation will be performed in the usual 3+3 fashion. See Figure 2. Briefly, 3 patients will 
be enrolled on cohort 1. If zero of three patients experience dose-limiting toxicities (DLT), proceed 
to enroll cohort 2. If one of three patients experience DLT, enroll an additional three patients for a 
total of six patients on cohort 1. If still only one of six total patients experience DLT, proceed to 
enroll cohort 2. If 2 or more (of either three total or six total patients) experience DLT, accrual will 
be stopped and a safety review and consideration of further dose level reductions will be discussed 
between PI, CTEP, and stakeholders. Cohort 2 will be evaluated likewise, except that no further 
dose level increases will be made, and if toxicity is unacceptable in cohort 2, the dosing plan for 
cohort 1 will move forward into the expansion phase. Otherwise, the dosing plan for cohort 2 will 
move forward into phase II expansion. 
 
 
6.3 
Monitoring 
 
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. 
 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of pinometostat with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other drugs, over- 
the-counter medications, or alternative therapies. For example, the potential targets for drug 
interaction can involve, but are not limited to CYP450, glucuronidation, P-glycoprotein, protein 
binding, or reduced absorption from proton-pump inhibitors. Check the study agent 
Investigator’s Brochure for potential sources of drug interactions.  The study team should check 
a frequently-updated medical reference for a list of drugs to avoid or minimize use of. As the 
study treatment is given only in the inpatient setting, a Patient Drug Information Handout and 
Wallet Card will not be provided to patients. 


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Pinometostat is metabolized by CYP3A and to a minor extent by CYP2C19. It is a substrate of 
MATE2K and likely a weak substrate for OATP1B3, MATE1, and P-gp. It is a weak to 
moderate inhibitor of CYP3A and also an inhibitor of MATE1 and MATE2K. Use caution when 
administered with strong inhibitors and inducers of CYP2C19, OATP1B3, P-gp, MATE1, and 
MATE2K. Use caution with concomitant use of other CYP3A and MATE1 and MATE2-K 
substrates, especially those with a narrow therapeutic window. 
 
6.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 35 days 
(note that this clock is reset in the event of reinduction and the treatment may continue for up to 
28 days thence) or until one of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.6 
Duration of Follow Up 
 
Patients will be followed until the earliest of progressive disease, allogeneic stem-cell transplant, 
other investigational anti-leukemia therapy including cell therapy given while in remission, or 
lost to follow-up which will lead to removal from the study, or until death, whichever occurs 
first. Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
No intra-patient adjustment of chemotherapy doses is permitted. No intra-patient escalation of 
study drug is permitted, except as outlined below and with permission of principal investigator. 
Dose reduction of pinometostat should occur for grade 3 toxicities possibly related to this agent, 


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excluding hematologic toxicities and select other toxicities that can occur in the phase 2 
expansion portion of the study. These select other toxicities for which a dose adjustment is not 
required include nausea, vomiting, or diarrhea that is manageable without parenteral or enteral 
feeding; electrolyte abnormalities that are correctable within 48 hours; and grade 3 infections 
which are expected in this population. 
 
Daunorubicin and cytarabine are only rarely held during the seven-day intensive induction 
therapy for AML. Dose modifications to daunorubicin or cytarabine are not recommended for 
treatment-emergent adverse events, and should be discussed with the principal investigator. For 
patients with a total bilirubin between 1 and 1.5xULN, the daunorubicin dose may be decreased 
by 75% after discussion with the principal investigator. 
 
 
Event 
Management/Next Dose for Pinometostat 
≤ Grade 1 
Full dose 
Grade 2 
Full dose 
Grade 3 
Hold until recovery of < grade 3, then re-initiate with a one-third dose 
reduction. For example, if the dose was 90 mg/m2/day, re-initiate at 60 
mg/m2/day. If the dose was 60 mg/m2/day, re-initiate at 40 
mg/m2/day. If toxicity reoccurs, therapy should be discontinued. 
See exceptions in section 6, Dose Limiting Toxicities 
Grade 4 
Discontinue therapy permanently. 
 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 10.1. 
 
 
8.1 
CTEP IND Agent 
 
8.1.1 
Pinometostat (NSC #795144) 
 
Chemical Name or Amino Acid Sequence: (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5- 
((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl) 
amino)methyl)tetrahydrofuran-3,4-diol 
 
Other Names: EPZ-5676, EPZ005676 
 
Classification: DOT1L inhibitor 
 
CAS Registry Number: 1380288-87-8 
 
Molecular Formula: C30H42N8O3 
M.W.: 562.71 g/mol 


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Mode of Action: Pinometostat is a selective human DOT1-like, histone H3 methyltransferase 
(DOT1L) inhibitor. Pinometostat exhibits concentration and time depending inhibition of global 
methylation of lysine 79 of histone H3 (H3K79) in cultured cells. Pinometostat induces apoptosis in 
cells that accumulate in the G1/G0 phase. It also inhibits the expression of the key MLL fusion target 
genes HOXA9 and MEIS1. 
 
Description: A clear to yellow liquid adjusted to a pH of 5.2-6.2 with 1N sodium hydroxide or 1N 
hydrochloric acid as needed. 
 
How Supplied: Pinometostat is supplied by Epizyme, Inc. and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI. Pinometostat injection is provided as 100 mg/10 mL (10 
mg/ml) solution in type 1 borosilicate glass serum single use vials closed with butyl rubber 
stoppers and aluminum overseals. The other components of the vial include hydroxypropyl betadex, 
citric acid, anhydrous, sodium hydroxide, hydrochloric acid, and water for injection. 
 
Preparation: Pinometostat must be diluted with 0.9% sodium chloride injection, USP prior to 
administration to a final concentration between 0.54 mg/ml and 5.63 mg/ml. Add the calculated dose 
of pinometostat to the appropriate volume of 0.9% sodium chloride in a non-DEHP PVC, polyolefin, 
or EVA IV infusion bag. Note: mixing of different drug lots in the same infusion bag should be 
avoided. Then gently agitate the infusion bag to ensure mixing. Up to a 90-hour dose may be prepared. 
An overfill volume of 10% or per institution policy can be prepared to allow for priming of the 
infusion set tubing. Sites should prepare the appropriate final infusion volume according to standard 
practice based on a constant flow rate. 
 
Storage: Store intact vials at room temperature between 15 °C -30 °C. 
 
If a storage temperature excursion is identified, promptly return pinometostat to 15 °C -30 
°C 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. The diluted solution for infusion can be stored for no more 
than 4 hours at room temperature or for no more than 24 hours stored refrigerated at 2-8 °C prior to 
infusion. The intravenous infusion is stable at room temperature and can be infused for a maximum 
of 90 hours. The total time in bag including both preparation and infusion time should not exceed 114 
hours. The infusion must be completed within 114 hours after infusion bag preparation. 
 
Route and Method of Administration: Continuous, intravenous infusion via central venous catheter 
with a pump for up to 90 hours at a constant flow rate. Compatible IV infusion sets are non-DEHP 
PVC, polyolefin, or EVA with or without a 0.2-micron filter. 
 
Potential Drug Interactions: Pinometostat is metabolized in vitro predominantly by CYP3A with a 
minor contribution from CYP2C19. It is also a substrate for MATE2-K and likely a weak substrate 
for OATP1B3, MATE1, and P-gp. Pinometostat is not a substrate for OCT1, OCT2, OATP1B1 or 
BCRP. Use of strong CYP3A inhibitors and inducers should be avoided. Use caution when 
administered with strong inhibitors and inducers of CYP2C19, OATP1B3, P-gp, MATE1, and 


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MATE2-K. 
 
Pinometostat is a weak to moderate inhibitor of CYP3A4/5 in vitro. Pinometostat is an inhibitor of 
MATE1 and MATE2-K in vitro but not CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, P-gp, BCRP, OAT1, 
OAT3, OCT1, OCT2, OATP1B1, OATP1B3 or BSEP. Use caution with concomitant use of other 
CYP3A and MATE1 and MATE2-K substrates, especially those with a narrow therapeutic window. 
 
Pinometostat is not an inducer of CYP1A2, 2B6, or 3A4/5 activity or mRNA levels. 
 
Patient Care Implications: Women of child-bearing potential (WOCP) must use acceptable 
contraceptives while on pinometostat and for 4 weeks after the last dose of pinometostat. Males with 
partners that are WOCP must use acceptable methods of contraception while on pinometostat and for 
90 days after the last dose of pinometostat. It is unknown if pinometostat is excreted in breast milk 
so should not be administered to nursing mothers. 
 
8.1.1.1 
Availability 
 
Pinometostat is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Pinometostat is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.4). 
 
8.1.1.2 
Agent Ordering and Agent Accountability 
 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution. The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents. The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF). If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for enrollment 
onto the study. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status. For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time. Refer to the PMB’s website for specific policies and guidelines 
related to agent management. 
 
8.1.1.3 
Agent Inventory Records 


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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. 
 
8.1.1.4 
Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application. Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password 
and active person registration status. Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.1.5 
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 
 IB Coordinator: IBCoordinator@mail.nih.gov 
 PMB email: PMBAfterHours@mail.nih.gov 
 PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
8.2 
Commercial Agents 
 
8.2.1 
Cytarabine 
 
Product description: Cytarabine Injection, an antineoplastic, is a sterile solution of cytarabine 
for intravenous and subcutaneous use which contains no preservative and is available in 20 
mg/mL (1000 mg/50 mL) Pharmacy Bulk Package. Each mL contains 20 mg Cytarabine, USP 
and the following inactive ingredients: sodium chloride 0.68% and Water for Injection q.s. When 
necessary, the pH is adjusted with hydrochloric acid and/or sodium hydroxide to a target pH of 
7.4. Each vial contains approximately 5.82 mEq sodium. Cytarabine is chemically 4-amino-1- β- 
Darabinofuranosyl- 2(1H)-pyrimidinone. Cytarabine is an odorless, white to off-white, 
crystalline powder which is freely soluble in water and slightly soluble in alcohol and in 
chloroform. Cytarabine Injection (non-preserved) can be administered by intravenous injection 
or infusion, subcutaneously, or intrathecally. Cytarabine is commercially available. 
 
Solution preparation: A Pharmacy Bulk Package is a container of a sterile preparation for 
parenteral use that contains many single doses. The contents are intended for use in a pharmacy 


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admixture program and are restricted to the preparation of admixtures for intravenous infusion. 
Store the vial at 20°C to 25°C (68°F to 77°F). Do not refrigerate. Protect from light. Withdraw 
the desired dose into a syringe and further dilute in 250 to 1000 mL of 0.9% Sodium Chloride or 
D5W. Store the diluted product for administration at 20°C to 25°C (68°F to 77°F) and use within 
24 hours. 
 
Route of administration: Continuous intravenous infusion 
 
Agent Ordering: Product is commercially available. 
 
8.2.2 
Daunorubicin 
 
Product description: Daunorubicin hydrochloride is the hydrochloride salt of an anthracycline 
cytotoxic antibiotic produced by a strain of Streptomyces coeruleorubidus. It is provided as a 
deep red sterile liquid in vials for intravenous administration only. Each mL contains 5 mg 
daunorubicin (equivalent to 5.34 mg of daunorubicin hydrochloride), 9 mg sodium chloride; 
sodium hydroxide and/or hydrochloric acid (to adjust pH), and water for injection, q.s. It has the 
following structural formula which may be described with the chemical name of (1S,3S)-3- 
Acetyl-1,2,3,4,6,11-hexahydro- 
3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy- 
α-L-lyxo-hexopyranoside hydrochloride. Its molecular formula is C27H29NO10•HCl with a 
molecular weight of 563.99. It is a hygroscopic crystalline powder. The pH of a 5 mg/mL 
aqueous solution is 4 to 5. 
 
Solution preparation: The desired dose can be given as a slow IV push or is withdrawn into a 
syringe containing 10 mL to 15 mL of 0.9% Sodium Chloride Injection, USP Daunorubicin 
should not be administered mixed with other drugs or heparin. Store intact vials at 2°C to 8°C 
(36°F to 46°F). Protect from light. Retain in carton until time of use. Solution prepared for 
infusion in D5W or NS may be stored at 20°C to 25°C (68°F to 77°F) for up to 24 hours. Discard 
unused portion. 
 
Route of administration: For IV administration only. Do not administer IM or SubQ. Dilute 
further into a total of 50-100 mL 0.9% (normal) saline and infuse over 10 to 30 minutes. Refer to 
the package insert for extravasation management. 
 
Agent Ordering: Product is commercially available. 
 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
This study is a multi-site phase 1b/2 study designed to confirm a safe and tolerable dose of 
pinometostat and to gauge preliminary evidence of efficacy when given as lead-in prior to and 
contemporaneous with standard intensive induction therapy for newly diagnosed AML with 
MLL rearrangement. The study design involves a brief safety run-in phase exploring two dosing 


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schemes, followed by a phase II efficacy expansion. The phase II expansion will use the higher 
dose-level of the two schedules if tolerated (see definitions below), otherwise, the lower dose- 
level if tolerated. The phase 1b/safety run-in portion will have a primary endpoint of dose 
limiting toxicity, while the phase 2 portion will have a primary endpoint of complete remission / 
complete remission with incomplete count recovery attainment, and will gather additional 
laboratory correlative data. 
 
The phase 1b safety run-in phase involves dividing patients into two cohorts (cohort 1 and cohort 
2) after appropriate screening. The goal will be to identify a maximum tolerated dose for 
expansion. Dose escalation will occur in the standard cohorts-of-3/3+3 design, which is 
described below. Cohort 1 will comprise of 3-6 patients and will be treated with pinometostat 90 
mg/m2 continuous IV infusion (CIVI) on days 1-7, then decrease dose to 60 mg/m2 CIVI for 
days 8-35, along with daunorubicin 60 mg/m2 daily on days 8-10 and cytarabine 100 mg/m2 
CIVI on days 8-14. Cohort 2 will comprise of 3-6 patients and will be treated with pinometostat 
90 mg/m2 CIVI on days 1-35, along with daunorubicin 60 mg/m2 daily on days 8-10 and 
cytarabine 100 mg/m2 CIVI on days 8-14. 
 
Safety and tolerability evaluation and dose escalation for phase 1b will be performed in the usual 
3+3 fashion. See Figure 1. Briefly, 3 patients will be enrolled on cohort 1. If zero of three 
patients experience dose-limiting toxicities (DLT) on pinometostat, proceed to enroll cohort 2. If 
one of three patients experience DLT, enroll an additional three patients for a total of six patients 
on cohort 1. If still only one of six total patients experience DLT, proceed to enroll cohort 2. If 2 
or more (of either three total or six total patients) experience DLT, accrual will be stopped and a 
safety review and consideration of further dose level reductions will be discussed between PI, 
CTEP, and stakeholders. Cohort 2 will be evaluated likewise, except that no further dose level 
increases of pinometostat will be made, and if toxicity is unacceptable in cohort 2, the dosing 
plan of pinometstat for cohort 1 will move forward into the expansion phase. Otherwise, the 
dosing plan for cohort 2 will move forward into phase II expansion. The highest dose of 
pinometostat that is tolerated as described here will be considered the maximally tolerated dose 
(MTD). 
 
 
Figure 1. A standard 3+3 dose escalation. With only two cohorts (dose levels), escalation stops 


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42 
 
 
after cohort 2; if 2-3/3 DLT at dose level 1 (cohort 1), a safety review will be initiated to decide 
whether dose level reductions below the starting dose should be considered. 
 
The phase 2 expansion phase will use the maximum tolerated dose/schedule as determined by 
phase1b above and accrue additional patients to gather preliminary evidence of efficacy. Patients 
will be treated in the same manner as in the phase 1b portion above, with the exception that only 
a single dose level/cohort will be expanded. 
 
The expansion cohort will comprise 4-25 patients who will be treated at the maximum tolerated 
dose schedule (see below; phase 1b patients who were treated at the MTD will be included in the 
statistical analysis of efficacy together with phase 2 patients, which in total comprises 10-31 
patients). 
 
Patients requiring re-induction, if any, will be treated at the assigned dose of pinometostat. 
Patients undergoing re-induction treatment will be analyzed jointly with patients not requiring re- 
induction for analysis of the primary efficacy endpoint, but a subgroup analysis consisting only 
of patients who did/did not require a second induction may be conducted. 
 
The primary efficacy objective is to calculate the rate of complete response (CR) or complete 
response with incomplete count recovery (CRi) after combination treatment and the primary 
efficacy hypothesis is that the rate of CR will be higher than among historical controls. 
H0: The CR rate is ≤ 65% 
Ha: The CR rate is ≥ 85% 
We will use a Simon two-stage design (minimax) to test the hypothesis that the CR rate is greater 
than 65%. Assuming that the true CR rate among those treated is at least 85%, and setting type I 
and type II error rates to 10% (yielding alpha=beta=0.1), we will enroll 13 patients in the first 
stage. If 8 or fewer responses are observed during stage 1, the study will be stopped early. If 
there are 9 or more responses, an additional 18 patients will be enrolled in stage 2 for a total of 
31 patients. At the completion of the second stage, the drug will be declared efficacious and the 
probability of an unacceptable CR rate ≤ 64% ruled out if at least 24 CRs are observed out of all 
31 patients. This design has a 90% power to correctly rule out a CR rate ≤ 65% if the true rate is 
85%, with a type 1 error rate of 0.0951. 
 
N 
31 
n1 
13 
r1 
8 
n2 
18 
r2 
23 
NOTE: Patients treated at the maximum tolerated dose in the phase 1b portion (3, or 6) will be 
counted toward the total needed to satisfy the statistical design. This means that possible total 
accrual ranges for the whole trial are not [6, 12+31] = [6, 43] but [6, 12 + 31 - 6] = [6, 37] 
 
For both phases, early response evaluation will occur at day 21 (day 14 of 7+3) with a bone 
marrow examination, and if > 5% myeloid blasts are seen, or ≤ 5% myeloid blasts but with an 


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43 
 
 
aberrant immunophenotype matching the pretreatment immunophenotype, a re-induction attempt 
may be made with 5 and 2 days of cytarabine and daunorubicin, respectively, both medications 
at the same doses as initial induction. Pinometostat will be given at 90 mg/m2, unless 60 mg/m2 
was previously established as the RP2D, in which case it shall be given at 60 mg/m2. The clock 
will be reset, and pinometostat will be administered for an additional 28 days (unless stopped 
early for reasons of toxicity, withdrawal from study, or death). 
 
Exploratory pharmacodynamics biomarkers will be collected at screening, at day 8, and at 
relapse if applicable for both phases (these are described above). 
 
Length of study treatments 
Study treatment will end after either 35 days (first induction) or 28 days (with calendar reset to 
day 1 on the first day of 5+2 in second induction attempt) of pinometostat. Patients should then 
receive standard of care consolidative therapy including allogeneic bone marrow transplant, but 
these are not considered study treatments. No specific consolidation is mandated. 
 
Follow-up period 
Patients will be followed until the soonest of death, alternative leukemia therapy (i.e. for relapsed 
or refractory disease; this is excluding the planned consolidation that may directly follow the 
study treatment) initiated, enrollment on another therapeutic clinical trial, bone marrow 
transplantation, voluntary or involuntary withdrawal from study (see section 6.5) or lost to 
follow-up. 
 
Toxicity assessment 
All patients who receive any amount of the study drug will be evaluable for toxicity. Toxicity 
will be graded and reported according to the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5. The CTEP Active Version of the CTCAE is identified and located on the 
CTEP website at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTEP Active Version of 
CTCAE. 
 
It is recognized that drug-related toxicity in this population may be difficult to ascertain, given 
the aggressive hematologic disease. Investigators will attempt to assign attribution of toxicities to 
each drug if possible. Toxicity attributed to any of the three agents will be considered dose 
limiting. Dose limiting toxicity will be divided into non-hematologic and hematologic toxicity. 
Dose-limiting toxicity 
Definitions of dose-limiting toxicities are in section 6.2. 
 
Patients who receive at least 1 dose of pinometostat during cycle 1 will be considered to be 
evaluable for toxicity/DLT and will not be replaced during the dose escalation phase of the trial 
unless the PI determines that further additional patients at that dose level are required for safety 
purposes; the context in which DLTs are noted (before or after the introduction of 7+3) will be 
considered in this decision. Patients with transient liver function test abnormalities (AST, ALT, 
bilirubin, or alkaline phosphatase) that resolve to < grade 1 within 5 days will not be considered 
DLT. Infection will not constitute DLT unless it is felt that the infection resulted from 


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unexpectedly complicated myelosuppression (degree or duration). 
 
 
9.2 
Sample Size/Accrual Rate 
 
The planned sample size for both the phase 1b/2 portions is between 6 and 37 patients, and the 
planned accrual rate is 1/month/site (4-6 monthly across ETCTN) based on data from similar 
trials completed by our organization during the previous 5 years. 


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45 
 
 
PLANNED ENROLLMENT REPORT, PHASE 1b 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
1 
1 
0 
0 
2 
White 
4 
4 
1 
1 
10 
More Than One Race 
0 
0 
0 
0 
0 
Total 
5 
5 
1 
1 
12 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
OMB No. 0925-0001/0002 


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46 
 
 
PLANNED ENROLLMENT REPORT, PHASE 2 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
2 
2 
0 
0 
4 
White 
8 
10 
1 
2 
21 
More Than One Race 
0 
0 
0 
0 
0 
Total 
10 
12 
1 
2 
25 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
OMB No. 0925-0001/0002 
 
 
9.3 
Analysis of Secondary Endpoints 
 
Secondary endpoints we are evaluating are: 
 
• Toxicity frequencies for each patient, according to CTCAE v5 
• Time to hematologic count recovery will be analyzed using lab evaluation of complete 
blood counts and differential 
• Differential blast counts between screening and day 8 will be analyzed using lab 
evaluation of complete blood counts and differential 
• Rate of MRD positivity will be evaluated by multiparameter flow cytometry, next- 
generation sequencing (or both) after induction therapy among those patients who attain 
morphologic and cytogenetic CR 
• Progression free survival for all patients, defined as the time from the start of study 
treatment until progression or death, whichever occurs earliest. Patients will be censored 
at earliest of loss to follow-up, allogeneic stem-cell transplantation, or initiation of other 
anti-leukemia therapy when in remission 
• Overall survival for all patients 


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47 
 
 
Every report will contain all patients included in the study. For the response calculation, the 
report will contain at least a section with all eligible patients. Another section of the report may 
detail the response rate for evaluable patients only.  The maximum grade for each type of 
toxicity will be recorded for each patient, and frequency tables will be reviewed to determine 
toxicity patterns. CR rate and Rate of MRD positivity will be calculated with the exact binomial 
95% confidence intervals. The Kaplan-Meier method will be used to estimate time to progression 
and overall survival. 
 
9.4 
Phase 2 portion: Reporting and Exclusions 
 
9.4.1 
Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with pinometostat. 
 
9.4.2 
Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are later deemed ineligible. Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) stable 
disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). 
[Note: By arbitrary convention, category 9 usually designates the “unknown” status of any type 
of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be 
protocol specific. 
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. The 95% confidence intervals should also be provided. 
 
Analysis of all correlative studies during this trial will be exploratory. Descriptive statistics 
(means, medians, standard deviations, interquartile ranges) and graphical explorations will be 
used to characterize central tendency and variability over time. Values will be log transformed as 
appropriate to reflect biologic plausibility. 
 
10. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 


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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 adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
10.1.1 CAEPRs for CTEP IND Agent(s) 
 
10.1.1.1 
CAEPR for pinometostat 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR)  
for  
Pinometostat (EPZ-5676, NSC 795144) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. 
In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting 
(SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. The CAEPR does not provide frequency data; refer to the Investigator's Brochure for this 
information. Below is the CAEPR for Pinometostat (EPZ-5676). 
 
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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 Version 1.1, January 7, 20191 
Adverse Events with Possible Relationship to Pinometostat  
(EPZ-5676) (CTCAE 5.0 Term) 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
  
Febrile neutropenia 
 Febrile neutropenia (Gr 2) 
Leukocytosis 
  
CARDIAC DISORDERS 
  
Heart failure 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
  
Nausea 
  
Vomiting 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
  
INVESTIGATIONS 
  
Alanine aminotransferase increased 
  
Aspartate aminotransferase increased 
  
Blood bilirubin increased 
  
Electrocardiogram QT corrected interval prolonged 
  
Lymphocyte count decreased 
  
Neutrophil count decreased 
  
Platelet count decreased 
  
White blood cell decreased 
  
METABOLISM AND NUTRITION DISORDERS 
  
Hypocalcemia 
  
Hypophosphatemia 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Rash maculo-papular 
  
 
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 pinometostat (EPZ-5676) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that pinometostat (EPZ-5676) caused the adverse 
event: 
 
CARDIAC DISORDERS - Cardiac arrest 
EYE DISORDERS - Periorbital edema 
GASTROINTESTINAL DISORDERS - Colitis; Constipation; Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Generalized edema; 
Localized edema; Malaise; Multi-organ failure 
INFECTIONS AND INFESTATIONS - Device related infection; Folliculitis; Fungemia; Lung infection; Sepsis; 
Thrush 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; Ejection fraction decreased; INR 
increased; Investigations - Other (ECG PR prolongation); Investigations - Other (ejection fraction increased); 
Investigations - Other (increase in polymorphonuclear neutrophils and/or monocytes) 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Hyperkalemia; Hypermagnesemia; Hypernatremia; 
Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Tumor lysis syndrome 


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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Pain in extremity 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Headache; Intracranial hemorrhage; Ischemia 
cerebrovascular; Lethargy; Presyncope; Tremor 
PSYCHIATRIC DISORDERS - Irritability 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Apnea; Cough; Hypoxia; Pleural effusion; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (tachypnea); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Pruritus 
VASCULAR DISORDERS - Hematoma; Hypertension 
 
 
Note: Pinometostat (EPZ-5676) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
10.1.2 Adverse Event List(s) for Commercial Agent(s) 
 
10.1.2.1 
Cytarabine 
 
Adverse events that are most likely to occur with cytarabine on this study are: blood clot, rash, 
swelling in the rectum which may cause rectal pain, diarrhea, loss of appetite, nausea, vomiting, 
sores in mouth which may cause difficulty swallowing, anemia which may cause tiredness, or 
may require blood transfusions, and fever. Please refer to the package insert for the 
comprehensive list of adverse events. 
 
10.1.2.2 
Daunorubicin 
 
Adverse events that are most likely to occur with cytarabine on this study are: pink or red 
colored urine, sweat, or saliva, nausea, vomiting, cytopenias, and hair loss. Please refer to the 
package insert for the comprehensive list of adverse events. 
 
 
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 web site 
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 10.1.1.1) should be reported through CTEP-AERS only if 
the grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 10.3.4. 
 
• Attribution of the AE: 


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- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps- 
ctep.nci.nih.gov/ctepaers). The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm . 
These requirements are briefly outlined in the tables below (Section 10.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 


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made to CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
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. 
 
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 


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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 
 
 
10.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
All SAEs, regardless of causality, must be reported to the OSU PI and Multi-Institution 
Coordinator within 24 hours of knowledge of the event. Initial 24-hour notification using 
secure email or fax is acceptable. For SAEs not requiring expedited reporting via CTEP-
AERS, a complete report accompanied by the SAE Submission Form (refer to 
Supplemental Forms Document) must be submitted to the OSU PI and Multi-Institution 
Coordinator via secure email or fax within 5 days of knowledge of the event. 
 
All sites will directly report SAEs requiring expedited reporting to CTEP  as outlined  in  
the previous sections. 
 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS. However, they still must be reported through the routine reporting 
mechanism (Section 10.4): 
 
CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
Infection 
Any 
Any 
Regardless 
Blood and lymphatic system 
disorders 
Anemia 
Bone marrow hypocellular 
Any 
Regardless 


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CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
Investigations 
Lymphocyte count decreased 
Neutrophil count decreased 
Platelet count decreased 
White blood cell decreased 
Any 
Regardless 
Cardiac disorders 
Heart failure 
Any 
Regardless 
Gastrointestinal disorders 
Mucositis oral 
Any 
Regardless 
Renal and urinary disorders 
Urine discoloration 
Any 
Regardless 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient. 
 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS. In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP. 
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
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 


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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 should also be reported via the routine 
reporting mechanisms outlined in each protocol. Given that this treatment protocol is for primary 
acute myeloid leukemia, it is not anticipated that any secondary leukemia or MDS should be 
reported. 
 
 
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. 
 
11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy. In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated in 
order to decide if therapy should be continued. 


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Table 11.1: Initial treatment plan. 
 
Pre-Study 
/       
Screening 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Off Studyc 
Long Term 
Follow-Upf 
Pinometostat 
A 
A 
A 
A 
A 
Cytarabine 
B 
Daunorubicin 
C 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Height and Weight 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
CBC w/diff, plts, PT/INR, aPTT 
X 
X 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
X 
EKG (as indicated) 
X 
Echocardiogram/MUGA 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
B-HCG 
Xb 
Bone marrow aspiration and 
biopsy 
X 
X 
X 
Xd 
Bone marrow metphase karyotype 
X 
X 
X 
Xd 
Bone marrow MLL (KMT2A) 
translocation by FISH 
X 
X 
X 
Xd 
Immunophenotyping (BM and PB) 
X 
X 
Xd 
Differentiation analysis 
X 
Xe 
Xd 
Comprehensive mutational profile 
X 
Xe 
Xd 
X 
Survival 
Xf 
A: Pinometostat: Dose as assigned; weeks 1-5, days 1-35 
B: 
Cytarabine: 100 mg/m2 continuous IV infusion; week 2, days 8-14 
C: Daunorubicin: 60 mg/m2 IV; daily days 8-10 of week 2 
a 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, uric acid, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium. 
b. 
Serum or urine pregnancy test (women of childbearing potential). 
c. 
Off-study evaluation. 
d. 
And at count recovery in week 5 or beyond 
e. 
Day 8 of week 2, and at relapse (if applicable) 
f. 
Long-term follow-up for survival should be conducted at least monthly after patient has completed treatment and should include reporting of 
survival, subsequent therapy, transplant (if performed). This should be done in person if patient is being followed clinically at the treating center, or 
by telephone otherwise. After 1 year, this can be done every 3 months. After 5 years, further follow-up is not required. 


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Table 11.2: Treatment plan for re-induction. 
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Off Studyc 
Long Term 
Follow-Upg 
Pinometostat 
A 
A 
A 
A 
Cytarabine 
B 
Daunorubicin 
C 
Concurrent meds 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
Height and Weight 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
CBC w/diff, plts, PT/INR, aPTT 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
Echocardiogram/MUGAf 
Xf 
Adverse event evaluation 
X 
X 
X 
X 
Bone marrow aspiration and 
biopsy 
X 
Xd 
Bone marrow metphase karyotype 
X 
Xd 
Bone marrow MLL (KMT2A) 
translocation by FISH 
X 
Xd 
Immunophenotyping (BM and PB) 
X 
Xd 
Differentiation analysis 
Xe 
Xd 
Comprehensive mutational profile 
Xe 
Xd 
X 
Survival 
Xg 
A: Pinometostat:  Dose as assigned; weeks 1-4, days 1-28 of a “reset” calendar where day 1 is the start of 5+2 reinduction 
B: 
Cytarabine: 100 mg/m2 continuous IV infusion; days 1-5 of re-induction 
C: Daunorubicin: 60 mg/m2 IV; daily days 1,2 of re-induction 
a 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, uric acid, LDH, phosphorus, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium. 
b. 
Serum pregnancy test (women of childbearing potential). 
c. 
Off-study evaluation. 
d. 
At count recovery in week 4 or beyond 
e. 
Day 8 of week 2, and at relapse (if applicable), and off-study 
f. 
Echocardiogram or MUGA should demonstrate EF ≥45% before the second induction cycle (“re-induction”) is initiated 
g. 
Long-term follow-up for survival should be conducted at least monthly after patient has completed treatment and should include reporting of survival, 
subsequent therapy, transplant (if performed). This should be done in person if patient is being followed clinically at the treating center, or by telephone otherwise. 
After 1 year, this can be done every 3 months. After 5 years, further follow-up is not required. 


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12. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of this drug 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 daily during their admission for induction chemotherapy and then 
no less than every four weeks, depending on clinical context, after discharge. 
 
12.1 
Antitumor Effect – Hematologic Tumors 
 
Complete Remission (CR; with minimal residual disease or unknown): Bone marrow blasts 
<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; 
ANC ≥1.0 x 109 /L; platelet count ≤100 x 109 /L 
 
CR without minimal residual disease (CR without MRD): If studied pretreatment, CR with 
negativity for a genetic marker by RT-qPCR, or CR with negativity by multiparameter flow 
cytometry (MFC) 
 
CR with incomplete hematologic recovery (CRi): All CR criteria except for residual neutropenia 
(ANC ≥1.0 x 109 /L) or thrombocytopenia (platelet count ≤100 x 109 /L) 
 
Morphologic leukemia-free state (MLFS): Bone marrow blasts <5%; absence of blasts with Auer 
rods; absence of extramedullary disease; no hematologic recovery required. Marrow should not 
merely be “aplastic”; at least 200 cells should be enumerated or cellularity should be at least 
10%. 
 
Partial remission (PR): All hematologic criteria of CR; decrease of bone marrow blast percentage 
to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50% 
 
Primary refractory disease: No CR or CRi after 2 courses of intensive induction treatment; 
excluding patients with death in aplasia or death due to indeterminate cause 
 
Stable disease: Absence of CR without MRD, CR, CRi , PR, MLFS; and criteria for progressive 
disease not met. Period of stable disease should last at least 3 months. 
 
Progressive disease: Evidence for an increase in bone marrow blast percentage and/or increase of 
absolute blast counts in the blood: >50% increase in marrow blasts over baseline (a minimum 
15% point increase is required in cases with <30% blasts at baseline; or persistent marrow blast 
percentage of >70% over at least 3 months; without at least a 100% improvement in ANC to an 
absolute level >0.5 x 109 /L, and/or platelet count to >50 x 109 /L non-transfused); or >50% 
increase in peripheral blasts (WBC x % blasts) to >25 x 109/L (in the absence of differentiation 
syndrome); or New extramedullary disease 


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12.2 
Other Response Parameters 
 
Rate of Death before 30 days after starting treatment protocol 
 
Death in aplasia: Deaths occurring ≥7 d following completion of initial treatment while 
cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 days of death, without 
evidence of persistent leukemia 
 
Death from indeterminate cause: Deaths occurring before completion of therapy, or <7 days 
following its completion; or deaths occurring ≥7 days following completion of initial therapy 
with no blasts in the blood, but no bone marrow examination available 
 
Hematologic relapse (after CR without MRD, CR, CRi): Bone marrow blasts ≥5%; or 
reappearance of blasts in the blood; or development of extramedullary disease 
 
Molecular relapse: If studied pretreatment, reoccurrence of MRD as assessed by RT-qPCR or by 
multiparameter flow cytometry 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section. The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s). 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. 
 
For a Phase 1/2 trial, enrollment to the Phase 2 portion of the trial will not begin until a protocol 
amendment has been submitted which summarizes the Phase 1 results, the recommended Phase 2 
dose, and the rationale for selecting it.  The amendment must be reviewed and approved by 
CTEP before enrollment to the Phase 2 portion can begin. 
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 


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Officer(s) to review accrual, progress, and pharmacovigilance. Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study. This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave. Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS). To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA Lab Admin, SLA or Site Investigator) on 
either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA 
role or CRA Lab Admin role, the user must hold a minimum of an AP registration type. To hold 
the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR. 
Associates can hold read-only roles in Rave. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e- 
mail at ctsucontact@westat.com. 
 
13.2.1 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 


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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) 799-7580 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave. 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. 
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received. Queries will be issued by CTMS directly within Rave. The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. Monthly web- 
based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D) and a description of any dose-limiting toxicities (DLTs). CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and- 
semantics/metadata-and-models). Customized eCRFs will be included when appropriate to meet 
unique study requirements. The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation. CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly 
basis. The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 


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above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
13.3 
Data and Safety Monitoring 
 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness. Investigators will conduct continuous review of data and patient safety at 
their regular Disease Group meetings and the discussion will be documented in minutes. For 
each cohort, the PI, study coordinator, and statistician, in consultation with treating physicians 
as appropriate will review all toxicities at a given dose level to inform the model for dose level 
adjustments. The PI of the trial will review toxicities and responses of the trial where applicable 
at these disease center meetings and determine if the risk/benefit ratio of the trial changes. 
Frequency and severity of adverse events will be reviewed by the PI and compared to what is 
known about the agent/device from other sources; including published literature, scientific 
meetings and discussions with sponsors, to determine if the trial should be terminated before 
completion. 
Serious adverse events will be reviewed by the OSUCCC Data and Safety Monitoring 
Committee (DSMC). All reportable SAEs will be reported to the IRB of record as per the 
policies of the IRB. 
 
Safety and trial review teleconferences will be scheduled and moderated by the Multi-Institution 
Program. All sites involved in the study are required to have a representative present every 2 
weeks to review and discuss patients on study and other applicable agenda items. Meeting 
minutes will be used to document each teleconference. The minutes will be stored in the Multi- 
Institution Program protocol files at OSU. 
 
 
13.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 


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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 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non- 
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review. Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 


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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. 
 
13.5 
Genomic Data Sharing Plan 
 
Data Sharing Plan for CTEP study NCI#10212 
 
Acute Myeloid Leukemia is a devastating, difficult-to-treat, and rarely cured malignancy. The 
timely and accurate dissemination of data generated as part of this project is critical to ensure the 
broadest possible access for researchers to advance the field. 
 
What data will be generated: 
We will generate targeted DNA resequencing ( < 100 genes ), and mass cytometry (CyTOF) data 
from patient tumor and blood samples at different time points. We may generate RNA- 
sequencing and chromatin profiling (e.g. ChIP-seq) in the future. We do not plan to generate 
whole-genome or whole-exome sequencing data. The risk of reidentification is therefore low. 
 
What data will be shared: 
We will share joint phenotypic and genotype data associated with the patient samples by 
depositing these data as controlled-access dataset(s) in dbGaP (and Genomic Data Commons 
[GDC] if permitted), which is an NIH-funded repository that has appropriate controls for 
protection of data. Additional data documentation and de-identified data will be deposited for 
sharing along with phenotypic data, which includes demographics (unless a HIPAA protected 
health identifier), clinical data including cytogenetic studies, and pertinent medical history, 
consistent with applicable laws and regulations. We will comply with the NIH Genomic Data 
Sharing Policy (as outlined in NOT-OD-14-124 and updates) and the NCI’s existing policies on 
sharing data on genetics to include secondary analysis of data through the repository. Submitted 
data will conform to relevant data and terminology standards. Data and associated interpretations 
will be made available in scientific presentations at local, national, and international meetings, 
and in published form, on an ongoing basis. 
 
Who will have access to the data: 
We agree that data will be deposited and made available through dbGaP (and possibly GDC) 
which is an NIH-funded repository, and that protected data in dbGaP/GDC will be shared with 
investigators working under an institution with a Federal Wide Assurance (FWA) and could be 
used for secondary study purposes such as finding genes that contribute to AML pathobiology. 
We agree that the names and Institutions of persons either given or denied access to the data, and 
the bases for such decisions, will be summarized and shared with CTEP. Meta-analysis data and 
associated phenotypic data, along with data content, format, and organization, will be made 


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available to investigators. All relevant analyses and interpretations will be disseminated as 
posters, presentations, and papers. 
 
Where will the data be available: 
We agree to deposit and maintain the joint genotypic and phenotypic data, and secondary 
analyses at dbGaP which is an NIH-funded repository and has data access policies and procedures 
consistent with NIH data sharing policies. 
 
When will the data be shared: 
We agree to deposit genetic data into dbGaP repository as soon as possible but no later than 
within one year of the completion of the clinical study follow up period or upon acceptance of the 
data for publication, or public disclosure of a submitted patent application, whichever is earlier. 
 
How will researchers locate and access the data: 
We agree that we will identify where the data will be available and how to access the data in any 
publications and presentations that we author or co-author about these data, as well as 
acknowledge the repository and CTEP in any publications and presentations. As we will be using 
dbGaP/GDC, which are NIH-funded repositories, these repositories have policies and procedures 
in place that will provide data access to qualified researchers, fully consistent with NIH data 
sharing policies and applicable laws and regulations. 
 
 
13.6 
Incidental/Secondary Findings Disclosure Procedure 
 
Samples are not being submitted to the Biobanking and Molecular Characterization Initiative, 
and neither whole genome sequencing nor whole exome sequencing is otherwise planned under 
this protocol. 


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14. REFERENCES 
 
1. Rowe, J. M. & Tallman, M. S. How I treat acute myeloid leukemia. Blood 116, 3147–3156 
(2010). 
2. Blum, W. et al. Clinical response and miR-29b predictive significance in older AML patients 
treated with a 10-day schedule of decitabine. Proc. Natl. Acad. Sci. U. S. A. 107, 7473–7478 
(2010). 
3. Byrd, J. C. et al. Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior 
failure-free and overall survival when repetitive cycles of high-dose cytarabine are 
administered. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 17, 3767–3775 (1999). 
4. Grimwade, D. et al. Refinement of cytogenetic classification in acute myeloid leukemia: 
determination of prognostic significance of rare recurring chromosomal abnormalities among 
5876 younger adult patients treated in the United Kingdom Medical Research Council trials. 
Blood 116, 354–365 (2010). 
5. Eisfeld, A.-K. et al. The mutational oncoprint of recurrent cytogenetic abnormalities in adult 
patients with de novo acute myeloid leukemia. Leukemia (2017). doi:10.1038/leu.2017.86 
6. Eisfeld, A.-K. et al. Mutational Landscape and Gene Expression Patterns in Adult Acute 
Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Res. 77, 207–218 
(2017). 
7. Bhatnagar, B. et al. Clinical features and gene- and microRNA-expression patterns in adult 
acute leukemia patients with t(11;19)(q23;p13.1) and t(11;19)(q23;p13.3). Leukemia 30, 
1586–1589 (2016). 
8. The Cancer Genome Atlas Research Network. Genomic and Epigenomic Landscapes of 
Adult De Novo Acute Myeloid Leukemia. N. Engl. J. Med. 368, 2059–2074 (2013). 


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9. Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modifications and 
leukaemia stem-cell development. Nat. Rev. Cancer 7, 823–833 (2007). 
10. Neff, T. & Armstrong, S. A. Recent progress toward epigenetic therapies: the example of 
mixed lineage leukemia. Blood 121, 4847–4853 (2013). 
11. Döhner, H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations 
from an international expert panel. Blood 129, 424–447 (2017). 
12. Reimer, J. et al. CRISPR-Cas9-induced t(11;19)/MLL-ENL translocations initiate leukemia 
in human hematopoietic progenitor cells in vivo. Haematologica 102, 1558–1566 (2017). 
13. Daigle, S. R. et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 
 
122, 1017–1025 (2013). 
 
14. Campbell, C. T. et al. Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent 
Resistance in MLL -Rearranged Leukemia. Mol. Cancer Ther. 16, 1669–1679 (2017). 
15. Waters, N. J. et al. Metabolism and disposition of the DOT1L inhibitor, pinometostat (EPZ- 
5676), in rat, dog and human. Cancer Chemother. Pharmacol. 77, 43–62 (2016). 
16. Stein, E. M. et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has 
modest clinical activity in adult acute leukemia. Blood 131, 2661–2669 (2018). 
17. Moore, J. O. Sequential multiagent chemotherapy is not superior to high-dose cytarabine 
alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 
years of age: Cancer and Leukemia Group B Study 9222. Blood 105, 3420–3427 (2005). 
18. Döhner, H., Weisdorf, D. J. & Bloomfield, C. D. Acute Myeloid Leukemia. N. Engl. J. Med. 
 
373, 1136–1152 (2015). 
 
19. O’Donnell, M. R. et al. Acute Myeloid Leukemia, Version 3.2017, NCCN Clinical Practice 
Guidelines in Oncology. J. Natl. Compr. Canc. Netw. 15, 926–957 (2017). 


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20. Lavallée, V.-P. et al. The transcriptomic landscape and directed chemical interrogation of 
MLL-rearranged acute myeloid leukemias. Nat. Genet. 47, 1030–1037 (2015). 
21. Bernt, K. M. et al. MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 
Methylation by DOT1L. Cancer Cell 20, 66–78 (2011). 


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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 
CTEP MULTICENTER GUIDELINES 
 
Not applicable. 


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APPENDIX C 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
Not applicable; the study agent is being given for a fixed time period in the inpatient setting only. 


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APPENDIX D 
BIOASSAY TEMPLATES 
 
See supplemental bioassay and laboratory SOP attachments. 


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APPENDIX E 
COLLECTION OF SPECIMENS 
 
Collection procedures described in this Appendix E apply to the ETCTN Biobanking and 
Molecular Characterization Initiative. 
 
Not applicable. 

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# 
Section 
Page(s) 
Change 
1.  
Header 
All 
Updated Header Version Date to match updated 
protocol version 
 
2. 
What bad things 
might happen to 
me if I am in the 
study? 
 
2 
Updated risks for pinometastat, per the revised 
condensed risk profile based on CAEPR (Version 1.1,  
January 7,2019) 
 
x Added New Risk: 
x Possible: Diarrhea, nausea, vomiting; Tiredness; 
Change in the heart rhythm; Rash 
x Increase in Risk Attribution: 
x Changed to Possible from Also Reported on 
Pinometostat Trials But With Insufficient 
Evidence for Attribution (i.e., added to the Risk 
Profile): Anemia which may require blood 
transfusion; Bruising, bleeding 
x Decrease in Risk Attribution:  
x Changed to Also Reported on Pinometostat 
Trials But With Insufficient Evidence for 
Attribution from Possible (i.e., removed from 
the Risk Profile): Constipation; Severe blood 
infection; Bleeding in the brain which may 
cause headache, confusion 
 
 


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Page 1 of 4 
 
 
 
Research Study Assent Document 
 
Study Title for Participants: Testing the addition of a new anti-cancer drug, pinometostat, 
to the usual chemotherapy treatment (cytarabine and daunorubicin) in patients with Acute 
Myeloid Leukemia 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: “NCI-
10212: A Phase 1b/2 study of Pinometostat in combination with standard induction 
chemotherapy in newly diagnosed Acute Myeloid Leukemia with MLL rearrangement,” 
(NCT#PENDING) 
 
 
x You are being asked to be in a research study.  Studies are done to find better ways to 
treat people or to understand things better.   
x This form will tell you about the study to help you decide whether or not you want to 
participate.  
x You should ask any questions you have before making up your mind.  You can think 
about it and discuss it with your family or friends before you decide. 
x It is okay to say “No” if you don’t want to be in the study.  If you say “Yes” you can 
change your mind and quit being in the study at any time without getting in trouble. 
x If you decide you want to be in the study, an adult (usually a parent) will also need to 
give permission for you to be in the study. 
 
 
1.   What is this study about?  
This study is being done to see if we can better treat AML by adding a new drug to the usual 
drug treatment and determine if the drug is safe for patients with AML. 
 
2.   What will I need to do if I am in this study? 
If you decide to take part in this study, you will take a drug called pinometostat, for up to 35 
days, in combination with the usual drug treatment. In addition, the doctors will take some bone 
marrow up to 4 different times from you, using a needle, for testing. 
 
After you finish your 35 days of pinometostat your doctor will continue to follow your condition 
and watch you for side effects, and watch you for side effects. The follow up will occur either 
until your AML comes back or worsens, or until you get a different treatment for your AML. 
The follow up will occur during regular clinic visits with your hematologist at least every month. 
 
If you choose to participate in having an optional research sample drawn on Day 8, 1 teaspoon of 
blood and 1 teaspoon of bone marrow aspirate will be collected from you for research purposes. 
 


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Page 2 of 4 
 
 
 
3.   Can I stop being in the study? 
You may stop being 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. 
 
4.  What bad things might happen to me if I am in the study? 
You may experience side effects from the Pinometostat which include: 
x Anemia which may require blood transfusion 
x Infection, especially when white blood cell count is low 
x Heart Failure, which may cause shortness of breath, swelling of ankles, and tiredness 
x Diarrhea, nausea, vomiting 
x Tiredness 
x Change in the heart rhythm 
x Bruising, Bleeding 
x Rash 
 
You may also experience side effects from your usual care:  
x Diarrhea, loss of appetite, nausea, vomiting 
x Anemia 
x Fever 
x Rash 
x Blood clots 
x Mouth Sores 
 
You may experience side effects from the bone marrow collection: 
x Small amount of bleeding 
x Bruising 
x Pain 
 
Risks to an unborn child or a baby: 
If you are a female it is important that you do not get pregnant or breastfeed a baby while 
participating in this study (at least 4 weeks after your last dose of study treatment).  If you are a 
male it is important that you do not father a baby while taking part in this study (at least 90 days 
after your last dose of study treatment).   
 
5.   What good things might happen to me if I am in the study? 
You may or may not have any benefit from participating in this study.  The information gained 
from this study could help others with AML in the future. 


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6.   Will I be given anything for being in this study? 
You will not receive any payments or reimbursements for participating in this study 
 
7.   Who can I talk to about the study? 
 
For questions about the study you may contact _________________at                         .      
 
To discuss other study-related questions with someone who is not part of the research team, 
you may contact                                              at                                                    . 
 
8. Optional Studies that you can choose to take part in 
Taking part in these optional studies is your choice. You will not benefit from taking part.  If you 
choose to take part in this optional study, researchers will collect 1 teaspoon of blood and 1 
teaspoon of bone marrow on Day 8 for research on AML.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
  
If you decide you no longer want your samples to be used or if you have questions, you can call 
the study doctor,                                 at                            .   
Please circle either yes or no below to indicate whether or not you would like to participate 
in the optional research studies: 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
 


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Signing the assent form 
 
 
I have read (or someone has read to me) this form.  I have had a chance to ask questions before 
making up my mind.  I want to be in this research study.     
 
 
 
 
 
 
 
AM/PM 
Signature or printed name of subject 
 
Date and time 
 
 
 
 
 
Investigator/Research Staff 
 
I have explained the research to the participant before requesting the signature above.  There are 
no blanks in this document.  A copy of this form has been given to the participant or his/her 
representative. 
 
 
 
 
 
Printed name of person obtaining assent 
 
Signature of person obtaining assent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
 
 
 
 
This form must be accompanied by an IRB approved parental permission form signed by a 
parent/guardian. 

ICF_003.pdf: 
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SUMMARY OF CHANGES 
 
NCI Protocol #:         10212 
Local Protocol #: 
OSU 18296 
 
NCI Version Date: March 26, 2019 
Protocol Date: March 26, 2019 
 
I. NCI Rapid Request Amendment (RRA) 03/26/2019 
 
# 
Section 
Page(s) 
Change 
1.  
Header 
All 
Updated Header Version Date to match updated 
protocol version 
 
2. 
What risks, side 
effects or 
discomforts can my 
child expect from 
being in the study? 
 
2 
Updated risks for pinometastat, per the revised 
condensed risk profile based on CAEPR (Version 1.1,  
January 7,2019) 
 
x Added New Risk: 
x Possible: Diarrhea, nausea, vomiting; Tiredness; 
Change in the heart rhythm; Rash 
x Increase in Risk Attribution: 
x Changed to Possible from Also Reported on 
Pinometostat Trials But With Insufficient 
Evidence for Attribution (i.e., added to the Risk 
Profile): Anemia which may require blood 
transfusion; Bruising, bleeding 
x Decrease in Risk Attribution:  
x Changed to Also Reported on Pinometostat 
Trials But With Insufficient Evidence for 
Attribution from Possible (i.e., removed from 
the Risk Profile): Constipation; Severe blood 
infection; Bleeding in the brain which may 
cause headache, confusion 
 
 


Protocol Version Date 03/26/2019 
 
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Page 1 of 7 
 
 
 
Parental Permission Authorization  
for Child’s Participation in Research 
 
Study Title for Participants: Testing the addition of a new anti-cancer drug, pinometostat, 
to the usual chemotherapy treatment (cytarabine and daunorubicin) in patients with Acute 
Myeloid Leukemia 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: “NCI-
10212: A Phase 1b/2 study of Pinometostat in combination with standard induction 
chemotherapy in newly diagnosed Acute Myeloid Leukemia with MLL rearrangement,” 
(NCT#PENDING) 
 
 
x This is a parental permission form for research participation.  It contains important 
information about this study and what to expect if you permit your child to participate.  
Please consider the information carefully. Feel free to discuss the study with your friends and 
family and to ask questions before making your decision whether or not to permit your child 
to participate. 
x Your child’s participation is voluntary.  You or your child may refuse participation in 
this study.  If your child takes part in the study, you or your child may decide to leave the 
study at any time.  No matter what decision you make, there will be no penalty to your child 
and neither you nor your child will lose any of your usual benefits.  Your decision will not 
affect your future relationship with The Ohio State University.  If you or your child is a 
student or employee at Ohio State, your decision will not affect your grades or employment 
status. 
x Your child may or may not benefit as a result of participating in this study.  Also, as 
explained below, your child’s participation may result in unintended or harmful effects for 
him or her that may be minor or may be serious depending on the nature of the research. 
x You and your child will be provided with any new information that develops during 
the study that may affect your decision whether or not to continue to participate.  If you 
permit your child to participate, you will be asked to sign this form and will receive a copy of 
the form.  You are being asked to consider permitting your child to participate in this study 
for the reasons explained below.   
 
1.   Why is this study being done? 
This study is being done to answer the following question: 
  
Can we increase the chance of better treating AML by adding a new drug to the usual 
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 AML. The usual approach is defined as care most people get for AML. 


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2.   How many people will take part in this study? 
There will be about 6-37 people taking part in this study 
 
 
3.   What will happen if my child takes part in this study? 
If your child participates in this study, they will get Pinometostat for up to 35 days, in 
combination with standard intensive induction chemotherapy.  
 
After your child finishes their 35 days of pinometostat, the doctor will continue to follow their 
condition and watch them for side effects. The follow up will occur either until their AML comes 
back or worsens, or until they get a different treatment for their AML. The follow up will occur 
during regular clinic visits with their hematologist at least every month. 
 
Your child may choose to participate in an optional research bone marrow aspiration and biopsy 
to be performed on Day 8, where 1 teaspoon of blood and 1 teaspoon of bone  marrow aspirate 
would be collected from them for research purposes only. 
 
4. 
Can my child stop being in the study? 
You child may stop being in the study at any time.    
 
If they decide to stop, they should let the study doctor know as soon as possible.  It’s important 
that they stop safely.  If they stop, they can decide if they want to keep letting the study doctor 
know how they are doing. 
 
Their study doctor will tell them about new information or changes in the study that may affect 
their health or their willingness to continue in the study. 
 
5. 
What risks, side effects or discomforts can my child expect from being 
in the study? 
Your child may experience side effects from the pinometostat which include: 
x Anemia which may require blood transfusion 
x Infection, especially when white blood cell count is low 
x Heart Failure, which may cause shortness of breath, swelling of ankles, and tiredness 
x Diarrhea, nausea, vomiting 
x Tiredness 
x Change in the heart rhythm 
x Bruising, Bleeding 
x Rash 
 
Your child may also experience side effects from their usual care:  
x Diarrhea, loss of appetite, nausea, vomiting 
x Anemia 
x Fever 
x Rash 
x Blood clots 


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x Mouth Sores 
 
Your child may experience side effects from the bone marrow collection: 
x Small amount of bleeding 
x Bruising 
x Pain 
 
Risks to an unborn child or a baby: 
If your child is a female it is important that they do not get pregnant or breastfeed a baby while 
participating in this study (at least 4 weeks after their last dose of study treatment).  If your child 
is a male it is important that they do not father a baby while taking part in this study (at least 90 
days after their last dose of study treatment).   
 
6. 
What benefits can my child expect from being in the study? 
This study drug has shrunk or stabilized your child’s type of cancer in a limited number of 
people with their type of cancer. It is unlikely that it will work in everyone with their type of 
cancer or help you live longer.  This study may help the study doctors learn things that may help 
other people in the future. 
 
7. 
What other choices does my child have if he/she does not take part in 
the study? 
x They may choose to have the usual approach described above. 
x They may choose to take part in a different research study, if one is available. 
x They may choose not to be treated for cancer. 
x They may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
 
8.   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 AML. 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 daunorubicin and cytarabine. 
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.  
 


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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 Bone marrow aspiration and biopsy done before treatment 
x Bone marrow aspiration and biopsy done at relapse (if applicable) 
x Bone marrow aspiration on day 8, and the genetic and chemical tests done on this 
specimen 
 
You or your insurance provider will not have to pay for the Pinometostat while your child takes 
part in this study.  
 
You and your child 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. 
 
9. Will I or my child be paid for taking part in this study? 
You and your child will not receive any payments or reimbursements for participating in this 
study. 
 
10. What happens if my child is injured because he/she took part in this 
study? 
If your child is injured as a result of taking part in this study and need medical treatment, please 
talk with their study doctor right away about their 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 your child is in a 
study.  Agreeing to take part in this study does not mean you or your child give up these rights. 
 
11. What are my child’s rights if he/she takes part in this study? 
If you and your child choose to participate in the study, you and your child may discontinue 
participation at any time without penalty or loss of benefits.  By signing this form, you do not 
give up any personal legal rights your child may have as a participant in this study. 
 
You and your child will be provided with any new information that develops during the course of 
the research that may affect your decision whether or not to continue participation in the study. 
 
You and your child may refuse to participate in this study without penalty or loss of benefits to 
which they are otherwise entitled. 
 
12. Will my child’s study-related information be kept private?  
Your child’s 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 child’s records if there is a court 
case.  However, some of their medical information may be given out if required by law.  If this 


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should happen, the study doctors will do their best to make sure that any information that goes 
out to others will not identify who they are. 
  
Some of your child’s health information, such as their response to cancer treatment, results of 
study tests, and medicines they took, will be kept by the study sponsor in a central research 
database.  However, their name and contact information will not be put in the database.  If 
information from this study is published or presented at scientific meetings, their name and other 
personal information will not be used.  
 
There are organizations that may look at your child’s study records.  Their health information in 
the research database also may be shared with these organizations.  They must keep your child’s 
information private, unless required by law to give it to another group. Some of these 
organizations are: 
 
x The study sponsor and any drug company supporting the study 
x The 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. 
x The NCI’s National Clinical Trials Network and the groups it works with to conduct 
research 
 
Your child’s study records also will be stored for future use.  However, their name and other 
personal information will not be used.  Some types of future research may include looking at 
their records and those of other patients to see who had side effects across many studies or 
comparing new study data with older study data.  However, we don’t know what research may 
be done in the future using their information.  This means that: 
 
You and your child will not be asked if they agree to take part in the specific future research 
studies using their health information. 
   
You and your child and their study doctor will not be told when or what type of research will be 
done. You and your child will not get reports or other information about any research that is done 
using your information.  
 
There are laws that protect your child’s genetic information.  However, there is a risk that 
someone could get access to their genetic information and identify them by name.  In some 
cases, employers could use their genetic information to decide whether to hire or fire them.  The 
study doctors believe the risk of this happening is very small.  However, the risk may increase in 
the future as people find new ways of tracing information.  For more information about the laws 
that protect your child, ask your child’s study doctor.  
 
13. Who may use and give out information about your child? 
Researchers and study staff.   
 
 


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Signing the parental permission form 
 
I have read (or someone has read to me) this form and I am aware that I am being asked to 
provide permission for my child to participate in a research study.  I have had the opportunity to 
ask questions and have had them answered to my satisfaction.  I voluntarily agree to permit my 
child to participate in this study.  
 
I am not giving up any legal rights by signing this form.  I will be given a copy of this combined 
consent and HIPAA research authorization form. 
 
 
 
 
 
Printed name of subject 
 
 
 
 
 
 
 
 
 
Printed name of person authorized to provide permission for  
subject  
 
Signature of person authorized to provide permission for 
subject   
 
 
 
 
 
AM/PM 
Relationship to the subject 
 
Date and time 
 
 
If your child is participating in the optional Day 8 research sample collections, a signature 
from an additional person authorized to provide permission is needed below: 
 
 
 
 
 
Printed name of an additional person authorized to provide 
permission for subject  
 
Signature of an additional person authorized to provide 
permission for subject   
 
 
 
 
Relationship to the subject 
 
Date and time 
 
Investigator/Research Staff 
 
I have explained the research to the participant or his/her representative before requesting the 
signature(s) above.  There are no blanks in this document.  A copy of this form has been given to 
the participant or his/her representative. 
 
 
 
 
 
Printed name of person obtaining consent 
 
Signature of person obtaining consent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 


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Witness(es) - May be left blank if not required by the IRB 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
 
AM/PM 
 
 
Date and time