Early Assessment of Treatment Response in AML Using FLT PET/CT Imaging
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Sponsor: National Cancer Institute (NCI)

i
28 State Street, Suite 1100, Boston, MA 02109
p: 857.504.2900
f:617. 589.0914
ecog-acrin.org
February 6, 2018
Martha Kruhm, MS RAC
Head, Protocol and Information Office
Quality Assurance Section
CTEP, DCT, NCI
6130 Executive Blvd, EPN Room 7000
Bethesda, MD   20892
Dear Ms. Kruhm:
Enclosed is Addendum #3 to EAI141, Early Assessment of Treatment Response in AML using 
FLT PET/CT Imaging.
The below comments were received on November 22, 2017 from CTEP’s review of Addendum 
#3. PI responses to each comment appear in bold below.
I. Comments Requiring a Response– Major Issues:
#
Section
Comments
1.
Global
Even though the investigators only expect to have ten patients for the new 
exploratory objectives involving the reinduction FDG-PET/CT scans, they 
should include the specific summary statistics they plan to compute.  For 
instance, do they plan to compute the median SUVs (or median changes in 
SUV) between patients experiencing complete remission versus those that do 
not?
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction.
2.
Global
Multiple Sections:  The abbreviations AP, NPIVR, IVR, RA, etc, all new in the 
A05 document, need to be explained.
PI Response: These abbreviations are included in the template language 
provided by CTSU. The expansions for each acronym listed above are 
included in section 4 “CTEP Investigator Registration Procedures” prior 
to first acronym use. 
3.
Global
Regarding the reinduction scan and timing of imaging.
1. Please explain the reasoning for the adding optional post reinduction FLT 
PET CT at this time, half way through this Trial’s accrual plan? 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction.
2. How many patients are expected to undergo both induction and reinduction 
moving forward? 
Operations Office – Boston 

ii 
# 
Section 
Comments 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction. Based on the 
statistics of the patients accrued so far, we would expect less than 10 
patients that would receive re-induction and were candidates for a 
potential post re-induction scan.  
 
3. What are the biologic and clinical  differences between those patients who 
do and do not receive reinduction? 
 
PI Response: Patients with resistant disease that requires re-induction 
chemotherapy often have high risk features such as poor risk 
cytogenetics, poor risk molecular findings (i.e. FLT3), or age > 60 years. 
 
4. What is the anticipated accrual into each of the 2 optional FLT arms and will 
either reach any statistical ignificance? 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction.  
 
For the requested statistics, please reference the supplemental data 
provided separate from this resubmission. With regard to the optional 
baseline FLT scan: we initially projected that half of the cohort would 
be scanned at T=0 (or baseline) and powered up the study for the 
corresponding aim. However, the monitoring of our data showed that 
the actual rate was lower than expected, thus, this won’t reach 
statistical significance (the power calculation was mainly aimed to 
provide statistical significance for the primary endpoint). However, 
we anticipate that there will be a sufficient number of patients for 
providing a strong rationale for future follow-up studies specifically 
focusing on these exploratory imaging endpoints. 
 
5. Will the Bone Marrow Biopsy at Day 28-35 always be post reinduction FLT 
(for those patients in which this late FLT scan is performed)? Section 4.8 (and 
in Section 5; multiple places) suggests that this is not necessarily the case. Is it 
not possible that FLT scan could be positive simply due to effects of recent 
bone marrow biopsy? 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction. 
 
6. What is the expected time period from induction to reinduction? 
 
PI Response: Reinduction chemotherapy is started soon after the day 14 
marrow if there is persistent disease. The day 14 (nadir) marrow is 
performed 14 days after the initial chemotherapy is started. 

iii 
3. 
Global 
7. What is the maximal allowable time period between these for Trial purposes 
of obtaining a late FLT scan? 
 
PI Response: The protocol does not have a maximum allowable time 
period and we think this is best to keep in place to stay in line with 
institutional practice. However, the study team is no longer moving 
forward with the post reinduction FLT PET CT. 
 
8. What are the statistical accrual needs for the T = 0 scan? 
 
PI Response: Time T=0 (pre-treatment) has been revised to be 
exploratory as it won’t reach statistical significance (the power 
calculation was aimed to provide statistical significance for the primary 
endpoint). However, we anticipate that there will be a sufficient number 
of patients for providing a strong rationale for future follow-up studies, 
specifically focusing on these exploratory imaging endpoints. 
 
9. Is the new plan powered to account for the several patients that are likely to 
accrue into the T = 0 scan and therefore be inelegible for the late FLT scan? 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction. 
 
10. Will the new plan lead to insufficient accrual into the T = 0 day or baseline 
scan due to the accrual needs for the late scan? 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction. 
 
11. Is the new plan powered to account for the several deaths that are likely to 
occur during induction? 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction.  
 
12. Can the PI or ECOG ACRIN provide current accrual information for the 
following: 
- Number of patients who received the baseline or T = 0 day FLT scan 
- Number of patients who received the T = 14 day (day 10-17) FLT scan 
- A complete listing and correlation of the patients in the T = 0 and T = 14 
groups 
- Number of patients that have had the bone marrow biopsy and the dates 
(T=?) for these biopsies? Reasons why some patients did not receive a bon e 
marrow biopsy. 
A separate explanation for each patient that did not receive both the T = 0 and 
the   T = 14 day FLT scans. 
PI Response: For the requested statistics, please reference the 
supplemental data provided separate from this resubmission. 

iv 
# 
Section 
Comments 
4. 
Schema 
Lettering is too small to read.  
Day 10-17 FLT scan should be listed as mandatory.  
Schema notations for figure 1 and figure 2 could be added. 
 
PI Response: In the original amendment submission, the Post-Induction 
Imaging (occurs day 10-17) is noted as required in the schema. However, 
the study team is no longer moving forward with the new exploratory 
objectives involving FLT PET after reinduction.  
 
Footnote 3 has been amended to clarify that Day 10-17 FLT scan is 
mandatory.  
 
5. 
Objectives 
Exploaratory Objectives:  
 
1. What is purpose for this amendment for obtaining the post reinduction scan? 
 
2. Although technically correct, the terms induction and reinduction are very 
easy to confuse. Perhaps for the sake of maximal clarity it would be best to 
use completely different terminology for the post reinduction scan mentioned in 
this A5 document (Late scan, day ? 28 scan, or other similar name, etc). 
Adding a timeline with expected dates, eg T=0, T=14, etc, to the items noted 
on the schema would also add needed clarity. 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction. 
6. 
2 
Detail appears lacking especially in Section 2.3.2. 
Many wording changes are noted in Section 2 in keeping with PIs desire to 
perform an optinal late FLT scan. 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction. 
7. 
4.8 
Section 4.8 changes require discussion, especially as FLT scan should not 
occur with a few days following a bone marrow biopsy. In general molecular 
imaging should occur before biopsies or surgery, not immediately after. 
 
PI Response: study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction.  
8. 
5 
Section 5. A major change of the study design appears to be the introduction 
of chemotherapy choice number 2. Was this previously agreed to by CTEP 
Oncology? If so, please provide the details of this previous approval.  
 
Such requested therapy changes are subject to review via CTEP and possible 
review at PRC. 
 
Can the PI explain how this therapy choice might change the findings: 

v 
# 
Section 
Comments 
- 
on 18F FLT scan  
- 
of bone marrow biopsy. 
 
Is the Trial plan powered to allow for this change in therapy / choice? 
 
PI Response: This change is no longer included in the proposed 
addendum, but will be addressed in a future addendum.  
9. 
5.7 
Section 5.7.  Last sentence is not clear. A bone marrow biopsy will take place 
after induction. Please make clear the potential timeline differences between 
marrow biopsy date following induction (only) vs timeline in those patients who 
receive both induction and reinduction. 
 
For PIO: This is not noted on the Changes List. 
 
PI Response: Please see item #24 on the change list of the original 
submission for this proposed change. However, the study team is no 
longer moving forward with the new exploratory objectives involving FLT 
PET after reinduction, so no changes will be made at this time.  
 
10. 
7.1.6 
Section 7.1.6 There are many problems with the timelines and wording used 
throughout the A05 document. This is why the schema should have a very 
clear timeline from registration, to induction, to reinduction, to bone marrow 
biopsy, etc. Using terms like Day 14, 7-10 days after…. can lead to needless 
confusion. 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction. 
11. 
7.1.6 
Section 7.1.8 Table. 
There is no Footnote 8 in the footnotes on p 64 of 103, it is on p 65 of 103 pgs 
in the submitted pdf. 
 
PI Response: Footnote 8 was included in the original amendment 
submission. Please reference the clean version of the protocol. 
Additionally, no PDF versions of the protocol were submitted.   
 
However, the study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction, so footnote 8 
will no longer be included. 
II. Comments Requiring a Response– Administrative & Editorial Issues: 

vi 
# 
Section 
Comments 
12. 
ICD 
Optional Studies: The optional studies section of the informed consent document is 
not formatted per NCI Consent Template requirements and missing several sections. 
Please see copy of NCI Informed Consent Template 
under:  http://ctep.cancer.gov/protocolDevelopment/default.htm#informed_consent 
Specifically, the following sections were omitted and needs to be added: 
x 
It is unclear as to who will pay for the extra FLT PET/CT imaging scan following 
the second round of chemotherapy.  This was omitted in both the main consent and the 
optional consent section.  The cost information currently listed in the optional section 
only pertains to the research samples collected.  
 
The below section should also be addressed for the FLT PET/CT imaging that might be 
obtained for the optional section.  
x 
What is involved? 
x 
What are the possible risks? 
x 
How will information about me be kept private? 
x 
What are the possible benefits? 
x 
Are there any costs or payments? (please clearly state who will be responsible 
for the cost of all the optional studies requested) 
x 
What if I change my mind? 
x 
What if I have more questions? 
x 
 
PI Response: The study team is no longer moving forward with the new 
exploratory objectives involving FLT PET after reinduction, so no changes will be 
made at this time. 
III. Recommendations: 
# 
Section 
Comments 
13. 
4 
In Section 4 IRB Approval, please delete the text in RED and replace with the text 
in BLUE: 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
x 
An active Federal Wide Assurance (FWA) number 
x 
An active roster affiliation with the Lead Network or a participating organization 
x 
A valid IRB approval 
x 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
x 
Active registration status 
x 
The IRB number of the site IRB of record listed on their Form FDA 1572 
x 
An active status on a participating roster at the registering site. 

vii 
# 
Section 
Comments 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). Each 
investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to: an active Federal Wide Assurance (FWA) number, an active roster 
affiliation with the Lead Network or a participating organization, a valid IRB approval, 
and compliance with all protocol specific requirements. 
PI Response: This change has been made. 
14. 
4.1 
Please delete Section 4.1, in accordance with the new Registration and 
Credentialing Repository language: 
 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
PI Response: This change has been made. Subsequent sections have been 
renumbered accordingly.  
 
The following revisions to EAI141 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date. Updated Update Date. 
2. 
Global Changes 
General formatting, grammatical, and spelling corrections made throughout.  
3. 
Contact Page 
Revised contact information for Ryan Mattison, MD, Fenghai Duan, PhD, and 
Dona Alberti, BSN, RN, MSM.  
4. 
Study 
Objectives 
Revised third and fourth secondary objectives to be exploratory objectives. 
Increased accrual goal to 83 patients accrued over a minimum of 21 months. 
5. 
Schema 
Revised footnote 3 to clarify that Day 10-17 FLT scan is mandatory. 
6. 
2.2, 2.3 
Revised third and fourth secondary objectives to be exploratory objectives. 
Inserted section 2.3 “Exploratory Objectives” in its entirety. 

viii 
 
Section 
Change 
7. 
4 
Revised CTEP Registration Procedures per updated CTSU language. 
Subsequent sections renumbered accordingly 
8. 
4.1 
Revised IRB Approval information per updated CTSU language. 
9. 
4.5 
Revised CTSU Regulatory Office Address. 
10. 4.6 
Revised Required Protocol Specific Regulatory Documents information per 
updated CTSU language. 
11. 4.7 
Revised Patient Enrollment information per updated CTSU language. 
12. 4.9.3.4 
Revised data collection information per updated CTSU language. 
13. 4.10.1 
Inserted final sentence to note RAs may submit SOC imaging via TRIAD. 
14. 5 
Increased accrual goal to 83 patients.  
15. 5.4.2 
Removed ninth bullet for the “Serious Adverse Event (SAE)” definition, as it 
was included in duplicate. 
16. 5.4.3 
Revised ECOG-ACRIN AE team phone number. Removed “Secondary 
Malignancy” definition, as it was included in duplicate to section 5.4.4. 
17. 7.1.2 
Revised first bullet to note collection of total bilirubin and creatinine instead of 
serum bilirubin and serum creatinine. Revised fourth bullet to note AE 
evaluation with the “PET Adverse Event Assessment” form. 
18. 7.1.3 
Revised section title to “Visit 2: Mandatory FLT PET Imaging Study (FLT-post  
induction).” Revised first bullet to note collection of total bilirubin and creatinine 
instead of serum bilirubin and serum creatinine. Revised third bullet to note AE 
evaluation with the “PET Adverse Event Assessment” form. 
19. 7.1.5 
Revised first paragraph to clarify timing of remission bone marrow biopsy in 
cases where reinduction therapy is administered.  
20. 7.1.6 
Revised Study Procedures Table footnote 1 to note collection of total bilirubin 
and creatinine instead of serum bilirubin and serum creatinine.  
21. 8.2.7 
Revised FLT administration information to eliminate ≤ 10 mL requirement. 
22. 8.2.9.3 
Inserted hyperlink to access the CTEP Drug Accountability Record form. 
23. 10 
Revised sixth paragraph and inserted table to provide rationale for accrual goal 
increase to 83 patients. 
24. 10.2.3, 10.2.4, 
10.3 
Relocated third and fourth secondary objectives to 10.3.1 and 10.3.2 in new 
section 10.3 “Exploratory Objectives.” Subsequent sections renumbered 
accordingly.  
25. 10.4 
Revised gender and ethnicity distribution table to reflect increased accrual goal 
of 83 patients.  
26. Appendix II 
Removed scenario #4.  
The following revisions to EAI141 informed consent document have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date. Updated Update Date. 
2. 
Why is this study 
being done? 
Revised first paragraph to reflect increased accrual goal of 83 patients. 

ix 
3. 
During the 
research study 
Revised first bullet to clarify optional FLT PET/CT imaging study. 
If you have any questions regarding this addendum, please contact Colin Burnett at 
cburnett@ecog-acrin.org or 857-504-2900. 
We request review and approval of this addendum to EAI141 so ECOG-ACRIN may activate it 
promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Protocol Development Manager 
 
Enclosure: 
CC: 
 
Rober Jeraj, M.D. 
Ryan Mattison, M.D. 
Lale Kostakoglu, M.D., Ph.Dd 
Fenghai Duan, Ph.D. 
David Mankoff, M.D., Ph.D. 
Mark Litzow, M.D., Ph.D. 
Daniel Arber, M.D. 
Elisabeth Paietta, Ph.D. 
Charles Apgar, M.D. 
Donna Hartfeil 
 
 
 
 
Carol Chami, R.N. 
Donna Marinucci 
Melinda Flood 
Bruce Giantonio, M.D. 
Robert L. Comis, M.D 
Mitchell Schnall, M.D. 
Kerry Higgins 
Jean MacDonald 
Sally Vanture 
Colin Burnett 
 
 

EAI141
1
Early Assessment of Treatment Response in AML using 
FLT PET/CT Imaging
STUDY CHAIR:
Robert Jeraj, PhD
STUDY CO-CHAIR:
Ryan J. Mattison, MD
MODALITY CO-CHAIR(S):
Lale Kostakoglu, MD, PhD
STUDY STATISTICIAN:
Fenghai Duan, PhD
EXPERIMENTAL IMAGING SCIENCES 
COMMITTEE CHAIR:
David Mankoff, MD, PhD
DISEASE-ORIENTED COMMITTEE CHAIR:
Mark Litzow, MD
PATHOLOGY CO-CHAIR:
Daniel Arber, MD
LABORATORY CO-CHAIR:
Elisabeth Paietta, PhD
Version Date: February 6, 2018
Update Date:  July 26, 2017
STUDY PARTICIPANTS
ACTIVATION DATE
ALLIANCE / Alliance for Clinical Trials in 
Oncology
December 9, 2015
NRG / NRG Oncology
PRE-ACTIVATION DATE
SWOG / SWOG
October 7, 2015
Update #1 – Incorporated Prior to Activation
Participating sites will be required to obtain 
imaging qualification and have access to the FLT 
agent
Addendum #1 – 10/16
Addendum #2 – 7/17
Update #2 – 7/17
NOTE: This study is supported by the NCI 
Cancer Trials Support Unit (CTSU). 
Institutions not aligned with ECOG-
ACRIN will participate through the CTSU 
mechanism.
Addendum #3
Agents
IND#
NSC#
Supply
18F-FLT
NSC#743144
Academic site supply and approved commercial 
vendors authorized in the IND
Rev. 10/16

ECOG-ACRIN 
EAI141 
Cancer Research Group 
Version Date: February 6, 2018 
 
Update Date: July 26, 2017 
2 
Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ........................................................................................................ 9 
1.1 
Abstract ..................................................................................................... 9 
1.2 
FLT PET/CT in AML: A Potential Early Predictor of Response ................... 9 
1.3 
FLT PET/CT in AML: Preliminary Data ..................................................... 10 
1.4 
18F-fluoro-3’deoxy-3’-D-fluorothymidine (FLT) ...................................... 11 
1.5 
Previous Human FLT Imaging Studies ..................................................... 12 
1.6 
Rationale ................................................................................................. 12 
2. Hypothesis ........................................................................................................ 14 
2.1 
Primary Objectives .................................................................................. 14 
2.2 
Secondary Objectives .............................................................................. 14 
2.3 
Exploratory Objectives ............................................................................ 14 
3. Selection of Patients ......................................................................................... 15 
3.1 
Eligibility Criteria ..................................................................................... 15 
4. Registration Procedures .................................................................................... 17 
4.1 
IRB Approval ............................................................................................ 17 
4.2 
Downloading Site Registration Documents ............................................ 18 
4.3 
Requirements For EAI141 Site Registration ............................................ 18 
4.4 
Checking Your Site’s Registration Status ................................................. 18 
4.5 
Submitting Regulatory Documents ......................................................... 19 
4.6 
Required Protocol Specific Regulatory Documents ................................ 19 
4.7 
Patient Enrollment .................................................................................. 20 
4.8 
Preregistration (Step 0) ........................................................................... 20 
4.9 
Registration (Step 1)................................................................................ 21 
4.10 Digital Images Data Submission Using TRIAD ......................................... 23 
4.11 Instructions for Patients who do not Complete FLT PET/CT per Protocol24 
5. Study Design ..................................................................................................... 25 
5.1 
Imaging Schedule .................................................................................... 25 
5.2 
FLT Administered Dose ........................................................................... 25 
5.3 
Treatment Plan ........................................................................................ 25 
5.4 
Adverse Event Reporting Requirements ................................................. 25 
5.5 
Comprehensive Adverse Events and Potential Risks for 3'-deoxy-3'-[F-
18]fluorothymidine (FLT) (NSC 743144) ................................................. 34 
5.6 
Adverse Event Reporting Decision Tree .................................................. 35 
5.7 
Duration of Follow-up ............................................................................. 35 
6. Measurement of Effect ACUTE MYELOGENOUS LEUKEMIA (AML) RESPONSE 
CRITERIA ............................................................................................................ 36 
6.1 
Complete Remission (CR) ........................................................................ 36 
6.2 
Partial Remission (PR) ............................................................................. 36 
6.3 
Relapse .................................................................................................... 36 

ECOG-ACRIN 
EAI141 
Cancer Research Group 
Version Date: February 6, 2018 
 
Update Date: July 26, 2017 
3 
7. Study Parameters .............................................................................................. 37 
7.1 
Study Parameters .................................................................................... 37 
7.2 
Biological Sample Submissions ............................................................... 40 
8. Agent Formulation and Procurement ............................................................... 41 
8.1 
Supplier of the FLT Agent ........................................................................ 41 
8.2 
18F-FLT .................................................................................................... 41 
9. Imaging Protocol ............................................................................................... 44 
9.1 
FLT PET Imaging Studies .......................................................................... 44 
9.2 
FLT Administration .................................................................................. 44 
9.3 
Timing of FLT PET Studies ....................................................................... 44 
9.4 
Imaging Quality Assurance (QA)/Quality Control (QC) Procedure ......... 44 
9.5 
Imaging Sessions ..................................................................................... 45 
9.6 
Supportive Care Guidelines ..................................................................... 45 
9.7 
Dosing Delays/Dose Modifications ......................................................... 45 
9.8 
FLT PET/CT Image Analysis: Central Read ............................................... 45 
9.9 
Other Comparators ................................................................................. 46 
9.10 Data Analysis ........................................................................................... 47 
9.11 Image Analysis ......................................................................................... 47 
10. Statistical Considerations .................................................................................. 48 
10.1 Primary Objectives .................................................................................. 49 
10.2 Secondary Objectives .............................................................................. 49 
10.3 Exploratory Objectives ............................................................................ 50 
10.4 Gender and Ethnicity .............................................................................. 51 
11. Research Sample Submissions .......................................................................... 53 
11.1 Sample Collection and Submission Schedule .......................................... 53 
11.2 Submissions to ECOG-ACRIN Leukemia Translational Research 
Laboratory (LTRL) .................................................................................... 53 
11.3 ECOG-ACRIN Sample Tracking System .................................................... 55 
11.4 Use of Specimens in Research ................................................................ 56 
11.5 Sample Inventory Submission Guidelines ............................................... 56 
12. Leukemia Correlative Studies ........................................................................... 57 
12.1 Immunophenotype and Molecular Genetics .......................................... 57 
12.2 Lab Data Transfer Guidelines .................................................................. 57 
13. Electronic Data Capture .................................................................................... 58 
14. Patient Consent and Peer Judgment ................................................................ 58 
15. References ........................................................................................................ 58 
Appendix I  Patient Thank You Letter ...................................................................... 59 
Appendix II  EAI141 Adverse Event Reporting Guidance Document ....................... 60 
 

ECOG-ACRIN 
EAI141 
Cancer Research Group 
Version Date: February 6, 2018 
 
Update Date: July 26, 2017 
4 
STUDY-CHAIR 
STUDY CO-CHAIR 
Robert Jeraj, PhD 
Professor of  
Medical Physics and Radiology 
University of Wisconsin  
Carbone Cancer Center 
1111 Highland Ave 
Madison WI 53705 
Phone: 608-263-8619 
Fax: 608-262-2413 
Email: rjeraj@wisc.edu 
Ryan Mattison, MD 
Associate Professor of Medicine 
University of Wisconsin  
Carbone Cancer Center 
1111 Highland Ave 
Madison WI 53705 
Phone: 608-262-5697 
Fax: 608-262-4598 
Email: rjmattison@medicine.wisc.edu 
STUDY CO-CHAIR 
STUDY STATISTICIAN 
Lale Kostakoglu, MD, MPH, 
Professor of Radiology 
Mount Sinai School of Medicine 
One Gustave L. Levy Place, 
Box: 1141 
New York, NY 10029 
Phone: 212-241-6319 
Fax: 212-831-2851 
Email: lale.kostakoglu@msnyuhealth.org 
Fenghai Duan, Ph.D. 
Associate Professor (Research) 
Department of Biostatistics and Center for 
Statistical Sciences 
Brown University School of Public Health 
121 South Main Street 
Providence, RI 02912 
Phone: 401-863-2175 
Fax: 401-863-9182 
Email: fduan@stat.brown.edu 
STUDY COORDINATOR 
LEUKEMIA COMMITTEE CHAIR 
Dona Alberti, BSN, RN, MSM 
University of Wisconsin Institute for Medical 
Research 
1111 Highland Ave 
Madison WI 53705 
Phone: 608-712-8585 
Email: dalberti@uwhealth.org 
Mark R. Litzow, MD 
Division of Hematology 
Mayo Clinic 
200 First Street, S.W. 
Rochester, MN 55905-5905 
Phone: (507) 284-5362 
Fax: (507) 266-4972 
E-mail: litzow.mark@mayo.edu 
EXPERIMENTAL IMAGING SCIENCES 
COMMITTEE CHAIR 
 
David Mankoff, MD, PhD 
Professor of Radiology 
University of Pennsylvania 
116 Donner Building 
3400 Spruce Street 
Philadelphia, PA 19104-4283 
Phone: 215-615-3687 
Fax: 215-349-5843 
E-mail: david.mankoff@uphs.upenn.edu 
 
Rev. Add3 
Rev. 10/16 
Rev. Add3 
Rev. Add3 

ECOG-ACRIN 
EAI141 
Cancer Research Group 
Version Date: February 6, 2018 
 
Update Date: July 26, 2017 
5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and select 
the Regulatory Submission sub-tab 
under the Regulatory tab.) 
Institutions with patients waiting that 
are unable to use the Portal should 
alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 to 
receive further instruction and 
support. 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. 
Please see the data 
submission section of 
the protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
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ABBREVIATIONS 
 
AE: Adverse event 
APL: acute promyelocytic leukemia 
AML: acute myeloid leukemia 
BMBX: bone marrow biopsy 
CDUS: CTEP Data Update System 
CR: complete remission 
CRi: complete remission with incomplete platelet recovery 
CTEP: Cancer Therapy Evaluation Program 
CTSU: Cancer Trials Support Unit 
ECOG-ACRIN: Eastern Cooperative Oncology Group-American College of Radiology Imaging 
Network 
FLT: 18F-fluoro-3’deoxy-3’-D-fluorothymidine 
FLT-base: optional baseline FLT PET/CT 
FLT-post: post-treatment FLT PET/CT 
IMAC: Image Analysis Core 
LFS: leukemia-free state 
LTB: Leukemia Tissue Bank 
LTRL: Leukemia Translational Research Laboratory 
LVEF: left ventricular ejection fraction 
MRD: minimal residual disease 
NCCN: National Comprehensive Cancer Network 
NPV: negative predictive value 
OPEN: Oncology Patient Enrollment Network 
PET/CT: positron emission tomography/computed tomography 
PPV: positive predictive value 
PR: Partial Remission 
RD: residual disease 
RSS: Regulatory Support System 
STS: Sample Tracking System 
SUV: Standardized Uptake Value 
SUVmax: maximum FLT uptake across the total bone marrow compartment 
SUVmean: mean FLT uptake across the total bone marrow compartment 
SUVhetero: coefficient of variation of FLT uptake across the total bone marrow compartment 
 
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Schema 
Baseline Imaging
(optional)2
[F-18] FLT PET/CT
Nadir
Bone Marrow4
&
Post-Treatment Imaging3
[F-18] FLT PET/CT
1. Pre-treatment bone marrow aspirate, or peripheral blood should be sent for central review.
2. Optional Imaging must be done within 1 week prior to initiation of therapy.
3. Post-Treatment Imaging is mandatory and must be completed 10-17 days after initiation of first induction cycle and prior to reinduction.
4. Nadir Bone Marrow should be completed 7-10 days after completion of induction therapy. Remission Bone Marrow should be completed 28-35 days after initiation of first
induction therapy
5. Remission bone marrow aspirate should be sent for central analysis.
6. Participants will be followed for up to 1 year beyond the end of the accrual period.
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STUDY OBJECTIVES 
Primary Objective 
To evaluate the negative predictive value (NPV) of post-treatment FLT PET/CT imaging 
for complete remission (CR) in patients receiving induction chemotherapy for acute 
myeloid leukemia (AML).  
Secondary Objectives 
x 
To evaluate the positive predictive value (PPV) of post-treatment FLT PET/CT 
imaging for complete remission; 
x 
To estimate the sensitivity and specificity of post-treatment FLT PET/CT imaging for 
detecting complete remission; 
x 
To correlate FLT PET/CT imaging with biologic correlates (MRD Assessment) 
x 
To correlate FLT PET/CT imaging with relapse-free survival and overall survival. 
Exploratory Objectives 
x 
To evaluate pre-treatment FLT PET/CT imaging as a predictor of complete 
remission; 
x 
To evaluate the change between pre-treatment and post-treatment FLT PET/CT 
imaging as a predictor of complete remission; 
ELIGIBILITY (see Section 3 for details) 
Patients must be 18 years old and have previously untreated AML and be candidates for 
intensive induction chemotherapy. Patients are allowed to have had prior hydroxyurea. 
Patients must not have acute promyelocytic leukemia (APL) and must not have evidence 
of t(15;17)(q22;q21). Patients must have an ECOG performance status of 0-3 (restricted 
to ECOG PS 0-2 if age > 70 years).  
SAMPLE SIZE 
A total of 83 eligible AML patients who are candidates for induction chemotherapy will be 
enrolled into this trial from approved NCTN institutions. Anticipated accrual is four 
participants per month, to be accrued over a minimum of 21 months. All participants will 
receive the post-treatment FLT PET/CT within three days before or after the nadir bone 
marrow biopsy (between Days 10-17 after initiation of first induction cycle and prior to 
reinduction). Eligible participants will be actively involved in the trial until they complete 
all trial procedures, specifically the remission bone marrow biopsy (Day 28-35 biopsy). 
Patients will be followed for survival outcomes for at least 1 year (1 year beyond the end 
of the study accrual period). 
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1. 
Introduction 
1.1 
Abstract 
In patients with acute myeloid leukemia (AML), developing a more accurate early 
predictor of chemotherapy effectiveness is needed to avoid unnecessary therapy, 
to identify refractory AML patients earlier, and to improve overall clinical 
outcomes. One potential tool is to incorporate fluorothymidine positron emission 
tomography/computed tomography (FLT PET/CT) imaging as a surrogate of 
response during treatment. FLT PET/CT is a molecular imaging technique that 
has the ability to measure proliferative activity in the bone marrow before and 
after chemotherapy. As a whole body imaging modality, PET/CT provides the 
ability to assess to entire bone marrow compartment rather than the relatively 
small sample obtained during a bone marrow aspirate or biopsy. Given the need 
for a better method to assess chemotherapy effectiveness in AML, and the pilot 
results that indicate FLT PET/CT as a potential method, we plan to conduct a 
multicenter trial assessing the predictive value of FLT PET/CT in AML through 
ECOG-ACRIN. 
1.2 
FLT PET/CT in AML: A Potential Early Predictor of Response 
Acute myeloid leukemia (AML) is a devastating, clinically heterogeneous disease 
for which improved treatment strategies are needed. Long-term cure depends 
upon the ability to induce a complete remission, followed by consolidation 
treatment with either chemotherapy or stem cell transplantation. Standard 
induction chemotherapy is administered over 7 days, after which treatment 
response is usually assessed at two time points after initiation of chemotherapy: 
the nadir bone marrow at approximately Day 14, and at the time of peripheral 
blood count recovery, which is at approximately Day 28.  
If the Day 14 marrow has a significant number of residual leukemia blasts, a 
second induction therapy course can be administered. If the Day 14 marrow is 
hypoplastic, the patient will receive no further treatment at that time and the 
counts will be allowed to recover. However, the Day 14 marrow has limitations as 
a marker of the success of induction therapy. A substantial number of patients 
with no blasts in the nadir marrow will not achieve remission (a false negative 
result). On the other hand, some patients who have residual disease in the 
marrow at Day 14 will eventually achieve a complete remission (CR) even 
without another induction chemotherapy course (a false positive result). A review 
of the literature showed the nadir marrow as a test has a false negative rate 
ranging from 21% to 33% and a false positive rate of 19% to 36%. Possible 
explanations for these error rates include a fairly limited sample of an extensive 
marrow space, heterogeneity of AML involvement in the bone marrow, and lack 
of clarity about whether residual blasts are in the process of dying at the time of 
assessment or whether they are blasts resistant to chemotherapy.  
A better early predictor of residual disease that assesses chemotherapy 
effectiveness would give clinicians and patients an opportunity to modify 
therapeutic strategies. Preliminary, single-center data support proliferation 
imaging using an investigational agent known as 3'-deoxy-3'-18F-fluorothymidine 
(FLT) in positron emission tomography/computed tomography (PET/CT) as a 
method of assessing the entire burden of disease and avoid the confounding 

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effects of marrow blasts that are still viable but no longer proliferative and to 
marrow heterogeneity, which may overcome the limitations of the Day 14 bone 
marrow. The goal of the proposed trial is to validate these promising early results 
in a prospective, multi-center trial of FLT PET/CT as a predictor of CR for 
induction therapy in AML. 
The investigational agent FLT is a structural analog of thymidine, a DNA 
constituent. FLT is an 18F radiolabeled imaging agent that has been used in 
conjunction with PET/CT. FLT is trapped in the cell due to phosphorylation by 
thymidine kinase as part of the proliferation pathway. As such, FLT is a marker of 
proliferating tumor tissues in proportion to DNA synthesis rates. Prior studies 
have shown that FLT kinetics are particularly favorable in detecting proliferating 
normal marrow and leukemia cells, making FLT a potentially very sensitive tool 
for residual proliferating leukemia after induction therapy.  
FLT PET/CT thus has the potential for providing a whole-body assessment of 
leukemia and associated bone marrow proliferation in contrast to the point 
sample provided during bone marrow aspirate and biopsy. Agool et al. have 
investigated differences in spatial uptake patterns of FLT to distinguish different 
hematological disorders. Buck et al. have explored the use of FLT PET to stage 
patients with lymphoma by determining bone marrow involvement and have 
analyzed bone marrow uptake and extramedullary uptake in patients with AML, 
suggesting quantification of FLT uptake could lead to treatment response 
biomarkers. The most relevant to this proposal is a pilot study using FLT PET/CT 
in patients with AML conducted at the University of Wisconsin. The results of that 
study have been extremely promising (see Preliminary Data), but only included a 
limited cohort of patients. We now plan to open a larger multi-center trial to 
validate the single-center results and make this tool available to guide future AML 
therapy trials. 
A positive trial would contribute multi-center data on the validity of this predictive 
biomarker as a clinical assessment tool towards induction therapy and for further 
study as a potentially practice-changing metric for guiding treatment of AML. FLT 
PET/CT imaging would provide indication about which patients would benefit 
from post-remission allogeneic stem cell transplantation versus consolidation 
chemotherapy. It also would allow early identification of those in whom a 
standard anthracycline plus cytarabine therapeutic approach will be insufficient or 
completely ineffective. As such, FLT PET/CT could potentially provide an integral 
biomarker for future AML trials if validated as a predictor of induction CR. 
This trial will also have important consequences for a better understanding of 
AML. Demonstrating the phenotypic behavior of a disease through FLT PET/CT 
imaging will complement molecular, genotypic abnormalities in helping clinicians 
choose appropriate post-remission therapy (currently chemotherapy vs. 
transplant). 
1.3 
FLT PET/CT in AML: Preliminary Data 
In a pilot study by the University of Wisconsin group (Jeraj, Juckett PIs), 8 adult 
subjects with AML receiving induction chemotherapy underwent FLT PET/CT 
scans prior to therapy and at different time points during induction chemotherapy. 
A dramatic difference in the bone marrow FLT uptake in those patients who 
achieved a complete remission (CR) versus those who had residual disease 
(RD) present at count recovery was found (Figure 1).  

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Figure 1: Remarkably different bone marrow 
proliferation response between complete 
response (CR) and residual disease (RD) in 
patients, pre- and post-treatment. Pre-treatment, 
FLT PET maximum intensity projection image of 
bone marrow of RD patient (D) exhibited markedly 
greater uptake than CR patient (A). Post-treatment, 
FLT PET image of CR patient (B) revealed very low 
uptake, suggesting successful bone marrow 
ablation. However, post-treatment FLT PET image 
of RD patient (E) displayed significant uptake, 
indicating substantial remaining proliferative bone 
marrow and poor treatment response. Post-
treatment, bone marrow Standardized Uptake Value 
(SUV) distribution of CR patient (C) was completely 
within the SUV < 2 range, while that of RD patient 
contained a significant portion in the SUV > 2 range 
(F). 
 
Interestingly, the significant differences were observed in pre-treatment FLT 
PET/CT scans between patients with AML and normal subjects; however only for 
RD patients; the CR patients had “normal” looking proliferation characteristics 
(Figure 2). 
 
 
Figure 2: Significantly different pre-treatment 
bone marrow proliferation characteristics in 
normal subjects with that of patients with AML 
pre-treatment. FLT Standardized Uptake Value 
(SUV) distribution reveals similarity of normal 
marrow (blue) and marrow of CR patient pre-
treatment (green), with almost all uptake in SUV 
< 8 range. Distribution is quite different for RD 
patient (red) who displayed significant uptake in 
the SUV > 8 range (top panel). At all SUV, the 
ratio of CR patients’ pre-treatment marrow to 
normal marrow uptake was approximately 
unified. At SUV > 8, RD patients’ pre-treatment 
marrow often displayed uptake over 100 times 
greater than that of normal marrow (bottom 
panel). 
These data provide strong rationale for FLT PET as a test of residual AML that 
moves beyond the current dichotomy of presence/absence of blasts in marrow 
samples. These data support FLT PET as a marker for early AML response 
assessment and therapeutic guidance that deserves further evaluation. 
1.4 
18F-fluoro-3’deoxy-3’-D-fluorothymidine (FLT) 
3'-deoxy-3'-18F fluorothymidine ([F-18]FLT) (half life = 110 mins) is a structural 
analog of the DNA constituent, thymidine (Figure 3). It is a radiolabeled PET 
imaging agent that has been proposed for investigating cellular proliferation as 
an analogue of thymidine. Although FLT is not incorporated into DNA, it is 

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trapped in the cell due to phosphorylation by thymidine kinase 1. It is also 
relatively resistant to in vivo degradation and accumulates predominantly in 
proliferating tissues in proportion to the DNA synthesis rate. Hence it is 
considered as a potential marker of tumor cellular proliferation. Therefore, FLT is 
proposed as a radiolabeled imaging probe for in vivo assessment of cellular 
proliferation in malignant tumors using PET. 
 
 
 
Figure 3 (from Investigator’s Brochure, Edition Number 7; Edition Date: 2009) 
Briefly, FLT is taken up by cells and follows the salvage pathway of DNA 
synthesis and, like thymidine, undergoes phosphorylation by thymidine kinase 1 
(TK1), which leads to intracellular trapping within the cell. FLT is a selective 
substrate for TK1. In quiescent cells, TK1 activity is virtually absent but in 
proliferating cells, it is increased about 10-fold, as cells enter the DNA synthetic 
phase of the cell cycle.[1-3] The uptake of FLT has been found to increase with 
increasing TK1 activity in human tumor cell lines. As FLT is not incorporated into 
DNA, FLT uptake has been validated with an independent measure of DNA 
synthesis in tissue. The protein Ki-67 identified by MIB-1 antibody staining is a 
histopathologic measure of proliferation, which correlates with the level of FLT 
uptake measured by PET.  
1.5 
Previous Human FLT Imaging Studies 
Many clinical studies have used FLT PET imaging (UCLA, University of 
Washington in Seattle, Wayne State University, University of Wisconsin). The 
imaging protocols were pre-approved by their respective regulatory committees 
and conducted under the RDRC process or under NCI IND. FLT PET/CT has 
been used previously in the ACRIN 6688 multi-center clinical trial (Phase II Study 
of 3'-Deoxy-3'-18F Fluorothymidine [FLT] in Invasive Breast Cancer) under the 
NCI IND to be used for this study. ACRIN 6688 was successfully completed 
without any safety issues.  
1.6 
Rationale 
In patients with AML undergoing intensive induction treatment with anthracycline 
and infusional cytarabine, the nadir bone marrow evaluation can be useful as an 
early measure of chemotherapy effectiveness. However, the results of this 
evaluation are often inaccurate. In a review of six clinical trials, the nadir 
marrow’s ability to predict CR was highly variable [2]. The test characteristics of 
sensitivity and specificity ranged from 67-94% and 43-81%, respectively. 
Similarly, the negative predictive value (NPV) that predicts CR after a 
hypocellular nadir marrow ranged from 67-84%. The predictive value that 

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predicts lack of remission when persistent blasts were seen at the nadir ranged 
from 64-81%. One hypothesis that could partially explain the inaccuracy of the 
nadir marrow is that it is difficult to tell whether an intermediate blast count at the 
nadir represents refractory disease, or the dying leukemia cells. In addition, the 
marrow aspirate and biopsy is a relatively small tissue sample that may miss 
areas of active disease. Thus, there is a risk of undertreating patients who will 
not achieve a remission despite a negative nadir bone marrow, while on the other 
hand, overtreating others who would eventually achieve CR despite having 
persistent blasts during the early marrow evaluation.  
In a review of six Eastern Cooperative Oncology Group (ECOG) leukemia 
studies, Rowe and colleagues found that patients who entered a CR with 
induction chemotherapy had 5-year and 10-year survival rates that were similar, 
regardless of whether one of two induction cycles were required to achieve 
remission [1]. According to the treatment protocols, all patients with persistent 
disease during the nadir marrow were treated with a second chemotherapy 
course. Therefore, it is not known whether some patients with an intermediate 
blast count at the nadir would have achieved CR without a second course of 
treatment. Designing a study to randomize patients with an intermediate nadir 
blast burden to either observation until count recovery or to a second course of 
chemotherapy is technically possible, but would be difficult to conduct given 
clinicians’ reluctance to break from the standard treatment paradigm. In addition, 
spatial analysis of the FLT PET/CT response conducted at the University of 
Wisconsin indicated high spatial heterogeneity of response to chemotherapy. 
This response heterogeneity may help explain the weak predictive power of the 
biopsy, which typically samples only one small region of the pelvic bone marrow. 
Given the need for a better method to assess chemotherapy effectiveness in 
AML, and the pilot results that indicate FLT PET/CT may be one potential 
method, we plan to conduct this trial through ECOG-ACRIN.  

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2. 
Hypothesis  
The negative predictive value (NPV) of the post-treatment FLT PET/CT imaging for 
complete remission (CR) in patients receiving induction chemotherapy for AML will be 
higher than the NPV of the Day 14 bone marrow biopsy for CR.  
Objectives 
2.1 
Primary Objectives 
To evaluate the negative predictive value (NPV) of post-treatment FLT PET/CT 
imaging for complete remission (CR) in patients receiving induction 
chemotherapy for acute myeloid leukemia (AML).  
Three imaging parameters (SUVmean, SUVmax, SUVhetero) will be measured from an 
FLT PET/CT scan and SUVmax will be the primary endpoint. 
Note that the CR designation requires that the patient achieve the morphologic 
leukemia-free state and have an absolute neutrophil count of more than 1,000/uL 
and platelets of greater than 100,000/uL. Hemoglobin concentration or 
hematocrit has no bearing on remission status, although the patient must be 
independent of transfusions. Occasionally, a rare peripheral blood blast may be 
identified during regeneration; however, if the patient is in CR, the bone marrow 
would have less than 5% blasts and no Auer rods [4]. 
2.2 
Secondary Objectives 
2.2.1 
To evaluate the positive predictive value (PPV) of post-treatment FLT 
PET/CT imaging for complete remission; 
2.2.2 
To estimate sensitivity and specificity of post-treatment FLT PET/CT 
imaging for detecting complete remission; 
2.2.3 
To correlate FLT PET/CT imaging with biologic correlates (MRD 
assessment); 
2.2.4 
To correlate FLT PET/CT imaging with relapse-free survival and 
overall survival. 
2.3 
Exploratory Objectives 
2.3.1 
To evaluate pre-treatment FLT PET/CT imaging as a predictor of 
complete remission; 
2.3.2 
To evaluate the change between pre-treatment and post-treatment 
FLT PET/CT imaging as a predictor of complete remission; 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
This study involves preregistration (Step 0, see Section 4). Bone marrow or 
peripheral blood specimens must be submitted to the ECOG-ACRIN 
Leukemia Translational Research Laboratory (LTRL). If bone marrow 
aspirate was performed prior to preregistration/patient consent, peripheral 
blood can be submitted after registration to Step 1, prior to protocol defined 
imaging. 
3.1 
Eligibility Criteria 
3.1.1 
Age ≥ 18 years 
3.1.2 
Patients must have previously untreated AML and be candidates for 
intensive induction chemotherapy. Patients are allowed to have had 
prior hydroxyurea  
3.1.3 
Patients must not have acute promyelocytic leukemia (APL) and must 
not have evidence of t(15;17)(q22;q21) 
3.1.4 
Patients must have an ECOG performance status of 0-3 (restricted to 
ECOG PS 0-2 if age >70 years) 
3.1.5 
Patients must have left ventricular ejection fraction (LVEF) > 45% or 
within institutional normal limits 
3.1.6 
Patients must be able to lie still for a 1.5 hour PET scan 
3.1.7 
Patient must NOT have a history of allergic reaction attributable to 
compounds of similar chemical or biologic composition to 18F-
fluorothymidine 
3.1.8 
Patient must NOT weigh more than the maximum weight limit for the 
PET/CT table for the scanner(s) to be used at each center 
3.1.9 
The patient is participating in the trial at an institution which has 
agreed to perform the imaging research studies, completed the 
ECOG-ACRIN defined scanner qualification procedures and received 
ECOG-ACRIN approval as outlined in Section 9.4 
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3.1.10 
Women must not be pregnant or breast-feeding due to unknown toxic 
effects of the FLT agent on a fetus 
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to registration to rule out pregnancy. 
A female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
 

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4. 
Registration Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
D 
D 
 
 
Financial Disclosure Form 
D 
D 
D 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
D 
D 
D 
 
HSP/GCP training 
D 
D 
D 
 
Agent Shipment Form (if applicable) 
D 
 
 
 
CV (optional) 
D 
D 
D 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
x 
Added to a site roster 
x 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
x 
Act as the site-protocol PI on the IRB approval 
x 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. 
For questions, please contact the RCR Help Desk by email at 
<RCRHelpDesk@nih.gov>. 
4.1 
IRB Approval  
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
x 
An active Federal Wide Assurance (FWA) number 
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x 
An active roster affiliation with the Lead Network or a participating 
organization 
x 
A valid IRB approval 
x 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
x 
Active registration status 
x 
The IRB number of the site IRB of record listed on their Form FDA 1572 
x 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for 
this study are not required to submit IRB approval documentation to the CTSU 
Regulatory Office. For sites using the CIRB, IRB approval information is received 
from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRB Manager to indicate their intent to open the study locally. The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office. In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
4.2 
Downloading Site Registration Documents  
Site registration forms may be downloaded from the EAI141 protocol page 
located on the CTSU members’ website.  
x 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
x 
Click on the Protocols tab in the upper left of your screen 
x 
Either enter the protocol # in the search field at the top of the protocol tree, or 
x 
Click on the By Lead Organization folder to expand 
x 
Click on the ECOG-ACRIN link to expand, then select trial protocol 
#EAI141 
x 
Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided. 
4.3 
Requirements For EAI141 Site Registration 
x 
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) 
x 
PET/CT Qualification (through the ACR Imaging Core Laboratory) 
4.4 
Checking Your Site’s Registration Status 
You can verify your site registration status on the members’ section of the CTSU 
website. 
x 
Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
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x 
Click on the Regulatory tab 
x 
Click on the Site Registration tab 
x 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation 
and institutional compliance with protocol-specific requirements 
outlined by the Lead Network. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol 
or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
4.5 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal, where they will be entered and tracked in the 
CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org  (members’ area) Æ Regulatory Tab  
Æ Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support 
4.6 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed 
consent document must be justified in writing by the investigator and 
approved by the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
x 
Indicate all sites approved for the protocol under an assurance 
number 
x 
OHRP assurance number of reviewing IRB 
x 
Full protocol title and number 
x 
Version Date 
x 
Type of review (full board vs. expedited) 
x 
Date of review 
x 
Signature of IRB official 
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4.7 
Patient Enrollment 
Patients must not start protocol procedures prior to Step 1 registration. 
The first, baseline FLT PET/CT scan is optional due to the time restriction, 
such as the two-day minimum requirement for ordering and delivery of the 
FLT agent when supplied by commercial distributors. Qualified institutions 
manufacturing their own FLT may be able to supply FLT for the study and 
minimize time delays due to FLT ordering (see Section 8.2.9.1). Such 
centers will complete the FLT PET/CT before treatment initiation when 
feasible and if it will not delay patient care.  
The second, post-treatment FLT PET/CT scan is mandatory and must be 
completed per study imaging protocol specifications. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at <https://ctepcore.nci.nih.gov/iam>) and a 'Registrar' role on either the 
LPO or participating organization roster. Registrars must hold a minimum of an 
AP registration type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN site staff should verify the following:  
x 
All eligibility criteria has been met within the protocol stated timeframes 
x 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation 
for your records.  
Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at 
https://open.ctsu.org. For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com. 
4.8 
Preregistration (Step 0) 
NOTE: 
Patients must not start protocol procedures prior to Step 1 
registration. 
4.8.1 
The following information will be collected at time of preregistration. 
4.8.1.1 
Protocol Number 
4.8.1.2 
Investigator Identification 
x 
Institution and affiliate name (Institution CTEP ID) 
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x 
Investigator’s name (NCI number) 
x 
Cooperative Group Credit 
x 
Credit Investigator 
x 
Protocol specific contact information 
4.8.1.3 
Patient Identification 
x 
Patient’s initials (first and last) 
x 
Patient’s Hospital ID and/or Social Security number 
x 
Patient demographics 
x 
Gender 
x 
Birth date 
x 
Race 
x 
Ethnicity 
x 
Nine-digit ZIP code 
x 
Method of payment 
x 
Country of residence 
4.8.2 
Eligibility Verification 
Patient must be consented to and be considered a viable candidate 
for registration to Step 1 on ECOG-ACRIN EAI141. 
If bone marrow aspirate has been performed prior to preregistration to 
Step 0, patient must meet all of the eligibility requirements listed in 
Section 3. 
4.8.3 
Additional Requirements 
4.8.3.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office. However the 
ECOG-ACRIN Leukemia Translational 
Research Laboratory (LTRL) requires 
institutions to submit a copy of the EAI141 
consent and a copy of the HIPAA Authorization 
form. 
4.8.3.2 
Bone marrow aspirates or peripheral blood specimens 
must be submitted for defined laboratory research 
studies. See Section 11. 
NOTE: Peripheral blood can be submitted after registration (Step 1) to coincide 
with clinical assessments if bone marrow aspirates had been obtained prior to 
consent and will not be submitted at preregistration. 
4.9 
Registration (Step 1) 
4.9.1 
The following information will be collected at time of registration. 
4.9.1.1 
Protocol Number  
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4.9.1.2 
Investigator Identification  
x 
Institution and affiliate name 
x 
Investigator’s name 
4.9.1.3 
Patient Identification  
x 
Patient’s initials (first and last) 
x 
Patient’s Hospital ID and/or Social Security number 
x 
Patient demographics 
x 
Gender 
x 
Birth date (mm/yyyy) 
x 
Race 
x 
Ethnicity 
x 
Nine-digit ZIP code 
x 
Method of payment 
x 
Country of residence 
4.9.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3. 
4.9.3 
Additional Requirements  
4.9.3.1 
Images are to be submitted as indicated in Section 4.10. 
4.9.3.2 
Bone marrow smears are to be submitted for future 
undefined research as outlined in Section 11. 
4.9.3.3 
Bone marrow aspirates must be submitted for defined 
laboratory research studies as outlined in Section 11. 
4.9.3.4 
Data collection for this study will be done exclusively 
through the Medidata Rave clinical data management 
system. Access to the trial in Rave is granted through the 
Medidata application to all persons with the appropriate 
roles assigned in Regulatory Support System (RSS). To 
access Rave via Medidata, the site user must have an 
active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam>) and the appropriate 
Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA 
or Site Investigator)) on either the LPO or participating 
organization roster at the enrolling site. To the hold Rave 
CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type.  To hold the Rave Site 
Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in 
Rave. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent a study invitation e-mail from Medidata. 
To accept the invitation, site users must log into the Select 
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Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the Medidata 
screen. 
Users that have not previously activated their 
Medidata/Rave account at the time of initial site registration 
approval for the study in RSS will also receive a separate 
invitation from Medidata to activate their account. Account 
activation instructions are located on the CTSU website, 
Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). 
Additional information on Medidata/Rave is available on 
the CTSU members’ website under the Rave tab at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk 
at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.10 
Digital Images Data Submission Using TRIAD  
TRIAD is the American College of Radiology’s (ACR) image exchange 
application. TRIAD provides sites participating in clinical trials a secure method to 
transmit DICOM RT and other objects. TRIAD anonymizes and validates the 
images as they are transferred. 
4.10.1 
TRIAD Access Requirements 
Site radiology staff who will submit images through TRIAD will need to 
be registered with the Cancer Therapy Evaluation Program (CTEP) 
and have a valid and active CTEP Identity and Access Management 
(IAM) account and be registered as an AP, NPIVR or IVR. Please 
refer to CTEP Registration Procedures of the protocol in Section 
Error! Reference source not found. for instructions on how to 
request a CTEP-IAM account and complete registration in RCR. 
To submit images, the site user must be on the site’s affiliate rosters 
and be assigned the 'TRIAD site user' role on the CTSU roster. Users 
should contact the site’s CTSU Administrator or Data Administrator to 
request assignment of the TRIAD site user role. RAs are able to 
submit standard of care imaging through the same method. 
4.10.2 
TRIAD Installations 
When a user applies for a CTEP-IAM account with the proper user 
role, he/she will need to have the TRIAD application installed on 
his/her workstation to be able to submit images. TRIAD installation 
documentation can be found by following this link 
https://triadinstall.acr.org/triadclient/  
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This process can be done in parallel to obtaining your CTEP-IAM 
account username and password. 
If you have any questions regarding this information, please send an 
e-mail to the TRIAD Support mailbox at TRIAD-Support@acr.org. 
4.11 
Instructions for Patients who do not Complete FLT PET/CT per Protocol 
The patients, who NEITHER complete the optional FLT PET/CT scan NOR the 
required FLT PET/CT scan, will be considered off-study. No further data beyond 
the post-treatment FLT PET/CT scan time point need to be submitted through 
Medidata Rave, including data related to the remission bone marrow biopsy (Day 
28-35). However, all data related to enrollment, the initial screening visit, and 
treatment should still be submitted. 
 
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5. 
Study Design 
The overall goal of this study is to evaluate the Negative Predictive Value (NPV) of post-
treatment FLT uptake parameters for complete remission (CR) in patients with AML. 
Patients with AML who are candidates for induction chemotherapy will be enrolled in this 
prospective imaging trial. Participants will receive an anthracycline (IV days 1-3 x 1-2 
cycles) plus infusional cytarabine (100-200 mg/m2, IV days 1-7 x 1-2 cycles)-based 
regimen. A total of 83 eligible patients will be accrued in the study. All participants will 
receive one imaging study according to study protocol: mandatory post-treatment FLT 
PET/CT within three days before or after the nadir bone marrow biopsy (between 
Days 10-17 of treatment). The pre-treatment FLT PET/CT is optional. Eligible 
participants will be actively involved in the trial until remission bone marrow biopsy 
results are available. Patients will be followed for survival outcomes for at least 1 year (1 
year beyond the end of the study accrual period). 
5.1 
Imaging Schedule 
Optional Baseline Imaging: An optional FLT PET/CT imaging study per 
protocol should be considered prior to induction chemotherapy, only if it does not 
interfere with commencement of treatment. Note that institutions working with 
commercial vendors to receive their FLT should allow for 2 days between 
ordering the agent and receiving it for same-day imaging. 
Mandatory Post-Treatment Imaging: All participants will receive one imaging 
study according to study protocol: post-treatment FLT PET/CT within three days 
before or after the nadir bone marrow biopsy (between Days 10-17 of treatment).  
5.2 
FLT Administered Dose 
The injectable activity of FLT for most studies will be ≤ 0.07 mCi/kg of 
Fluorine-18, not to exceed 5 mCi with a specific activity greater than 200 Ci/mmol 
at the time of injection. The amount of injected drug is ≤ 6.1 μg (≤ 25 nmol per 
dose) of FLT. FLT is administered to subjects by intravenous injection of ≤ 10 
mL. The drug solution is stored at room temperature in a gray butyl septum 
sealed, sterile, pyrogen-free glass vial and has an expiration time of 8 hours. 
There is no evidence that nonradioactive and radioactive FLT molecules display 
different biochemical behavior. 
5.3 
Treatment Plan 
Participants will receive an anthracycline (IV days 1-3 x 1-2 cycles) plus 
infusional cytarabine (100-200 mg/m2, IV days 1-7 x 1-2 cycles)-based regimen. 
Patients will be followed for up to 1 year beyond the end of study accrual period. 
Patients enrolled on this imaging trial also may be enrolled in a cooperative 
group AML treatment study, with an understanding of data sharing between the 
groups to ensure the data requirements for the EAI141 project are available. 
5.4 
Adverse Event Reporting Requirements 
5.4.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
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x 
Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave.  
x 
Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
5.4.2 
Terminology 
x 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug/ IND imaging agent in humans, 
whether or not considered related to the IND itself. Therefore, an 
AE can be ANY unfavorable or unintended sign (including an 
abnormal laboratory finding), symptom, or disease that worsens or 
is emergent after and temporally associated with the use of an 
IND. Note: events which begin before the reporting period are 
considered Medical History/Baseline events and events occurring 
after the reporting period are generally unknown. 
x 
Serious Adverse Event (SAE): SAEs are generally Grade 3, 4 or 
5 events as outlined in FDA guidance (21 CFR Part 312.32). 
x 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
x 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List): An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND. Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.  
x 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
x 
Hospitalization (or prolongation of hospitalization): For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.  
x 
Life Threatening Adverse Event: Any AE that places the subject 
at immediate risk of death from the AE as it occurred.  
x 
Investigational New Drug (IND):  Drug/agent whose use is being 
investigated. 
x 
Monitoring/Reporting period: The period for which AEs will be 
actively monitored and reported.  This period is defined on a per 
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agent basis. For some studies this may be the entire time the 
patient is on study. For imaging IND agents this is generally from 
at least 24 hours to up to 30 days after administration depending 
on the half-life of the agent.  Patients always are to be 
evaluated/contacted at the end of the reporting period to 
determine if any AEs occurred during the reporting period. 
x 
Routine reporting: All adverse events are reported in a routine 
manner within the monitoring/reporting period during a trial using 
the approved routine reporting system. Sites must report adverse 
events into the approved electronic data capture system (Eg., 
Medidata RAVE). This data will be used by the lead organization 
to update the patient record in the CDUS. 
x 
Expedited reporting: In addition to routine reporting, certain 
serious adverse events must be reported in an expedited manner 
directly to NCI (e.g., via CTEP-AERs) for timelier monitoring of 
patient safety and care. 
x 
Reportable AEs:  AEs are reportable if they meet the explicit 
reporting criteria for the protocol. For imaging agent trials, all 
events within the monitoring period are reportable. In addition, the 
death of any patient while on-study is reportable regardless of 
temporal relationship to use of an IND imaging agent. 
x 
CTEP-AERS (also CAERS): CTEP Adverse Reporting System – 
used by sites for expedited reporting of adverse events to the NCI 
(formerly known as AdEERs). 
x 
Medidata RAVE (RAVE): the current electronic data capture 
(EDC) system for cooperative group studies.  
x 
Clinical Data Update System (CDUS): the primary resource of 
clinical trial data for the Division of Cancer Treatment and 
Diagnosis (DCTD) and the Division of Cancer Prevention (DCP). 
The Lead Group or the Lead Institution for the protocol is 
responsible for compiling and submitting the CDUS data for all 
participants (data for this report is entered by sites into the group 
data capture system [RAVE]).  
x 
Grades: Grade refers to the severity of the AE. The CTCAE 
displays Grades 1 through 5 with unique clinical descriptions of 
severity for each AE based on this general guideline: 
x 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
x 
Grade 2: Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental ADL. 
x 
Grade 3: Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL. 
x 
Grade 4: Life-threatening consequences; urgent intervention 
indicated.  
x 
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x 
Activities of Daily Living (ADL): Instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. Self-care ADL refer to bathing, 
dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
5.4.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use the 
NCI CTEP Adverse Event Reporting System (CTEP-AERS). The 
CTEP’s guidelines for CTEP-AERS can be found at 
http://ctep.cancer.gov. A CTEP-AERS report must be submitted 
electronically to ECOG-ACRIN and the appropriate regulatory 
agencies via the CTEP-AERS Web-based application located at 
https://eapps-ctep.nci.nih.gov/ctepaers. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
x 
the AE Team at ECOG-ACRIN (857-504-2900) 
x 
the NCI/CIP (240-276-6510) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI/CIP (240-276-7890) in the 
same timeframe. 
NCI Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
CTCAE term (AE description) and grade: The descriptions and 
grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 
can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ct
c.htm 
5.4.4 
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 via CTEP-
AERS. Three options are available to describe the event: 
x 
Leukemia secondary to oncology chemotherapy (e.g., acute 
myelocytic leukemia [AML]) 
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x 
Myelodysplastic syndrome (MDS) 
x 
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. 
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 
reporting via CDUS unless otherwise specified. 
5.4.5 
Mechanisms for Adverse Event Reporting 
Within the monitoring period: 
x 
Routine Reporting (RAVE) 
x 
All adverse events (Grades 1-5) both serious and non-
serious worsening or emergent after IND 
administration/intervention, within the monitoring period, 
regardless of hospitalization or attribution, must be reported 
using the routine reporting system. 
x 
Expedited Reporting (CTEP-AERS) 
x 
All serious adverse events (Grades 1 and 2) worsening or 
emergent after IND administration/intervention, within the 
monitoring period, and resulting in hospitalization or 
prolongation of hospitalization for 24 hours or more, regardless 
of attribution, must be entered by the site using expedited 
reporting. 
x 
All serious adverse events (Grades 3, 4 and 5) worsening or 
emergent after IND administration/intervention, within the 
monitoring period, regardless of hospitalization or attribution, 
must be entered by the site using expedited reporting. 
After the monitoring period: 
x 
Routine Reporting (RAVE) 
x 
All adverse events, regardless of grade and attribution, that 
are reported through the expedited reporting system also must 
be reported using the routine reporting system. 
x 
All Deaths (Grade 5) While a patient is on-study, without 
exception, deaths must be entered via routine reporting. 
x 
Expedited Reporting (CTEP-AERS) 
x 
All serious grade 2 events, resulting in hospitalization or 
prolongation of hospitalization for 24 hours or more, and 
having an attribution of possible, probable, or definite, must be 
entered by the site using expedited reporting. 
x 
All serious adverse events (Grades 3-5) having an attribution 
of possible, probable, or definite, must be entered by the site 
using expedited reporting. 
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x 
All Deaths (Grade 5) on-study, regardless of attribution, must 
be entered by the site using expedited reporting if it is within 
30 days of IND agent administration/intervention. After the 30 
day period and through the one year follow-up, only routine 
reporting is required. 
AE monitoring period for F-18 (18F-FLT ) PET IND: 
The AE monitoring period for 18F-FLT, an 18F based radioisotope 
imaging agent with a half-life (t ½ of 110 minutes and a 10 half-life 
equivalent of 18.33 hours) is 24 hours after administration of the IND. 
During the 24hours period (the “Monitoring period”) after 
administration (including the infusion of the IND), the patient will be 
evaluated for Adverse events (AEs) at each imaging session, during 
any follow up (in person, by phone or by email), and at the end of the 
monitoring period. 
AEs for IND Imaging Agents are defined as any signs of illness or 
symptoms that have appeared or worsened since the infusion of the 
IND Imaging Agent. Participants will be queried for potential AEs at 
multiple time points. These may include: 
x 
At the time of injection; 
x 
Before leaving the PET suite; 
x 
If they call the site as instructed for any concerns at any time 
during the monitoring period; 
x 
At the end of the monitoring period 
The AEs that will be specifically monitored during and after the 
administration include, but are not limited to: 
x 
localized discomfort at the intravenous (IV) injection site; 
x 
pain; 
x 
respiratory difficulties; 
x 
blood pressure instability; 
x 
flushing; 
x 
dizziness; 
x 
pruritus/rash/hives; 
x 
any other symptoms that could be related to an allergic or 
anaphylactoid-type reaction; 
x 
Any previously unreported AE which occurred during the 
monitoring period should be reported using the defined reporting 
procedures at the time the originating site or PI discovers the 
unreported AE; 
When any AE is reported, concomitant medication taken by the 
participant in the 2 weeks prior to the event and/or during the time of 
the AE need to be collected and documented in the patient record and 
within the approved data collection system. This is currently CAERS 
for events requiring expedited reporting and Medidata RAVE for 

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routine reporting so that the patient’s record may be updated in the 
CDUS. 

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Phase 1 and Phase 2 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 24 Hours of the Last Administration of 18-F 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). 
Within the 24 hours Reporting Period 
ALL SERIOUS adverse events occurring within the reporting period that meet the above criteria MUST 
be immediately reported to the NCI via CTEP-AERS within the timeframes detailed in the table below, 
regardless of attribution. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hours: Initial report; 
 5 Calendar Days: Compete 
report 
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: 
x 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
x 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1 Serious adverse events that occur after the reporting period of the 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: 
x 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using Isotope based agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, up to a maximum of 30 days, after the agent/intervention was 
last administered.  MR, CT, US, and Optical Imaging contrast agents will have a 30-day post-IND 
administration monitoring period.  Footnote “1” above applies after this reporting period. 

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5.4.6 
Additional instructions, requirements and exceptions for FLT IND 
Please refer to FLT Adverse Event Reporting Guidance Document in 
Appendix II. 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the CIP 
Help Desk at CIPSAEReporting@tech-res.com or 240-276-6510. 
This will need to be discussed on a case-by-case basis. 
 
FLT specific expedited reporting requirements: 
Pregnancies: Pregnancies and suspected pregnancies (including 
a positive or inconclusive pregnancy test, regardless of age or 
disease state) occurring while the subject is on FLT, or within 28 
days of the subject’s last dose of FLT, are considered immediately 
reportable events. The pregnancy, suspected pregnancy, or 
positive/ inconclusive pregnancy test must be reported via CTEP-
AERS within 24 hours of the Investigator’s knowledge. 
 
FLT specific expedited reporting exceptions: 
For this protocol, the adverse events listed below (Section 5.5) do 
not require expedited reporting via CTEP-AERS: 
x 
If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported via 
CTEP-AERS if the grade being reported exceeds the grade 
listed in the parentheses next to the event. 
5.4.7 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
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5.5 
Comprehensive Adverse Events and Potential Risks for 3'-deoxy-3'-[F-
18]fluorothymidine (FLT) (NSC 743144) 
The Comprehensive Adverse Event 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 Agent Specific Adverse Event List (ASAEL), 
appears in a separate column and is identified with bold and italicized text. This 
subset of AEs (ASAEL) contains events that are considered 'expected' for 
expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' for further clarification. The CAEPR does not 
provide frequency data; refer to the Investigator's Brochure for this information. 
Below is the CAEPR for 3'-deoxy-3'-[F-18]fluorothymidine. 
Version 1.0, July 1, 20101 
Category 
(Body 
System) 
Adverse Events2 with Possible 
Relationship to 3'-deoxy-3'-[F-
18]fluorothymidine 
(CTCAE v4.0 Term) 
EXPECTED AEs FOR CTEP-AERS 
REPORTING 
Agent Specific Adverse Event List 
(ASAEL) 
 
 
 
No AEs reported in human studies2,3. 
 
1 This 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. 
2 No adverse events have been attributed to Positron-Emission Tomography (PET) imaging/diagnostic 
administration of [3'-deoxy-3'-[F-18]fluorothymidine at the levels described in the Investigators Brochure. 
Therefore, no adverse events are expected as a result of the intravenous (IV) administration of 3'-deoxy-
3'-[F-18]fluorothymidine for typical PET imaging applications.  
3 As with many intravenously administered agents, 3'-deoxy-3'-[F-18]fluorothymidine could cause an 
allergic reaction that could potentially pose a threat to life (anaphylaxis). This has not been observed in 
limited human exposure to date. Reasonable precautions should be taken, consistent with normal 
radiologic and clinical facility practice. The patient should be monitored until the PET procedure is 
completed, and trained personnel and emergency equipment should be available per facility standards. 
For purposes of informed consent regarding reasonably foreseeable risks to subjects in 
trials utilizing 3’-deoxy-3’-[F-18]fluorothymidine, the following potential adverse events 
are considered extremely rare: 
x 
Injection-related risks that may include infection, or accidental extravasation of the dose that 
may lead to discomfort, localized pain, or infection.  
x 
Risks related to allergic reaction/anaphylaxis that may be life threatening. 
NOTE: 
As with all PET imaging agents, 3'-deoxy-3'-[F-18]fluorothymidine is a 
radiopharmaceutical that decays with positron emission. As such, it poses an 
intrinsic radiation exposure risk. However, when administered in accordance with the 
Investigator’s Brochure as a PET imaging agent, this risk is felt to be extremely 
small. The organ and total body doses associated with FLT PET imaging are 
comparable to or lower than those associated with other widely used clinical nuclear 
medicine procedures.  
NOTE: 
3'-deoxy-3'-[F-18]fluorothymidine in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent.  

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5.6
Adverse Event Reporting Decision Tree
5.7
Duration of Follow-up 
Participants will stay on the trial for at least 1 year (1 year beyond the end of the 
study accrual period) until they complete all trial procedures, specifically the 
remission bone marrow biopsy (Day 28-35 biopsy), and follow-up collection of 
relapse free survival and overall survival.
Yes
Rev. 7/17
No
No
Adverse Event presented 
or Grade worsened w/in 24 
hrs after IND administration
Grade 2-5 AE meets SAE
criteria and is
possibly, probably or 
definitely related to the 
No
Death on 
Study
(Grade 5)
No reporting required
Grade 1-5 AE and 
meets SAE criteria
Report the event 
via CTEP-AERS
Death w/in 30 
days after IND 
administration
Report the event 
via RAVE
Yes
Yes
Yes
Yes
Yes
No
No
Investigator believes
AE is due to IND.
No
Yes
Using CTCAE v4.0 identify
AE type and Grade 
Using SAE criteria (21 CFR 
312.64)
Determine if event is serious
AE specifically listed as an 
exception for the IND
(not the therapy)?
No

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6. 
Measurement of Effect ACUTE MYELOGENOUS LEUKEMIA (AML) RESPONSE 
CRITERIA 
6.1 
Complete Remission (CR)  
Requires that all of the following be present for at least 4 weeks. 
x 
Peripheral Blood Counts  
x 
Neutrophil count ≥ 1.0 x 109 /L. 
x 
Platelet count ≥ 100 x 109 /L. 
x 
Reduced hemoglobin concentration or hematocrit has no bearing on 
remission status. 
x 
Leukemic blasts must not be present in the peripheral blood. 
x 
Bone Marrow Aspirate and Biopsy  
x 
Cellularity of bone marrow biopsy must be > 20% with maturation of all 
cell lines. 
x 
≤ 5% blasts 
x 
Auer rods must not be detectable. 
x 
Extramedullary leukemia, such as CNS or soft tissue involvement, must 
not be present. 
6.2 
Partial Remission (PR)  
x 
Requires that all of the criteria for complete remission be satisfied except 
that the bone marrow may contain > 5% blasts but < 25% blasts. 
x 
If all other criteria for CR are met, then a value of ≤ 5% blasts with Auer 
rods or abnormal morphology is considered a partial remission. 
6.3 
Relapse  
Relapse following complete remission is defined as: 
x 
Peripheral Blood Counts  
x 
Reappearance of blasts in the blood. 
x 
Bone Marrow Aspirate and Biopsy  
x 
Presence of > 5% blasts, not attributable to another cause (e.g., bone 
marrow regeneration). 
x 
If there are no circulating blasts and the bone marrow contains 5% to 
20% blasts, then a repeat bone marrow performed ≥ 1 week later 
documenting more than 5% blasts is necessary to meet the criteria for 
relapse. 
 

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7. 
Study Parameters 
7.1 
Study Parameters  
7.1.1 
Visit 1: Screening Visit 
x 
A screening assessment will occur to determine eligibility for the 
study.  
x 
Patients will undergo pre-treatment bone marrow biopsy if one has 
not already been performed 
NOTE:  
Pre-treatment bone marrow aspirates are required to 
be submitted to the ECOG-ACRIN LTRL, see Sections 
7.2 and 11 for additional information. If biopsy has 
already been performed, peripheral blood must be 
submitted instead at preregistration or after 
registration. 
x 
A signed consent form will be obtained prior to study trial 
procedures. Medical history, demographics, height, weight, and 
physical exam will be obtained. If patient data are available from 
clinical records in the appropriate time window, they need not be 
repeated for the pre-study evaluation.  
7.1.2 
Visit 1A: OPTIONAL FLT PET Imaging Study (FLT-base) 
NOTE: 
Per Eligibility Criteria, any pre-menopausal women or 
women of childbearing potential MUST not be pregnant as 
general practice and per institution’s standard of care prior 
to performing any scans. 
x 
Screening labs will be obtained within the one-week period prior to 
administration of FLT. Total bilirubin and creatinine should be 
collected per institutional standard of care. If patient data are 
available from clinical records in the appropriate time window, they 
need not be repeated for the pre-study evaluation. 
x 
The optional baseline FLT PET (FLT-base) scan will take place 
within 1 week prior to chemotherapy.  
x 
Specific image acquisition and reconstruction protocols will be 
provided in a Site Imaging Manual to participating institutions. 
x 
An adverse event evaluation will be performed at 24 hours. Sites 
will be required to submit the ‘PET Adverse Event Assessment’ 
after the 24 hour monitoring period, even if there are no adverse 
events to report. 
7.1.3 
Visit 2: MANDATORY FLT PET Imaging Study (FLT-post 
induction) 
NOTE: 
Per Eligibility Criteria, any pre-menopausal women or 
women of childbearing potential MUST not be pregnant as 
general practice and per institution’s standard of care prior 
to performing any scans. 
x 
Screening labs will be obtained within the one-week period prior to 
administration of FLT. Total bilirubin and creatinine should be 
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collected per institutional standard of care. If patient data are 
available from clinical records in the appropriate time window, they 
need not be repeated for the pre-study evaluation. 
x 
The post treatment FLT PET (FLT-post induction) scan will take 
place after completion of the induction therapy and within 3 days 
before or after nadir bone marrow (approximately Days 10-17 after 
the initiation of the first cycle of the chemotherapy and prior to re-
induction if required). 
x 
An adverse event evaluation will be performed at 24 hours (+/- 4 
hours). Sites will be required to submit the ‘PET Adverse Event 
Assessment’ after the 24 hour monitoring period, even if there are 
no adverse events to report. 
7.1.4 
Visit 3: Nadir Bone Marrow at Day 10 to 17 
Following completion of induction chemotherapy, the subject will 
undergo standard of care nadir bone marrow evaluation (Day 14 bone 
marrow biopsy) 7-10 days after the completion of induction 
chemotherapy. Local pathology report data will be collected from this 
time point as part of follow up for the EAI141 study. 
7.1.5 
Visit 4: Remission Bone Marrow at Day 28 to 35 
Participants will undergo remission bone marrow biopsy at Day 28 to 
35 after initial induction chemotherapy, if reinduction chemotherapy is 
not administered; at Day 28 to 35 after reinduction chemotherapy if 
reinduction chemotherapy was administered; local pathology report 
data will be collected from this time point as part of follow up for the 
EAI141 study. 
NOTE:  
Remission specimens are REQUIRED to be submitted to 
ECOG-ACRIN LTRL, see sections 7.2 and 11 for additional 
information. 
7.1.6 
Sharing of Results 
The final results of the study will be shared with the participating 
centers at the completion of the study. With agreement between the 
patient and the treating physician, and at the discretion of the 
participating center, the treating physician may share the experimental 
results of the FLT PET/CT imaging scans with the participant. The 
sharing of the informal results should be done with caution, as the 
FLT PET/CT is still experimental and the significance of these results 
is unknown. The results from the FLT PET/CT scans should not be 
part of the patient’s medical record and should not be used to 
direct or change therapy. We emphasize that sharing of imaging 
results with patients remains optional and at the discretion of the 
participating center, the patient and the treating physician. 
 
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Study Procedures Table 
Study Procedures 
VISIT 1: 
SCREENING 
VISIT 1A: OPTIONAL 
Baseline FLT PET/CT 
(FLT-base)2 
VISIT 2: Post-
Treatment FLT 
PET/CT (FLT-post)3 
VISIT 3: Nadir 
Bone Marrow 
(Day 10 to 17)4 
VISIT 4: Remission 
Bone Marrow  
(Day 28 to 35)5 
Informed Consent 
X 
 
 
 
 
Demographics1 
X 
 
 
 
 
Medical History1 
X 
 
 
 
 
Height1 
X 
 
 
 
 
Weight1 
X 
X 
X 
 
 
Physical Exam1 
X 
 
 
 
 
Pre-Scan Pregnancy and Serum Creatinine Evaluations1 
 
X 
X 
 
 
[F-18]FLT PET/CT6 
 
X 
X 
 
 
Bone Marrow Biopsy 
X 
 
 
X 
X 
Other Clinical Evaluations7  
X 
 
 
X 
X 
Adverse Event Evaluation 
 
X 
X 
 
 
Biological Sample Submissions 
See Sections 7.2 and 11 
Follow-Up Data Collection 
Standard Practice Clinical Data Will Be Collected for 1 Year  
from Enrollment of the Last Participated Accrued to the Study 
1. If patient data are available from clinical records in the appropriate time window, they will not be repeated for the pre-study evaluation. Total 
bilirubin and creatinine should be collected per institutional standard of care before FLT PET/CT. 
2.  Baseline FLT PET/CT imaging (FLT-base) is optional, and must be done within 1 week prior to initiation of therapy protocol. 
3.  Post-treatment FLT PET/CT imaging (FLT-post) must be done after the completion of the induction chemotherapy and within 3 days before or 
after nadir bone marrow and prior to reinduction if required (Days 10-17 after the initiation of the first cycle of the chemotherapy and prior to 
reinduction if required) 
4.  Nadir bone marrow will be performed per standard clinical practice, typically within 7-10 days after the completion of induction therapy.  
5. Remission bone marrow will be performed per standard clinical practice, typically at Day 28-35 after treatment began and upon count recovery.  
6. NOTE: Per Eligibility Criteria, any pre-menopausal women or women of childbearing potential MUST not be pregnant as general practice and 
per institution’s standard of care prior to performing any scans. 
7. Other clinical evaluations include: Cytogenetics and molecular studies as mandated by the treatment study in which the patient is enrolled. If the 
patient is not enrolled in another study, the cytogenetic and molecular studies should be done according to the treating institution’s standard of 
care. 
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7.2 
Biological Sample Submissions  
All specimens submitted must be entered and tracked via the on-line ECOG-
ACRIN Sample Tracking System (STS) 
 
Pre-
Treatment 
1 
Day 28 to 35 
(Remission) 
Submit 
To: 
MANDATORY: Bone Marrow Aspirate  
(Heparin, First Pull)2,3 
X 
X 
LTRL 
MANDATORY (Only if Bone Marrow Aspirate 
not submitted): Peripheral Blood (heparin, 
green or purple [EDTA] top tubes, 30-40mL)3 
X4 
 
LTRL 
From patients who answer “Yes” to “I agree to provide additional samples for 
research.”  
Bone Marrow Smears (Wright-Giesma 
Stained) 
X 
X 
LTRL 
1. Signed EAI141 patient consents and HIPAA authorizations must be submitted to the 
ECOG-ACRIN Leukemia Translational Research Laboratory (LTRL) prior to or at the 
time of submission of the bone marrow to the LTRL. 
2. The laboratory will accept any amount of bone marrow as long as it represents a first 
pull. Ideally, 2-3mL of aspirate from a separate aspiration site should be submitted. 
For the MRD assessments, aspirate from a separate bone marrow aspiration site 
must be submitted. ONLY SUBMIT ASPIRATES FROM THE FIRST PULL OF AN 
ASPIRATION SITE FOR MRD TESTING. DO NOT SUBMIT ASPIRATES FROM 
THE SECOND OR THIRD PULL OF THE SAME ASPIRATION SITE. 
For patients with an insapirable bone marrow (“dry tap”), or if a bone marrow has 
been done previously and that patients refuses another aspiration done, call Dr. 
Paietta’s laboratory at (718) 920-4100 to discuss the case and the possibility for 
submitting peripheral blood only. Be prepared to report the WBC count and the blast 
count in the peripheral blood at the time of the call. 
3. Leftover samples will be stored for future undefined research studies from patients 
who answer “YES” to “My samples and related information may be kept in a Biobank 
for use in future health research.” 
4. Peripheral blood can be submitted after registration to Step 1 to coincide with clinical 
assessments performed prior to protocol specified imaging. Peripheral blood must be 
submitted only if bone marrow aspirate will not be submitted at preregistration. 
 
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8. 
Agent Formulation and Procurement 
NCI Supplied Agent(s) – General Information 
8.1 
Supplier of the FLT Agent 
8.1.1 
Drug Ordering 
FLT will be supplied by a commercial vendor of radioisotopes in most 
cases. The vendor must be authorized within the NCI IND, and the 
site had been qualified for production by NCI and ECOG-ACRIN. FLT 
can only be synthesized on site if the chemistry manufacturing and 
control procedures are filed within the NCI IND and the site has been 
approved for FLT production under the NCI IND and notified of 
approval by the NCI Cancer Imaging Program. All other sites will be 
required to use an approved commercial supplier. 
The investigational pharmacist or qualified nuclear medicine 
technologist at the participating institution will be the responsible party 
for receiving the FLT, as designated by the site principle investigator.  
8.1.2 
Drug Returns  
If for any reason the study imaging is unable to be completed, sites 
will allow the radioactivity of the FLT solution to decay and then 
discard it appropriately per site’s policies and procedures. A copy of 
the policy should be available upon request.  
8.1.3 
Drug Accountability  
The investigator or the investigator-designee must maintain a detailed 
record of receipt, disposition, and destruction dates of FLT solution, 
using the Drug Accountability Record form available through CTSU. 
In accordance with regulations, the radioisotope vendor conducts 
several quality control tests on the FLT product prior to release for 
human administration. Once delivered to the participating institution, 
doses will be stored in the appropriate storage area in the nuclear 
medicine facility until they are administered to the patient. 
8.2 
18F-FLT 
For complete information, please refer to the Investigator’s Brochure: 
 “3'-deoxy-3'-[F-18] fluorothymidine: [F-18]FLT, An Investigational Positron 
Emission Tomography (PET) Radiopharmaceutical for Injection and intended for 
use as an in vivo diagnostic for imaging active cellular proliferation of malignant 
tumors”, Edition Number 7, Edition date 2009. 
8.2.1 
Other Names  
3'-deoxy-3'-[F-18] fluorothymidine, [F-18]FLT, FLT 
8.2.2 
Classification  
Investigational new drug: Radiopharmaceutical/radiotracer 

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8.2.3 
Mode of Action  
The pharmacology of FLT as a therapeutic agent is based on its 
action as an inhibitor of DNA synthesis. As a diagnostic imaging 
agent, phosphorylation by thymidine kinase leads to tracer retention in 
proliferating tissue. 
8.2.4 
Storage and Stability  
In accordance with regulations, the radioisotope vendor conducts 
several quality control tests on the FLT product prior to release for 
human administration. Once delivered to the participating institution, 
doses will be stored in the appropriate storage area in the nuclear 
medicine facility until they are administered to the patient.  
The drug solution is stored at room temperature in a gray butyl 
septum sealed, sterile, pyrogen-free glass vial and has an expiration 
time of 8 hours. 
8.2.5 
Dose Specifics  
The administered activity will be 0.07 mCi/kg with a maximum of 5 
mCi. The amount of injected drug is ≤ 6.1 μg (≤ 25 nmol per dose) of 
FLT.  
8.2.6 
Preparation  
The injectable activity of FLT for most studies will be ≤ 0.07 mCi/kg of 
fluorine-18, not to exceed 5 mCi with a specific activity greater than 
200 Ci/mmol at the time of injection. In the dose of FLT, only a small 
fraction of the FLT molecules are radioactive.  
8.2.7 
Route of Administration  
FLT is administered to subjects by intravenous injection. There is no 
evidence that nonradioactive and radioactive FLT molecules display 
different biochemical behavior. 
8.2.8 
Incompatibilities  
N/A 
8.2.9 
Availability  
8.2.9.1 
Drug Ordering 
There are two ways to obtain the FLT agent for this study: 
1) Commercial vendor supply 
2) On-site manufacturing  
1) Commercial Vendor Supply. FLT may be supplied by 
a commercial vendor of radioisotopes if authorized and 
approved by the NCI CIP. Please see informational 
document posted on the CTSU regarding FLT dose supply 
for a listing of the approved commercial vendors and 
process for set up. The investigator or the investigator-
designee will order patient doses of FLT. The investigative 
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radiopharmaceutical FLT solution will be shipped to the 
site the same day the participant is to be injected.  
2) On-Site Manufacturing. FLT can be manufactured on-
site only after the site had been qualified and approved for 
production by NCI Cancer Imaging Program (CIP) and 
ECOG-ACRIN. For additional information about on-site 
manufacturing, see “Regulatory approach to approve 
manufacturing sites to make IND PET agenda to be used 
under a Cancer Imaging Program (CIP IND for a specified 
trial)”. 
The investigational pharmacist or qualified nuclear 
medicine technologist at the participating institution will be 
the responsible party designated by the investigator.  
8.2.9.2 
Drug Returns  
If for any reason the study imaging is unable to be 
completed, sites will allow the radioactivity of the FLT 
solution to decay and then discard it appropriately per 
site’s policies and procedures. A copy of the policy should 
be available upon request.  
8.2.9.3 
Drug Accountability  
The investigator or the investigator-designee must 
maintain a detailed record of receipt, disposition, and 
destruction dates of FLT solution, using the Drug 
Accountability Record form. 
https://ctep.cancer.gov/forms/docs/agent_accountability.pd
f 
8.2.10 
Side Effects  
See Section 5.5 for side effects. 
8.2.11 
Nursing/Patient Implications  
Standard safety precautions required when handling radioactive 
materials, predominantly during the injection and uptake period should 
be followed. FLT requirements are similar to those used for other PET 
tracers, such as FDG. 
 
 
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9. 
Imaging Protocol 
9.1 
FLT PET Imaging Studies 
Specific image acquisition and reconstruction protocols will be made available 
through the CTSU. Instructions for images submission is provided in Section 
4.10. 
9.2 
FLT Administration 
FLT will be synthesized according to the standard operating procedures provided 
by the NCI. A summary of the synthesis procedure and associated quality control 
can be found in the investigator’s brochure.  
FLT will be administered in the PET imaging suite under physician supervision. 
The imaging technologist or nurse will administer the FLT by intravenous infusion 
over one minute, followed by a saline flush. A fully equipped emergency cart and 
ACLS certified personnel will be available. Reported adverse events and 
potential risks are described in Section 5.5. The infusion and imaging procedure 
will be terminated in any patient who exhibits anaphylaxis, chest pain, dyspnea, 
or grand mal seizure. 
9.3 
Timing of FLT PET Studies  
Two imaging sessions, an optional baseline and mandatory post-treatment will 
be performed (see Study Procedures Table).  
Optional Baseline: The optional baseline FLT PET/CT imaging must be 
completed within one week prior to beginning of induction chemotherapy.  
Mandatory Post-Treatment: Post-treatment FLT PET/CT must be done after 
the completion of the induction chemotherapy and within 3 days before or after 
nadir bone marrow (approximately Days 10-17 after the initiation of the first 
cycle of the chemotherapy and prior to re-induction if required). 
9.4 
Imaging Quality Assurance (QA)/Quality Control (QC) Procedure 
Participant must be scanned on PET/CT scanners that have been qualified by 
the ACR Imaging Core Laboratory per the protocol-specific instructions made 
available to participating sites. 
Qualification Utility for the Imaging Core Laboratory (QUIC) is the web-based tool 
for managing the qualification process and communicating with the core lab staff. 
The QUIC User Guide will be made available to participating sites. 
Refer to the instructions about uploading images and completing the required 
application forms. 
A hybrid PET/CT scanner is mandatory. The ability to calculate standardized 
uptake values (SUVs) is also mandatory. All sequential imaging sessions should 
be performed on the same PET/CT scanner, whenever possible. Any deviations 
should be reported to ECOG-ACRIN. QA/QC procedures will include review of 
DICOM files against study protocols. The PET/CT scanner must be kept 
calibrated in accordance with the manufacturer’s recommendations. The scanner 
should routinely be assessed for quantitative integrity and stability by being 
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measurements, this assessment should include a comparison against a dose 
calibrator to ensure accuracy; that is, a comparison of the absolute activity 
measured versus the measured activity injected, should be performed. 
A daily QC check must be performed at the beginning of the day, including 
PET/CT scanner and dose calibrator, in accordance with the manufacturer 
recommendations. If any of the QC results are outside of the manufacturer’s 
guidelines, the study must be rescheduled and the problem rectified before 
scanning any patients. 
9.5 
Imaging Sessions 
The participant will report to the PET suite and undergo FLT injection. 
Approximately 60 minutes (± 10 min) after injection, a static whole body image 
will be acquired. If both optional baseline and mandatory post-treatment FLT 
PET/CT scans are completed, the participant should be scanned on the same 
scanner for each session. The whole body scan (top of the head [vertex] to below 
the knees) will be obtained. Details of the imaging procedure are specified in the 
Site Imaging Manual. 
9.6 
Supportive Care Guidelines 
Any adverse effects, related or non-related to the injection of FLT, will be treated 
as clinically indicated with no study-related restrictions. 
9.7 
Dosing Delays/Dose Modifications 
9.7.1 
FLT Dose 
The dose of FLT is based on the radiation dosimetry estimates. Due 
to the potential of a poor radiosynthetic yield or unavoidable time 
delays, a lesser amount of radioactivity may be administered at the 
discretion of the site PI, based on whether clinically acceptable 
images can be acquired with the dose administered. Any such 
modifications of the agent infusion will be recorded. 
9.8 
FLT PET/CT Image Analysis: Central Read 
Quantitative Total Marrow Imaging (QTMI) image analysis will be performed at a 
central analysis laboratory and will include extraction of the whole bone marrow 
proliferative activity as assessed by analysis of the full FLT PET/CT images as 
follows [5]:  
x 
The CT images are thresholded to extract the bone;  
x 
These CT bone volumes are expanded to include the marrow resulting in 
bone + marrow CT masks;  
x 
The masks are applied to the PET images to isolate the PET voxels 
representing the bone and marrow;  
x 
An SUV threshold of 0.5 is applied to the masked PET images to extract 
the marrow PET voxels, yielding PET images of the bone marrow.  
After the extraction of the spatial bone marrow compartment from the FLT 
PET/CT imaging, the FLT uptake reflecting the rate of bone marrow proliferation 
across the bone marrow is analyzed. Preliminary data suggests that image 
analysis should ideally include analysis of the whole bone marrow to determine a 
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number of bone marrow proliferation parameters, such as the mean proliferation, 
maximum proliferation, as well as heterogeneity of proliferation. While each of 
the proliferation parameters appears predictive of the clinical outcome, each of 
these parameters likely has different performance characteristics, making them 
more or less suitable for clinical use.  
The extraction analysis will include three imaging parameters (SUVmean, SUVmax, 
SUVhetero). 
x 
Maximum FLT uptake (SUVmax), defined as the maximum FLT uptake 
across the total bone marrow compartment 
x 
Mean FLT uptake (SUVmean), defined as the mean FLT uptake across the 
total bone marrow compartment 
x 
Heterogeneity of FLT uptake (SUVhetero), defined as the coefficient of 
variation of FLT uptake across the total bone marrow compartment 
While all of these parameters will be extracted and analyzed for each patient, 
only SUVmax will be used as the primary endpoint in the statistical analysis. All 
other parameters will be used and reported in descriptive manner (see 
Statistical Considerations). 
9.9 
Other Comparators 
9.9.1 
Pathologic Response 
This nadir or “day 14 bone marrow” is recommended in the 2012 
National Comprehensive Cancer Network (NCCN) Guidelines for the 
treatment of AML. The ideal response by the NCCN is defined as a 
hypoplastic marrow with < 10-20% cellularity and < 5-10% residual 
blasts. This biopsy is a standard measure of induction chemotherapy 
effectiveness. The results of this analysis will be reported. 
9.9.2 
Clinical Response  
Clinical response will be assessed as below. Criteria are based upon 
the standard AML response criteria as published by Cheson et al [4]. 
Remission bone marrow will be performed per standard clinical 
practice, typically at Day 28-35 after treatment began and upon count 
recovery. The results of this analysis will be reported.   
Table 1. Clinical Response Criteria 
Response ANC (cells/uL) Platelet Count (cells/uL) 
Bone Marrow Blasts (%) 
CR 
> 1000 
> 100,000 
< 5% 
CRi 
> 1000 
> 50,000 
< 5% 
PR 
> 1000 
> 100,000 
> 5% and < 25% and 50% less than 
pre-therapy 
LFS 
Any 
Any 
< 5% 
RD 
 
 
> 5%, not attributable to marrow 
regeneration 
Abbreviations: CR (complete remission), CRi (complete remission with incomplete platelet recovery), 
PR (partial remission), LFS (leukemia-free state), RD (resistant disease) 
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9.10 
Data Analysis 
The primary goal of our endpoints will be to evaluate the negative predictive 
value (NPV) of post-treatment FLT PET/CT imaging for complete remission in 
patients receiving induction chemotherapy for AML. Additional comparisons with 
imaging, pathologic, clinical and outcome data will also be performed. These 
comparisons are summarized in Table 2. 
Table 2. Planned Comparisons with FLT Parameters 
FLT Parameters 
Compared To 
OPTIONAL Baseline FLT uptake 
parameters (FLT-base) 
CR, RD 
Nadir bone marrow, relapse-
free and overall survival  
Post-treatment FLT uptake 
parameters (FLT-post) 
CR, RD 
Nadir bone marrow, relapse-
free and overall survival  
Change in FLT uptake parameters 
(FLT-post vs FLT-base) 
CR, RD 
Nadir bone marrow, relapse-
free and overall survival 
9.11 
Image Analysis 
A central review and analysis of all FLT PET/CT imaging will be performed at the 
ACR Imaging Core Laboratory in coordination with the University of Wisconsin 
Image Analysis Core (IMAC). The centralized imaging analysis will be used for 
endpoint calculations. Radiologists will perform local reads of the images to help 
guide central review. Central review will subsequently be completed; data will be 
shared at the culmination of the study. 
 
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10. 
Statistical Considerations 
The overall objective of this trial is to evaluate the negative predictive value of post-
treatment FLT PET/CT imaging for complete remission (CR) in comparison with blast 
counts from bone marrow biopsy (BMBX) at Day 14.  
Definition of complete remission (CR): The CR designation requires that the patient 
achieve the morphologic leukemia-free state and have an absolute neutrophil count of 
more than 1,000/uL and platelets of greater than 100,000/uL. Hemoglobin concentration 
or hematocrit has no bearing on remission status, although the patient must be 
independent of transfusions. Occasionally, a rare peripheral blood blast may be 
identified during regeneration; however, if the patient is in CR, the bone marrow would 
have less than 5% blasts and no Auer rods [4].  
Definitions of FLT Positivity and Negativity for CR: 
x 
FLT PET “positive”Æ SUVmax ≤ 7 
x 
FLT PET “negative” Æ SUVmax > 7 
The post-treatment FLT PET/CT needs to be conducted within three days before or 
after the nadir bone marrow biopsy (between Days 10-17 after initiation of first induction 
cycle and prior to reinduction). After the imaging analysis to collect SUVmax, we define a 
positive testing result as a low uptake value, which corresponds to the lower blast count 
in the BMBX.  
Our primary aim is to evaluate the negative predictive value (NPV) of post-treatment FLT 
PET/CT imaging for achieving CR in patients receiving induction chemotherapy for AML. 
The results of the pilot study [5] show that there was a clear separation between 
responders and non-responders in terms of SUV measurements from FLT PET/CT 
imaging. For example, the means (standard deviation [SD]) of SUVmax for responders 
and non-responders are 3.6 (0.2) and 11.4 (0.8), respectively. Using the Newton-type 
algorithm, we found the best cutting point is around SUVmax = 7. This optimization was 
done using the nlm function in R package stats. Thus, our FLT PET data will be 
dichotomized at SUVmax = 7 whereas positive FLT PET testing results will be the ones 
with SUVmax ≤ 7 and the negative FLT PET testing results will be the ones with  
SUVmax > 7.  
Our sample size calculation is based on hypothesis testing to see if the NPV of post-
treatment FLT PET/CT is significantly better than that of the Day 14 bone marrow 
biopsy. The CR rate is assumed to be around 50% in the study population. In addition, 
we assume that the FLT PET-positivity rate in the study population is around 50% as 
well. Under these assumptions, we will need 21 FLT-negative patients to have the power 
of 80% to test if the NPV of FLT is higher than 0.64 (null hypothesis) given that the true 
NPV of FLT is 85% or above (alternative hypothesis). The test is one-sided with the 
target 0.10 significance level. The Exact Binomial test in PASS 2012 was used for the 
calculations [6]. Since the positivity rate is assumed to be around 50% in the study 
population, we need to enroll 42 patients. Due to the random nature of the observed 
numbers of patients meeting the clinical criteria in a prospective study, a sample size 
correction technique attributed to Pepe (2003) was applied. Our calculation shows that 
after adding 9 extra patients, we can be 90% sure to yield the required numbers of 
patients meeting the clinical criteria, which brings the sample size to 51. After an 
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sample size of 57 participants. The sample size is 86 evaluable if the true NPV of FLT 
PET/CT is 80% or above. The sample size is 38 if the true NPV is 90% or above. 
According to our interim monitoring of the early enrollment, the attrition rate is around 
38%. The main reason was attributed to the failed remission bone marrow biopsy due to 
poor health or death. This accounted for ~1/2 of attrition. In addition, there were ~1/3 of 
attrition due to the failure of completing the post-treatment FLT PET/CT scans (e.g., 
equipment failure, patients withdrew).  We will closely monitor these issues and the 
enrollment may stop early if we observe a lower attrition rate. Thus, the overall sample 
size is up to 83 participants. The below table shows the required number of 
participants at various attrition rates. 
Attrition rate 
Sample size 
10% 
57 
25% 
68 
38% 
83 
Futility Analysis 
A futility analysis will be performed when half of the analyzable participants have 
completed the trial. The method of conditional power [7] will be used for the futility 
analysis, which will estimate the probability that NPV with all subjects would be greater 
than 0.64, conditional on the results accumulated at the time of the futility analysis. If this 
probability is too small (i.e., < 0.20), implying that it is unlikely that the FLT PET/CT is 
useful, then a decision may be made to terminate the study early. 
Objectives 
10.1 
Primary Objectives 
10.1.1 
To evaluate the negative predictive value (NPV) of post-treatment FLT 
PET/CT imaging for complete remission (CR) in patients receiving 
induction chemotherapy for acute myeloid leukemia (AML). 
Three imaging parameters (SUVmean, SUVmax, SUVhetero) will be 
measured from an FLT PET/CT scan, and SUVmax will be the primary 
endpoint. The binomial proportion of NPV and the corresponding 
Exact confidence intervals will be calculated. In addition, the 
calculated NPV will be tested against the null hypothesis to see if it’s 
significantly larger than 0.64 (NPV of Day-14 BMBX in CR prediction). 
10.2 
Secondary Objectives 
10.2.1 
To evaluate the positive predictive value (PPV) of post-treatment FLT 
PET/CT imaging for complete remission; 
The binomial proportion of PPV and the corresponding Exact 
confidence intervals will be calculated. In addition, the calculated PPV 
will be tested to see if it’s significantly larger than 0.79 (PPV of Day-14 
BMBX in CR prediction). 
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10.2.2 
To estimate the sensitivity and specificity of post-treatment FLT 
PET/CT for detecting complete remission; 
The binomial proportions and the corresponding Exact confidence 
intervals will be calculated for sensitivity and specificity estimation.  
10.2.3 
To correlate FLT PET/CT imaging parameters with biologic correlates 
(MRD assessment). 
Correlation and regression analysis will be used to assess this aim. 
10.2.4 
To correlate FLT PET/CT imaging parameters with relapse-free 
survival and overall survival. 
Kaplan-Meier method and Cox proportional hazard regression will be 
used to assess this aim 
10.3 
Exploratory Objectives 
10.3.1 
To evaluate pre-treatment FLT PET/CT activity as a predictor of 
complete remission; 
No previous studies were available to determine the cutoff for the pre-
treatment SUVmax. The ROC approach will be used to test the 
continuous measurement of this variable in predicting CR. 
10.3.2 
To evaluate the change between pre-treatment and post-treatment 
FLT PET/CT activity as a predictor of complete remission; 
No previous studies were available to determine the cutoff for the 
change from pre-treatment to post-treatment SUVmax. The ROC 
approach will be used to test the continuous measurement of this 
variable in predicting CR. 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required, as described in Section Error! 
Reference source not found.. 
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10.4 
Gender and Ethnicity  
Based on previous data from E1900 the anticipated accrual in subgroups defined 
by gender and race is: 
Racial Categories 
Ethnic Categories 
Total 
Hispanic or 
Latino 
Not Hispanic or 
Latino 
Females Males Females Males 
American Indian or Alaskan Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
2 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
3 
2 
5 
White 
4 
3 
35 
34 
76 
Total 
4 
3 
40 
36 
83 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Coordinating Center. 
Evaluation of Toxicity  
All subjects will be evaluable for toxicity from the time of injection of FLT until 24 
hours after injection. 
Evaluation of Preliminary Efficacy  
A futility analysis will be performed when half of the participants (i.e., 34) have 
completed the trial. The method of conditional power [7] will be used for the 
futility analysis, which will estimate the probability that NPV with all subjects 
would be greater than 0.64, conditional on the results accumulated at the time of 
the futility analysis. If this probability is too small (i.e., < 0.20), implying that it is 
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11. 
Research Sample Submissions 
Bone marrow aspirates and/or peripheral blood must be submitted for defined laboratory 
research studies being performed at the ECOG-ACRIN LTRL. These laboratory 
research studies are defined in Section 12. 
Bone marrow smears are to be submitted for future undefined research per patient 
consent. 
It is required that all samples submitted on this trial be entered and tracked using the 
ECOG-ACRIN Sample Tracking System (STS) (see Section 11.3). An STS shipping 
manifest form is to be included with every submission. 
All samples must be labeled clearly with the ECOG-ACRIN protocol number (EAI141), 
ECOG-ACRIN patient sequence number, patient’s initials, date of collection and sample 
type. 
11.1 
Sample Collection and Submission Schedule 
Samples are to be submitted as follows: 
11.1.1 
Bone marrow and/or peripheral blood are to be submitted to the 
ECOG-ACRIN LTRL as outlined in Section 11.2. Samples are to be 
collected at the following time points: 
Bone marrow aspirates (or peripheral blood) and bone marrow 
smears: 
x 
Pre-Treatment 
Bone marrow aspirates and bone marrow smears: 
x 
Day 28-35 (Remission) 
11.2 
Submissions to ECOG-ACRIN Leukemia Translational Research Laboratory 
(LTRL)  
Dr. Paietta’s institutional regulations require that she receive a copy of the 
patient’s consent and a copy of the HIPAA authorization at the time of or prior to 
the submission of the bone marrow samples. 
11.2.1 
Sample Preparation Guidelines 
NOTE: 
FOR MRD ASSESSMENTS, AN ASPIRATE FROM A 
SEPARATE BONE MARROW ASPIRATION SITE 
MUST BE SUBMITTED (THE NEEDLE CAN BE RE-
DIRECTED THROUGH THE SAME SKIN PUNCTURE 
SITE). ONLY SUBMIT ASPIRATES FROM THE FIRST 
PULL OF AN ASPIRATION SITE FOR MRD TESTING. 
DO NOT SUBMIT SAMPLES FROM THE SECOND 
OR THIRD PULL OF THE SAME ASPIRATION SITE. 
NOTE:  
Results of MRD assessments will not be reported to 
the site. 
The following are to be submitted: 
1. MANDATORY: Heparinized bone marrow aspirate (the laboratory 
will accept any amount as long as it represents a first pull). Ideally, 
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2-3mL of aspirate from a separate aspiration site should be 
submitted. 
For patients with an inaspirable bone marrow (“dry tap”), or if a 
bone marrow has been done previously and the patient refuses to 
have another aspiration done, call Dr. Paietta's laboratory at (718) 
920-4100 to discuss the case and the possibility for submitting 
peripheral blood only. Be prepared to report the WBC count and 
the blast count in the peripheral blood at the time of the call. 
ALTERNATIVE TO BONE MARROW ASPIRATE SUBMISSION 
AT BASELINE: Heparin or EDTA peripheral blood (four [4] green 
or purple top tubes, 30-40mL). 
NOTE:  
Peripheral blood must be submitted only if bone 
marrow aspirates will not be submitted at 
preregistration and can be submitted after registration 
to Step 1 to coincide with clinical assessments. 
2. At least two (2) Wright-Giemsa stained bone marrow smears. 
Submit from patients who answer “Yes” to “I agree to provide 
additional samples for research.” 
3. MANDATORY: A copy of the institutional pathology report on the 
bone marrow must be submitted. The pathology report must 
include cytogenetic results and any results from fluorescence-in-
situ (FISH) hybridization and/or molecular studies done at the 
submitting institution. 
Please fax to the LTRL at (718) 920-1161 
11.2.2 
Shipping Procedures  
The LTRL must be notified by telephone the day of shipment.  
Fax or Email to Dr. Paietta is not acceptable. 
Telephone: (718) 920-4100 
During off hours, all information regarding the shipment should be left 
on the answering machine in the LTSL including: 
EAI141 patient sequence number 
Patient Initials 
Type of specimens shipped 
Name, telephone number, and institution  
For questions regarding the shipment, Dr. Paietta and her staff can be 
reached at the phone numbers provided on the recorded message, 
please always try Dr. Paietta first. Questions can also be addressed to 
Dr. Paietta via e-mail (epaietta@earthlink.net), however, please do 
not use e-mail for the notification of shipments. 
Bone marrow smears should be submitted within one week of 
collection.  
Heparinized bone marrow aspirate and peripheral blood or EDTA 
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(do not freeze and do not use ice cubes) by overnight courier 
(preferably FedEx) to arrive within 24 hours to: 
Elisabeth Paietta, Ph.D. 
Department of Oncology 
Hofheimer 3rd Floor 
Leukemia Oncology Laboratory 
111 East 210th Street 
Bronx, NY 10467 
Tel: (718) 920-4100 
FAX: (718) 920-1161 
The LTRL is open to receive shipments Monday through Saturday. 
Shipments on Fridays for Saturday delivery must have “Saturday 
Delivery” marked on the overnight courier slip. 
In general, always ship specimens the day before a holiday for 
delivery the day after the holiday. 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.  
Please enter all information into the STS, including time and date of 
specimen collection and peripheral blood WBC count and blast count. 
If samples need to be drawn late at night, on Sunday, or on a holiday 
when FedEx does not operate, keep the samples in a refrigerator 
between 10 and 15 degrees Celsius until the next day when it can be 
shipped. 
11.3 
ECOG-ACRIN Sample Tracking System 
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.  
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important: 
Please note that the STS software creates pop-up windows, so 
you will need to enable pop-ups within your web browser while 
using the software. A user manual and interactive demo are 
available by clicking this link: 
http://www.ecog.org/general/stsinfo.html 
Please take a moment to familiarize yourself with the software prior to using the 
system. 
An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to ecog-
acrin.tst@jimmy.harvard.edu.  

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11.3.1 
Study Specific Notes 
Generic Specimen Submission Form (#2981) will be required only if 
STS is unavailable at time of sample submission. Notify the laboratory 
of the shipment by faxing a copy of the completed form to the 
laboratory. Indicate the appropriate laboratory on the submission 
form: 
x 
ECOG-ACRIN Leukemia Translational Research Laboratory 
Retroactively, enter all specimen collection and shipping information 
when STS is available. 
11.4 
Use of Specimens in Research 
Specimens from patients who consented to allow their specimens to be used for 
future ECOG-ACRIN approved research studies will be retained in the ECOG-
ACRIN Leukemia Tissue Bank (LTB). 
Specimens submitted will be processed to maximize their utility for current and 
future research projects.  
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study.  
11.5 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. 
Inventories of samples forwarded by the LTRL/LTB and utilized for approved 
laboratory research studies will be submitted by the LTRL/LTB to the ECOG-
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12. 
Leukemia Correlative Studies 
12.1 
Immunophenotype and Molecular Genetics  
Immunophenotyping has become an essential part of the diagnostic work-up of 
all leukemia patients. In fact, the diagnosis of leukemia without 
immunophenotypic characterization is no longer acceptable. ECOG-ACRIN has, 
therefore, developed a model system for antigenic data collection that requests 
specimens from all patients entered on ECOG-ACRIN leukemia trials be studied 
by the ECOG-ACRIN LTRL. In addition to establishing the leukemia subtype, this 
centralized testing and data collection has allowed research questions of clinical 
relevance to be applied to a growing database (e.g., definition of prognostically 
significant antigen expression levels to eventually yield specific treatment 
subcategories). In EAI141, an additional significance for central 
immunophenotyping is provided by the flow cytometric assessment of minimal 
residual disease (MRD). Sample submissions for MRD determination in bone 
marrow aspirates will coincide with clinically required bone marrow examinations. 
The LTRL will use multiparameter 6-color flow cytometry of bone marrow 
aspirates using leukemia-associated immunophenotypes to detect residual blast 
cells. 
Bone marrow from patients entered on studies of hematologic malignancies are 
stored in ECOG-ACRIN's LTB for EAI141 embedded and future laboratory 
studies. The bank provides the scientific community with a source of leukemia 
specimens that are collected, processed, and maintained following quality control 
and quality assurance guidelines. The bank will accommodate requests from 
investigators within and outside ECOG-ACRIN in a timely and efficient manner, 
with respect to tissue type, tissue preparation, and most importantly, biologic 
characteristics of specimens.  
12.2 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secure data transfer to the ECOG-ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. 
 

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13. 
Electronic Data Capture 
Please refer to the EAI141 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Coordinating 
Center to CTEP by electronic means. 
14. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
15. 
References 
1. Rowe, J.M., Prognostic factors in adult acute lymphoblastic leukaemia. Br J 
Haematol, 2010. 150(4): p. 389-405. 
2. Mattison, R.J., S.M. Luger, and H.M. Lazarus, New strategies for the evaluation of 
the nadir bone marrow following induction in acute myeloid leukemia. Curr Opin 
Hematol, 2013. 20(2): p. 93-9. 
3. Muzi, M., D.A. Mankoff, J.R. Grierson, J.M. Wells, H. Vesselle, and K.A. Krohn, 
Kinetic modeling of 3'-deoxy-3'-fluorothymidine in somatic tumors: mathematical 
studies. J Nucl Med, 2005. 46(2): p. 371-80. 
4. Cheson, B.D., et al., Revised recommendations of the International Working Group 
for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol, 
2003. 21(24): p. 4642-9. 
5. Vanderhoek, M., M.B. Juckett, S.B. Perlman, R.J. Nickles, and R. Jeraj, Early 
assessment of treatment response in patients with AML using [(18)F]FLT PET 
imaging. Leuk Res, 2011. 35(3): p. 310-6. 
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1988;44(2):579-85. 

ECOG-ACRIN 
EAI141 
Cancer Research Group 
Version Date: February 6, 2018 
 
Update Date: July 26, 2017 
59 
Early Assessment of Treatment Response in AML using FLT PET/CT Imaging 
 
Appendix I 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog-acrin.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the help of people like you who participate in clinical 
trials, we will achieve our goal of effectively treating and ultimately curing cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 

ECOG-ACRIN 
EAI141 
Cancer Research Group 
Version Date: February 6, 2018 
 
Update Date: July 26, 2017 
60 
Early Assessment of Treatment Response in AML using FLT PET/CT Imaging 
 
Appendix II 
 
EAI141 Adverse Event Reporting Guidance Document 
Below are scenarios that a site may be faced with when assessing patients prior to and after the 
Day 14 FLT scan on EAI141.  The below scenarios are to provide guidance on how to handle 
reporting on these issues.  This is not an exhaustive list; if there is a situation you are unclear on 
for reporting please contact the Study Team.   
When assessing patients prior to the Day 14 scan, ensure you document the patient was 
physically and mentally able to undergo the Day 14 scan.   
Scenario #1 
A subject develops grade 3 febrile neutropenia on hospital day 10 after the beginning of 
therapy. The grade 3 febrile neutropenia persists despite antibiotics through day 17. FLT is 
administered and imaging performed on day 14. 
Does febrile neutropenia need to be reported as an SAE? No, the SAE is not a new event 
that occurred after FLT was given. If a fever is documented during the hospitalization 
prior to the scan, the day 15 fever should not be considered a new AE, therefore no 
reporting will occur.   
Scenario #2 
A subject develops grade 3 anemia (hemoglobin < 8 requiring transfusion) on hospital day 7. 
The patient requires transfusions every 2-3 days through day 20. FLT is administered and 
imaging performed on day 14. The anemia never becomes life-threatening (grade 4). 
Does anemia need to be reported as an SAE? No, anemia was present prior to FLT 
administration and it has not changed in severity. 
Scenario #3 
A subject develops grade 3 mucositis. This occurs on day 15, and is attributed to chemotherapy. 
FLT was administered and imaging conducted on day 14. 
Does this need to be reported as an SAE? Yes, though mucositis is not attributed to FLT 
but instead to chemotherapy, it occurred within the 24 hour monitoring period and must 
be reported within 24 hours via the AERS.