Clinical trial NCT03701295
Conditions: Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL Leukemia Cutis Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Sponsor: National Cancer Institute (NCI)
Start date: 2020-03-06; Completion date: 2021-01-12
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase Ib/II trial studies the side effects and best dose of pinometostat when given together with azacitidine and to see how well it works in treating patients with acute myeloid leukemia that has come back (relapsed), does not respond to treatment (refractory), or is newly diagnosed, with an 11q23 rearrangement. Pinometostat and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine if the combination of pinometostat, at a dose of 54 or 90 mg/m\^2/day, and azacitidine, at a dose of 75 mg/m\^2 daily for 7 days, is safe and tolerable in patients with MLL-rearranged acute myeloid leukemia, either in the relapsed/ refractory setting or in those who choose not to undergo standard induction therapy in the previously untreated setting. (Phase Ib) II. To determine the preliminary efficacy, as determined by overall response rate (complete response \[CR\], complete response with incomplete bone marrow recovery \[CRi\], partial response \[PR\], and morphologic leukemia-free state \[MLFS\]), of pinometostat administered at the maximum tolerated dose from the phase 1b, combined with azacitidine administered at 75 mg/m\^2 daily for 7 days, in patients with MLL-rearranged acute myeloid leukemia, either in the relapsed/refractory setting or in those who choose not to undergo standard induction therapy in the previously untreated setting. (Phase II)

SECONDARY OBJECTIVES:

I. Perform correlative studies to evaluate for on-target effects, cellular differentiation, and decreased leukemia cell proliferation in these patients. (Phase Ib and II) II. To observe and record anti-tumor activity. (Phase Ib)

OUTLINE: This is a phase Ib, dose-escalation study of pinometostat followed by a phase II study.

Patients receive pinometostat intravenously (IV) continuously on days 1-28 and azacitidine IV over 10-40 minutes or subcutaneously (SC) for 7 of the first 10 days of the cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 month.

Arms: arm 1: Patients receive pinometostat IV continuously on days 1-28 and azacitidine IV over 10-40 minutes or SC for 7 of the first 10 days of the cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Azacitidine intervention 2: Pinometostat
Intervention descriptions: intervention 1: Given IV or SC intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol #: 10200 
Version Date: 07/24/2020 
 
i 
 
 
DATE: 
July 24, 2020 
 
TO:  
CTEP Protocol and Information Office 
 
FROM:  
Kamal Menghrajani, MD 
 
SUBJECT: 
Amendment to update the participating organizations and other 
administrative changes.   
 
 
SUMMARY OF CHANGES – Protocol: 
 
I. 
PIO Recommendations: 
 
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Section 
Comments 
1. 
4.1 
Please delete the information within this subsection and replace with the 
following language. 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored trials to register 
and to renew their registration annually.  To register, all individuals must obtain a 
Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) account at https://ctepcore.nci.nih.gov/iam.  In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to Oncology 
Patient Enrollment Network (OPEN), Rave, or acting as a primary site contact) 
must complete their annual registration using CTEP’s web-based Registration and 
Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• IVR:  MD, DO, or international equivalent, 
• NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD), 
• AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System [RUMS], OPEN, 
Rave,), 
• Associate (A):  other clinical site staff involved in the conduct of NCI-
sponsored trials, and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company 
employees) with limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 


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Documentation Required 
I
V
R 
NPIV
R 
A
P 
A 
A
B 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, 
license, and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and Cancer Trials Support Unit (CTSU) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
Institutional Review Boards (IRBs) covering their practice sites on the FDA Form 
1572 in RCR to allow the following: 
 
• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks 
in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, 
and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 
participating organization (i.e., Alliance).  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please 
contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
RESPONSE: This has been updated. 
 
2. 
4.2 
Please delete the information within this subsection and replace with the 
following language. 
 
4.2 
Site Registration 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) 
must submit the Study Specific Worksheet for Local Context (SSW) to the CIRB 
using IRBManager to indicate their intent to open the study locally.  The NCI 


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CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network.  Site preferences can be set at the 
network or protocol level.  Questions about establishing site preferences can be 
addressed to the CTSU Regulatory Office by emailing the email address above or 
calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) 
must meet the following five criteria to complete processing of the IRB/REB 
approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian 
sites only) and on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 
 
RESPONSE: This has been updated. 
 
3. 
4.2.2 
Please delete the following bullet point. 
 
• IRB approval (For sites not participating via the NCI CIRB; local 
IRB documentation, an IRB-signed CTSU IRB Certification Form, 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted.) 
 
RESPONSE: This has been updated. 
 
4. 
4.2.3 
Please delete the information within this subsection and replace with the 
following language. 
 
4.2.3 Submitting Regulatory Documents 
 


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Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website 
 Regulatory  Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in 
order to receive further instruction and support. 
 
RESPONSE: This has been updated. 
 
5. 
4.2.4 
Please delete the information within this subsection and replace with the 
following language. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site’s registration status on the members’ side of the CTSU 
website.  
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration  
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status shown only reflects institutional compliance with site registration 
requirements as outlined above.  It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
RESPONSE: This has been updated. 
 
6. 
4.3.1, 
4.3.2 
Please delete the information within these 2 subsections and replace with the 
following language. 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration 
system available on a 24/7 basis.  OPEN is integrated with CTSU regulatory and 
roster data and with the Lead Protocol Organization (LPOs) 
registration/randomization systems or Theradex Interactive Web Response System 
(IWRS) for retrieval of patient registration/randomization assignment.  OPEN will 
populate the patient enrollment data in NCI’s clinical data management system, 
Medidata Rave. 
 


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Requirements for OPEN access:   
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, 
ETCTN Corresponding roster, or Participating Organization roster with the 
role of Registrar.  Registrars must hold a minimum of an AP registration 
type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN 
Registrar task on the DTL for the site. 
• Have an approved site registration for a protocol prior to patient 
enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving investigator 
for a patient transfer in OPEN, the IVR or NPIVR must list the IRB number used 
on the site’s IRB approval on their Form FDA 1572 in RCR.  If a DTL is required 
for the study, the IVR or NPIVR must be assigned the appropriate OPEN-related 
tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, 
and  
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  Please print this confirmation for your 
records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website.  Further instructional information is in the OPEN section of the 
CTSU website at https://www.ctsu.org or https://open.ctsu.org.  For any additional 
questions, contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
RESPONSE: This has been updated. Subsection 4.3.2 was deleted and 
subsequent sections were renumbered. 
 
7. 
4.2.2 
Please add this information to this section. 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
 
• All biospecimens collected for this trial must be submitted using the 


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ETCTN Specimen Tracking System (STS) unless otherwise noted.   
• The system is accessed through special Rave user roles:  “CRA Specimen 
Tracking” for data entry at the treating institutions and “Biorepository” for 
users receiving the specimens for processing and storage at reference labs 
and the Biorepository.   
• Please refer to the Medidata Account Activation and Study Invitation 
Acceptance link on the CTSU website under the Rave/DQP tab. 
• Important:  Failure to complete required fields in STS may result in a 
delay in sample processing.  Any case reimbursements associated with 
sample submissions will not be credited if samples requiring STS 
submission are not logged into STS. 
 
RESPONSE: This has been added. 
 
8. 
10.3.1 
If this study will use Rave Cancer Therapy Evaluation Program Adverse 
Event Reporting System (CTEP-AERS) Integration, include this section.   
 
1.1.1 Rave-CTEP-AERS Integration 
 
The Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) integration enables evaluation of post-baseline AEs entered 
in Rave to determine whether they require expedited reporting, and 
facilitates entry in CTEP-AERS for those AEs requiring expedited 
reporting.    
 
All AEs that occur after baseline are collected in Medidata Rave using the 
Adverse Event form, which is available for entry at each treatment or 
reporting period, and used to collect AEs that start during the period or 
persist from the previous reporting period.  The Clinical Research 
Associate (CRA) will enter AEs that occur prior to the start of treatment on 
a baseline form that is not included in the Rave-CTEP-AERS integration.  
AEs that occur prior to enrollment must begin and end on the baseline 
Adverse Event form and should not be included on the standard Adverse 
Events form that is available at treatment unless there has been an increase 
in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should 
verify the following on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is 
query-free (fields added to the form during study build do not need 
to be query-free for the integration call with CTEP-AERS to be a 
success). 
 


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The CRA reports AEs in Rave at the time the Investigator learns of the 
event.  If the CRA modifies an AE, it must be re-submitted for rules 
evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE 
for rules evaluation by completing the Expedited Reporting Evaluation 
form.  Both NCI and protocol-specific reporting rules evaluate the AEs 
submitted for expedited reporting.  A report is initiated in CTEP-AERS 
using information entered in Medidata Rave for AEs that meet reporting 
requirements.  The CRA completes the report by accessing CTEP-AERS 
via a direct link on the Medidata Rave Expedited Reporting Evaluation 
form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour 
notification is to be made to CTEP by telephone at 301-897-7497.  Once 
Internet connectivity is restored, the 24-hour notification that was phoned 
in must be entered immediately into CTEP-AERS using the deep link from 
Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on 
the CTSU website: 
 
• Study specific documents:  Protocols > Documents > Education and 
Promotion, and   
• Expedited Safety Reporting Rules Evaluation user guide:  
Resources > CTSU Operations Information > User Guides. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
• NCI Guidelines for Investigators:  Adverse Event Reporting 
Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_application
s/docs/aeguidelines.pdf. 
 
RESPONSE: This has been updated. 
 
9. 
13.2 
Please delete the information within this subsection and replace with the 
following language. 
 
13.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection 
for this trial/study.  Access to the trial in Rave is controlled through the CTEP-
IAM system and role assignments.  To access Rave via iMedidata: 
 


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• 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account, and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol 
Organization (LPO) or Participating Organization roster at the enrolling 
site:  Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or 
Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must 
hold a minimum of an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as 
an NPIVR or IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) 
registration type. 
 
Upon initial site registration approval for the study in Regulatory Support System 
(RSS), all persons with Rave roles assigned on the appropriate roster will be sent a 
study invitation e-mail from iMedidata.  To accept the invitation, site staff must 
log in to the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM username and password, and click on the accept link in the upper 
right-corner of the iMedidata page.  Site staff will not be able to access the study in 
Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the iMedidata 
screen.  If an eLearning is required and has not yet been taken, the link to the 
eLearning will appear under the study name in iMedidata instead of the Rave EDC 
link; once the successful completion of the eLearning has been recorded, access to 
the study in Rave will be granted, and a Rave EDC link will display under the 
study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in RSS will also receive a 
separate invitation from iMedidata to activate their account.  Account activation 
instructions are located on the CTSU website in the Rave section under the Rave 
resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or 
by e-mail at ctsucontact@westat.com.   
 
RESPONSE: This has been updated. 
 
10. 
13.3 
Please add this subsection. 
 
 


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Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to 
manage unanswered queries and form delinquencies, monitor data quality 
and timeliness, generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data 
Management.  The Rave Home section displays a table providing summary 
counts of Total Delinquencies and Total Queries.  DQP Queries, DQP 
Delinquent Forms, and the DQP Reports modules are available to access 
details and reports of unanswered queries, delinquent forms, and timeliness 
reports.  Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have 
access to the CTSU website.  Staff that have Rave study access can access 
the Rave study data using a direct link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed 
on the Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note:  Some Rave protocols may not have delinquent form details or 
reports specified on the DQP.  A protocol must have the Calendar 
functionality implemented in Rave by the Lead Protocol Organization 
(LPO) for delinquent form details and reports to be available on the 
DQP.  Site staff should contact the LPO Data Manager for their protocol 
regarding questions about Rave Calendaring functionality.  
 
RESPONSE: This has been added and subsequent section renumbered. 
 
 
 
II. 
Changes Requested by the PI: 
 
# 
Section 
Comments 
11. 
Header, 
Title 
Page 
Updated the protocol version date. 
12. General General formatting throughout the document. 
13. 
Title 
Page 
Added the ClinicalTrials.gov number. 
Removed LAOs MN026, NC010, and NJ066 from the Participating Organizations. 


NCI Protocol #: 10200 
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Removed the Non-Member Collaborators, as requested by CTEP. 
Changed the Study Contact individual. 
14. 
3.1.3 
Clarified the targetable mutations. 
15. 
4.2.2 
Clarified who to contact to schedule the SIV. 
16. 
6.1, 
6.4 
Clarified that hydroxyurea may be given concurrently. 
 
 
SUMMARY OF CHANGES – Consent Form: 
 
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17. Header 
Updated the version date. 


NCI Protocol #:10200 
Version Date: 07/24/2020 
 
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NCI Protocol #: 
10200 
 
Local Protocol #: 
N/A 
 
ClinicalTrials.gov Identifier:  NCT03701295 
 
TITLE: A Phase Ib/II Study of the Histone Methyltransferase Inhibitor Pinometostat in 
Combination with Azacitidine in Patients with 11q23-Rearranged Acute Myeloid Leukemia  
 
Corresponding Organization: LAO-MD017 JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
Kamal Menghrajani 
 
Memorial Sloan Kettering Cancer Center 
 
menghrak@mskcc.org  
 
Co-Investigator:  
Eytan Stein 
Memorial Sloan Kettering Cancer Center 
1275 York Ave 
New York, NY 10065 
 
212-639-2000 
 
steine@mskcc.org 
 
 
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-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 #:10200 
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Statistician: 
Protocol Contact: 
 
Sean Devlin 
Judy Murray, CCRC 
 
1275 York Ave 
Johns Hopkins University 
 
New York, NY 10065 
201 N. Broadway, Suite 9130 
 
212-639-2000 
Baltimore, MD 21287 
 
DevlinS@mskcc.org 
Telephone: (410) 955-4044 
 
 
jmurra33@jhmi.edu   
 
 
NCI-Supplied Agent(s):  Pinometostat NSC# 795144 
Other Agent(s): Azacitidine, NSC#102816 Supplier: Commercial 
IND Sponsor:  DCTD, NCI 
 
 
Protocol Type / Version # / Version Date: 
Original / v 1.0 / 04/18/2018 
 
 
                  Original / v.2.0 / 06/25/2018 
 
 
 
 
      Original / v.3.0 / 07/20/2018 
 
 
 
 
      Original / v.4.0 / 08/15/2018 
 
 
 
 
      Original / v.5.0 / 09/13/2018 
 
 
 
 
      Original / v.6.0 / 10/17/2018 
 
 
 
 
      Original / v.7.0 / 11/27/2018 
 
 
 
 
      Original / v.8.0 / 02/27/2019 
 
 
 
 
      Original / v. 9.0 / 04/10/2019 
 
 
 
 
      Original / v.10.0 / 05/03/2019 
 
 
 
 
      Original / v.11.0 / 09/10/2019 
 
 
 
 
      Original / v.12.0 / 10/25/2019 
 
Original / v.13.0 / 07/24/2020 
 
 


NCI Protocol #:10200 
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13 
SCHEMA 
 
 
 
Azacitidine 75 
mg/m
2 daily x 7 
days 
Pinometostat CIV Infusion 
Azacitidine 75 
mg/m
2 daily x 7 
days 
Day 1 
Baseline Assessment: Bone 
Marrow Biopsy,  
ELISA, qPCR  
Day 28 
End of Cycle 1 Assessment:  
Bone Marrow Biopsy 
ELISA, qPCR 
Up to 6 cycles 


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TABLE OF CONTENTS 
 
SCHEMA ................................................................................................................................. 13 
1. 
OBJECTIVES ............................................................................................................... 16 
1.1 
Primary Objectives ............................................................................................. 16 
1.2 
Secondary Objectives ......................................................................................... 16 
2. 
BACKGROUND ........................................................................................................... 18 
2.1 
Study Disease(s) ................................................................................................ 18 
2.2 
CTEP IND Agent ............................................................................................... 19 
2.3 
Other Agent: Azacitidine.................................................................................... 21 
2.4 
Rationale ............................................................................................................ 21 
2.5 
Correlative Studies Background ......................................................................... 22 
3. 
PATIENT SELECTION ................................................................................................ 23 
3.1 
Eligibility Criteria .............................................................................................. 23 
3.2 
Exclusion Criteria .............................................................................................. 24 
3.3 
Inclusion of Women and Minorities ................................................................... 25 
4. 
REGISTRATION PROCEDURES ................................................................................ 27 
4.1 
Investigator and Research Associate Registration with CTEP ............................. 27 
4.2 
Site Registration ................................................................................................. 28 
4.3 
Patient Registration ............................................................................................ 30 
4.4 
General Guidelines ............................................................................................. 31 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................... 33 
5.1 
Biomarker Plan .................................................................................................. 33 
5.2 
Integral Laboratory or Imaging Studies .............................................................. 37 
5.3 
Integrated Correlative Studies ............................................................................ 37 
5.4 
Exploratory/Ancillary Correlative Studies .......................................................... 38 
5.5 
Special Studies ................................................................................................... 38 
6. 
TREATMENT PLAN .................................................................................................... 39 
6.1 
Agent Administration ......................................................................................... 39 
6.2 
Definition of Dose-Limiting Toxicity ................................................................. 40 
6.3 
Dose Expansion Cohorts: ................................................................................... 41 
6.4 
General Concomitant Medication and Supportive Care Guidelines ..................... 41 
6.5 
Duration of Therapy ........................................................................................... 42 
6.6 
Duration of Follow Up ....................................................................................... 43 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................. 44 
7.1 
Guidelines for Management of QT Prolongation ................................................ 48 
7.2 
Tumor Lysis Syndrome ...................................................................................... 50 
7.3 
Differentiation Syndrome ................................................................................... 50 


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8. 
PHARMACEUTICAL INFORMATION....................................................................... 51 
8.1 
CTEP IND Agent(s) ........................................................................................... 51 
8.2 
Commercial Agent: Azacitidine (NSC # 102816) ............................................... 54 
9. 
STATISTICAL CONSIDERATIONS ........................................................................... 56 
9.1 
Study Design/Endpoints ..................................................................................... 56 
9.2 
Sample Size/Accrual Rate .................................................................................. 57 
9.3 
Stratification Factors .......................................................................................... 58 
9.4 
Analysis of Secondary Endpoints ....................................................................... 58 
9.5 
For phase 2 protocols only: Reporting and Exclusions ........................................ 60 
9.6 
Early Stopping Criteria ...................................................................................... 61 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................... 62 
10.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) .............. 62 
10.2 
Adverse Event Characteristics ............................................................................ 68 
10.3 
Expedited Adverse Event Reporting ................................................................... 68 
10.4 
Routine Adverse Event Reporting ...................................................................... 73 
10.5 
Pregnancy .......................................................................................................... 74 
10.6 
Secondary Malignancy ....................................................................................... 74 
10.7 
Second Malignancy ............................................................................................ 74 
11. 
STUDY CALENDAR ................................................................................................... 75 
12. 
MEASUREMENT OF EFFECT .................................................................................... 78 
12.1 
Antitumor Effect ................................................................................................ 78 
12.2 
Antitumor Effect – Hematologic Tumors ........................................................... 81 
12.3 
Other Response Parameters ................................................................................ 81 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ........................................................................................................ 82 
13.1 
Study Oversight ................................................................................................. 82 
13.2 
Data Reporting ................................................................................................... 82 
13.3 
Data Quality Portal ............................................................................................ 85 
13.4 
CTEP Multicenter Guidelines ............................................................................ 85 
13.5 
Collaborative Agreements Language .................................................................. 85 
13.6 
Genomic Data Sharing Plan ............................................................................... 87 
13.7 
Incidental/Secondary Findings Disclosure Procedure ......................................... 87 
14. 
REFERENCES .............................................................................................................. 88 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................ 90 
APPENDIX B 
BIOASSAY TEMPLATES .................................................................... 91 
APPENDIX C:  PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD .......................................................................................................... 93 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Phase Ib Safety / Tolerability Run In - Primary Objective:  
• To determine if the combination of pinometostat, at a dose of 54 or 
90mg/m2/day, and azacitidine, at a dose of 75 mg/m2 daily for 7 days, is safe and 
tolerable in patients with MLL-rearranged acute myeloid leukemia, either in the 
relapsed / refractory setting or in those who choose not to undergo standard 
induction therapy in the previously untreated setting 
1.1.2 Phase II Primary Objective: 
• To determine the preliminary efficacy, as determined by overall response rate 
(CR, CRi, PR, and MLFS), of pinometostat administered at the maximum 
tolerated dose from the phase 1b, combined with azacitidine administered at 75 
mg/m2 daily for 7 days, in patients with MLL-rearranged acute myeloid 
leukemia, either in the relapsed / refractory setting or in those who choose not to 
undergo standard induction therapy in the previously untreated setting. Patients 
will be treated with 6 cycles of therapy on trial, with the option to continue if they 
are deriving significant clinical benefit. As only two dose levels are being 
studied, the MTD may not be reached. In this case, a recommended phase 2 dose 
(RP2D) of either 54 or 90 mg/m2 pinometostat will be evaluated in the Phase 2 
portion of the study, based on the dosing used in the previous phase 1 trial of 
single-agent pinometostat1.  
 
1.2 
Secondary Objectives 
 
1.2.1 Phase Ib Safety / Tolerability Run In - Secondary Objectives:  
• Perform correlative studies to evaluate for on-target effects, cellular 
differentiation, and decreased leukemia cell proliferation in these patients 
• Correlative studies will include assessment of patterns of histone methylation at 
H3K79 by ELISA; evaluation of expression of downstream targets of DOT1L-
mediated hypermethylation (HOXA9 and Meis1) by qPCR; measurement of 
myeloid cell differentiation by differential and flow cytometry on bone marrow 
biopsy samples and peripheral blood samples  
• To observe and record anti-tumor activity.  Although the clinical benefit of these 
drug(s) 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. 
 
1.2.2 Phase II Secondary Objectives: 
• Perform correlative studies to evaluate for on-target effects, cellular 
differentiation, and decreased leukemia cell proliferation in these patients. 
• Correlative studies will include assessment of patterns of histone methylation at 
H3K79 by ELISA; evaluation of expression of downstream targets of DOT1L-
mediated hypermethylation (HOXA9 and Meis1) by qPCR; measurement of 


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myeloid cell differentiation by differential and flow cytometry on bone marrow 
biopsy samples and peripheral blood samples  
 
 
 


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2. 
BACKGROUND 
 
2.1 
Study Disease(s) 
 
Acute myeloid leukemia (AML) is a cancer of proliferative, clonal, abnormally differentiated 
cells of the hematopoietic system.1 Genomic profiling and cytogenetics have significantly 
improved our ability to discern prognosis and likelihood of response to therapy for patients with 
AML.2  Patients at high risk for poor response to standard induction therapy or early relapse 
include those with unfavorable abnormalities seen on routine cytogenetic testing, including 
partial tandem duplications and rearrangements in the 11q23 locus, also known as the Mixed 
Lineage Leukemia (MLL) locus2. MLL rearrangements are not uncommon and are found in about 
10% of adult AML3–5.  
 
In MLL-rearranged AML, aberrant recruitment of the disruptor of telomeric silencing 1-like 
(DOT1L), a histone H3 lysine 79 (H3K79) methyltransferase, and subsequent hypermethylation 
of downstream targets HOXA9 and Meis1 is central to leukemogenesis3,6 (Figure 1).  
 
Figure 1. Role of DOT1L and histone 
methylation in leukemogenesis3. A. RNA 
polymerase II (Pol II) can bind the promoter 
region of a gene but cannot proceed with 
transcription without specific methylation marks 
on the histone core. B. Unique histone marks 
can be found on different regions of a gene, and 
may impart unique activities. RNA transcription 
may be initiated when a promoter region (I) 
carries histone H3 lysine 4 (H3K4) methylation 
marks, and extend when an open-reading frame 
region (II) carries a histone H3 lysine 36 
(H3K36). Histone H3 lysine 79 (H3K79) 
methylation marks have a broad distribution 
across promoter and open-reading frame regions 
(III). C. Mixed lineage leukemia (MLL) is a 
member of a multiprotein complex that mediates 
methylation of H3K4 within the promoter region 
of genes occupied by RNA polymerase II. D. A 
hypothetical function for MLL fusion proteins is 
presented. MLL fusion(s) that lack the SET 
(Su(var)3-9, Enhancer-of-zeste, Trithorax) 
domain H3K4 methyltransferase activity may 
recruit the H3K79 methyltransferase DOT1L. 
MLL fusion-mediated recruitment of DOT1L to 
promoters normally occupied by MLL, (such as 
the HoxA cluster) allows H3K79 methylation of 
the HoxA cluster, which may lead to aberrant 
expression of HoxA cluster genes. 


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DOT1L has been previously shown to be necessary for the development and maintenance of 
MLL-rearranged leukemia7. In one pre-clinical study, a conditional DOT1L deletion model was 
used to show that DOT1L-deficient cells are depleted of the global H3K79 methylation mark. 
Loss of DOT1L activity in MLL-rearranged cells attenuated cell viability and colony formation 
potential. The effect was found to contribute to the viability of cells immortalized by multiple 
MLL oncoproteins, and not only the fusion products that are known to directly recruit DOT1L8. 
 
While MLL-rearranged AML is the most well-studied instance of DOT1L-mediated 
leukemogenesis, recent studies have shown that this pathway also drives other types of AML. 
Several researchers have shown that DOT1L-mediated aberrant methylation of downstream 
targets (HOXA9 and Meis1) is also seen in AML with DNMT3A, NPM1, and IDH1/2 mutations, 
with the strongest signal seen in NPM1-mutated disease9–11. Not only are similar patterns of 
DOT1L-mediated changes seen, but these types of AML have also been shown to be responsive 
to small-molecule inhibition of DOT1L. As such, patients with these mutations could be 
considered candidates for further studies of combination DOT1L inhibitor and hypomethylating 
agent therapy. 
 
2.2 
CTEP IND Agent 
 
A small molecule inhibitor, pinometostat, discovered by Epizyme and now under the purview of 
CTEP, was found to be a potent and selective inhibitor of DOT1L histone methyltransferase 
activity. Use of this agent in a continuous IV infusion in a rat xenograft model of MLL-
rearranged leukemia showed complete, sustained tumor regressions without significant 
appreciable toxicities12.  
 
Pinometostat was then moved into the clinic for first-in-human studies. This agent directly 
targets DOT1L with sub-nanomolar affinity and >37,000 fold selectivity as compared to other 
histone methyltransferases12.  
 
 
Figure 2. Structure, binding, 
and inhibitory activity of 
Pinometostat (EPZ-
5676)12. A. Chemical structure 
of EPZ-5676, now called 
pinometostat. B. Superposition 
of DOT1L-EPZ-5676 (green) 
and DOT1L-SAM (gray; 
Protein Data Base accession 
number 3QOW). To 
accommodate the extended 
hydrophobic tail of the 
inhibitor, significant 
rearrangement of the protein is 
required, including the loop between β-strands 10 and 11 (L10-11). C. Selectivity profile of 


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pinometostat inhibitory activity against representative members of the lysine (left) and arginine 
(right) enzyme families. The diameter of the sphere for each enzyme is directly related to the 
magnitude of inhibition by pinometostat. Larger circles correlate to increased potency; gray 
circles indicate no measurable inhibition up to 10 µM of pinometostat. D. Comparison of 
pinometostat and EPZ004777 potency, selectivity, and cell-based activity. The enzyme inhibition 
Ki values for EPZ004777 and pinometostat in DOT1L enzymatic assays are listed (n = 3; mean 
values ± SD are shown). Residence time for each compound is listed and was calculated as the 
reciprocal of the enzyme-ligand dissociation rate as determined by surface plasmon resonance. 
Also listed are inhibitory activities for both compounds in MV4-11 proliferation assays (n = 3 
[pinometostat] or n = 2 [EPZ004777]; mean values ± SD are shown), MV4-11 cell H3K79me2 
ELISA assays (n = 2; mean values ± SD are shown) and MV4-11 cell HOXA9 and MEIS1qRT-
PCR assays (n = 2; mean values ± SD are shown). 
 
A Phase I trial of pinometostat in patients with advanced hematologic malignancies, including 
acute leukemia with MLL rearrangements, showed some promise. Eight of 34 patients with 
MLL-rearranged leukemia showed a response to the drug, with one patient in a morphologic CR, 
one in a cytogenetic CR, two patients with resolution of leukemia cutis, and the remaining with 
signs of differentiation or leukocytosis (Table 1). Correlative studies showed that pinometostat 
plasma concentrations in these patients were correlated with the inhibition of global H3K79 
methylation, as well as with reductions in methylation of target genes HOXA9 and Meis1.13  
 
Table 1. Dose of pinometostat, number of patients enrolled at each dose, and corresponding 
response from the phase I trial of this drug as a single agent in relapsed / refractory 
hematologic malignancies. 
 
 
As the dose of 54 mg/m2/day showed two CRs in the single-agent trial and the dose of 90 
mg/m2/day showed one PR in the single-agent trial, these are the two doses planned for use in 
this combination study. Plasma pinometostat concentrations and H3K79 methyltransferase 
inhibition were found to decline rapidly between days 21 and 28 when the infusion was 
discontinued at day 21, and thus this trial will use a 28-day continuous IV infusion1. 


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2.3 
Other Agent: Azacitidine 
 
Azacitidine is a nucleoside analogue of the cytosine which functions as an antineoplastic agent 
by incorporating into DNA and RNA, leading to chain termination, and by acting as a DNA 
methyltransferase inhibitor. In recent years, azacitidine has come into practice as a promising 
treatment for adult AML patients who are not candidates for induction chemotherapy, and is 
listed as a therapeutic option by the NCCN. Azacitidine was previously shown to prolong overall 
survival in comparison to best supportive care in the phase 3 AZA-001 trial for treatment-naïve 
older adults with 20-30% bone marrow blasts14. Newer data from the international phase 3 study 
of azacitidine compared to conventional care regimens in treatment-naive older adults with > 
30% blasts shows that the response rate to this hypomethylating agent is around 30% (27.8% for 
CR / CRi and 1.2% for PR) with a 4-month overall survival benefit15. Similarly, a 2011 Italian 
study showed an overall response rate of 32% to single-agent azacitidine in adults with AML16. 
Azacitidine is administered IV or subcutaneously at a dose of 75mg/m2 per day for 7 days. 
Therapy may be administered over seven sequential days, but is often administered with a two-
day break in clinical practice. 
 
2.4 
Rationale 
 
Given that DOT1L-mediated leukemogenesis is mediated by both histone and DNA 
hypermethylation, a combination approach employing both pinometostat and a DNA 
hypomethylating agent would be a rational next step in developing up-front therapies for adults 
with AML with aberrant DOT1L signaling who are unable to tolerate or unwilling to undergo 
treatment with induction chemotherapy. A previous study by Epizyme showed that the 
combination of pinometostat with the hypomethylating agent azacitidine led to synergistic 
antiproliferative effects in vitro in MOLM-13 and MV4-11 MLL cell lines. Their previously 
published data showed that AML cell lines with a translocation t(9;11) or t(4;11) treated with 
both azacitidine and pinometostat had increased rates of cytotoxicity when compared to 
treatment with either drug alone17.  
 
Figure 3. Synergistic effects of EPZ-5676 (Pinometostat) and azacitidine on cell viability as 
measured by flow cytometry and ATP depletion17. 
 


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2.5 
Correlative Studies Background 
 
The objective of the correlative studies is to better understand whether this combination is having 
the anticipated on-target effects and, if so, what the sequelae of those on-target effects may be.  
 
Correlative studies will include morphology, flow cytometry, cytogenetics, and a myeloid 
genetics panel, all of which are standard of care. Integrated biomarkers for identification of 
11q23 / MLL rearrangements would be performed as part of these assessments.  
 
Additionally, we seek to study changes in methylation patterns with the use of this combination. 
This is important for understanding on-target effects as MLL-rearranged leukemia is driven by 
hypermethylation, and pinometostat works to inhibit DOT1L methyltransferase activity and 5-
azacytidine is a DNA hypomethylating agent. The assay of choice would be an ELISA assay to 
quantitate the extent of H3K79 methylation in leukemia cells.  
 
As the mechanism of leukemogenesis in MLL-rearranged leukemia relies on hypermethylation 
of H3K79 by DOT1L, leading to increased transcription of HOXA9 and Meis1, we anticipate 
that expression levels of these two genes will decrease with treatment. As such, we plan to use 
qPCR to evaluate gene expression level prior to and while on treatment. 
 
We anticipate that pinometostat will induce differentiation of myeloid blasts into more mature 
myeloid forms, based on previous research on pinometostat. We anticipate that MLL 
rearrangements will be detectable in more mature myeloid cells, e.g. neutrophils, allowing us to 
evaluate the extent of differentiation. We will perform these assays on selected samples.  
 
We considered running ChIP-seq for H3K27 methylation (as these histones may be mono-, di-, 
or trimethylated, and each of these is mediated by DOT1L). Pinometostat’s inhibiton of DOT1L 
may lead to an accumulation of non-methylated or hypomethylated forms of H3K79 and ChIP-
seq can help measure the valence of that histone methylation, as the amount of methylation has 
previously been described to correlate to the robustness of gene expression. However, the use of 
this assay would be limited by cost.  
 
Determining azacitidine incorporation and DNA methylation would be an exploratory 
biomarker, also performed by the Sidney Kimmel Comprehensive Cancer Center Analytical 
Pharmacology Core. This would allow for the assessment of 5-aza-2`-deoxycytidine 
incorporation into genomic DNA and the extent of global DNA methylation. This will be one of 
the first assessments of 5-aza-2`-deoxycytidine incorporation relative to the extent of global 
DNA methylation in human samples and may give further insight into the mechanism of action 
of azacitidine. 
 
 
 


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3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed acute myeloid leukemia.  
 
3.1.2 Patients must have an 11q23 translocation or partial tandem duplication, confirmed by 
cytogenetics, FISH, or myeloid panel. Both de novo and therapy-related AML with an 
11q23 rearrangement or PTD are considered eligible. 
 
3.1.3 Patients may not have any other targetable mutations (such as FLT3, IDH1, and IDH2) 
identified on myeloid mutational panel testing or must refuse treatment with a targeted 
agent if such a mutation is detected. 
 
3.1.4 Age >18 years.   
 
3.1.5 ECOG performance status < 3 (Karnofsky >60%; see Appendix A). 
 
3.1.6 Patients must have adequate organ function as defined below, unless thought to be related 
to the underlying disease: 
 
-     PT and aPTT    
 
 
 
< 1.5x ULN 
- 
total bilirubin 
 
 
 
 
< 2 times the upper limit of institutional normal 
(ULN) unless due to Gilbert’s disease 
- 
AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal 
- 
creatinine  
 
 
 
 
< 2 times the upper limit of institutional normal 
(ULN)  
 
 
 
 
 
OR 
- 
creatinine clearance  
 
 
GFR >30 mL/min/1.73 m2  
 
3.1.7 Patients treated in the up-front setting must decline standard-of-care therapy. 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 
Participants with impaired decision-making capacity with a close legal guardian / 
caregiver may be considered. 
 
3.1.9 Patients must have measurable disease, defined as abnormal blasts detectable in the 
peripheral blood or bone marrow or the presence of extramedullary disease, including 
leukemia cutis. Patients with extramedullary disease but no bone marrow disease are still 
considered eligible. See Section 12 (Measurement of Effect) for the evaluation of 
measurable disease.  
 
3.1.10 Patients may have had previous treatment with standard-of-care or experimental agents. 
Patients who have previously undergone bone marrow transplantation may also be 
included.  
 
3.1.11 Patients who are HIV+, HBV+, and / or HCV+ may be eligible as follows: 


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24 
- 
Human Immunodeficiency Virus (HIV)-infected patients on effective antiretroviral 
therapy with undetectable viral load within 6 months are eligible for this trial. The 
antiretroviral therapy should not strongly induce or inhibit CYP3A4. 
- 
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. 
 
3.1.12 The effects of pinometostat on the developing human fetus are unknown.  For this reason 
and because histone methyltransferase inhibitors as well as hypomethylating agents are 
known to be teratogenic, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, and for the duration of study participation 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 
contraception prior to the study, for the duration of study participation, and 90 days after 
completion of pinometostat and azacitidine administration. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who are receiving any other investigational agents. 
 
3.2.2 Patients with active CNS disease are excluded from this clinical trial because they may 
develop progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events. Patients with a prior history of CNS disease will not 
be excluded. 
 
3.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to pinometostat or azacitidine 
 
3.2.4 Patients receiving medications or substances that are inhibitors or inducers of the 
CYP3A4 or CYP450 system should have their medications reviewed and adjusted for 
interactions as appropriate for local institutional practice. 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. 
 
3.2.5 Patients receiving any medications or substances that are inhibitors or inducers of 
MATE1 and MATE2-K transporters should have their medications reviewed and 
adjusted for interactions as appropriate for local institutional practice. Pinometostat has 
been demonstrated to be an inhibitor of MATE1 and MATE2-K transporters in vitro, 
although the clinical significance of this is unclear. Drug interactions may occur between 
Pinometostat and other therapies that are MATE substrates, including metformin. 


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25 
Consultation with a frequently updated medical reference and / or pharmacist should be 
sought to guide necessary changes in the patient’s other medications. 
 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, uncontrolled or clinically 
significant cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. Patients with these conditions that are medically 
well controlled may be considered for enrollment. 
 
3.2.7 Pregnant women are excluded from this study because pinometostat is an agent 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. 
 
3.2.8 HIV-positive patients on combination antiretroviral therapy should have their regimen 
reviewed for potential pharmacokinetic interactions with pinometostat and azacitidine. In 
the event of a potential interaction, alternative therapies may be considered in 
consultation with the patient’s primary HIV physician. 
 
3.2.9 Absence of an 11q23 rearrangement or absence of an 11q23 partial tandem duplication 
 
3.2.10 Patients with an active bleeding diathesis. 
 
3.2.11 Patients at increased risk of QT prolongation (e.g. from known long-QT syndrome) or 
who have a corrected QT interval that is persistently longer than 450ms despite 
adjustments to other medications 
 
3.2.12 Patients who are eligible for or willing to receive intensive induction therapy for de novo 
AML 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
See section 9.2 for the planned distribution of subjects by sex/gender, race, and ethnicity in the 
Planned Enrollment Report table. 


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27 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to Oncology Patient Enrollment Network (OPEN), Rave, or acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• IVR:  MD, DO, or international equivalent, 
• NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
• AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System [RUMS], OPEN, Rave,), 
• Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IV
R 
NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 
• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 


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28 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance).  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 10020 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 


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29 
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-MD017, 
and protocol #10200 
• 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 10200 Site Registration 
 
• A Site initiation visit (SIV) is required for each participating site prior to 
activation. The local site PI must participate on the call as well as their research 
nurse, study coordinator, and pharmacist. To schedule a SIV, please email the 
Protocol Contact and reference the protocol in the subject line of the email.   
 
• Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site 
will need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual. If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU. However, new versions of the Specimen Tracking system 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o  Peter Clark and Diana Vulih are the main points of contact at Theradex for the 
training (PClark@theradex.com and DVulih@theradex.com, Theradex phone: 609-
799-7580).  
 
This Study will use the ETCTN Specimen Tracking System (STS).  
 
• All biospecimens collected for this trial must be submitted using the ETCTN 
Specimen Tracking System (STS) unless otherwise noted.   
• The system is accessed through special Rave user roles:  “CRA Specimen Tracking” 
for data entry at the treating institutions and “Biorepository” for users receiving the 
specimens for processing and storage at reference labs and the Biorepository.   
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link 


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30 
on the CTSU website under the Rave/DQP tab. 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions 
will not be credited if samples requiring STS submission are not logged into STS. 
 
4.2.3 Submitting Regulatory Documents 
 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website  
Regulatory  Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
 
4.2.4 Checking Site Registration Status 
 
 
You can verify your site’s registration status on the members’ side of the CTSU website.  
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration  
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status shown only reflects institutional compliance with site registration 
requirements as outlined above.  It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  OPEN will populate the patient enrollment data 
in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access:   
 


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31 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, 
ETCTN Corresponding roster, or Participating Organization roster with the role 
of Registrar.  Registrars must hold a minimum of an AP registration type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar 
task on the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website.  Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
4.3.2 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 
 


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32 
Following registration, patients should begin protocol treatment as soon as possible.  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. 
 
 
 
 


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33 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Biomarker Plan  
 
Biomarker Name 
AND Lab PI and Site 
Assay 
(CLIA: Y/N) 
 
Use (Integral, 
Integrated, or 
Exploratory) AND 
Purpose  
Tissue/Body Fluid 
Tested 
and Timing of Sample 
Collection 
M/O  
Use of NCI 
Resources 
(No / Pending 
Approval / 
Approved) 
Funding 
Source(s) 
11q23 rearrangement 
or partial tandem 
duplication 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
Cytogenetics 
and FISH 
CLIA: Y 
BRC Review: 
No 
Integral 
Evaluate eligibility 
Bone marrow aspirate, 
peripheral blood 
Prior to enrollment and 
therapy cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
Myeloid mutational 
panel for NPM1 and no 
other targetable 
mutations 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
Myeloid 
Mutations 
CLIA: Y  
BRC Review: 
No 
Integral 
Evaluate eligibility 
Bone marrow aspirate 
Prior to enrollment and 
therapy cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
Myeloid differentiation 
by Flow/FISH 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
FACS, Flow 
cytometry, FISH 
CLIA: N 
BRC Review: 
Yes  
Submission 
Deadline: 
Integrated 
Evaluate 
differentiation of 
cells with treatment 
Bone marrow aspirate, 
peripheral blood 
End of cycle 1, end of 
cycle 3, and therapy 
cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
H3K79 ELISA 
Scott Armstrong / 
Dana-Farber Cancer 
Institute (DFCI) 
Lab PI email: 
H3K79 ELISA 
CLIA: N 
BRC Review: 
No 
Integrated 
Quantitate 
methylation 
Bone marrow aspirate 
Prior to enrollment, end 
of cycle 1, end of cycle 
3, and therapy cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
qPCR for HOXA9 and 
Meis1 Expression 
Scott Armstrong / 
Dana-Farber Cancer 
Institute (DFCI) 
Lab PI email: 
qPCR 
CLIA: N 
BRC Review: 
No 
Integrated 
Quantitate gene 
expression 
Bone marrow aspirate 
Prior to enrollment, end 
of cycle 1, end of cycle 
3, and therapy cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
MRD Negativity by 
Flow Cytometry 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
Flow cytometry 
CLIA:  Y 
BRC Review: 
No 
Integrated 
Evaluate response 
to therapy 
Bone marrow aspirate 
End of cycle 1, end of 
cycle 3, and therapy 
cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
Azacitidine PK profile 
Michelle A. Rudek / 
Johns Hopkins  
Lab PI email: 
LC-MS/MS 
CLIA: N 
GLP: Y 
BRC Review: 
No 
Integrated 
Pharmacokinetic 
profile of 
azacitidine alone 
Blood with THU to 
stabilize azacitidine 
C1D1 pre, and 0.25, 
0.5, and 1 hr post 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
UM1 for 
sample 
processing; 
CTEP / NIH 
/ foundation 
grants for 
PK 
assessment 
Cell storage / DNA 
storage 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
Cell storage / 
DNA storage 
CLIA: N 
BRC Review: 
No 
Exploratory 
Evaluate valence 
of methylation in 
future 
Bone marrow aspirate, 
nail clippings 
Prior to enrollment, end 
of cycle 1, end of cycle 
3, and therapy 
cessation; nail clippings 
only prior to enrollment 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 


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34 
Biomarker Name 
AND Lab PI and Site 
Assay 
(CLIA: Y/N) 
 
Use (Integral, 
Integrated, or 
Exploratory) AND 
Purpose  
Tissue/Body Fluid 
Tested 
and Timing of Sample 
Collection 
M/O  
Use of NCI 
Resources 
(No / Pending 
Approval / 
Approved) 
Funding 
Source(s) 
5-aza-2’-deoxycytidine 
Genomic Incorporation 
(from azacitidine) and 
DNA demethylation 
Michelle A. Rudek / 
Johns Hopkins 
Lab PI email: 
LC-MS/MS 
CLIA: N 
GLP: Y 
BRC Review: 
No 
Exploratory 
Pharmacodynamic 
profile of 
azacitidine 
conversion to 5-
aza-2’-
deoxycytidine 
triphosphate and 
incorporation into 
DNA and its effect 
on DNA 
demethylation 
PBMC and bone 
marrow aspirate 
PBMC:  C1D8; 
Bone marrow aspirate:  
End of cycle 1, end of 
cycle 3, and therapy 
cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
 
 
The objective of the correlative studies is to better understand whether this combination is having 
the anticipated on-target effects and, if so, what the sequelae of those on-target effects may be.  
 
Correlative studies will include morphology, flow cytometry, cytogenetics, and a myeloid 
genetics panel, all of which are standard of care. These will be performed on bone marrow 
biopsy samples taken at each time point - prior to therapy initiation and at the end of cycle 1 for 
the phase Ib, and prior to therapy initiation, end of cycle 1, end of cycle 3, end of cycle 6 and / or 
after therapy cessation for the phase II. Specimen collection for these assays will be mandatory. 
Integral biomarkers for identification of 11q23 / MLL rearrangements would be performed as 
part of these assessments. The assays will be performed at MSKCC or local CLIA-certified 
pathology laboratories, which have experience processing samples from patients with leukemia. 
 
Additionally, we seek to study changes in methylation patterns with the use of this combination. 
This is important for understanding on-target effects as MLL-rearranged leukemia is driven by 
hypermethylation, and pinometostat works to inhibit DOT1L methyltransferase activity and 5-
azacytidine is a DNA hypomethylating agent. The assay of choice would be an ELISA assay to 
quantitate the extent of H3K79 methylation in leukemia cells, performed on mandatory samples 
from bone marrow samples identified above. The ELISA would be performed in Dr. Scott 
Armstrong’s lab at DFCI, which has extensive experience with this assay.  
 
The ELISA would not be a CLIA-certified test and would be solely performed for research 
purposes as part of an integrated biomarker. Samples would be viably cryopreserved at each 
institution and shipped to the study coordinator MSKCC for storage. At the end of the study, the 
samples would be shipped to DFCI, care of Dr. Armstrong’s laboratory, and the assay would be 
batch run on all samples.  
 
As the mechanism of leukemogenesis in MLL-rearranged leukemia relies on hypermethylation 
of H3K79 by DOT1L, leading to increased transcription of HOXA9 and Meis1, we anticipate 
that expression levels of these two genes will decrease with treatment. As such, we plan to use 
qPCR to evaluate gene expression level prior to treatment on mandatory bone marrow samples at 
the time points identified above. The qPCR assays will be run in the Armstrong lab at DFCI, 
which has extensive experience running these qPCR assays. This would not be a CLIA-certified 


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35 
test and would be solely performed for research purposes as an integrated biomarker.  
Samples would be viably cryopreserved at each institution and shipped to the study coordinator 
MSKCC for storage. At the end of the study, the samples would be shipped to DFCI, care of Dr. 
Armstrong’s laboratory, and the assay would be batch run on all samples. 
 
We anticipate that pinometostat will induce differentiation of myeloid blasts into more mature 
myeloid forms, based on previous research on pinometostat. As such, we will prospectively 
viably cryopreserve bone marrow aspirates in anticipation of flow-sorting blasts and myeloid 
cells. We will perform flow cytometry to assess for the upregulation of myeloid differentiation 
markers (such as CD11b) on each myeloid subtype, as well as perform FISH to track the 
compartmentalization of the MLL rearrangement. We anticipate that MLL rearrangements will 
be detectable in more mature myeloid cells, e.g. neutrophils, allowing us to evaluate the extent of 
differentiation.  
 
We will perform these assays on selected samples. CD11B is part of the standard myeloid panel 
run by the CLIA-certified flow cytometry lab at MSKCC. Bone marrow samples from the above 
delineated timepoints will be collected and will be a mandatory part of the trial. Bone marrow 
aspirate samples will be centrifuged and the buffy coat will be viably cryopreserved in DMSO.  
 
Bone marrow will be used to ensure that more blasts can be recovered and myeloid forms at 
different phases of maturation can be included. While we could consider assays to evaluate for 
synergy of these two agents, this falls outside the scope of this phase I study – we would need 
reference evaluations of patient treatment on each agent alone, which is not the goal of this trial. 
Additionally, in vitro assays of synergy have previously been performed in pre-clinical work. 
Western blots for H3K79 methylation were considered, however we would perform the ELISA 
first as it provides more throughput with a single assay. 
 
We also considered running ChIP-seq for H3K27 methylation (as these histones may be mono-, 
di-, or trimethylated, and each of these is mediated by DOT1L). Pinometostat’s inhibiton of 
DOT1L may lead to an accumulation of non-methylated or hypomethylated forms of H3K79 and 
ChIP-seq can help measure the valence of that histone methylation, as the amount of methylation 
has previously been described to correlate to the robustness of gene expression. However, the use 
of this assay would be limited by cost. As such, we could consider storing chromatin cross-
linked in formaldehyde or freezing down viable cells. If we were to choose to run the assay in 
future, we would then shear the DNA to obtain nucleosomal DNA and run the assay at that time. 
 
Cell storage / DNA storage will be performed on both bone marrow samples and nail clippings, 
the latter to be used for comparison to germline DNA so that relevant acquired mutations will be 
easier to detect.  
 
The analysis of azacitidine drug concentration in plasma would be performed by Dr. Michelle A. 
Rudek, PhD, PharmD, an Associate Professor of Oncology and the director of the Sidney 
Kimmel Comprehensive Cancer Center at Johns Hopkins (SKCCC) Analytical Pharmacology 
Core. She has expertise in bioanalysis, drug metabolism, and pharmacokinetic and 
pharmacodynamic analysis. The core operates according to Good Laboratory Practices (GLP) 
and would analyze the samples from cycle 1, day 1 taken prior to therapy administration and at 


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36 
15 min, 30 min, and 60 min after administration for both the phase Ib and phase II portions of the 
trial. This analysis would involve liquid chromatography coupled with tandem mass 
spectrometry (LC-MS/MS) and would be performed on mandatory peripheral blood samples 
which will be cryopreserved at the local site and shipped to Dr. Rudek’s lab at SKCCC. 
 
Determining azacitidine incorporation and DNA methylation would be an exploratory 
biomarker, also performed by the SKCCC Analytical Pharmacology Core. This would allow for 
the assessment of 5-aza-2`-deoxycytidine incorporation into genomic DNA and the extent of 
global DNA methylation. Decitabine, 2'-deoxycytidine, and 5-methyl-2'-deoxycytidine levels 
from digested DNA will be measured by LC-MS/MS in the DNA from bone marrow samples 
taken at the end of cycle 1, the end of cycle 3, and at the end of treatment for both the phase Ib 
and phase II portions of the trial. The analytical assay has been developed and validated by the 
SKCCC Analytical Pharmacology Core.  
 
This will be one of the first assessments of 5-aza-2`-deoxycytidine incorporation relative to the 
extent of global DNA methylation in human samples and may give further insight into the 
mechanism of action of azacitidine. 
 
Correlative studies will be performed at the intervals outlined in the table so as to produce 
meaningful and interpretable results. As sample collection at these intervals is commonly 
performed as standard of care, these timepoints should be feasible for assessment.  
 
 
Specimen Collection Schedule 
 
Specimen Type 
Baseline 
(Pre-
treatment) 
C1D1 prior to 
azacitidine, and 
0.25hr, 0.5hr, and 1 
hr post azacytidine 
treatment 
 
C1D8 
End of 
cycle 1 
End of 
cycle 3 
End of 
cycle 6 and 
/ after 
cessation of 
therapy, 
whichever 
is first 
Bone marrow 
X 
 
 
X 
X 
X 
Peripheral Blood 
X 
X 
X 
 
 
 
 
 


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37 
5.2 
Integral Laboratory or Imaging Studies 
 
5.2.1.1 
11q23 rearrangement or partial tandem duplication 
5.2.1.2 
Collection of Specimen(s): Locally performed 
5.2.1.3 
Handling of Specimens(s): Locally performed 
5.2.1.4 
Shipping of Specimen(s): N/A 
5.2.1.5 
Site(s) Performing Correlative Study: Local laboratory or per local practice of using a 
commercial laboratory 
 
5.2.1.6 
Myeloid mutational panel for NPM1 and no other targetable mutations 
5.2.1.7 
Collection of Specimen(s): Locally performed 
5.2.1.8 
Handling of Specimens(s): Locally performed 
5.2.1.9 
Shipping of Specimen(s): N/A 
5.2.1.10 
Site(s) Performing Correlative Study: Local laboratory or per local practice of using a 
commercial laboratory 
 
5.3 
Integrated Correlative Studies 
 
5.3.1.1 
H3K79 ELISA 
5.3.1.2 
Collection of Specimen(s): Locally performed 
5.3.1.3 
Handling of Specimens(s): Local study coordinator 
5.3.1.4 
Shipping of Specimen(s): To Armstrong Lab at DFCI 
5.3.1.5 
Site(s) Performing Correlative Study: Armstrong Lab at DFCI 
 
5.3.1.6 
qPCR for HOXA9 and Meis1 Expression 
5.3.1.7 
Collection of Specimen(s): Locally performed 
5.3.1.8 
Handling of Specimens(s): Local study coordinator 
5.3.1.9 
Shipping of Specimen(s): To Armstrong Lab at DFCI 
5.3.1.10 
Site(s) Performing Correlative Study: Armstrong Lab at DFCI 
 
5.3.1.11 
Myeloid differentiation by Flow / FISH 
5.3.1.12 
Collection of Specimen(s): Locally performed 
5.3.1.13 
Handling of Specimens(s): Local study coordinator 
5.3.1.14 
Shipping of Specimen(s): To MSKCC 
5.3.1.15 
Site(s) Performing Correlative Study: MSKCC 
 
5.3.1.16 
MRD Negativity by Flow Cytometry 
5.3.1.17 
Collection of Specimen(s): Locally performed 
5.3.1.18 
Handling of Specimens(s): Local study coordinator 
5.3.1.19 
Shipping of Specimen(s): To MSKCC 
5.3.1.20 
Site(s) Performing Correlative Study: MSKCC 
 
5.3.1.21 
Azacitidine PK profile 
5.3.1.22 
Collection of Specimen(s): Locally performed 
5.3.1.23 
Handling of Specimens(s): Local study coordinator 
5.3.1.24 
Shipping of Specimen(s): To Rudek lab at SKCCC 


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38 
5.3.1.25 
Site(s) Performing Correlative Study: Rudek lab at SKCCC 
 
5.4 
Exploratory/Ancillary Correlative Studies 
 
5.4.1.1 
Cell storage / DNA storage 
5.4.1.2 
Collection of Specimen(s): Locally performed 
5.4.1.3 
Handling of Specimens(s): Local study coordinator 
5.4.1.4 
Shipping of Specimen(s): To MSKCC 
5.4.1.5 
Site(s) Performing Correlative Study: MSKCC 
 
5.4.1.6 
5-aza-2′-deoxycytidine Genomic Incorporation (from Azacitidine) and DNA 
Demethylation 
5.4.1.7 
Collection of Specimen(s): Locally performed 
5.4.1.8 
Handling of Specimens(s): Local study coordinator 
5.4.1.9 
Shipping of Specimen(s): To Rudek lab at SKCCC 
5.4.1.10 
Site(s) Performing Correlative Study: Rudek lab at SKCCC 
 
5.5 
Special Studies 
 
5.5.1.1.1 
N/A 
 
 
 
 


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39 
6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 10. Appropriate dose modifications are described in Section 7.  
Hydroxyurea may be given concurrently for cytoreduction. No other investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the patient's malignancy. 
 
Dose Escalation Schedule 
Dose Level 
Dose 
Pinometostat 
Azacitidine 
Level -1 
36 mg/m2/day CIV infusion 
75 mg/m2/day for 7 days / cycle 
Level 1* 
54 mg/m2/day CIV infusion 
75 mg/m2/day for 7 days / cycle 
Level 2 
90 mg/m2/day CIV infusion 
75 mg/m2/day for 7 days / cycle 
*Starting dose levels 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Pinometostat 
None 
 
**  in NS 
to a final 
concentrati
on between 
0.54 mg/ml 
and 5.63 
mg/ml 
Continuous IV 
infusion 
Days 1-28 
28 days  
(4 weeks) 
 
 
 
Azacitidine 
Consider 
antiemetic 
premedication 
as per local 
institutional 
practicess, e.g. 
8mg 
ondansetron 
60min prior to 
administration 
75 
mg/m2/day 
 
IV or SC, as per 
local 
institutional 
preference; 
given daily for 7 
of the first 10 
days of each 
cycle, e.g. given 
for 5 days, 2-
day break, and 
given for an 
additional 2 
days 
Given for 7 
of the first 
10 days of 
each cycle 
**Doses as appropriate for assigned dose level. 


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40 
 
6.1.1 CTEP IND Agent: Pinometostat 
Pinometostat is given as IV continuous infusion administered at a constant flow rate.  
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. 
 
Patients should have a peripherally inserted central catheter (PICC) or similar central 
venous access device with a dedicated lumen for pinometostat alone.  
 
Pinometostat will be administered as a continuous IV infusion through the dedicated 
lumen of the central venous access device. The patient will return to the study center 
approximately every 72 hours to have the infusion medication refilled. The use of pumps 
to administer the medication should follow manufacturer’s and institutional guidelines. 
The patient or caregiver should be trained on how to use the pump or other device used to 
administer the medication. The patient or caregiver should also be trained on signs that 
may indicate that there is an issue with drug delivery. 
 
Refer to section 8.1 for compatible IV infusion bags and sets.  
The starting dose of pinometostat in the phase 1b will be 54 mg/m2/day (actual body 
surface area (BSA)). BSA is calculated as per institutional policy; alternatively, the Du 
Bois Method (Arch Intern Med. 1916; 17:863-871) may be used. 
 
BSA should be calculated prior to each cycle. The administered dose should be adjusted 
if the patient’s weight changes > 10% from baseline and may be rounded to the nearest 
mg.  
 
6.1.2 Other Agent(s) 
 
Prophylactic antiemetics can be given prior to azacitidine administration as per local 
institutional practices. One example of this would be the administration of 8mg 
ondansetron 60 min prior to azacitidine administration. 
 
6.1.3 Other Modality(ies) or Procedures 
 
N/A 
 
6.2 
Definition of Dose-Limiting Toxicity 
 
Definition of dose-limiting toxicities, as well as guidelines for DLT management and dose 
modifications are outlined in Section 7. 
 
Dose escalation will proceed within each cohort according to the following scheme.  
 
 
 


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41 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
6.3 
Dose Expansion Cohorts: 
 
This study will be performed as a phase Ib / II. No expansion cohort will be studied; instead, 
patients will be added to the phase II study and treated at the RP2D. Monitoring of all safety and 
toxicity data is done by the Principal Investigator and the Corresponding Organization on a real-
time basis as data are entered into Medidata Rave using the Web Reporting Module.  All 
participating sites are expected to notify the Principal Investigator when a DLT has occurred. 
 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients who are neutropenic should be given appropriate prophylaxis as per the local 
institutional practice.   
 
Pinometostat is metabolized by CYP3A and is a mild, time-dependent inhibitor of CYP3A. 
Those patients receiving medications metabolized by CYP3A with narrow therapeutic windows 
should be monitored carefully while receiving pinometostat. All strong CYP3A4 inhibitors or 
inducers, including azole antifungals that are strong CYP3A4 inhibitors, are excluded from use 
in these patients.  
 
Pinometostat is metabolized by CYP450 and patients receiving any medications or substances 
that are inhibitors or inducers of the CYP450 system should have their medications reviewed and 
adjusted for interactions as appropriate for local institutional practice.   
 
Medications metabolized by CYP3A with narrow therapeutic windows should be used with 
caution, as EPZ-5676 is potentially a mild, time-dependent inhibitor of CYP3A. The use or 
initiation of strong CYP3A4 substrates, inhibitors or inducers will be considered on a case-by-


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42 
case basis (based on risk-benefit) only after discussion with the Medical Monitor, and only when 
no alternative medication is possible. 
 
An updated listing of CYP substrates, inhibitors, and inducers can be found at 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 
 
Pinometostat is also metabolized 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 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. 
 
The use of hydroxyurea in patients with acute myeloid leukemia, for control of circulating blast 
count, is allowed to be given concurrently. 
 
Supportive care measures and symptomatic treatment for any drug-related toxicity may be 
instituted if clinically indicated. Intermittent use of dexamethasone (10 mg) is permitted as an 
antiemetic, though chronic steroid use should be discouraged as steroids may be regarded as anti-
cancer treatment. 
 
The prophylactic use of hematopoietic colony stimulating factors is prohibited. The therapeutic 
use of hematopoietic colony stimulating factors should be conducted according to the 2015 
ASCO Guideline for use of white blood cell growth factors19. Blood transfusions may also be 
administered as needed per the judgment of the Investigator. 
 
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.  The Principal Investigator should be alerted if 
the patient is taking any agent known to affect or with the potential for drug interactions. The 
study team should check a frequently-updated medical reference for a list of drugs to avoid or 
minimize use of.  Appendix C (Patient Drug Information Handout and Wallet Card) should be 
provided to patients if available. 
 
6.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 6 cycles. 
Patients may continue on the study combination if they are deriving clinical benefit. Patients will 
be taken off the study if 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 


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43 
 
• 
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 for 1 month after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
 
 


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7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
The period of assessment for a dose-limiting toxicity (DLT) will be the first cycle of the phase 
1B study.  
 
The starting dose of pinometostat in the phase 1b will be 54 mg/m2/day (actual BSA). The dose 
will be escalated in two successive cohorts of patients who will be entered sequentially to each 
dose level (54 mg/m2/day or 90 mg/m2/day). Dose escalation will be performed until ≥Grade 2 
(National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0) drug-related (defined as: any AE which cannot be clearly attributed by the 
Investigator to another cause, such as intercurrent illness or concomitant medication) toxicity in 
any patient occurs. Dose escalation will stop when the dose reaches 90 mg/m2/day and no further 
doses will be tested. If the maximum tolerated dose (MTD) is not reached, a recommended phase 
2 dose (RP2D) may be used in its place. 
 
Three patients will be assigned to the cohort at which any ≥Grade 2 drug-related toxicity 
occurred and dose escalation will proceed according to the common 3+3 design. If none of the 
first 3 patients at the 54 mg/m2/day dose experience first cycle dose limiting toxicity (DLT; see 
DLT definition below), new patients may be entered at the next higher dose level. If 1 of 3 
patients experience a first cycle DLT, up to 3 more patients will be started at that same dose 
level. If 2 or more experience first cycle DLT, no further patients are started at that dose and a 
lower dose level of 36 mg/m2/day may be tried.  
 
The MTD is defined as the dose level below which >1 patient out of 3 or ≥2 patients 
out of 6 experience a DLT. The second dose level may begin accrual only if all patients at the 
first dose level have been observed for a minimum of 28 days, i.e. through the first 28-day cycle. 
However, if at Day 28 the patient has Grade 3 or 4 neutropenia or thrombocytopenia, (not 
attributable to persistent leukemia; see DLT definition below), the patient will not begin Cycle 2 
and must be observed until Day 42 in order to determine whether a DLT has occurred. In this 
instance, dose escalation cannot proceed until at least Day 42 so that resolution may be assessed. 
If patients do not fulfill the definition of severe myelosuppression at Day 28, or if they recover 
between Days 28 and 42, no hematological DLT will be deemed to have occurred. Patients may 
then proceed to cycle 2 for further treatment of persistent disease or in the setting of a response.  
 
Once the MTD is reached, the cohort at the MTD will be expanded in the phase II portion of the 
trial. 
 
A DLT will be defined as a significant suspected adverse reaction or clinically significant 
abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or 
concomitant medications (only AEs that are incontrovertibly due to an extraneous cause will be 
excluded as a DLT) and of onset within the first 28 days on study that meets any of the following 
criteria: 
 
• 
Any Grade 5 toxicity 
• 
Grade 4 neutropenia lasting ≥ 42 days from start of cycle in absence of evidence of active 
leukemia 


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• 
Any Grade ≥ 3 non-hematologic toxicity not clearly resulting from the underlying 
leukemia EXCEPT: 
 Alopecia 
 Grade 3 fatigue, asthenia, fever, anorexia, or constipation 
 Grade 3 nausea, vomiting, or diarrhea not requiring tube feeding, total 
parenteral nutrition, or requiring or prolonging hospitalization 
 Infection, bleeding, or other expected direct complication of cytopenias 
due to active underlying leukemia 
 Grade 3 infusion reaction including cytokine release syndrome, if 
successfully managed and which resolves within 72 hours 
 Grade 3 or 4 tumor lysis syndrome if it is successfully managed clinically 
and resolves within 7 days without end-organ damage 
 Grade 3 or 4 isolated electrolyte abnormalities (i.e., those occurring 
without clinical consequence) that resolve, with or without intervention, to 
less than Grade 2 in less than 72 hours will not be considered DLT 
 
The above criteria should also be used for AEs for the phase 2 part of the trial. Safety will be 
assessed by AEs, SAEs, vital signs, physical examinations, and review of biochemistry and 
hematology laboratory values. 
 
After completion of the first cycle / DLT-assessment period, further toxicities will be managed 
as for patients treated on the phase 2 portion of the study. Patients who do not achieve a CR or 
PR after the first cycle of therapy may continue therapy, with the duration of therapy determined 
as outlined in section 6.5. 
 
During the phase 2, guidance on how to manage common non-hematologic toxicities is given 
below. If a patient tolerates pinometostat at the MTD and azacitidine at 75 mg/m2 but has a 
hematologic toxicity, the next cycle of azacitidine administration may be delayed out to day 42 
while the pinometostat is continued. If the most recent bone marrow on treatment shows 
persistent leukemia, the patient may continue to be treated with combination therapy with 
supportive care given for cytopenias. 
 
After discussion with the medical monitor, a lower dose of pinometostat therapy may be 
considered after the DLT period in the event of toxicities. The dose of azacitidine should remain 
constant at 75mg/m2 daily for 7 days given over a 10-day period at the start of each cycle.  
 
If recurrent hematologic toxicity occurs in someone who has achieved a remission, alternative 
dosing schedules of pinometostat could be explored as follows:  
 
If the recommended phase II dose is 90 mg/m2/day 
 
Dose Level 
Pinometostat Dose 
-1 
54 mg/m2/day CIV infusion 
0 
90 mg/m2/day CIV infusion 
 
 


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46 
If the recommended phase II dose is 54 mg/m2/day 
 
Dose Level 
Pinometostat Dose 
-1 
36 mg/m2/day CIV infusion 
0 
54 mg/m2/day CIV infusion 
 
Azacitidine administration may be held until up to day 42 of the cycle, but the dosage should not 
be reduced. 
 
Indications for dose modifications of pinometostat are as follows. For specific concerns not 
outlined here, please contact the medical monitor. 
 
Nausea 
Management/Next Dose for Pinometostat 
≤ Grade 1 
Continue administration, provide supportive care, monitor 
Grade 2 
Continue administration, provide supportive care, monitor 
Grade 3 
Provide supportive care. If tube feeding or TPN are required due to 
nausea and there is no improvement to < Grade 2 after three days of 
supportive treatment as per local institutional practice, hold 
pinometostat until nausea has resolved to < Grade 2. Pinometostat 
should restarted at one dose level lower. 
 
Grade 4 
N/A 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > one dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
Vomiting 
Management/Next Dose for Pinometostat 
≤ Grade 1 
Continue administration, provide supportive care, monitor 
Grade 2 
Continue administration, provide supportive care, monitor 
Grade 3 
Provide supportive care. If tube feeding or TPN are required due to 
vomiting and there is no improvement to < Grade 2 after three days of 
supportive treatment as per local institutional practice, hold 
pinometostat until vomiting has resolved to < Grade 2.  Pinometostat 
should restarted at one dose level lower. 
 
Grade 4 
Hold therapy until vomiting has resolved to < Grade 2, restart at lower 
dose if appropriate** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > 1 dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
Diarrhea 
Management/Next Dose for Pinometostat 
≤ Grade 1 
Continue administration, provide supportive care, monitor 
Grade 2 
Continue administration, provide supportive care, monitor 
Grade 3 
If ongoing x 48h, hold therapy until < Grade 2, restart at same dose. 


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47 
Diarrhea 
Management/Next Dose for Pinometostat 
Pinometostat should restarted at one dose level lower*. 
Grade 4 
Hold therapy until < Grade 2, restart at lower dose if appropriate** 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  Adults- 4 mg at first onset, followed by 2 mg with each loose motion until 
diarrhea-free for 12 hours (maximum dosage:  16 mg/24 hours) 
Children – 2mg TID dosing may be used for children who are small for their chronological age 
but are 30kg or greater 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > one dose reduction should go off protocol therapy. 
 
Fever 
Management/Next Dose for Pinometostat 
≤ Grade 1 
Continue administration, monitor 
Grade 2 
Continue administration, monitor 
Grade 3 
Hold pinometostat until fever has resolved. Pinometostat should 
restarted at one dose level lower. 
Grade 4 
Hold pinometostat until fever has resolved. Pinometostat should 
restarted at one dose level lower. 
Recommended management: antimicrobial or supportive therapy as appropriate based on 
clinical evaluation  
 
Anemia 
Management/Next Dose for Pinometostat 
≤ Grade 1 
Continue administration, monitor 
Grade 2 
Continue administration, monitor 
Grade 3 
Continue administration, monitor 
Grade 4 
If anemia thought to be related to underlying leukemia, continue 
administration. If anemia thought to be related to drug effect and lasts   
> 14 days, hold pinometostat until anemia has resolved to < Grade 1 and 
restart at dose level -1* 
Anemia is anticipated with treatment.  
*Patients requiring > one dose reduction should go off protocol therapy. 
 
Neutropenia 
Management/Next Dose for Pinometostat 
≤ Grade 1 
Continue administration, monitor 
Grade 2 
Continue administration, monitor 
Grade 3 
Continue administration, monitor 
Grade 4 
If neutropenia is thought to be related to underlying leukemia, continue 
administration. If neutropenia is thought to be related to drug effect and 
lasts > 14 days, hold pinometostat until neutropenia has resolved to < 
Grade 1 and restart at dose level -1* 
Neutropenia is anticipated with treatment. Persistent grade 4 neutropenia (lasting > 14 days) 
would necessitate dose de-escalation. Fever with neutropenia necessitating ICU admission 
should be discussed with the medical monitor. 
*Patients requiring > one dose reduction should go off protocol therapy. 


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48 
 
Thrombocytopenia 
Management/Next Dose for Pinometostat 
≤ Grade 1 
Continue administration, monitor 
Grade 2 
Continue administration, monitor 
Grade 3 
Continue administration, monitor 
Grade 4 
If thrombocytopenia is thought to be related to underlying leukemia, 
continue administration. If thrombocytopenia is thought to be related to 
drug effect and lasts > 14 days, hold pinometostat until 
thrombocytopenia has resolved to < Grade 1 and restart at dose level -1* 
Thrombocytopenia is anticipated with treatment. 
*Patients requiring > one dose reduction should go off protocol therapy. 
 
Bone Marrow 
Hypocellular 
Management/Next Dose for 
Pinometostat 
Management/Next Dose for 
Azacitidine 
≤ Grade 1 
Continue administration, monitor 
Continue administration, 
monitor 
Grade 2 
Continue administration, monitor 
Continue administration, 
monitor 
Grade 3 
Continue administration, monitor 
If hypocellular with no 
morphologic evidence of 
leukemia, then hold azacitidine 
for 2 weeks and repeat a bone 
marrow biopsy 
Grade 4 
If persistent aplasia with no morphologic 
evidence of leukemia after two week 
azacitidine hold, hold pinometostat for 2 
weeks and repeat a bone marrow biopsy 
 
Inform medical monitor of grade 4 toxicity.  
 
7.1 
Guidelines for Management of QT Prolongation  
 
The discussion of the emergency management of torsade de pointes and its hemodynamic 
consequences is beyond the scope of this guideline.  
 
Both nonclinical and clinical data provided suggest a risk of QT prolongation with pinometostat, 
and the risk may be additive in combination with azacitidine. As such, a baseline EKG should be 
performed to evaluate for QT prolongation. A weekly EKG should be performed during cycle 1 
to monitor for QT prolongation. 
 
Subjects may be at increased risk for the development of QT prolongation when treated with 
pinometostat and azacitidine in combination with fluoroquinolones, azole antifungal agents or 
serotonin (5-HT3) antagonists. Investigators need to be vigilant; refrain from administering 
concomitant medications associated with QT prolongation and if no other therapeutic options are 
available, monitor subjects receiving pinometostat and azacitidine with the combination of these 
drugs, and evaluate EKG and electrolytes (including potassium, magnesium, and calcium) 
particularly in subjects presenting with nausea, vomiting or diarrhea.  


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49 
Subjects who experience prolongation of the QTc interval using Fridericia’s equation (QTcF) 
interval to > 480 msec (CTCAE Grade ≥ 2) while treated with pinometostat and azacitidine 
should be promptly evaluated for causality of the QTcF prolongation and managed according to 
the following guidelines:  
 
• 
Levels of electrolytes (potassium, calcium and magnesium) should be checked and 
supplementation given to correct any values outside the normal range.  
 
• 
Concomitant therapies should be reviewed and adjusted as appropriate for medication 
with known QT prolonging effects.  
 
• 
If no other cause is identified and the Investigator believes it is appropriate, particularly if 
QTcF remains elevated (after above measures have been implemented, or as determined 
by the Investigator), study drug may be interrupted, and an EKG should be rechecked in 
approximately 1 week after the QTcF prolongation was first observed or more frequently 
as clinically indicated. If QTcF has recovered or improved and the Investigator believes it 
is safe to do so, re-challenge with pinometostat should be considered if held.  
 
• 
EKGs should be conducted at least weekly (e.g., at every scheduled visit) for 2 weeks 
following QTcF reduction ≤ 480 msec.  
 
Grade 2 (QTcF > 480 and ≤ 500 msec)  
 
• 
The dose of pinometostat may be reduced to a dose approved by the Medical Monitor 
without interruption of dosing. The pinometostat dose may be re-escalated to the prior 
dose in ≥ 14 days after QT prolongation has decreased to ≤ Grade 1.  
 
Grade 3 (QTcF > 500 msec)  
 
• 
Hospitalization for continuous cardiac monitoring and evaluation by a cardiologist should 
both be considered.  
 
• 
Dosing with pinometostat will be interrupted. If QTcF returns to within 30 msec of 
baseline or < 450 msec within 14 days, treatment may be resumed at a reduced dose  
 
• 
The pinometostat dose cannot be re-escalated following dose reduction for Grade 3 QTcF 
prolongation unless the prolongation was associated with an electrolyte abnormality or 
concomitant medication  
 
Grade 4 (QTcF > 500 msec or > 60 msec change from baseline with torsade de pointes or 
polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia)  
 
• 
Subjects should be admitted to hospital for continuous cardiac monitoring and discharged 
only after review by a cardiologist.  
 
• 
Dosing with pinometostat and azacitidine should be permanently discontinued. 


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50 
 
7.2 
Tumor Lysis Syndrome 
 
Patients should be monitored for tumor lysis syndrome (TLS), which may be most likely to occur 
at the time of therapy initiation in patients with high tumor burden. TLS should be defined by the 
Howard criteria, with laboratory TLS defined by uric acid > 8.0mg/dL, phosphorus > 4.5 mg/dL, 
potassium > 6.0 mmol/L, and corrected calcium < 7.0 mg/dL with the presence of at least two 
abnormalities present during the same 24-hour period within 3 days prior to the start of therapy 
or 7 days afterward. Clinical tumor lysis syndrome is defined by car20diac dysrhythmia, sudden 
death, seizure, neuromuscular irritability, hypotension, heart failure, increasing creatinine of 0.3 
mg/dL or a single value of 1.5 times the ULN, or oliguria (< 0.5 ml/kg/hr over 6 hours on 
average). See reference for further details. 
 
Patients may receive prophylaxis and treatment for tumor lysis syndrome, including hydration, 
allopurinol, or rasburicase, as is appropriate per local institutional guidelines. 
 
7.3 
Differentiation Syndrome 
 
Symptoms of differentiation syndrome may include fever, weight gain or edema, respiratory 
symptoms with or without infiltrates, pleural or pericardial effusions, hypotension, and acute 
renal failure. If differentiation syndrome is clinically suspected, initiate prompt administration of 
corticosteroids at a suggested dose of 10 mg dexamethasone IV or PO every 12 hours until 
resolution of symptoms and signs as well as hemodynamic monitoring, for a minimum of 3 days 
is recommended, until improvement. Hydroxyurea at a suggested dose of 1–4 g PO twice or 
three times per day may be used for subjects with leukocytosis in the setting of differentiation 
syndrome. Additionally, initiation of furosemide and/or prompt initiation of leukapheresis is 
recommended if clinically required. For all cases of suspected differentiation syndrome, 
pinometostat should be immediately held. 
 
 
 


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51 
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(s) 
 
8.1.1 CTEP IND Agent #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 
 
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 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. 


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52 
 
Storage: 
Store 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 intravenous infusion is stable at room 
temperature and can be infused for a maximum of 90 hours. The infusion bag can be stored 
at room temperature prior to infusion; the total time in bag, including both preparation and 
infusion time, should not exceed 114 hours total. 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 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. 
 
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 


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53 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.4). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 
 
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.   
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.3 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. 
 
8.1.4 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:  


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54 
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 Agent: Azacitidine (NSC # 102816) 
 
Product description:   
 
Chemical Name: 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one 
 
Other Names: 5-azacitidine, 5-aza, azacitidine, Vidaza® 
 
Classification: antimetabolite, DNA hypomethylating agent 
 
CAS Registry Number: 320-67-2 
 
Molecular Formula: C8H12N4O5 
 
M.W.:  244.2 
 
Approximate Solubility: 89 g/L at 25° C in water 
 
Mode of Action: Azacitidine is a pyrimidine nucleoside analog of cytidine. 
Azacitidine is incorporated into DNA and RNA at high doses and causes direct 
cytotoxicity as a result of inhibiting DNA and RNA functions. It also inhibits DNA 
methyltransferase at low doses, therefore causing DNA hypomethylation and 
subsequent alterations in gene expression. 
 
How Supplied: Azacitidine for injection is supplied as a lyophilized powder in 100 
mg single-use vials packaged in cartons of 1 vial (NDC 67211-102-01). It is 
commercially available. Each vial contains 100 mg of azacitidine and 100 mg of 
mannitol as a freeze-dried cake or powder. 
 
Solution preparation: As per package insert 
 
Route of administration:  Azacitidine may be administered either subcutaneously or 
intravenously, depending on local institutional practice. 
 
Subcutaneous: The manufacturer recommends equally dividing volumes >4 mL into 2 syringes 
and injecting into 2 separate sites; however, policies for maximum SubQ administration volume 
may vary by institution; interpatient variations may also apply. Rotate sites for each injection 
(thigh, abdomen, or upper arm). Administer subsequent injections at least 1 inch from previous 
injection sites; do not inject into tender, bruised, red, or hard areas. Allow refrigerated 


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55 
suspensions to come to room temperature (up to 30 minutes) prior to administration. Resuspend 
by inverting the syringe 2 to 3 times and then rolling the syringe between the palms for 30 
seconds. 
 
IV: Infuse over 10 to 40 minutes; infusion must be completed within 1 hour of (vial) 
reconstitution. 
 
Agent Ordering:  The agent is commercially available and is considered a standard-of-care drug 
in this setting. 
 
 
 


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56 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
Phase Ib Safety / Tolerability Run In - Primary Endpoint:  
• Safety and tolerability will be assessed by evaluating the number of patients out of 6 
who experience a dose-limiting toxicity by cycle 1, day 42, using a standard 3+3 
design. Two out of 6 events will lead to a dose-reduction or trial discontinuation as 
described in the analytic plan. 
 
Phase Ib Safety / Tolerability Run In - Primary Endpoint Analytic Plan:  
• An incidence of one in six (or fewer) patients experiencing a DLT, as described in 
section 7, will be considered a safe and tolerable dose.  
• Patients who receive at least a full course of therapy will be considered to be 
evaluable for toxicity/DLT and will not be replaced unless the PI determines that 
further additional patients at that dose level are required for safety purposes. Patients 
who experience a DLT prior to completing a full course of therapy will be accounted 
for in the safety assessment. 
• A standard 3+3 design will be used to study patients on an initial pinometostat dose 
of 54 mg/m2/day continuous IV infusion, in combination with azacitidine at a dose 
of 75mg/m2 daily for 7 days starting on cycle 1, day 1. If two of six experience a 
DLT within the first 42 days as defined above, the dose of pinometostat will be 
decreased to 36 mg/m2/day, and it will be combined with azacitidine at a dose of 
75mg/m2 daily for 7 days in a separate cohort of patients. If two of six experience a 
DLT within the first 42 days as defined above, the combination will be deemed 
intolerable and the study will be terminated. If three patients tolerate the combination 
of standard-dose azacitidine with pinometostat at 54 mg/m2/day, the pinometostat 
dose may be escalated to 90 mg/m2/day and tested as per standard 3+3 design. 
Patients who complete cycle 1 would be allowed to stay on single-agent pinometostat 
through their day 42 evaluation. Patients who achieve count recovery prior to day 42 
may be considered for additional combination therapy with azacitidine and may 
complete up to 6 cycles of combination therapy as described for patients directly 
enrolled on the phase II protocol. 
 
Phase II Primary Endpoint: 
• Response to combination therapy defined as CR, CRi, PR, or MLFS, with or without 
minimal residual disease (MRD), on bone marrow biopsy as defined by the 2017 
European Leukemia Network guidelines will be assessed. Baseline bone marrow 
biopsy will be performed within 14 days prior to starting therapy, at the end of cycle 
1 (day 28 +/- 2 days or time of count recovery), at the end of cycle 3 (+/- 2 days or at 
the time of count recovery after three cycles of azacitidine administration), at the end 
of cycle 6 (+/- 2 days or at the time of count recovery after six cycles of azacitidine 
administration), and / or at the time of therapy discontinuation +/- 3 days. Patients 
who have stable disease after 4 cycles of combination therapy or progressive disease 
at any time should be taken off the trial. 
 


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57 
Phase II Primary Endpoint Analytic Plan: 
• Response rate will be defined as the number of patients who achieve a CR, CRi, PR, 
or morphologic leukemia-free state (MLFS), with or without MRD, at any time point. 
Patients will be evaluated through the time of count recovery after 6 cycles of 
combination therapy. 
• A Simon two-stage minimax design will be employed whereby a 20% response rate is 
considered not promising, a 40% response rate is considered promising, and the 
probabilities of a type I error (falsely accepting a non-promising therapy) and type II 
error (falsely rejecting a promising therapy) are set at 0.10 and 0.10, respectively.  In 
the first stage of this design, 19 patients will be accrued. All patients will be followed 
for a minimum of 24 weeks.  If at least 4 patients respond then an additional 17 
patients will be accrued to the second stage.   At the end of the trial, if 11 or more 
patients respond out of a total of 36 patients, then this combination will be considered 
worthy of further investigation.  This design yields at least a 0.90 probability of a 
positive result if the true response rate is at least 40% and yields a 0.90 probability of 
a negative result if the true response rate is 20%. 
 
9.2 
Sample Size/Accrual Rate 
 
Maximum planned sample size is 48 patients, with estimated monthly accrual rate of 3-6 patients 
among all sites per month. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
2 
2 
0 
0 
4 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
3 
4 
0 
0 
7 
White 
8 
9 
2 
2 
21 
More Than One Race 
2 
2 
0 
0 
4 
Total 
15 
17 
2 
2 
36 


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58 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
9.3 
Stratification Factors 
 
N/A 
 
9.4 
Analysis of Secondary Endpoints 
 
Phase Ib Safety / Tolerability Run In - Secondary Endpoints:  
• Assess safety and tolerability by evaluating the number of patients who experience a 
dose-limiting toxicity at any time during therapy as defined above.  
• H3K79 methylation (assessed by ELISA) on the bone marrow biopsy specimen from 
prior to therapy initiation and on bone marrow biopsy from day 28 (or time of count 
recovery)  
• Expression levels of HOXA9 and Meis1 (assessed by qPCR), Absolute neutrophil 
and absolute monocyte count at baseline and day 28 
• Evaluate fraction of cells with 11q23 rearrangements before treatment and at day 28 
• Evaluate for a rise in absolute neutrophil / absolute monocyte count from baseline  
 
Phase Ib Safety / Tolerability Run In - Secondary Endpoint Analytic Plans:  
• Compare quantitative methylation and methylation valence (e.g. if H3K27 has been 
methylated once, twice, or three times) from baseline and subsequent bone marrow 
samples using descriptive statistics and graphical displays. A Wilcoxon signed rank 
test will be used to assess post-treatment differences as compared to baseline. The 
variability in the assay will be evaluated by collecting a sample at the time of 
enrollment and at the time of combination therapy initiation, and by running the same 
sample on the assay multiple times. This variability will be taken into account in 
determining what percentage change in methylation will be considered significant.  
• Compare expression level by qPCR of HOXA9 and Meis1 levels from baseline and 
subsequent bone marrow samples using descriptive statistics and graphical displays. 
A Wilcoxon signed rank test will be used to assess post treatment differences as 
compared to baseline. The variability in the assay will be evaluated by collecting a 
sample at the time of enrollment and at the time of combination therapy initiation, 
and by running the same sample on the assay multiple times. This variability will be 
taken into account in determining what percentage change in methylation will be 
considered significant. 
• Evaluate differentiation by performing a differential on the bone marrow biopsy and 
peripheral blood samples at baseline and from subsequent time points and assessing 
percentage of monocytes / neutrophils, bands, and myeloid forms present. Samples 
will be banked and cytogenetic and FISH analysis of these cells will be performed to 
evaluate for the presence of MLL-rearrangement in patients who respond to therapy, 
given funding limitations on performing such an assessment on all patients. 
 
Phase Ib Safety / Tolerability Run In - Exploratory Endpoints:  
• Correlative studies will include assessment of incorporation of 5-aza-2`-
deoxycytidine incorporation into genomic DNA and the extent of global DNA 


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methylation and correlation with systemic azacitidine exposure and 
pharmacodynamics effects. 
 
Phase Ib Exploratory Endpoint Analytic Plans: 
• Expect global DNA demethylation / correlation between decitabine systemic PK 
and decitabine incorporation into genomic DNA;  ratio of DAC content/1000 2dC 
or 5mC content/1000 2dC to express DAC incorporation  or global DNA 
methylation, respectively & methylation changes calculated relative to control 
5mC content/1000 2dC ratio. Correlation between systemic azacitidine PK and  
decitabine incorporation into genomic DNA and other PD measures. 
 
Phase II Secondary Endpoints: 
• Assess safety and tolerability by evaluating the number of patients who experience a 
dose-limiting toxicity at any time during therapy as defined above.  
• Assess patient response based on relapsed / refractory or previously untreated status 
• H3K79 methylation (assessed by ELISA) on the bone marrow biopsy specimen from 
prior to therapy initiation and on subsequent bone marrow biopsy samples  
• Expression levels of HOXA9 and Meis1 (assessed by qPCR), Absolute neutrophil 
and absolute monocyte at baseline and on subsequent bone marrow biopsy samples 
• Evaluate fraction of cells with 11q23 rearrangements before treatment and on 
subsequent bone marrow biopsy samples 
• Evaluate for a rise in absolute neutrophil / absolute monocyte count at the end of 
cycle 1 as compared to baseline  
 
Phase II Secondary Endpoint Analytic Plans: 
• Patients will be followed for the development of DLTs as described above. All DLTs 
will be tracked to detect potential toxicities with combination therapy 
• Patients will be stratified based on treatment for relapsed / refractory or previously 
untreated disease. The response of each stratum to combination therapy, defined as 
CR, CRi, MLFS, or PR, with or without MRD, on bone marrow biopsy as defined by 
the 2017 European Leukemia Network guidelines, will be described. Kaplan-Meier 
estimates will be calculated and compared for each stratum, however the small 
number of patients likely to be enrolled in each stratum will limit the power of this 
study to detect a difference among them. A report will be generated to look at all 
patients, all eligible patients who were enrolled, and all evaluable patients. 
• Compare quantitative methylation and methylation valence (e.g. if H3K27 has been 
methylated once, twice, or three times) from baseline and subsequent bone marrow 
samples using descriptive statistics and graphical displays. A Wilcoxon signed rank 
test will be used to assess post treatment differences as compared to baseline. The 
variability in the assay from the phase Ib studies will be taken into account in 
determining what percentage change in methylation will be considered significant.  
• Compare expression level by qPCR of HOXA9 and Meis1 levels from baseline and 
subsequent bone marrow samples using descriptive statistics and graphical displays. 
A Wilcoxon signed rank test will be used to assess post treatment differences as 
compared to baseline. The variability in the assay from the phase Ib studies will be 


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60 
taken into account in determining what percentage change in methylation will be 
considered significant. 
• Compare 11q23 translocation level as determined by FISH from baseline and 
subsequent bone marrow samples using descriptive statistics and graphical displays. 
A Wilcoxon signed rank test will be used to assess post treatment differences as 
compared to baseline. The variability in the assay from the phase Ib studies will be 
taken into account in determining what percentage change in translocation detection 
will be considered significant. 
• Evaluate differentiation by performing a differential on the bone marrow biopsy 
sample and peripheral blood samples at baseline and subsequent bone marrows and 
assessing percentage of monocytes / neutrophils, bands, and myeloid forms present. 
Samples will be banked and cytogenetic and FISH analysis of these cells will be 
performed to evaluate for the presence of MLL-rearrangement in patients who 
respond to therapy, given funding limitations on performing such an assessment on 
all patients. 
 
Phase II Exploratory Endpoints: 
• Correlative studies will include assessment of incorporation of 5-aza-2`-
deoxycytidine incorporation into genomic DNA and the extent of global DNA 
methylation and correlation with systemic azacitidine exposure and 
pharmacodynamics effects. 
 
Phase II Exploratory Endpoint Analytic Plans: 
• Expect global DNA demethylation / correlation between decitabine systemic PK 
and decitabine incorporation into genomic DNA;  ratio of DAC content/1000 2dC 
or 5mC content/1000 2dC to express DAC incorporation  or global DNA 
methylation, respectively & methylation changes calculated relative to control 
5mC content/1000 2dC ratio. Correlation between systemic azacitidine PK and  
decitabine incorporation into genomic DNA and other PD measures. 
 
9.5 
For phase 2 protocols only: Reporting and Exclusions 
 
9.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
pinometostat. 
 
9.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) morphologic leukemia-free state, 5) early death from malignant disease, 
6) early death from toxicity, 7) early death because of other cause, 8) progressive disease, 
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 


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61 
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 5-9 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.  
 
9.6 
Early Stopping Criteria 
 
The study includes sequential stopping rules to monitor for safety in the phase II study after 
safety has been confirmed in the first six patients. These rules are based on the 30 patients who 
will accrue after the safety run-in. The toxicity definitions for these rules mirror the DLT 
definition. In the event that three in the first six patients, five in the first 12 patients, six in the 
first 18 patients, seven in the first 24 patients, or eight patients at any point among the remaining 
30 patients fulfill the toxicity criteria, accrual to the study will stop due to a lack of safety. If the 
true risk of toxicity is 15%, the probability the intervention will be ruled unsafe is 10%. If the 
true risk increases to 40%, the probability increases to 95%. 
 
 
 


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62 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks 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 
 
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. 
Version 1.1, January 7, 20191 


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63 
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 


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64 
syndrome 
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) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Azacitidine (NSC 102816) 
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. Frequency is provided based on 1800 patients. Below is the CAEPR for 
Azacitidine. 
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. 
 
                                                                                                   Version 2.7, July 30, 20191 
 
 Adverse Events with Possible  
 Relationship to Azacitidine 
 (CTCAE 5.0 Term) 
[n= 1800] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)    
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
  
 
Heart failure 
 
 Heart failure (Gr 2) 
 
Pericardial effusion 
 
 Pericardial effusion (Gr 2) 
 
Sinus tachycardia 
 
 Sinus tachycardia (Gr 2) 
 
Supraventricular tachycardia 
 
 Supraventricular tachycardia (Gr 
2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 


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65 
 
 Adverse Events with Possible  
 Relationship to Azacitidine 
 (CTCAE 5.0 Term) 
[n= 1800] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)    
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Colitis 
 
 Colitis (Gr 2) 
Constipation 
 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Esophagitis 
 
 Esophagitis (Gr 2) 
 
Gastrointestinal hemorrhage2 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
Fever 
 
 
 Fever (Gr 3) 
Injection site reaction 
 
 
 Injection site reaction (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
 Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
Infection3 
 
 
 Infection3 (Gr 4) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
 Bruising (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 4) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased 
(Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 4) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
GGT increased 
 
 GGT increased (Gr 2) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 
4) 
Neutrophil count decreased  
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Acidosis 
 
 Acidosis (Gr 2) 
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Hypokalemia 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Generalized muscle weakness 
 
 Generalized muscle weakness (Gr 
2) 
 
Myalgia 
 
 Myalgia (Gr 2) 


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66 
 
 Adverse Events with Possible  
 Relationship to Azacitidine 
 (CTCAE 5.0 Term) 
[n= 1800] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)    
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
Peripheral motor neuropathy 
 
 Peripheral motor neuropathy (Gr 
2) 
 
Somnolence 
 
 Somnolence (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Confusion 
 
 Confusion (Gr 2) 
 
Insomnia 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Bronchopulmonary 
hemorrhage 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 4) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
 
Pharyngolaryngeal pain 
 
  
 
Postnasal drip 
 
 Postnasal drip (Gr 2) 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(abnormal breath sound)4 
 
 Respiratory, thoracic and 
mediastinal disorders - Other 
(abnormal breath sound)4 (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Purpura 
 
 Purpura (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
 
Hematoma 
 
 Hematoma (Gr 2)  
 
Hypotension 
 
 Hypotension (Gr 3) 
 
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. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
3Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
4Abnormal breath sounds include rales and rhonchi. 


NCI Protocol #:10200 
Version Date: 07/24/2020 
 
67 
 
Adverse events reported on azacitidine trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that azacitidine caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(agranulocytosis); Blood and lymphatic system disorders - Other (lymphadenopathy); Blood and lymphatic 
system disorders - Other (pancytopenia); Blood and lymphatic system disorders - Other (splenomegaly); 
Blood and lymphatic system disorders - Other (transfusion: platelets); Bone marrow hypocellular; 
Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Atrioventricular block complete; Cardiac arrest; 
Cardiac disorders - Other (cardiac valve vegetation); Cardiac disorders - Other (Wolff-Parkinson-White 
syndrome); Chest pain - cardiac; Myocardial infarction; Palpitations; Pericarditis; Restrictive 
cardiomyopathy; Sinus bradycardia; Ventricular fibrillation 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
EYE DISORDERS - Eye disorders - Other (eye/conjunctival hemorrhage); Eye disorders - Other (retina 
hemorrhage); Papilledema; Uveitis 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Duodenal ulcer; Dyspepsia; 
Dysphagia; Enterocolitis; Esophageal pain; Esophageal ulcer; Flatulence; Gastritis; Gastrointestinal 
disorders - Other (enteritis); Gastrointestinal disorders - Other (inguinal hernia, obstructive); 
Gastrointestinal disorders - Other (intestinal ischemia); Gastrointestinal disorders - Other 
(intussusception); Gastrointestinal pain; Hemorrhoids; Pancreatitis; Periodontal disease; Small intestinal 
obstruction; Visceral arterial ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; Flu 
like symptoms; Gait disturbance; General disorders and administration site conditions - Other (systemic 
inflammatory response syndrome); Generalized edema; Malaise; Multi-organ failure; Non-cardiac chest 
pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (bile duct 
stone); Hepatobiliary disorders - Other (hepatic cirrhosis) 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder; Immune system disorders - Other (GVHD) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Burn; Fall; Fracture; Hip fracture; Injury, 
poisoning and procedural complications - Other (excoriation); Injury, poisoning and procedural 
complications - Other (transfusion reaction); Postoperative hemorrhage; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood lactate dehydrogenase 
increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; INR increased; 
Investigations - Other (blood urea increased); Investigations - Other (cardiac murmur); Investigations - 
Other (coagulopathy); Investigations - Other (protein total decreased); Investigations - Other 
(thrombocytosis); Lipase increased; Lymphocyte count increased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypomagnesemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (gout exacerbation); 
Metabolism and nutrition disorders - Other (hypovolemia); Metabolism and nutrition disorders - Other (low 
carbon dioxide) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Bone pain; Chest wall pain; 
Flank pain; Muscle cramp; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - 
Other (chondritis); Musculoskeletal and connective tissue disorder - Other (intervertebral disc protrusion); 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness); Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Myelodysplastic syndrome; Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(colonic polyp, vaginal polyp); Neoplasms benign, malignant and unspecified (incl cysts and polyps) - 
Other (metastases to central nervous system); Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dysesthesia; Dysgeusia; Hydrocephalus; Intracranial hemorrhage; 
Lethargy; Memory impairment; Nervous system disorders - Other (head injury); Paresthesia; Peripheral 
sensory neuropathy; Seizure; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Delirium; Depression; Hallucinations; Psychiatric disorders - Other (mental 
status changes) 


NCI Protocol #:10200 
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68 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Dysuria; Hematuria; Proteinuria; Renal 
and urinary disorders - Other (bladder distention); Renal and urinary disorders - Other (calculus urinary); 
Renal calculi; Urinary frequency; Urinary retention 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Reproductive system and 
breast disorders - Other (benign prostatic hyperplasia); Uterine hemorrhage; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Hypoxia; Laryngeal 
hemorrhage; Nasal congestion; Oropharyngeal pain; Pleural effusion; Pleuritic pain; Pneumonitis; 
Pneumothorax; Productive cough; Pulmonary edema; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (chronic obstructive pulmonary disease); Respiratory, thoracic and 
mediastinal disorders - Other (pharyngeal erythema); Rhinorrhea; Sinus pain; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Palmar-plantar 
erythrodysesthesia syndrome; Skin and subcutaneous tissue disorders - Other (skin laceration); Skin and 
subcutaneous tissue disorders - Other (skin lesion); Skin and subcutaneous tissue disorders - Other (skin 
nodule); Skin and subcutaneous tissue disorders - Other (Sweet's Syndrome); Skin induration; Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Thromboembolic event; Vascular disorders - Other 
(pallor); Vascular disorders - Other (poor venous access); Vasculitis 
 
Note: Azacitidine in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
10.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP 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) 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: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
 


NCI Protocol #:10200 
Version Date: 07/24/2020 
 
69 
The Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) integration enables evaluation of post-baseline AEs entered in 
Rave to determine whether they require expedited reporting, and facilitates entry 
in CTEP-AERS for those AEs requiring expedited reporting.    
 
All AEs that occur after baseline are collected in Medidata Rave using the 
Adverse Event form, which is available for entry at each treatment or reporting 
period, and used to collect AEs that start during the period or persist from the 
previous reporting period.  The Clinical Research Associate (CRA) will enter AEs 
that occur prior to the start of treatment on a baseline form that is not included in 
the Rave-CTEP-AERS integration.  AEs that occur prior to enrollment must begin 
and end on the baseline Adverse Event form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been 
an increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify 
the following on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-
free (fields added to the form during study build do not need to be query-
free for the integration call with CTEP-AERS to be a success). 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If 
the CRA modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for 
rules evaluation by completing the Expedited Reporting Evaluation form.  Both 
NCI and protocol-specific reporting rules evaluate the AEs submitted for 
expedited reporting.  A report is initiated in CTEP-AERS using information 
entered in Medidata Rave for AEs that meet reporting requirements.  The CRA 
completes the report by accessing CTEP-AERS via a direct link on the Medidata 
Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is 
restored, the 24-hour notification that was phoned in must be entered immediately 
into CTEP-AERS using the deep link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the 
CTSU website: 
 
• Study specific documents:  Protocols > Documents > Education and 
Promotion, and   
• Expedited Safety Reporting Rules Evaluation user guide:  Resources > 
CTSU Operations Information > User Guides. 
 


NCI Protocol #:10200 
Version Date: 07/24/2020 
 
70 
NCI requirements for SAE reporting are available on the CTEP website:  
 
NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.p
df. 
 
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 


NCI Protocol #:10200 
Version Date: 07/24/2020 
 
71 
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 
 
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 
Blood and lymphatic disorders 
Bone marrow hypocellular 
4 
Regardless 
Cardiac Disorders 
Atrial fibrillation 
2 
Regardless 
Cardiac Disorders 
Atrial flutter 
2 
Regardless 
Ear and labyrinth disorders 
Vertigo 
2 
Regardless 
Gastrointestinal disorders 
Belching 
2 
Regardless 
Gastrointestinal disorders 
Bloating 
2 
Regardless 
Gastrointestinal disorders 
Constipation 
3 
Regardless 
Gastrointestinal disorders 
Dental caries 
3 
Regardless 
Gastrointestinal disorders 
Dry mouth 
2 
Regardless 
Gastrointestinal disorders 
Dyspepsia 
3 
Regardless 
Gastrointestinal disorders 
Gastroesophageal reflux disease 
2 
Regardless 
Gastrointestinal disorders 
Gingival pain 
2 
Regardless 
Gastrointestinal disorders 
Hemorrhoids 
2 
Regardless 
Gastrointestinal disorders 
Lip pain 
3 
Regardless 


NCI Protocol #:10200 
Version Date: 07/24/2020 
 
72 
CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
Gastrointestinal disorders 
Toothache 
3 
Regardless 
General disorders and 
administration site conditions 
Infusion site extravasation 
2 
Regardless 
General disorders and 
administration site conditions 
Malaise 
3 
Regardless 
General disorders and 
administration site conditions 
Pain 
2 
No 
Injury, poisoning and 
procedural complications 
Fracture 
2 
Regardless 
Investigations 
Activated partial thromboplastin 
time prolonged 
3 
No 
Investigations 
Blood lactate dehydrogenase 
increased 
1 
Regardless 
Investigations 
INR increased 
3 
No 
Metabolism and nutrition 
disorders 
Glucose intolerance 
3 
Regardless 
Metabolism and nutrition 
disorders 
Hypercalcemia 
2 
No 
Metabolism and nutrition 
disorders 
Hyperglycemia 
3 
No 
Metabolism and nutrition 
disorders 
Hyperkalemia 
2 
No 
Metabolism and nutrition 
disorders 
Hypernatremia 
2 
No 
Metabolism and nutrition 
disorders 
Hyperphosphatemia 
3 
No 
Metabolism and nutrition 
disorders 
Hyperuricemia 
3 
No 
Metabolism and nutrition 
disorders 
Hypalbuminemia 
3 
No 
Metabolism and nutrition 
disorders 
Hypocalcemia 
2 
No 
Metabolism and nutrition 
disorders 
Hypoglycemia 
2 
No 
Metabolism and nutrition 
disorders 
Hypokalemia 
3 
No 
Metabolism and nutrition 
disorders 
Hypomagnesemia 
2 
No 


NCI Protocol #:10200 
Version Date: 07/24/2020 
 
73 
CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
Metabolism and nutrition 
disorders 
Hyponatremia 
3 
No 
Metabolism and nutrition 
disorders 
Hypophosphatemia 
3 
No 
Metabolism and nutrition 
disorders 
Obesity 
4 
Regardless 
Metabolism and nutrition 
disorders 
Tumor lysis syndrome 
3 
No 
Psychiatric disorders 
Agitation 
3 
Regardless 
Psychiatric disorders 
Anxiety 
3 
Regardless 
Psychiatric disorders 
Delirium 
3 
Regardless 
Psychiatric disorders 
Depression 
3 
Regardless 
Psychiatric disorders 
Insomnia 
3 
Regardless 
Renal and urinary disorders 
Chronic kidney disease 
4 
Regardless 
Renal and urinary disorders 
Dysuria 
1 
Regardless 
Renal and urinary disorders 
Urinary frequency 
2 
Regardless 
Respiratory, thoracic, and 
mediastinal disorders 
Hiccups 
3 
No 
Respiratory, thoracic, and 
mediastinal disorders 
Nasal congestion 
3 
Regardless 
Respiratory, thoracic, and 
mediastinal disorders 
Sneezing 
2 
Regardless 
Respiratory, thoracic, and 
mediastinal disorders 
Sore throat 
3 
No 
Respiratory, thoracic, and 
mediastinal disorders 
Sleep apnea 
3 
Regardless 
Skin and subcutaneous tissue 
disorders 
Dry skin 
3 
Regardless 
Skin and subcutaneous tissue 
disorders 
Eczema 
3 
No 
Vascular disorders 
Hypertension 
3 
No 
Vascular disorders 
Thromboembolic event 
2 
No 
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 


NCI Protocol #:10200 
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74 
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 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
 


NCI Protocol #:10200 
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75 
11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. Scans 
and x-rays must be done <4 weeks prior to the start of therapy.   
In the event that the patient’s condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours prior to initiation of the next cycle of therapy. 
 
 
 
 
 
Pre- 
Study 
 
Wk 
1 
Cyc 1 
Day 1 
 
Cyc 1 
Day 8 
 
Wk 
3 
 
Wk 
4 
 
Wk 
5 
Cyc 2 
Day 1 
 
Wk 
6 
 
Wk 
7 
 
Wk 
8 
 
Wk 
9 
Cyc 3 
Day 1 
 
Wk 
10 
 
Wk  
11 
 
Wk  
12 
 
Pinometostat 
 
 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
Azacitidine 
 
 
 
B 
 
 
 
 
 
 
 
B 
 
 
 
 
 
 
 
B 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C testing 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
X-------------------------------------------------------------------------------------------------X 
 
 
 
 
 
Physical exam 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Urine Pregnancy Test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Performance status 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, plts 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
Serum chemistrya 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
PT / PTT 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
Uric Acid 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum PK assessmentsb 
 
 
    X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 5-aza-2′-
deoxycytidine genomic 
incorporationc 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
EKG (as indicated) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
 
X-------------------------------------------------------------------------------------------------X 
 
 
 
 
Nail clippings collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


NCI Protocol #:10200 
Version Date: 07/24/2020 
 
76 
 
Bone Marrow Biopsy and 
Aspirate (with 
morphology, flow 
cytometry, cytogenetics, 
FISH) 
 
X 
 
 
 
 
 
 
 
 
 
X‡ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
Marrow aspirate myeloid 
genomic panel 
 
 
     X 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Marrow 
aspirate 
for 
banking samples  
 
X 
 
 
 
 
 
 
X‡ 
 
 
 
 
 
 
 
 
  
 
 
 
 
Marrow aspirate for qPCR 
for HOXA9 & Meis1 and 
H3K79 ELISA 
 
X 
 
 
 
 
 
 
 
 
 
X‡ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Marrow aspirate for 5-
aza-2’-deoxycytidine 
Genomic Incorporation 
and DNA demethylationc 
 
 
X 
 
 
 
 
 
 
 
 
 
X‡ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: 
Pinometostat:  Dose as assigned 
B: 
Azaciridine:  Standard dosing of 75mg/m2 given over 7 of the first 10 days of the cycle 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium, magnesium. 
b:       PK assessments should be done prior to treatment and at 15, 30, and 60 min after azacitidine is started in cycle 1 
c:        Serum and marrow 5-aza-2’-deoxycytidine genomic incorporation and DNA demethylation samples must be collected 
in green-top vacutainer containing THU 
‡:        Bone marrow tests should be performed at the end of cycle 1, end of cycle 3, and end of cycle 6, prior to the start of 
the next cycle of azacitidine. These can be performed on the first day of the following cycle, prior to the start of 
azacitidine therapy. 
 
 
 
 
 
Wk 13 
Cyc 4  
Day 1 
 
Wk 
14 
 
Wk 
15 
 
Wk 
16 
 
Wk  
17  
Cyc 5 
Day 1 
 
Wk 
18 
 
Wk 
19 
 
Wk 
20 
 
Wk 
21 
Cyc 6 
Day 1 
 
Wk 
22 
 
Wk 
23 
 
Wk 
24 
 
Off 
Stu
dyc 
 
 
1-
mo 
f/u 
 
Pinometostat 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
# 
 
 
 
Azacitidine 
 
B 
 
 
 
 
 
 
B 
 
 
 
 
 
 
 
B 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
 
X-------------------------------------------------------------------------------------------------X 
 
 
 
 
Physical exam 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Vital signs 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #:10200 
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77 
Performance status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, plts 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Serum chemistrya 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
PT/PTT 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
EKG (as indicated) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
X-------------------------------------------------------------------------------------------------X 
 
 
 
 
Bone Marrow Biopsy and 
Aspirate (with 
morphology, flow 
cytometry, cytogenetics, 
FISH) 
 
X‡ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X* 
 
 
   
  
 
 
 
Marrow 
aspirate 
for 
banking samples  
 
X‡ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X* 
 
 
  
 
 
 
Marrow aspirate for qPCR 
for HOXA9 & Meis1 and 
H3K79 ELISA 
 
X‡ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  X* 
 
 
 
Marrow aspirate for 5-
aza-2’-deoxycytidine 
Genomic Incorporation 
and DNA demethylationc 
 
 
X‡ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X* 
 
 
 
A: 
Pinometostat:  Dose as assigned 
B: 
Azacitidine:  Standard dosing of 75 mg/m2 given over 7 of the first 10 days of the cycle 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium, magnesium. 
c:        Serum and marrow 5-aza-2’-deoxycytidine genomic incorporation and DNA demethylation samples must be collected in 
green-top vacutainer containing THU 
 
‡:        Bone marrow tests should be performed at the end of cycle 1, end of cycle 3, and end of cycle 6, prior to the start of the next 
cycle of azacitidine. These tests can be performed on the first day of the following cycle, prior to the start of azacitidine 
therapy. 
*:        Bone marrow tests should be done at the end of cycle 6. If a patient receives fewer than 6 cycles or more than 6 cycles, bone 
marrow tests should be done at the time of therapy cessation as long as at least one month has elapsed since the prior 
bone marrow test. 
#:        For patients who continue on pinometostat beyond 6 months, they should follow the same evaluation schedule as outlined for 
cycle 2.  
 
 
 
 


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12. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drugs has not yet been established, the intent of offering 
this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability.  Patients 
with measurable disease will be assessed by standard criteria.  For the purposes of this study, 
patients should be re-evaluated at the end of cycle 1, end of cycle 3, and end of cycle 6.  
 
12.1 
Antitumor Effect  
 
For the purposes of this study, patients should be re-evaluated for response at the end of cycle 1, 
end of cycle 3, and end of cycle 6. 
 
Response and progression will be evaluated in this study using the 2017 European Leukemia Net 
Guidelines19. 
 
12.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with pinometostat. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
12.1.2 Disease Parameters 
 
Measurable disease.  For previously untreated patients, the presence of at least 20% blasts 
in the peripheral blood on a complete blood count differential or on a bone marrow 
aspirate differential, with cytogenetics or FISH studies showing a translocation or 
cytogenetics or FISH or a myeloid mutational panel showing partial tandem duplication 
of the 11q23 / MLL locus would qualify as measurable disease. For patients with 
relapsed / refractory disease, any abnormal disease burden as detected by morphology, 
flow cytometry, cytogenetics, or molecular testing which has a detectable 11q23 
rearrangement or PTD would qualify as having measurable disease. Patients in either 
setting with a myeloid sarcoma or extramedullary involvement with detectable 11q23 
rearrangement / PTD would also qualify as having measurable disease. Diagnosis should 
be confirmed with a bone marrow biopsy within 14 days prior to the start of therapy. 
 
Measurable extramedullary lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest 
x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 


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Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
Hematopathology – The percentage of blasts found on the aspirate differential as read by 
the hematopathologist at the enrolling institution will be used to evaluate response.  
  
Peripheral Blood CBC and Differential – The ANC, platelet count, and differential, 
including blast percentage from both automated and manual differentials, will be used. If 
both an automated and manual differential are performed, the latter will be used to 
evaluate the peripheral blast percentage. 
 
FDG-PET - While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to assess diagnosis and 
progression (particularly possible 'new' disease). This would only be applicable to 
patients with extramedullary disease. New lesions on the basis of FDG-PET imaging can 
be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease, this area should be biopsied to 
determine if it represents progression of disease. Such cases should be discussed with 
the medical monitor. 
c. FDG-PET may be used to upgrade a response to a CR for a patient with 
extramedullary disease, no bone marrow involvement, and no other means by which 
to evaluate their disease involvement (e.g. physical exam) in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  However, it must be acknowledged that such an approach may 
lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Response as per 2017 ELN Guidelines19 
 


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Complete Remission (CR): Bone marrow blasts < 5%; no circulating blasts, no blasts 
with Auer rods, no extramedullary disease; ANC > 1000 per microliter, platelets > 
100,000 per microliter 
 
Complete Remission with Incomplete Count Recovery(CRi): Bone marrow blasts < 
5%; no circulating blasts, no blasts with Auer rods, no extramedullary disease; ANC 
< 1000 per microliter and / or platelets < 100,000 per microliter 
 
Morphologic Leukemia-Free State (MLFS):  Bone marrow blasts < 5%; no blasts 
with Auer rods, no extramedullary disease; no hematologic recovery required 
 
Partial Remission (PR): All hematologic criteria of CR; decrease in bone marrow 
blasts to 5-25%; decrease in pre-treatment bone marrow blasts by at least 50%  
 
Progressive Disease (PD): 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 mo; without at least a 100% 
improvement in ANC to an absolute level (>0.5 x 109 /L [500/µL], and/or 
platelet count to >50 x 109 /L [50,000/µL] nontransfused); or 
• > 50% increase in peripheral blasts (WBC x % blasts) to >25 x 109 /L (>25 
000/µL) (in the absence of differentiation syndrome); or  
• New extramedullary disease 
 
 
Stable Disease (SD): Absence of CR, CRi, MLFS, PR; criteria for progressive disease 
not met 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
N/A 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
The overall response rate includes achievement of CR, CRi, MLFS, and PR. 
 
12.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 


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for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
12.1.6 Progression-Free Survival 
 
Progression-free survival (PFS) will be assessed, defined as the duration of time from 
start of treatment to time of progression or death, whichever occurs first. 
 
12.1.7 Response Review 
 
All responses will be reviewed by an independent hematopathologist at the study’s 
completion. 
 
12.2 
Antitumor Effect – Hematologic Tumors 
 
See above 
 
12.3 
Other Response Parameters 
 
N/A 
 
 
 


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13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  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 
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. A central data safety monitoring board consisting of study team members will hold a 
conference, approximately once per week, to discuss safety issues that arise with the trial. 
 
13.2 
Data Reporting 
 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  To access Rave via iMedidata: 


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• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site:  Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
• 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata.  To accept the invitation, site staff must log in to the 
Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM username 
and password, and click on the accept link in the upper right-corner of the iMedidata 
page.  Site staff will not be able to access the study in Rave until all required Medidata 
and study specific trainings are completed.  Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right 
pane of the iMedidata screen.  If an eLearning is required and has not yet been taken, the 
link to the eLearning will appear under the study name in iMedidata instead of the Rave 
EDC link; once the successful completion of the eLearning has been recorded, access to 
the study in Rave will be granted, and a Rave EDC link will display under the study 
name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.  
 
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 
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. 


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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 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
). 
 


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13.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries.  DQP Queries, DQP Delinquent Forms, and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports.  Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website.  Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports 
specified on the DQP. A protocol must have the Calendar functionality 
implemented in Rave by the Lead Protocol Organization (LPO) for delinquent 
form details and report to be available on the DQP. Site staff should contact the 
LPO Data Manager for their protocol regarding questions about Rave Calendering 
functionality. 
 
13.4 
CTEP Multicenter Guidelines 
 
N/A 
 
13.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 


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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. 
 
13.6 
Genomic Data Sharing Plan 
 
Genomic data will be generated from samples centrally sequenced at MSKCC. Data pertinent to 
the interpretation of genomic data, including the minimal phenotype information needed to 
reproduce the primary analysis —such as associated phenotype data (e.g., clinical information), 
exposure data, relevant metadata, and descriptive information (e.g., protocols or methodologies 
used)—will be collected from participating sites and incorporated into the analysis of genomic 
data. The investigators and statistician and/or bioinformaticians for a study will have access to all 
data on mutations and variants. This information will be sequestered from access throughout the 
study until it is analyzed for purposes of reporting and publishing of the study results.  As 
specified in the CRADA for the agents used in the clinical study, the pharmaceutical collaborator 
will have at least 6 months, longer if needed for a regulatory filing, to review the data and or 
receive copies of the data once the study is completed and analyzed, or sooner, if specified for 
purposes of generating Intellectual Property.  Once these timeframes have been exceeded, the 
data will be available through a Data Access Committee (DAC) in the GDC following NCI and 
Collaborator review of the proposals.  
 
13.7 
Incidental/Secondary Findings Disclosure Procedure 
 
This protocol involves genomic testing of the tumor sample, as well as of the patient’s normal 
DNA. A myeloid genomic panel should be performed at the time of diagnosis and results should 
be relayed to the patient and their family as per local institutional practice. Paired analysis of 
tumors and patient-matched normal samples will be performed for the sole purpose of 
unambiguous detection of somatic mutations. Germline DNA will not be annotated for 
pathogenic mutations. Testing of germline DNA will not be conducted in a CLIA lab but instead 
as part of the IWG myeloid research panel and, as such, results will not be returned to the 
patient. 
 
 
 


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(2015). 
19. Döhner, H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations 


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from an international expert panel. Blood 129, 424–447 (2017). 
 


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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 
BIOASSAY TEMPLATES 
 
Biomarker Name 
AND Lab PI and Site 
Assay 
(CLIA: Y/N) 
 
Use (Integral, 
Integrated, or 
Exploratory) AND 
Purpose  
Tissue/Body Fluid 
Tested 
and Timing of Sample 
Collection 
M/O  
Use of NCI 
Resources 
(No / Pending 
Approval / 
Approved) 
Funding 
Source(s) 
11q23 rearrangement 
or partial tandem 
duplication 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
Cytogenetics 
and FISH 
CLIA: Y 
BRC Review: 
No 
Integral 
Evaluate eligibility 
Bone marrow aspirate, 
peripheral blood 
Prior to enrollment and 
therapy cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
Myeloid mutational 
panel for no targetable 
mutations 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
Myeloid 
Mutations 
CLIA: Y  
BRC Review: 
No 
Integral 
Evaluate eligibility 
Bone marrow aspirate 
Prior to enrollment and 
therapy cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
Myeloid differentiation 
by Flow/FISH 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
FACS, Flow 
cytometry, FISH 
CLIA: N 
BRC Review: 
Yes  
Submission 
Deadline: 
Integrated 
Evaluate 
differentiation of 
cells with treatment 
Bone marrow aspirate, 
peripheral blood 
End of cycle 1, end of 
cycle 3, and therapy 
cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
H3K79 ELISA 
Scott Armstrong / 
Dana-Farber Cancer 
Institute (DFCI) 
Lab PI email: 
H3K79 ELISA 
CLIA: N 
BRC Review: 
No 
Integrated 
Quantitate 
methylation 
Bone marrow aspirate, 
peripheral blood 
Prior to enrollment, end 
of cycle 1, end of cycle 
3, and therapy cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
qPCR for HOXA9 and 
Meis1 Expression 
Scott Armstrong / 
Dana-Farber Cancer 
Institute (DFCI) 
Lab PI email: 
qPCR 
CLIA: N 
BRC Review: 
No 
Integrated 
Quantitate gene 
expression 
Bone marrow aspirate, 
peripheral blood 
Prior to enrollment, end 
of cycle 1, end of cycle 
3, and therapy cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
MRD Negativity by 
Flow Cytometry 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
Flow cytometry 
CLIA:  Y 
BRC Review: 
No 
Integrated 
Evaluate response 
to therapy 
Bone marrow aspirate 
End of cycle 1, end of 
cycle 3, and therapy 
cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 
Azacitidine PK profile 
Michelle A. Rudek / 
Johns Hopkins  
Lab PI email: 
LC-MS/MS 
CLIA: N 
GLP: Y 
BRC Review: 
No 
Integrated 
Pharmacokinetic 
profile of 
azacitidine alone 
Blood with THU to 
stabilize azacitidine 
C1D1 pre, and 0.25, 
0.5, and 1 hr post 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
UM1 for 
sample 
processing; 
CTEP / NIH 
/ foundation 
grants for 
PK 
assessment 
Cell storage / DNA 
storage 
Eytan Stein / Memorial 
Sloan-Kettering Cancer 
Center (MSKCC) 
Lab PI email: 
Cell storage / 
DNA storage 
CLIA: N 
BRC Review: 
No 
Exploratory 
Evaluate valence 
of methylation in 
future 
Bone marrow aspirate, 
peripheral blood 
Prior to enrollment, end 
of cycle 1, end of cycle 
3, and therapy 
cessation; nail clippings 
only prior to enrollment 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
CTEP 
CRADA 


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Biomarker Name 
AND Lab PI and Site 
Assay 
(CLIA: Y/N) 
 
Use (Integral, 
Integrated, or 
Exploratory) AND 
Purpose  
Tissue/Body Fluid 
Tested 
and Timing of Sample 
Collection 
M/O  
Use of NCI 
Resources 
(No / Pending 
Approval / 
Approved) 
Funding 
Source(s) 
5-aza-2’-deoxycytidine 
Genomic Incorporation 
(from azacitidine) and 
DNA demethylation 
Michelle A. Rudek / 
Johns Hopkins 
Lab PI email: 
mrudek2@jhmi.edu 
LC-MS/MS 
CLIA: N 
GLP: Y 
BRC Review: 
No 
Exploratory 
Pharmacodynamic 
profile of 
azacitidine 
conversion to 5-
aza-2’-
deoxycytidine 
triphosphate and 
incorporation into 
DNA and its effect 
on DNA 
demethylation 
PBMC and bone 
marrow aspirate 
PBMC:  C1D8; 
Bone marrow aspirate:  
End of cycle 1, end of 
cycle 3, and therapy 
cessation 
M 
ETCTN Tissue 
Bank: No 
CIMAC: No 
MoCha: No 
PADIS: No 
UM1 for 
sample 
processing 
and 
analysis 
 
BRC Document Submission Deadline Key: 
A = Documents should be submitted to PIO as soon as possible but not later than 4 weeks upon receipt of this consensus review.  
BRC approval is required prior to LOI approval for this study. 
B = Documents should be submitted to PIO as soon as possible but not later than 4 weeks upon receipt of this consensus review.  
BRC approval is required prior to protocol approval in order to allow sufficient time for BRC review and to comply with OEWG 
deadlines. 
C = Documents should be submitted to PIO as soon as possible but not later than 4 weeks upon receipt of this consensus review.  
BRC approval is required prior to protocol activation in order to allow sufficient time for BRC review and to comply with OEWG 
deadlines. 
D = Documents should be submitted to PIO as soon as ready, but no later than the protocol submission. 


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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  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, Pinometostat.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Pinometostat interacts with certain specific enzyme(s) in your liver, certain transport proteins 
that help move drugs in and out of cells.  
 
• The enzymes in question are CYP3A4/5 and 2C19. Pinometostat is broken down by these 
enzymes and may be affected by other drugs that inhibit or induce these enzymes. 
Pinometostat also inhibits CYP3A4/5 and must be used carefully with other drugs that 
are broken down by these enzymes. 
• The proteins in question are OATP1B3, P-gp, MATE1 and MATE2-K. Pinometostat is 
moved in and out of cells/organs by OATP1B3, P-gp, MATE1, and MATE2-K and may 
be affected by other drugs that inhibit or induce these proteins. Pinometostat also inhibits 
MATE1 and MATE2-K and must be used carefully with other drugs that are moved in and 
out of cells/organs by these proteins.  
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Pinometostat may interact with other drugs which can cause side effects. For this reason, it is 
very important to tell your study doctors of any medicines you are taking before you enroll onto 
this clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know:  
 
Pinometostat must be used very carefully with other medicines that use certain liver enzymes or 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto 
the clinical trial, your study doctor will work with your regular health care providers to review 
any medicines and herbal supplements that are considered strong inducers/inhibitors or 
substrates of CYP3A4/5, transport proteins MATE1 or MATE2-K. 
 
 


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• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is _____________________________________ 
and he or she can be contacted at _____________________________________. 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
pinometostat.  This clinical trial is sponsored by the NCI.  
Pinometosta may interact with drugs that are processed by your 
liver, or use certain transport proteins in your body.  Because of 
this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
Pinometostat interacts with specific liver enzymes called 
CYP3A4/5, transport protein MATE1 and MATE2-K, and must 
be used very carefully with other medicines that interact with these 
enzymes, transporters, or agent.  
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered strong 
inducers/inhibitors or substrates of CYP3A4/5 or transporters 
MATE1 and MATE2-K.  
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.